Bio

Bio


Dr. Robert A. Harrington is an interventional cardiologist and the Arthur L. Bloomfield Professor of Medicine and Chairman of the Department of Medicine at Stanford University. Dr. Harrington was previously the Richard Sean Stack, MD Distinguished Professor and the Director of the Duke Clinical Research Institute (DCRI) at Duke University. His research interests include evaluating antithrombotic therapies to treat acute ischemic heart disease and to minimize the acute complications of percutaneous coronary procedures, studying the mechanism of disease of the acute coronary syndromes, understanding the issue of risk stratification in the care of patients with acute ischemic coronary syndromes, building local, national and international collaborations for the efficient conduct of innovative clinical research and trying to better understand and improve upon the methodology of clinical research. His research has been extensively funded through NIH, NIA, other peer reviewed agencies and private industry. Committed to training and mentorship, Harrington has served as the principal mentor for more than 20 post-doctoral clinical research fellows focused on cardiovascular research.

He has authored more than 520 peer-reviewed manuscripts, reviews, book chapters, and editorials. Thomson Reuters lists him as one of the most cited investigators in clinical medicine from 2002-2014. He is a deputy editor of JAMA Cardiology and an editorial board member for the Journal of the American College of Cardiology. He has served as editor of five textbooks and is a senior editor of the 13th and 14th editions of Hurst’s The Heart, one of the leading textbooks of cardiovascular medicine. He has been a member of the NHLBI’s Clinical Trials Study Section and the IOM’s Working Group on Data Sharing. He served as a member of the NIH NCATS Advisory Council Working Group on the IOM CTSA Program. He is currently serving a second term as a member and the chair of the US Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee.

Harrington was recently a member of the American College of Cardiology (ACC) Board of Trustees and is currently a member of the American Heart Association’s (AHA) Board of Directors and its Science Advisory and Coordinating Committee and served as the Chair for the AHA’s Scientific Sessions in 2013 and 2014. Harrington is a Fellow of the American College of Cardiology, the American Heart Association, the Society for Cardiac Angiography and Intervention, the European Society of Cardiology, the American College of Chest Physicians and the American College of Physicians. He is an elected member of the Association of American Physicians and the Association of University Cardiologists. In 2015, he was elected to membership in the National Academy of Medicine/Institute of Medicine. In 2016, he was named a Master of the American College of Cardiology.

Harrington received his BA in English at the College of the Holy Cross, Worcester, MA. He attended Dartmouth Medical School and received his MD from Tufts University School of Medicine, Boston MA. He did his internship, residency and served as the chief resident in internal medicine at the University of Massachusetts Medical Center, Worcester MA. He trained in cardiology, interventional cardiology and clinical research (Duke Databank for Cardiovascular Disease) at Duke University Medical Center, Durham NC where he was a faculty member from 1993-2012 before joining the Stanford University faculty in 2012. Interested in innovative learning tools, including novel methods of communicating scientific information, Harrington hosts a regular podcast on theheart.org, The Bob Harrington Show, and can be followed on Twitter @HeartBobH.

Clinical Focus


  • Internal Medicine
  • General Cardiology

Academic Appointments


Administrative Appointments


  • Chair, Department of Medicine (2012 - Present)

Professional Education


  • Fellowship:Duke University GME Training Verifications (1993) NC
  • Residency:Univ Of Ma Med Sch - Worcester (1990) MA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1989)
  • Internship:Univ Of Ma Med Sch - Worcester (1987) MA
  • Medical Education:Tufts University School of Medicine (1986) MA

Teaching

2017-18 Courses


Publications

All Publications


  • Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Banerjee, S., Angiolillo, D. J., Boden, W. E., Murphy, J. G., Khalili, H., Hasan, A. A., Harrington, R. A., Rao, S. V. 2017; 69 (14): 1861-1870

    Abstract

    Dual antiplatelet therapy (DAPT) is prescribed to millions of patients worldwide following coronary stenting. DAPT is indicated to lower the risk of ischemic events, such as myocardial infarction, including stent thrombosis, ischemic stroke, or death from cardiovascular causes. A significant number of these patients undergo noncardiac surgery and may require DAPT interruption. This poses a significant clinical dilemma because DAPT interruption exposes patients to the potential risk of stent thrombosis, perioperative myocardial infarction, or both. Conversely, continuing DAPT may be associated with excess bleeding complications. Observational data in this area are conflicting, and there are no randomized clinical trials to guide practitioner decision making. On the basis of predominantly consensus recommendations, various strategies for managing DAPT during the perioperative period have been proposed. This review presents 3 commonly encountered clinical scenarios that lead into an evidence-based discussion of practical strategies for managing perioperative antiplatelet therapy in patients following percutaneous coronary intervention.

    View details for DOI 10.1016/j.jacc.2017.02.012

    View details for Web of Science ID 000398065100012

    View details for PubMedID 28385315

  • Potent P2Y(12) Inhibitors in Men Versus Women A Collaborative Meta-Analysis of Randomized Trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Lau, E. S., Braunwald, E., Murphy, S. A., Wiviott, S. D., Bonaca, M. P., Husted, S., James, S. K., Wallentin, L., Clemmensen, P., Roe, M. T., Ohman, E. M., Harrington, R. A., Mega, J. L., Bhatt, D. L., Sabatine, M. S., O'Donoghue, M. L. 2017; 69 (12): 1549-1559

    Abstract

    Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease.A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.

    View details for DOI 10.1016/j.jacc.2017.01.028

    View details for Web of Science ID 000396730200005

  • Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial EUROPEAN HEART JOURNAL Valgimigli, M., Costa, F., Lokhnygina, Y., Clare, R. M., Wallentin, L., Moliterno, D. J., Armstrong, P. W., White, H. D., Held, C., Aylward, P. E., Van de Werf, F., Harrington, R. A., Mahaffey, K. W., Tricoci, P. 2017; 38 (11): 804-?

    Abstract

    Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS.In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event.In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

    View details for DOI 10.1093/eurheartj/ehw525

    View details for Web of Science ID 000396777300005

    View details for PubMedID 28363222

  • The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial. American heart journal Gibson, C. M., Halaby, R., Korjian, S., Daaboul, Y., Arbetter, D. F., Yee, M. K., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Lu, S., Bandman, O., Leeds, J. M., Gold, A., Harrington, R. A., Cohen, A. T. 2017; 185: 93-100

    Abstract

    The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor.This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial.The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin.The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

    View details for DOI 10.1016/j.ahj.2016.12.004

    View details for PubMedID 28267480

  • Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation Gibson, C. M., Chi, G., Halaby, R., Korjian, S., Daaboul, Y., Jain, P., Arbetter, D., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Gold, A., Bandman, O., Harrington, R. A., Cohen, A. T. 2017; 135 (7): 648-655

    Abstract

    Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee.The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96; P=0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30-0.94; P=0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26-0.90; P=0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24-0.87; P=0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin.Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218.

    View details for DOI 10.1161/CIRCULATIONAHA.116.025427

    View details for PubMedID 27881569

  • Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome CLINICAL CHEMISTRY Lindholm, D., James, S. K., Bertilsson, M., Becker, R. C., Cannon, C. P., Giannitsis, E., Harrington, R. A., Himmelmann, A., Kontny, F., Siegbahn, A., Steg, P. G., Storey, R. F., Velders, M. A., Weaver, W. D., Wallentin, L. 2017; 63 (2): 573-584

    Abstract

    Risk stratification in non-ST-elevation acute coronary syndrome (NSTE-ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE-ACS.In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI).For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13-1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs.In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF-15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment. ClinicalTrials.gov Identifier: NCT00391872.

    View details for DOI 10.1373/clinchem.2016.261271

    View details for Web of Science ID 000393360000020

    View details for PubMedID 27932413

  • Cangrelor With and Without Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vaduganathan, M., Harrington, R. A., Stone, G. W., Deliargyris, E. N., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Menozzi, A., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 69 (2): 176-185

    Abstract

    Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI).This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs).This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator's discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization.Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms.Cangrelor's efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571).

    View details for DOI 10.1016/j.jacc.2016.10.055

    View details for Web of Science ID 000392993100009

    View details for PubMedID 28081827

  • The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting with ST-Elevation Myocardial Infarction PLOS ONE Hamo, C. E., Klem, I., Rao, S. V., Songco, V., Najjar, S., Lakatta, E. G., Raman, S. V., Harrington, R. A., Heitner, J. F. 2017; 12 (1)

    Abstract

    Identification of the infarct-related artery (IRA) in patients with STEMI using coronary angiography (CA) is often based on the ECG and can be challenging in patients with severe multi-vessel disease. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on cardiac magnetic resonance imaging (CMR).We evaluated 113 patients from the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, who underwent CMR within 4±2 days of revascularization. Blinded reviewers interpreted CA to determine the IRA and CMR to determine the location of infarction on a 17-segment model. In patients with multiple infarcts on CMR, acuity was determined with T2-weighted imaging and/or evidence of microvascular obstruction.A total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and CA. In 4/5 cases, there were multiple infarcts noted on CMR. Thirteen patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts.In this select population of patients, the identification of the IRA by CA was incorrect in 4% of patients presenting with STEMI. Four patients with a mismatch had an acute infarction in more than one coronary artery territory on CMR. The role of CMR in patients presenting with STEMI with multi-vessel disease on CA deserves further investigation.

    View details for DOI 10.1371/journal.pone.0169108

    View details for Web of Science ID 000391641500054

    View details for PubMedID 28060863

  • Impact of Cerebrovascular Events Older Than One Year on Ischemic and Bleeding Outcomes With Cangrelor in Percutaneous Coronary Intervention CIRCULATION-CARDIOVASCULAR INTERVENTIONS Sawlani, N. N., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 10 (1)

    Abstract

    Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding.CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81).Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.004380

    View details for Web of Science ID 000393178000006

    View details for PubMedID 28039321

  • Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I) CIRCULATION Gibson, C. M., Korjian, S., Tricoci, P., Daaboul, Y., Yee, M., Jain, P., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D. M., Deckelbaum, L. I., Merkely, B., Zarebinski, M., Ophuis, T. O., Harrington, R. A. 2016; 134 (24): 1918-?
  • Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial AMERICAN HEART JOURNAL Mehta, R. H., van Diepen, S., Meza, J., Bokesch, P., Leimberger, J. D., Tourt-Uhlig, S., Swartz, M., Parrotta, J., Jankowich, R., Hay, D., Harrison, R. W., Fremes, S., Goodman, S. G., Luber, J., Toller, W., Heringlake, M., Anstrom, K. J., Levy, J. H., Harrington, R. A., Alexander, J. H. 2016; 182: 62-71

    Abstract

    Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB.LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 μg kg(-1) min(-1) for the first hour followed by 0.1 μg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017.LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB.ClinicalTrials.gov (NCT02025621).

    View details for DOI 10.1016/j.ahj.2016.09.001

    View details for Web of Science ID 000389136600008

    View details for PubMedID 27914501

  • The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? Academic medicine Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534-1539

    Abstract

    The medical student performance evaluation (MSPE), a letter summarizing academic performance, is included in each medical student's residency application. The extent to which medical schools follow Association of American Medical Colleges (AAMC) recommendations for comparative and transparent data is not known. This study's purpose was to describe the content, interpretability, and transparency of MSPEs.This cross-sectional study examined one randomly selected MSPE from every Liaison Committee on Medical Education-accredited U.S. medical school from which at least one student applied to the Stanford University internal medical residency program during the 2013-2014 application cycle. The authors described the number, distribution, and range of key words and clerkship grades used in the MSPEs and the proportions of schools with missing or incomplete data.The sample included MSPEs from 117 (89%) of 131 medical schools. Sixty schools (51%) provided complete information about clerkship grade and key word distributions. Ninety-six (82%) provided comparative data for clerkship grades, and 71 (61%) provided complete key word data. Key words describing overall performance were extremely heterogeneous, with a total of 72 used and great variation in the assignment of the top designation (median: 24% of students; range: 1%-60%). There was also great variation in the proportion of students awarded the top internal medicine clerkship grade (median: 29%; range: 2%-90%).The MSPE is a critical component of residency applications, yet data contained within MSPEs are incomplete and variable. Approximately half of U.S. medical schools do not follow AAMC guidelines for MSPEs.

    View details for PubMedID 26703411

  • Radial access in patients with acute coronary syndrome without persistent ST-segment elevation: Systematic review, collaborative meta-analysis, and meta-regression INTERNATIONAL JOURNAL OF CARDIOLOGY Ando, G., Porto, I., Montalescot, G., Bolognese, L., Trani, C., Oreto, G., Harrington, R. A., Bhatt, D. L. 2016; 222: 1031-1039

    Abstract

    Consistent evidence of benefit exists for radial access (RA) in ST-elevation acute myocardial infarction (STEMI). Patients with non ST-elevation acute coronary syndrome (NSTE-ACS) have a more varied ischemic and bleeding profile. No randomized trial of vascular access ever focused on NSTE-ACS and landmark studies did not provide conclusive results in this heterogeneous subset of patients.We assessed in a meta-analysis whether RA is associated with improved outcomes in NSTE-ACS patients. Included studies had to meet the following criteria: 1) enrolling patients with NSTE-ACS undergoing invasive management; 2) reporting outcomes with respect to RA as compared with femoral access (FA); 3) reporting short-term (procedural, in-hospital and up to 30-day) or long-term clinical outcomes. Studies were pooled with fixed and random effects models and heterogeneity was investigated by weighted meta-regression.Eleven studies were included encompassing 131.339 patients, 46.451 receiving RA and 84.888 receiving FA. Thirty-day mortality and MACE were lower with RA (p<0.001 with fixed effects, p=NS with random effects model), but these results depended on one large observational database. Major bleeding was consistently reduced by RA (p<0.001), albeit an inverse relationship with the proportion of patients in each study receiving FA and experiencing major bleeding was evident. The association of RA with reduced long-term mortality was of borderline significance (p=0.054 with random-effects, p=0.001 with fixed-effect model) and also depended on major bleeding in FA patients.RA is associated with better outcomes as compared with FA in NSTE-ACS, although this observation is influenced by nonrandomized comparisons. Large heterogeneity exists among studies.This study is registered in the PROSPERO database (CRD42015029459).

    View details for DOI 10.1016/j.ijcard.2016.07.228

    View details for Web of Science ID 000384698300217

    View details for PubMedID 27537543

  • The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jones, W. S., Roe, M. T., Antman, E. M., Pletcher, M. J., Harrington, R. A., Rothman, R. L., Oetgen, W. J., Rao, S. V., Krucoff, M. W., Curtis, L. H., Hernandez, A. F., Masoudi, F. A. 2016; 68 (17): 1898-1907

    Abstract

    Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.

    View details for DOI 10.1016/j.jacc.2016.07.781

    View details for Web of Science ID 000386826700011

    View details for PubMedID 27765193

  • Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction AMERICAN HEART JOURNAL Gibson, C. M., Korjian, S., Tricoci, P., Daaboul, Y., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D., Merkely, B., Zarebinski, M., Ophius, T. O., Harrington, R. A. 2016; 180: 22-28

    Abstract

    Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease.The AEGIS-I trial (ClinicalTrials.govNCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period.The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.

    View details for DOI 10.1016/j.ahj.2016.06.017

    View details for Web of Science ID 000384157800003

    View details for PubMedID 27659879

  • Efficacy and Safety of Cangrelor in Preventing Periprocedural Complications in Patients With Stable Angina and Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention The CHAMPION PHOENIX Trial JACC-CARDIOVASCULAR INTERVENTIONS Abtan, J., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C. W., Price, M. J., Abnousi, F., Prats, J., Deliargyris, E. N., White, H. D., Harrington, R. A., Bhatt, D. L. 2016; 9 (18): 1905-1913

    Abstract

    The purpose of this study was to examine the safety and efficacy of cangrelor in patients with stable angina (SA) or acute coronary syndrome (ACS).The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial demonstrated that cangrelor significantly reduced periprocedural ischemic events in all-comer percutaneous coronary intervention with a modest increase in mild and moderate bleeding. Whether this benefit is consistent across SA and ACS has not been explored fully.The CHAMPION PHOENIX trial compared periprocedural administration of cangrelor or clopidogrel, with either a 300- or 600-mg loading dose for the prevention of periprocedural complications in patients undergoing percutaneous coronary intervention. Among the 10,942 patients in the modified intention to treat population, 6,358 patients were classified as having SA, and 4,584 patients had ACS (including unstable angina, non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction) at randomization. The primary composite endpoint was death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h. A key secondary endpoint was stent thrombosis, and the primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding.Cangrelor consistently reduced the primary endpoint in SA and ACS (odds ratio [OR]: 0.83 [95% confidence interval (CI): 0.67 to 1.01] and OR: 0.71 [95% CI: 0.52 to 0.96], respectively; interaction p = 0.41). Cangrelor also consistently reduced stent thrombosis in SA and ACS (OR: 0.55 [95% CI: 0.30 to 1.01] and OR: 0.67 [95% CI: 0.42 to 1.06], respectively; interaction p = 0.62). The impact of cangrelor on GUSTO severe/moderate bleeding was also similar for SA and ACS (OR: 1.49 [95% CI: 0.67 to 3.33] and OR: 1.79 [95% CI: 0.79 to 4.07], respectively; interaction p = 0.75).The benefits and risks of cangrelor were consistent in patients with SA and ACS. (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]; NCT01156571).

    View details for DOI 10.1016/j.jcin.2016.06.046

    View details for Web of Science ID 000385713800010

    View details for PubMedID 27659566

  • Consistent Reduction in Periprocedural Myocardial Infarction With Cangrelor as Assessed by Multiple Definitions: Findings From CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation Cavender, M. A., Bhatt, D. L., Stone, G. W., White, H. D., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Leonardi, S., Prats, J., Deliargyris, E. N., Mahaffey, K. W., Harrington, R. A. 2016; 134 (10): 723-733

    Abstract

    Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not pretreated with a P2Y12 inhibitor.A total of 11 145 patients were randomized to cangrelor or clopidogrel in the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). We explored the effects of cangrelor on myocardial infarction (MI) using different definitions and performed sensitivity analyses on the primary end point of the trial.A total of 462 patients (4.2%) undergoing percutaneous coronary intervention had an MI as defined by the second universal definition. The majority of these MIs (n=433, 93.7%) were type 4a. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67-0.97; P=0.02). When the Society of Coronary Angiography and Intervention definition of periprocedural MI was applied to potential ischemic events, there were fewer total MIs (n=134); however, the effects of cangrelor on MI remained significant (OR, 0.65; 95% CI, 0.46-0.92; P=0.01). Similar effects were seen in the evaluation of the effects of cangrelor on MIs with peak creatinine kinase-MB ≥10 times the upper limit of normal (OR, 0.64; 95% CI, 0.45-0.91) and those with peak creatinine kinase-MB ≥10 times the upper limit of normal, ischemic symptoms, or ECG changes (OR, 0.63; 95% CI, 0.48-0.84). MIs defined by any of these definitions were associated with increased risk of death at 30 days. Treatment with cangrelor reduced the composite end point of death, MI (Society of Coronary Angiography and Intervention definition), ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51-0.92).MI in patients undergoing percutaneous coronary intervention, regardless of definition, remains associated with increased risk of death in the current era. Cangrelor compared with clopidogrel significantly reduces MI regardless of the definition.URL: http://clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.020829

    View details for PubMedID 27482008

  • A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 2016; 11 (9): 646-649

    Abstract

    The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.

    View details for DOI 10.1002/jhm.2590

    View details for PubMedID 27079160

  • Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. New England journal of medicine Cohen, A. T., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Wiens, B. L., Gold, A., Hernandez, A. F., Gibson, C. M. 2016; 375 (6): 534-544

    Abstract

    Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55).Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

    View details for DOI 10.1056/NEJMoa1601747

    View details for PubMedID 27232649

  • Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. American heart journal Armaganijan, L. V., Alexander, K. P., Huang, Z., Tricoci, P., Held, C., Van de Werf, F., Armstrong, P. W., Aylward, P. E., White, H. D., Moliterno, D. J., Wallentin, L., Chen, E., Harrington, R. A., Strony, J., Mahaffey, K. W., Lopes, R. D. 2016; 178: 176-184

    Abstract

    Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety.Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding.The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574).Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

    View details for DOI 10.1016/j.ahj.2016.05.012

    View details for PubMedID 27502866

  • Arterial access site and outcomes in patients undergoing percutaneous coronary intervention with and without vorapaxar. Catheterization and cardiovascular interventions Déry, J., Mahaffey, K. W., Tricoci, P., White, H. D., Podder, M., Westerhout, C. M., Moliterno, D. J., Harrington, R. A., Chen, E., Strony, J., Van de Werf, F., Ziada, K. M., Held, C., Aylward, P. E., Armstrong, P. W., Rao, S. V. 2016; 88 (2): 163-173

    Abstract

    We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial.Vorapaxar reduces ischemic events but increases the risk of major bleeding.We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access.Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE.Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ccd.26335

    View details for PubMedID 26698636

  • Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial. American heart journal Åkerblom, A., Clare, R. M., Lokhnygina, Y., Wallentin, L., Held, C., Van de Werf, F., Moliterno, D. J., Patel, U. D., Leonardi, S., Armstrong, P. W., Harrington, R. A., White, H. D., Aylward, P. E., Mahaffey, K. W., Tricoci, P. 2016; 178: 1-8

    Abstract

    Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes.Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported.Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98).High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

    View details for DOI 10.1016/j.ahj.2016.04.013

    View details for PubMedID 27502846

  • Defining a Mobile Health Roadmap for Cardiovascular Health and Disease. Journal of the American Heart Association Eapen, Z. J., Turakhia, M. P., McConnell, M. V., Graham, G., Dunn, P., Tiner, C., Rich, C., Harrington, R. A., Peterson, E. D., Wayte, P. 2016; 5 (7)

    View details for DOI 10.1161/JAHA.115.003119

    View details for PubMedID 27405809

    View details for PubMedCentralID PMC5015362

  • Impact of glycoprotein IIb/IIIa inhibitors on the efficacy and safety of ticagrelor compared with clopidogrel in patients with acute coronary syndromes: Analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial AMERICAN HEART JOURNAL Shimada, Y. J., Bansilal, S., Wiviott, S. D., Becker, R. C., Harrington, R. A., Himmelmann, A., Neely, B., Husted, S., James, S. K., Katus, H. A., Lopes, R. D., Steg, P. G., Storey, R. F., Wallentin, L., Cannon, C. P. 2016; 177: 1-8

    Abstract

    Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel.PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours.A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05).In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment.

    View details for DOI 10.1016/j.ahj.2016.03.015

    View details for Web of Science ID 000377473100002

    View details for PubMedID 27297843

  • Variation in Patient Profiles and Outcomes in US and Non-US Subgroups of the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2016; 9 (6)

    Abstract

    The Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention compared with clopidogrel.We analyzed all patients included in the modified intention-to-treat analysis in US (n=4097; 37.4%) and non-US subgroups (n=6845; 62.6%). The US cohort was older, had a higher burden of cardiovascular risk factors, and had more frequently undergone prior cardiovascular procedures. US patients more frequently underwent percutaneous coronary intervention for stable angina (77.9% versus 46.2%). Almost all US patients (99.1%) received clopidogrel loading doses of 600 mg, whereas 40.5% of non-US patients received 300 mg. Bivalirudin was more frequently used in US patients (56.7% versus 2.9%). At 48 hours, rates of the primary composite end point were comparable in the US and non-US cohorts (5.5% versus 5.2%; P=0.53). Cangrelor reduced rates of the primary composite end point compared with clopidogrel in US (4.5% versus 6.4%; odds ratio 0.70 [95% confidence interval 0.53-0.92]) and in non-US patients (4.8% versus 5.6%; odds ratio 0.85 [95% confidence interval 0.69-1.05]; interaction P=0.26). Similarly, rates of the key secondary end point, stent thrombosis, were reduced by cangrelor in both regions. Rates of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined severe bleeding were low and not significantly increased by cangrelor in either region.Despite broad differences in clinical profiles and indications for percutaneous coronary intervention by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic end points compared with clopidogrel without an excess in severe bleeding in both the US and non-US subgroups.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.003612

    View details for Web of Science ID 000378134200013

    View details for PubMedID 27313282

  • Lipoprotein-Associated Phospholipase A(2) Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease JOURNAL OF THE AMERICAN HEART ASSOCIATION Wallentin, L., Held, C., Armstrong, P. W., Cannon, C. P., Davies, R. Y., Granger, C. B., Hagstrom, E., Harrington, R. A., Hochman, J. S., Koenig, W., Krug-Gourley, S., Mohler, E. R., Siegbahn, A., Tarka, E., Steg, P. G., Stewart, R. A., Weiss, R., Ostlund, O., White, H. D. 2016; 5 (6)

    Abstract

    We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes.Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

    View details for DOI 10.1161/JAHA.116.003407

    View details for Web of Science ID 000386712700045

    View details for PubMedID 27329448

  • Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes The TRACER Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vranckx, P., White, H. D., Huang, Z., Mahaffey, K. W., Armstrong, P. W., Van de Werf, F., Moliterno, D. J., Wallentin, L., Held, C., Aylward, P. E., Cornel, J. H., Bode, C., Huber, K., Nicolau, J. C., Ruzyllo, W., Harrington, R. A., Tricoci, P. 2016; 67 (18): 2135-2144

    Abstract

    The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed.This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries).We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death.During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding.In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2016.02.056

    View details for Web of Science ID 000375406100007

    View details for PubMedID 27151345

  • Extended-Duration Thromboprophylaxis Among Acute Medically Ill Patients: An Unmet Need JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS Korjian, S., Daaboul, Y., Halaby, R., Goldhaber, S. Z., Cohen, A. T., Singh, K., Susheela, A. T., Harrington, R. A., Hull, R. D., Hernandez, A. F., Gibson, C. M. 2016; 21 (3): 227-232

    Abstract

    Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.

    View details for DOI 10.1177/1074248415601894

    View details for Web of Science ID 000373751000001

    View details for PubMedID 26341120

  • Tooth loss is independently associated with poor outcomes in stable coronary heart disease EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Vedin, O., Hagstrom, E., Budaj, A., Denchev, S., Harrington, R. A., Koenig, W., Soffer, J., Sritara, P., Stebbins, A., Stewart, R. H., Swart, H. P., Viigimaa, M., Vinereanu, D., Wallentin, L., White, H. D., Held, C. 2016; 23 (8): 839-846

    Abstract

    We investigated associations between self-reported tooth loss and cardiovascular outcomes in a global stable coronary heart disease cohort.We examined 15,456 patients from 39 countries with stable coronary heart disease (prior myocardial infarction, prior revascularisation or multivessel coronary heart disease) in the STABILITY trial. At baseline, patients reported number of teeth (26-32 (all), 20-25, 15-19, 1-14 and no teeth) and were followed for 3.7 years. Cox regression models adjusted for cardiovascular risk factors and socioeconomic status, determined associations between tooth loss level (26-32 teeth: lowest level; no teeth: highest level) and cardiovascular outcomes.After adjustment, every increase in tooth loss level was associated with an increased risk of the primary outcome, the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (hazard ratio 1.06; 95% confidence interval 1.02-1.10), cardiovascular death (1.17; 1.10-1.24), all-cause death (1.16; 1.11-1.22) and non-fatal or fatal stroke (1.14; 1.04-1.24), but not with non-fatal or fatal myocardial infarction (0.99; 0.94-1.05). Having no teeth, compared to 26-32 teeth, entailed a significantly higher risk of the primary outcome (1.27 (1.08, 1.49)), cardiovascular death (1.85 (1.45, 2.37), all-cause death (1.81 (1.50, 2.20)) and stroke (1.67 (1.15, 2.39)).In this large global cohort of patients with coronary heart disease, self-reported tooth loss predicted adverse cardiovascular outcomes and all-cause death independent of cardiovascular risk factors and socioeconomic status.

    View details for DOI 10.1177/2047487315621978

    View details for Web of Science ID 000374971500007

    View details for PubMedID 26672609

  • Lack of Concordance Between Local Investigators, Angiographic Core Laboratory, and Clinical Event Committee in the Assessment of Stent Thrombosis Results From the TRACER Angiographic Substudy CIRCULATION-CARDIOVASCULAR INTERVENTIONS Popma, C. J., Sheng, S., Korjian, S., Daaboul, Y., Chi, G., Tricoci, P., Huang, Z., Moliterno, D. J., White, H. D., Van de Werf, F., Harrington, R. A., Wallentin, L., Held, C., Armstrong, P. W., Aylward, P. E., Strony, J., Mahaffey, K. W., Gibson, C. M. 2016; 9 (5)

    Abstract

    Stent thrombosis (ST) is an important end point in cardiovascular clinical trials. Adjudication is traditionally based on clinical event committee (CEC) review of case report forms and source documentation rather than angiograms. However, the degree to which this method of adjudication is concordant with the review of independent angiographic core laboratories (ACLs) has not been studied. This report represents the first assessment of variability between local investigators (LIs), a CEC, and an ACL.Serial angiograms of 329 patients with acute coronary syndrome without ST-segment-elevation who underwent percutaneous coronary intervention at entry in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRACER) and who met criteria for possible ST subsequent to the index event were reviewed by an ACL. The ACL was blinded to the assessment by both LIs and the CEC regarding the presence or absence of ST. CEC adjudication was based on Academic Research Consortium definitions of ST, using case report form data and source documents, including catheterization laboratory reports. The ACL, CEC, and LIs agreed on the presence or absence of ST in 52.9% events (κ=0.32; 95% confidence interval, 0.26-0.39). The ACL and CEC agreed on 82.7% of events (κ=0.57; 95% confidence interval, 0.47-0.67); the ACL and LIs agreed on 61.1% of events (κ=0.25; 95% confidence interval, 0.16-0.34); and the CEC and LIs agreed on 62% of events (κ=0.28; 95% confidence interval, 0.21-0.36).ST reporting by an ACL, a CEC, and LIs is discordant. The assessment of ST is more often detected by direct review of angiograms by an ACL.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.003114

    View details for Web of Science ID 000376742000002

    View details for PubMedID 27162212

  • Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment-Elevation Acute Coronary Syndromes Clinical Trials CIRCULATION Kragholm, K., Goldstein, S. A., Yang, Q., Lopes, R. D., Schulte, P. J., Bernacki, G. M., White, H. D., Mahaffey, K. W., Giugliano, R. P., Armstrong, P. W., Harrington, R. A., Tricoci, P., Van de Werf, F., Alexander, J. H., Alexander, K. P., Newby, L. K. 2016; 133 (16): 1560-?

    Abstract

    Representation by age ensures appropriate translation of clinical trial results to practice, but, historically, older patients have been underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel.We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76 141 patients with non-ST-segment-elevation acute coronary syndrome enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were ≥75 years; this proportion increased from 16% during 1994 to 1997 to 21% during 1998 to 2001 and 23.2% during 2002 to 2005, but declined to 20.2% in 2006 to 2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in the use of evidence-based medication in-hospital and at discharge regardless of age. Although predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 versus 2006-2010: <65 years: 3.0% versus 1.9%; 65-74 years: 7.5% versus 3.4%; 75-79 years: 13.0% versus 6.5%; 80-84 years: 17.6% versus 8.2%; and ≥85 years: 24.8% versus 12.6%).The distribution of enrollment by age in phase III non-ST-segment-elevation acute coronary syndrome trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017299

    View details for Web of Science ID 000374553400011

    View details for PubMedID 26957532

  • The effect of cangrelor and access site on ischaemic and bleeding events: insights from CHAMPION PHOENIX EUROPEAN HEART JOURNAL Gutierrez, J. A., Harrington, R. A., Blankenship, J. C., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Genereux, P., Prats, J., Deliargyris, E. N., Mahaffey, K., White, H. D., Bhatt, D. L. 2016; 37 (14): 1122-1130

    Abstract

    To assess whether the use of the femoral or radial approach for percutaneous coronary intervention (PCI) interacted with the efficacy and safety of cangrelor, an intravenous P2Y12 inhibitor, in CHAMPION PHOENIX.A total of 11 145 patients were randomly assigned in a double-dummy, double-blind manner either to a cangrelor bolus and 2-h infusion or to clopidogrel at the time of PCI. The primary endpoint, a composite of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and the primary safety endpoint, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) defined severe bleeding, were evaluated at 48 h. Of the patients undergoing PCI and receiving study drug treatment, a total of 8064 (74%) and 2855 (26%) patients underwent femoral or radial PCI, respectively. Among the femoral cohort, the primary endpoint rate was 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI] = 0.79 [0.65-0.96]); among the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] = 0.76 [0.54-1.06]), P-interaction 0.83. The rate of GUSTO severe bleeding in the femoral cohort was 0.2% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.73 [0.51-5.93]). Among the radial cohort, the rate of GUSTO severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.02 [0.14-7.28]), P-interaction 0.65. The evaluation of safety endpoints with the more sensitive ACUITY-defined bleeding found major bleeding in the femoral cohort to be 5.2% with cangrelor vs. 3.1% with clopidogrel (OR [95% CI] = 1.69 [1.35-2.12]); among the radial cohort the rate of ACUITY major bleeding was 1.5% with cangrelor vs. 0.7% with clopidogrel (OR [95% CI] = 2.17 [1.02-4.62], P-interaction 0.54).In CHAMPION PHOENIX, cangrelor reduced ischaemic events with no significant increase in GUSTO-defined severe bleeding. The absolute rates of bleeding, regardless of the definition, tended to be lower when PCI was performed via the radial artery.http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1093/eurheartj/ehv498

    View details for Web of Science ID 000373558500011

    View details for PubMedID 26400827

    View details for PubMedCentralID PMC4823635

  • Sudden Cardiac Death After Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA cardiology Hess, P. L., Wojdyla, D. M., Al-Khatib, S. M., Lokhnygina, Y., Wallentin, L., Armstrong, P. W., Roe, M. T., Ohman, E. M., Harrington, R. A., Alexander, J. H., White, H. D., Van de Werf, F., Piccini, J. P., Held, C., Aylward, P. E., Moliterno, D. J., Mahaffey, K. W., Tricoci, P. 2016; 1 (1): 73-79

    Abstract

    In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely.To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD.This pooled cohort analysis merged individual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015.Sudden cardiac death.Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men; 32.6% women; median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7% (C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrent myocardial infarction (hazard ratio [HR], 2.95; 95% CI, 2.29-3.80; P < .001) and any hospitalization (HR, 2.45; 95% CI, 1.98-3.03; P < .001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75; 95% CI, 0.58-0.98; P = .03).In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.

    View details for DOI 10.1001/jamacardio.2015.0359

    View details for PubMedID 27437658

  • Safety and efficacy of ticagrelor and clopidogrel in primary percutaneous coronary intervention HEART Velders, M. A., Abtan, J., Angiolillo, D. J., Ardissino, D., Harrington, R. A., Hellkamp, A., Himmelmann, A., Husted, S., Katus, H. A., Meier, B., Schulte, P. J., Storey, R. F., Wallentin, L., Steg, P. G., James, S. K. 2016; 102 (8): 617-625
  • Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial CIRCULATION O'Donoghue, M. L., Bhatt, D. L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2016; 133 (3): 248-255
  • Frequency, clinical and angiographic characteristics, and outcomes of high-risk non-ST-segment elevation acute coronary syndromes patients with left circumflex culprit lesions INTERNATIONAL JOURNAL OF CARDIOLOGY Halim, S. A., Clare, R. M., Newby, L. K., Lokhnygina, Y., Schweiger, M. J., Hof, A. W., Hochman, J. S., James, S. K., White, H. D., Widimsky, P., Betriu, A., Bode, C., Giugliano, R. P., Harrington, R. A., Zeymer, U. 2016; 203: 708-713

    View details for DOI 10.1016/j.ijcard.2015.11.036

    View details for Web of Science ID 000367007200185

    View details for PubMedID 26587725

  • Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes Insights From the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial CIRCULATION Harskamp, R. E., Alexander, J. H., Ferguson, T. B., Hager, R., Mack, M. J., Englum, B., Wojdyla, D., Schulte, P. J., Kouchoukos, N. T., de Winter, R. J., Gibson, C. M., Peterson, E. D., Harrington, R. A., Smith, P. K., Lopes, R. D. 2016; 133 (2): 131-138
  • Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia The Case for Community Equipoise JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Stone, G. W., Hochman, J. S., Williams, D. O., Boden, W. E., Ferguson, T. B., Harrington, R. A., Maron, D. J. 2016; 67 (1): 81-99
  • Autologous CD34(+) Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study CELL TRANSPLANTATION Henry, T. D., Schaer, G. L., Traverse, J. H., Povsic, T. J., Davidson, C., Lee, J. S., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Patel, A. N., Riedel, N., Junge, C., Hunt, A., Kereiakes, D. J., White, C., Harrington, R. A., Schatz, R. A., Losordo, D. W. 2016; 25 (9): 1701-1711

    Abstract

    An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34(+) stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34(+) stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10(5) CD34/kg body weight), and high dose (5 × 10(5) CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA(®) mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III-IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34(+) cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34(+) cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

    View details for DOI 10.3727/096368916X691484

    View details for Web of Science ID 000382800300011

    View details for PubMedID 27151378

  • High-degree atrioventricular block, asystole, and electro-mechanical dissociation complicating non-ST-segment elevation myocardial infarction AMERICAN HEART JOURNAL Pokorney, S. D., Radder, C., Schulte, P. J., Al-Khatib, S. M., Tricocci, P., Van de Werf, F., James, S. K., Cannon, C. P., Armstrong, P. W., White, H. D., Califf, R. M., Gibson, C. M., Giugliano, R. P., Wallentin, L., Mahaffey, K. W., Harrington, R. A., Newby, L. K., Piccini, J. P. 2016; 171 (1): 25-32

    View details for DOI 10.1016/j.ahj.2015.09.004

    View details for Web of Science ID 000367126200004

    View details for PubMedID 26699597

  • Acquisition, Analysis, and Sharing of Data in 2015 and Beyond: A Survey of the Landscape A Conference Report From the American Heart Association Data Summit 2015 JOURNAL OF THE AMERICAN HEART ASSOCIATION Antman, E. M., Benjamin, E. J., Harrington, R. A., Houser, S. R., Peterson, E. D., Bauman, M. A., Brown, N., Bufalino, V., Califf, R. M., Creager, M. A., Daugherty, A., DeMets, D. L., Dennis, B. P., Ebadollahi, S., Jessup, M., Lauer, M. S., Lo, B., MacRae, C. A., McConnell, M. V., McCray, A. T., Mello, M. M., Mueller, E., Newburger, J. W., Okun, S., Packer, M., Philippakis, A., Ping, P., Prasoon, P., Roger, V. L., Singer, S., Temple, R., Turner, M. B., Vigilante, K., Warner, J., Wayte, P. 2015; 4 (11)

    View details for DOI 10.1161/JAHA.115.002810

    View details for Web of Science ID 000366615600032

    View details for PubMedID 26541391

  • Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Bhatt, D. L., Steg, P. G., Stone, G. W., White, H. D., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Mahaffey, K. W., Harrington, R. A. 2015; 40 (3): 317-322
  • Clinician Innovator: A Novel Career Path in Academic Medicine A Presidentially Commissioned Article From the American Heart Association JOURNAL OF THE AMERICAN HEART ASSOCIATION Majmudar, M. D., Harrington, R. A., Brown, N. J., Graham, G., McConnell, M. V. 2015; 4 (10)

    View details for DOI 10.1161/JAHA.115.001990

    View details for Web of Science ID 000364153000009

    View details for PubMedID 26450117

  • Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome HEART Khan, R., Lopes, R. D., Neely, M. L., Stevens, S. R., Harrington, R. A., Diaz, R., Cools, F., Jansky, P., Montalescot, G., Atar, D., Lopez-Sendon, J., Flather, M., Liaw, D., Wallentin, L., Alexander, J. H., Goodman, S. G. 2015; 101 (18): 1475-1484
  • Comparison of quality-of-life measures after radial versus femoral artery access for cardiac catheterization in women: Results of the Study of Access Site for Enhancement of Percutaneous Coronary Intervention for Women quality-of-life substudy AMERICAN HEART JOURNAL Hess, C. N., Krucoff, M. W., Sheng, S., Anstrom, K. J., Barham, W. B., Gilchrist, I. C., Harrington, R. A., Jacobs, A. K., Mehran, R., Messenger, J. C., Mark, D. B., Rao, S. V. 2015; 170 (2): 371-379
  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients Insights From Clinical Trials Over 17 Years CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367
  • Organizational Change, Leadership, and the Transformation of Continuing Professional Development: Lessons Learned From the American College of Cardiology JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS Beliveau, M. E., Warnes, C. A., Harrington, R. A., Nishimura, R. A., O'Gara, P. T., Sibley, J. B., Oetgen, W. J. 2015; 35 (3): 201-210

    View details for DOI 10.1002/chp.21301

    View details for Web of Science ID 000363878600007

    View details for PubMedID 26378426

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations AMERICAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750
  • Magnitude of troponin elevation and long-term clinical outcomes in acute coronary syndrome patients treated with and without revascularization. Circulation. Cardiovascular interventions Bagai, A., Huang, Z., Lokhnygina, Y., Harrington, R. A., Armstrong, P. W., Strony, J., White, H. D., Leonardi, S., Held, C., Van de Werf, F., Wallentin, L., Tricoci, P., Mahaffey, K. W. 2015; 8 (6)

    Abstract

    In patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization.We studied 12 635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5× URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (P for interaction=0.004). This relationship was unchanged after multivariable adjustment.There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.002314

    View details for PubMedID 26025218

  • Meta-Analysis of Intracranial Hemorrhage in Acute Coronary Syndromes: Incidence, Predictors, and Clinical Outcomes JOURNAL OF THE AMERICAN HEART ASSOCIATION Mahaffey, K. W., Hager, R., Wojdyla, D., White, H. D., Armstrong, P. W., Alexander, J. H., Tricoci, P., Lopes, R. D., Ohman, E. M., Roe, M. T., Harrington, R. A., Wallentin, L. 2015; 4 (6)

    Abstract

    Little is known about the incidence, predictors, or outcomes of intracranial hemorrhage (ICH) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). We aimed to determine the incidence and timing of ICH, characterize the location of ICH, and identify independent baseline predictors of ICH in NSTE ACS patients.We pooled patient-level data from 4 contemporary antithrombotic therapy trials. Multivariable modeling identified independent predictors of ICH. ICHs were adjudicated by a clinical events committee. Of 37 815 patients, 135 (0.4%) had an ICH. The median (25th, 75th percentiles) follow-up was 332 (184, 434) days but differed across trials. Locations of ICH were intracerebral (50%), subdural (31%), subarachnoid (18.5%), and intraventricular (11%). Independent predictors of ICH were older age (HR per 10 years, 1.61; 95% CI, 1.35 to 1.91); prior stroke/transient ischemic attack; HR, 1.95; 95% CI, 1.14 to 3.35), higher systolic blood pressure; HR per 10 mm Hg increase, 1.09; 95% CI, 1.01 to 1.18), and larger number of antithrombotic agents (HR per each additional agent, 2.06; 95% CI, 1.49 to 2.84). Of all ICHs, 45 (33%) were fatal.In patients with NSTE ACS enrolled in recent clinical trials of antithrombotic therapies, ICH was uncommon. Patients with older age, prior transient ischemic attack/stroke, higher systolic blood pressure, or larger number of antithrombotic agents were at increased risk. One-third of patients with ICH died. These data may be useful to trialists and data and safety monitoring committees for trial conduct and monitoring.URL: https://www.clinicaltrials.gov/. Unique identifiers: TRACER: NCT00527943, PLATO: NCT00391872, APPRAISE-2: NCT00831441, TRILOGY ACS: NCT00699998.

    View details for DOI 10.1161/JAHA.114.001512

    View details for Web of Science ID 000357025100007

    View details for PubMedID 26089177

  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial) AMERICAN JOURNAL OF CARDIOLOGY Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., de Werf, F. V., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332
  • Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial AMERICAN HEART JOURNAL Cornel, J. H., Lopes, R. D., James, S., Stevens, S. R., Neely, M. L., Liaw, D., Miller, J., Mohan, P., Amerena, J., Raev, D., Huo, Y., Urina-Triana, M., Cazorla, A. G., Vinereanu, D., Fridrich, V., Harrington, R. A., Wallentin, L., Alexander, J. H. 2015; 169 (4): 531-538

    Abstract

    Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations.High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding.Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF.In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF.

    View details for DOI 10.1016/j.ahj.2014.12.022

    View details for Web of Science ID 000351949500016

  • Outcomes With Cangrelor Versus Clopidogrel on a Background of Bivalirudin Insights From the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) JACC-CARDIOVASCULAR INTERVENTIONS White, H. D., Bhatt, D. L., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P. G., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. 2015; 8 (3): 424-433

    Abstract

    The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

    View details for DOI 10.1016/j.jcin.2014.09.025

    View details for Web of Science ID 000351221300014

    View details for PubMedID 25703887

  • Economic Analysis of Ticagrelor Therapy From a US Perspective JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cowper, P. A., Pan, W., Anstrom, K. J., Kaul, P., Wallentin, L., Davidson-Ray, L., Nikolic, E., Janzon, M., Levin, L., Cannon, C. P., Harrington, R. A., Mark, D. B. 2015; 65 (5): 465-476
  • D-Dimer elevation and adverse outcomes JOURNAL OF THROMBOSIS AND THROMBOLYSIS Halaby, R., Popma, C. J., Cohen, A., Chi, G., Zacarkim, M. R., Romero, G., Goldhaber, S. Z., Hull, R., Hernandez, A., Mentz, R., Harrington, R., Lip, G., Peacock, F., Welker, J., Martin-Loeches, I., Daaboul, Y., Korjian, S., Gibson, C. M. 2015; 39 (1): 55-59

    Abstract

    D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

    View details for DOI 10.1007/s11239-014-1101-6

    View details for Web of Science ID 000348660300008

    View details for PubMedID 25006010

  • Efficacy and Safety of Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Undergoing Noncardiac Surgery. Journal of the American Heart Association van Diepen, S., Tricoci, P., Podder, M., Westerhout, C. M., Aylward, P. E., Held, C., Van de Werf, F., Strony, J., Wallentin, L., Moliterno, D. J., White, H. D., Mahaffey, K. W., Harrington, R. A., Armstrong, P. W. 2015; 4 (12)

    Abstract

    Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS.In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment.NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

    View details for DOI 10.1161/JAHA.115.002546

    View details for PubMedID 26672080

  • More Than 10 Million Steps in the Right Direction: Results From the First American Heart Association Scientific Sessions Walking Challenge PROGRESS IN CARDIOVASCULAR DISEASES Harrington, R. A., Arena, R., Despres, J., Ciarochi, A., Croll, E., Bloch, K. D. 2015; 57 (4): 296-298

    Abstract

    In 2013, the Global Congress theme at the American Heart Association (AHA) Annual Scientific Sessions was Physical Activity (PA). As a key component of the Congress, iHealth working in collaboration with AHA provided a Bluetooth-enabled wireless PA and sleep tracker to up to 2,000 Scientific Sessions attendees. Approximately 1850 Scientific Sessions attendees registered for, received a PA tracker and participated in the Walking Challenge. More than 10 million steps were walked by participants (10,703,504) during the 2.5 days of the Walking Challenge. This translates into almost 6000 miles walked (5976.3 miles) and 656,716 calories burned by participants during the Challenge. The Global Congress of PA held at Scientific Sessions 2013 not only extensively reviewed the science of PA as a powerful/independent and, most importantly, modifiable cardiovascular risk factor, but it also provided evidence from a fun and entertaining challenge that PA as a risk behavior can be assessed and targeted. We just took 10 million steps in the right direction. Join us and make your steps count!

    View details for DOI 10.1016/j.pcad.2014.09.009

    View details for Web of Science ID 000348003900002

    View details for PubMedID 25269063

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: Results from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Tricoci, P., Lokhnygina, Y., Huang, Z., Van de Werf, F., Cornel, J. H., Chen, E., Wallentin, L., Held, C., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J., Mahaffey, K. W. 2014; 168 (6): 869-?
  • Predictors of contemporary coronary artery bypass grafting outcomes JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Weisel, R. D., Nussmeier, N., Newman, M. F., Pearl, R. G., Wechsler, A. S., Ambrosio, G., Pitt, B., Clare, R. M., Pieper, K. S., Mongero, L., Reece, T. L., Yau, T. M., Fremes, S., Menasche, P., Lira, A., Harrington, R. A., Ferguson, T. B. 2014; 148 (6): 2720-U1368

    Abstract

    The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG (RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes.The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting. The primary efficacy end point was a composite of all-cause death, nonfatal stroke, or the need for mechanical support for severe left ventricular dysfunction through postoperative day 28. Logistic regression modeling with stepwise variable selection identified which prespecified baseline characteristics were associated with the primary outcome. A second logistic model included intraoperative variables as potential covariates.The 4 independent preoperative risk factors predictive of the composite end point were (1) a history of heart failure (odds ratio, 2.9); (2) increasing age (odds ratio, 1.033 per decade); (3) a history of peripheral vascular disease (odds ratio, 1.6); and (4) receiving aspirin before coronary artery bypass grafting (odds ratio, 0.5), which was protective. The duration of the cardiopulmonary bypass (odds ratio, 1.8) was the only intraoperative variable that contributed to adverse outcomes.Patients who had heart failure and preserved systolic function had a similar high risk of adverse outcomes as those with low ejection fractions, and new approaches may mitigate this risk. Recognition of patients with excessive atherosclerotic burden may permit perioperative interventions to improve their outcomes. The contemporary risks of coronary artery bypass grafting have changed, and their identification may permit new methods to improve outcomes.

    View details for DOI 10.1016/j.jtcvs.2014.08.018

    View details for Web of Science ID 000345686100064

    View details for PubMedID 25218533

  • Extent, Location, and Clinical Significance ? of Non-Infarct-Related Coronary Artery Disease Among Patimts With ST-Elevation Myocardial Infarction JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Park, D., Clare, R. M., Schulte, P. J., Pieper, K. S., Shaw, L. K., Califf, R. M., Ohman, E. M., Van de Werf, F., Hirji, S., Harrington, R. A., Armstrong, P. W., Granger, C. B., Jeong, M., Patel, M. R. 2014; 312 (19): 2019-2027
  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial AMERICAN HEART JOURNAL Schwartz, G. G., Bessac, L., Berdan, L. G., Bhatt, D. L., Bittner, V., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Rorick, T., Sasiela, W. J., Shirodaria, C., Szarek, M., Tamby, J., Tricoci, P., White, H., Zeiher, A., Steg, P. G. 2014; 168 (5): 682-689
  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: Insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) AMERICAN HEART JOURNAL Jones, W. S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588-596
  • Usefulness and Safety of Vorapaxar in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (from the TRACER Trial). American journal of cardiology Valgimigli, M., Tricoci, P., Huang, Z., Aylward, P. E., Armstrong, P. W., Van de Werf, F., Leonardi, S., White, H. D., Widimsky, P., Harrington, R. A., Cequier, A., Chen, E., Lokhnygina, Y., Wallentin, L., Strony, J., Mahaffey, K. W., Moliterno, D. J. 2014; 114 (5): 665-673

    Abstract

    The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.

    View details for DOI 10.1016/j.amjcard.2014.05.054

    View details for PubMedID 25129064

  • Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial EUROPEAN HEART JOURNAL Lindholm, D., Varenhorst, C., Cannon, C. P., Harrington, R. A., Himmelmann, A., Maya, J., Husted, S., Steg, P. G., Cornel, J. H., Storey, R. F., Stevens, S. R., Wallentin, L., James, S. K. 2014; 35 (31): 2083-2093

    Abstract

    The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization.We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding.In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.

    View details for DOI 10.1093/eurheartj/ehu160

    View details for Web of Science ID 000342232600013

    View details for PubMedID 24727884

  • Vein Graft Preservation Solutions, Patency, and Outcomes After Coronary Artery Bypass Graft Surgery Follow-up From PREVENT IV Randomized Clinical Trail JAMA SURGERY Harskamp, R. E., Alexander, J. H., Schulte, P. J., Brophy, C. M., Mack, M. J., Peterson, E. D., Williams, J. B., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Harrington, R. A., Ferguson, T. B., Lopes, R. D. 2014; 149 (8): 798-805

    Abstract

    In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.Preservation of vein grafts in saline, blood, or buffered saline solutions.One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.clinicaltrials.gov Identifier: NCT00042081.

    View details for DOI 10.1001/jamasurg.2014.87

    View details for Web of Science ID 000340834300011

    View details for PubMedID 25073921

  • A Registry-Based Randomized Trial Comparing Radial and Femoral Approaches in Women Undergoing Percutaneous Coronary Intervention The SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) Trial JACC-CARDIOVASCULAR INTERVENTIONS Rao, S. V., Hess, C. N., Barham, B., Aberle, L. H., Anstrom, K. J., Patel, T. B., Jorgensen, J. P., Mazzaferri, E. L., Jolly, S. S., Jacobs, A., Newby, L. K., Gibson, C. M., Kong, D. F., Mehran, R., Waksman, R., Gilchrist, I. C., McCourt, B. J., Messenger, J. C., Peterson, E. D., Harrington, R. A., Krucoff, M. W. 2014; 7 (8): 857-867

    Abstract

    This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial.Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear.Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population.The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access.In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236).

    View details for DOI 10.1016/j.jcin.2014.04.007

    View details for Web of Science ID 000340894700012

    View details for PubMedID 25147030

  • Association of metabolic syndrome and its individual components with outcomes among patients with high-risk non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Mehta, R. H., Westerhout, C. M., Zheng, Y., Giugliano, R. P., Huber, K., Prabhakaran, D., Harrington, R. A., Newby, K. L., Armstrong, P. W. 2014; 168 (2): 182-?

    Abstract

    The relationship of metabolic syndrome and its individual components (obesity, hypertension, glucose intolerance, high triglycerides, and low high-density lipoprotein cholesterol) with 1-year mortality in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients is not known.The association of metabolic syndrome (and its individual components) with all-cause mortality within 1 year was assessed in NSTE ACS patients enrolled in the EARLY ACS trial. Adjusted hazard ratio (HR) and 95% CIs are reported.Of 9,406 patients, 2,596 (27.6%) had metabolic syndrome. Compared with those without metabolic syndrome, patients with this syndrome were younger, were more often female, and had a higher prevalence of comorbid conditions and higher-risk presenting features. Metabolic syndrome was not associated with increased 1-year mortality (HR 1.20, 95% CI 0.97-1.47; P = .09). The risk of 1-year mortality varied across the individual components: high-density lipoprotein <40 mg/dL (men)/<50 mg/dL (women; or dyslipidemia) was associated with higher risk (HR 1.52, 95% CI 1.15-2.02), and triglycerides >150 mg/dL (or dyslipidemia) was associated with lower risk (HR 0.66, 95% CI 0.54-0.81), whereas the other components (ie, body mass index >30 kg/m(2), fasting plasma glucose >100 mg/dL or diabetes, systolic blood pressure >130 mm Hg or diastolic >85 mm Hg [or hypertension]) were associated with neutral risk of this event.The individual components of metabolic syndrome had varying associations with 1-year mortality, and as an integrated diagnosis, metabolic syndrome was not significantly associated with 1-year mortality. Thus, patient case-mix of the studied NSTE ACS population may influence the observed relationship of metabolic syndrome with subsequent cardiovascular events.

    View details for DOI 10.1016/j.ahj.2014.04.009

    View details for Web of Science ID 000340207700012

    View details for PubMedID 25066557

  • Antiplatelet and Anticoagulation Therapy for Acute Coronary Syndromes CIRCULATION RESEARCH Bhatt, D. L., Hulot, J., Moliterno, D. J., Harrington, R. A. 2014; 114 (12): 1929-1943

    Abstract

    The past 2 decades have witnessed the introduction and demise of several different antithrombotic medications for acute coronary syndromes. Part of the assessment of these compounds has been their effect on thrombotic events relative to the degree of increase in bleeding events. This review will outline the data supporting various antiplatelet and anticoagulant therapies and their combinations in patients with acute coronary syndromes and related disorders in both the acute and chronic phases of therapy.

    View details for DOI 10.1161/CIRCRESAHA.114.302737

    View details for Web of Science ID 000337707200008

    View details for PubMedID 24902976

  • Comparison of Clinical Trial Outcome Patterns in Patients Following Acute Coronary Syndromes and in Patients With Chronic Stable Atherosclerosis CLINICAL CARDIOLOGY Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    View details for DOI 10.1002/clc.22255

    View details for Web of Science ID 000337597900003

  • Comparison of clinical trial outcome patterns in patients following acute coronary syndromes and in patients with chronic stable atherosclerosis. Clinical cardiology Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    Abstract

    The transition of patients with atherosclerotic vascular disease from the acute phase of the disease to the chronic stable atherosclerosis (CSA) phase has not been well characterized. We sought to compare ischemic and bleeding outcomes in hospitalized patients enrolled in clinical trials of non-ST-elevation acute coronary syndrome (ACS) with patients enrolled in outpatient trials of CSA.The risk for recurrent events will differ between the 2 populations.Patient-level outcome data were evaluated from 3 consecutive trials of patients with ACS with long-term follow-up and 2 trials of patients with CSA. Kaplan-Meier curves were generated for ischemic and bleeding outcomes.In total, 37 370 patients were included in these analyses. Of these, 28 489 (76.2%) were from ACS trials and 8881 (23.8%) from chronic trials. During the first year of follow-up, 1353 deaths, 1081 cardiovascular (CV) deaths, 2113 myocardial infarctions (MIs), and 397 strokes occurred across the trials. Six-month Kaplan-Meier event rates for CV death, MI, or stroke were higher in the ACS trials compared with the CSA trials (8.6% vs 2.7%), as were the 1-year CV death rate (3.6% vs 1.7%) and 1-year rates for GUSTO moderate or severe bleeding (6.0% vs 1.3%). Qualitatively, the Kaplan-Meier curves appear to show an early increased risk as well as a continued increased risk over time.Patients with ACS enrolled while in the hospital appear to have different risk profiles for ischemic and bleeding outcomes compared with outpatients enrolled with CSA, including those patients with ACS after the acute phase.

    View details for DOI 10.1002/clc.22255

    View details for PubMedID 24615711

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes THROMBOSIS AND HAEMOSTASIS Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891
  • Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease NEW ENGLAND JOURNAL OF MEDICINE White, H. D., Held, C., Stewart, R., Tarka, E., Brown, R., Davies, R. Y., Budaj, A., Harrington, R. A., Steg, P. G., Ardis-Sino, D., Armstrong, P. W., Avezum, A., Aylward, P. E., Bryce, A., Chen, H., Chen, M., Corbalan, R., Dalby, A. J., Danchin, N., de Winter, R. J., Denchev, S., Diaz, R., Elisaf, M., Flather, M. D., Goudev, A. R., Granger, C. B., Grinfeld, L., Hochman, J. S., Husted, S., Kim, H., Koenig, W., Linhart, A., Lonn, E., Lopez-Sendon, J., Manolis, A. J., Mohler, E. R., Nicolau, J. C., Pais, P., Parkhomenko, A., Pedersen, T. R., Pella, D., Ramos-Corrales, M. A., Ruda, M., Sereg, M., Siddique, S., Sinnaeve, P., Smith, P., Sritara, P., Swart, H. P., Sy, R. G., Teramoto, T., Tse, H., Watson, D., Weaver, W. D., Weiss, R., Viigimaa, M., Vinereanu, D., Zhu, J., Cannon, C. P., Wallentin, L. 2014; 370 (18): 1702-1711

    Abstract

    Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

    View details for DOI 10.1056/NEJMoa1315878

    View details for Web of Science ID 000335405200008

    View details for PubMedID 24678955

  • Ticagrelor Effects on Myocardial Infarction and the Impact of Event Adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) Trial. Journal of the American College of Cardiology Mahaffey, K. W., Held, C., Wojdyla, D. M., James, S. K., Katus, H. A., Husted, S., Steg, P. G., Cannon, C. P., Becker, R. C., Storey, R. F., Khurmi, N. S., Nicolau, J. C., Yu, C., Ardissino, D., Budaj, A., Morais, J., Montgomery, D., Himmelmann, A., Harrington, R. A., Wallentin, L. 2014; 63 (15): 1493-1499

    Abstract

    This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS).A clinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, excluded silent MI.Overall, 1,299 (610 ticagrelor, 689 clopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 clopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 clopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% clopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00).In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with clopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2014.01.038

    View details for PubMedID 24561148

  • Angiographic Outcomes With Early Eptifibatide Therapy in Non-ST-Segment Elevation Acute Coronary Syndrome (from the EARLY ACS Trial) AMERICAN JOURNAL OF CARDIOLOGY Kunadian, V., Giugliano, R. P., Newby, L. K., Zorkun, C., Guo, J., Bagai, A., Montalescot, G., Braunwald, E., Califf, R. M., Van de Werf, F., Armstrong, P. W., Harrington, R., Gibson, C. M. 2014; 113 (8): 1297-1305

    Abstract

    Early administration of glycoprotein IIbIIIa inhibitors results in improved angiographic parameters, including thrombolysis in myocardial infarction (TIMI) flow grade, corrected TIMI frame count, and TIMI myocardial perfusion grade (TMPG) among patients with ST-segment elevation myocardial infarction. Whether the same is true in the setting of non-ST-segment elevation acute coronary syndrome is unknown. The goal of the early glycoprotein IIbIIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY ACS) angiographic substudy was to compare angiographic outcomes among patients with non-ST-segment elevation acute coronary syndrome who were administered early routine versus delayed provisional eptifibatide. Of 9,406 patients in the EARLY ACS trial, 2,066 patients were included in the angiographic substudy (early routine eptifibatide [n=1,042] or early placebo [n=1,024] with delayed provisional eptifibatide after angiography and before percutaneous coronary intervention [PCI]). The angiographic substudy primary end point was the incidence of TMPG 3 before and after PCI. TMPG 3 before (43.7% vs 44.9%, p=0.58) and after PCI (52.4% vs 50.1%, p=0.73) was similar for early routine versus delayed provisional eptifibatide, respectively. Angiographic procedural complications consisting of a composite of loss of side branch, abrupt vessel closure, distal embolization, and no reflow occurred less frequently in early routine group versus delayed provisional group (9.3% vs 13.6%, respectively, p=0.01). In the EARLY ACS angiographic substudy, the use of early routine eptifibatide resulted in fewer angiographic procedural complications. These data provide support for the use of eptifibatide in the catheterization laboratory during high-risk cases merely to prevent angiographic procedural complications.

    View details for DOI 10.1016/j.amjcard.2014.01.404

    View details for Web of Science ID 000334648000006

    View details for PubMedID 24607027

  • Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial NEPHROLOGY DIALYSIS TRANSPLANTATION Onken, J. E., Bregman, D. B., Harrington, R. A., Morris, D., Buerkert, J., Hamerski, D., Iftikhar, H., Mangoo-Karim, R., Martin, E. R., Martinez, C. O., Newman, G. E., Qunibi, W. Y., Ross, D. L., Singh, B., Smith, M. T., Butcher, A., Koch, T. A., Goodnough, L. T. 2014; 29 (4): 833-842

    Abstract

    Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD.A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events.The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group.Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

    View details for DOI 10.1093/ndt/gft251

    View details for Web of Science ID 000336093700020

    View details for PubMedID 23963731

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery: Subgroup Analysis From the TRACER Trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for PubMedID 24211500

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057
  • Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial). American journal of cardiology Mahaffey, K. W., Huang, Z., Wallentin, L., Storey, R. F., Jennings, L. K., Tricoci, P., White, H. D., Armstrong, P. W., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Leonardi, S., Rorick, T., Held, C., Strony, J., Harrington, R. A. 2014; 113 (6): 936-944

    Abstract

    Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

    View details for DOI 10.1016/j.amjcard.2013.11.052

    View details for PubMedID 24444781

  • The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. American heart journal Cohen, A. T., Harrington, R., Goldhaber, S. Z., Hull, R., Gibson, C. M., Hernandez, A. F., Kitt, M. M., Lorenz, T. J. 2014; 167 (3): 335-341

    Abstract

    Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35-42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of "normal", or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE.

    View details for DOI 10.1016/j.ahj.2013.11.006

    View details for PubMedID 24576517

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention: Insights From the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Journal of the American College of Cardiology Généreux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for PubMedID 24184169

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Genereux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629
  • A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia TRANSFUSION Onken, J. E., Bregman, D. B., Harrington, R. A., Morris, D., Acs, P., Akright, B., Barish, C., Bhaskar, B. S., Smith-Nguyen, G. N., Butcher, A., Koch, T. A., Goodnough, L. T. 2014; 54 (2): 306-315

    Abstract

    BACKGROUND: Many patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses. STUDY DESIGN AND METHODS: We evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1 g/dL; Cohort 1) were assigned to Group A (two doses of FCM, 750 mg, 1 week apart) or Group B (oral iron, 325 mg, 3 × day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort 2) were assigned to Group C (FCM as above) or Group D (standard-of-care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper- or hypotensive events. RESULTS: Mean (± standard deviation [SD]) Hb increase was significantly greater in Group A-FCM than Group B-oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p = 0.001). Post hoc comparison of Group C-FCM and Group D-IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group C versus Group D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p = 0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups. CONCLUSION: Two 750-mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.

    View details for DOI 10.1111/trf.12289

    View details for Web of Science ID 000331382100010

    View details for PubMedID 23772856

  • Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Wallentin, L., Lindholm, D., Siegbahn, A., Wernroth, L., Becker, R. C., Cannon, C. P., Cornel, J. H., Himmelmann, A., Giannitsis, E., Harrington, R. A., Held, C., Husted, S., Katus, H. A., Mahaffey, K. W., Steg, P. G., Storey, R. F., James, S. K. 2014; 129 (3): 293-303

    Abstract

    Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial.Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive groupHs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT.URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.113.004420

    View details for Web of Science ID 000329880700006

    View details for PubMedID 24170388

  • Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data LANCET Steg, P. G., Bhatt, D. L., Hamm, C. W., Stone, G. W., Gibson, C. M., Mahaffey, K. W., Leonardi, S., Liu, T., Skerjanec, S., Day, J. R., Iwaoka, R. S., Stuckey, T. D., Gogia, H. S., Gruberg, L., French, W. J., White, H. D., Harrington, R. A. 2013; 382 (9909): 1981-1992

    Abstract

    Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI.This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h.Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001).Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding.The Medicines Company.

    View details for DOI 10.1016/S0140-6736(13)61615-3

    View details for Web of Science ID 000328223700025

    View details for PubMedID 24011551

  • Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting JOURNAL OF THROMBOSIS AND THROMBOLYSIS Williams, J. B., Lopes, R. D., Hafley, G. E., Ferguson, T. B., Mack, M. J., Gibson, C. M., Harrington, R. A., Peterson, E. D., Smith, P. K., Mehta, R. H., Alexander, J. H. 2013; 36 (4): 384-393
  • Association between bleeding and mortality among women and men with high-risk acute coronary syndromes: Insights from the Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes (EARLY ACS) trial AMERICAN HEART JOURNAL Kaul, P., Tanguay, J., Newby, L. K., Hochman, J. S., Westerhout, C. M., Califf, R. M., Tricoci, P., Gibson, C. M., Giugliano, R. P., Harrington, R. A., Van de Werf, F., Armstrong, P. W. 2013; 166 (4): 723-728

    Abstract

    Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population.We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds.Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P < .01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI 3.9-8.8) than among women (odds ratio 1.5, 95% CI 0.8-2.9; sex * bleeding interaction P < .01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors.In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women.

    View details for DOI 10.1016/j.ahj.2013.07.014

    View details for Web of Science ID 000325092300027

    View details for PubMedID 24093853

  • Age, treatment, and outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients: Insights from the EARLY ACS trial INTERNATIONAL JOURNAL OF CARDIOLOGY Lopes, R. D., White, J. A., Tricoci, P., White, H. D., Armstrong, P. W., Braunwald, E., Giugliano, R. P., Harrington, R. A., Lewis, B. S., Brogan, G. X., Gibson, C. M., Califf, R. M., Newby, L. K. 2013; 167 (6): 2580-2587

    Abstract

    BACKGROUND: Elderly patients with acute coronary syndromes (ACS) are at high risk for death and recurrent thrombotic events. We evaluated the efficacy and safety of intensive treatment with glycoprotein IIb/IIIa inhibitors in an elderly population, and the relationships between age, timing of administration, and clinical outcomes. METHODS: We used data from high-risk non-ST-segment elevation ACS patients randomized to early eptifibatide vs. delayed provisional use at percutaneous coronary intervention. In multivariable models, we included age×treatment interaction terms to assess whether treatment effect varied by age after adjusting for confounders. RESULTS: Of 9406 patients, 13.9% were aged <55years; 27.6%, 55-64years; 33.2%, 65-74years; and 25.3%, ≥75years. For each 10-year age increase, the adjusted odds ratio (OR) (95% confidence interval [CI]) for 96-hour death, myocardial infarction (MI), recurrent ischemia requiring urgent revascularization, or thrombotic bailout was 1.13 (1.04-1.23) and for 30-day death or MI was 1.13 (1.04-1.22). Increasing age was also associated with greater 1-year mortality (adjusted hazard ratio per 10years: 1.44, 95% CI 1.30-1.60). There was no interaction between age and treatment (p interaction=0.99, 0.54, and 0.87, respectively). Increasing age was associated with more non-coronary artery bypass grafting-related TIMI major bleeding (adjusted OR and 95% CI per 10years: 1.54 [1.24-1.92]), GUSTO moderate/severe bleeding (1.52 [1.33-1.75]), and transfusion (1.25 [1.07-1.45]). The amount by which TIMI major bleeding was increased with early vs. delayed provisional eptifibatide use was significantly greater with increasing age (p interaction=0.02), but the age×treatment interactions were not significant for GUSTO moderate/severe bleeding or transfusion (p interaction=0.33 and 0.54, respectively). CONCLUSION: Increasing age was associated with greater risk for ischemic events and more bleeding. Despite higher baseline ischemic risk in older patients, there was no preferential benefit of early vs. delayed provisional eptifibatide use for ischemic outcomes as age increased, but the incremental bleeding risk was amplified.

    View details for DOI 10.1016/j.ijcard.2012.06.053

    View details for Web of Science ID 000324478400046

    View details for PubMedID 22795720

  • Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial CIRCULATION Steg, P. G., Harrington, R. A., Emanuelsson, H., Katus, H. A., Mahaffey, K. W., Meier, B., Storey, R. F., Wojdyla, D. M., Lewis, B. S., Maurer, G., Wallentin, L., James, S. K. 2013; 128 (10): 1055-1065
  • A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial HEART Leonardi, S., Truffa, A. A., Neely, M. L., Tricoci, P., White, H. D., Gibson, C. M., Wilson, M., Stone, G. W., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2013; 99 (17): 1282-1287

    Abstract

    OBJECTIVE: To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). DESIGN: We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. SETTING: The CHAMPION PLATFORM trial. PATIENTS: Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). INTERVENTIONS: Cangrelor versus placebo. MAIN OUTCOME MEASURES: The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. RESULTS: Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). CONCLUSIONS: Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI.

    View details for DOI 10.1136/heartjnl-2012-303103

    View details for Web of Science ID 000323162800012

    View details for PubMedID 23434768

  • Routine early eptifibatide versus delayed provisional use at percutaneous coronary intervention in high-risk non-ST-segment elevation acute coronary syndromes patients: An analysis from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Bagai, A., White, J. A., Lokhnygina, Y., Giugliano, R. P., Van de Werf, F., Montalescot, G., Armstrong, P. W., Tricoci, P., Gibson, C. M., Califf, R. M., Harrington, R. A., Newby, L. K. 2013; 166 (3): 466-?

    Abstract

    In the EARLY ACS trial, routine early eptifibatide was not superior to delayed provisional use at percutaneous coronary intervention (PCI); however, among PCI-treated patients, numerically fewer ischemic end points occurred in the upstream eptifibatide group. We sought to further explore this finding using methods for examination of treatment effect in this postrandomization subgroup.Of 9,406 patients in the EARLY ACS primary analysis cohort, 9,166 (97.4%) underwent coronary angiography. We used Cox proportional hazards regression modeling, with PCI as a time-dependent covariate, to examine the effect of routine early versus delayed provisional eptifibatide among 5,541 patients undergoing PCI and to explore the interaction between treatment with PCI and randomized treatment strategy. After multivariable adjustment, compared with delayed provisional use, routine early eptifibatide was associated with lower rate of 30-day death or myocardial infarction (MI) after PCI (hazard ratio [HR] 0.80, 95% CI 0.68-0.95) but not with medical management (HR 0.97, 95% CI 0.74-1.29); PCI × randomized treatment interaction term P = .24. Excluding PCI-related MI, the adjusted HR for 30-day death or MI for routine early eptifibatide versus delayed provisional use was 0.80 (95% CI 0.60-1.08) for post-PCI treatment and 1.01 (95% CI 0.79-1.34) for medical management; PCI × randomized treatment interaction term P = .28.Consistent with previous literature, upstream treatment with eptifibatide was associated with improved outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients treated with PCI; however, a nonsignificant interaction term precludes a definite conclusion.

    View details for DOI 10.1016/j.ahj.2013.05.019

    View details for Web of Science ID 000324163600020

    View details for PubMedID 24016495

  • Quantitative ST-depression in Acute Coronary Syndromes: the PLATO Electrocardiographic Substudy AMERICAN JOURNAL OF MEDICINE Armstrong, P. W., Westerhout, C. M., Fu, Y., Harrington, R. A., Storey, R. F., Katus, H., James, S., Wallentin, L. 2013; 126 (8): 723-?

    Abstract

    We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial.There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined.At baseline, most patients had either no or ≤0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001).The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients.

    View details for DOI 10.1016/j.amjmed.2013.01.038

    View details for Web of Science ID 000322827200027

    View details for PubMedID 23795897

  • Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years INTERNATIONAL JOURNAL OF CARDIOLOGY Chan, M. Y., Sun, J., Newby, L. K., Lokhnygina, Y., White, H. D., Moliterno, D. J., Theroux, P., Ohman, E. M., Simoons, M. L., Mahaffey, K. W., Pieper, K. S., Giugliano, R. P., Armstrong, P. W., Califf, R. M., Van de Werf, F., Harrington, R. A. 2013; 167 (2): 548-554

    Abstract

    BACKGROUND: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15years. METHODS: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. RESULTS: Over time, in-hospital and discharge use of thienopyridines (p=0.001), statins (p<0.0001), and angiotensin-converting enzyme inhibitors (p<0.0001) increased, and hospital length-of-stay decreased (p=0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p=0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p=0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p=0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p=0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p=0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p=0.539). CONCLUSIONS: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

    View details for DOI 10.1016/j.ijcard.2012.01.065

    View details for Web of Science ID 000320768800050

    View details for PubMedID 22341697

  • Cardiac Troponin After Percutaneous Coronary Intervention and 1-Year Mortality in Non-ST-Segment Elevation Acute Coronary Syndrome Using Systematic Evaluation of Biomarker Trends JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tricoci, P., Leonardi, S., White, J., White, H. D., Armstrong, P. W., Montalescot, G., Giugliano, R. P., Gibson, C. M., Van de Werf, F., Califf, R. M., Harrington, R. A., Braunwald, E., Mahaffey, K. W., Newby, L. K. 2013; 62 (3): 242-251

    Abstract

    OBJECTIVES: We reviewed cardiac troponin (cTn) trends during non-ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in EARLY ACS and SYNERGY and studied the relationship between post-PCI cTn and mortality. BACKGROUND: The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). METHODS: Time and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-MB (CK-MB) and 1-year mortality. RESULTS: Patients with cTn (re)elevation post-PCI not evaluable were identified and excluded from further analysis (4198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (N=5772 [57%]), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10x ULN increase, 1.07; 95% confidence interval [CI], 1.02-1.11; p=0.0038). Peak post-PCI CK-MB was significantly associated with 1-year mortality (HR for 1x ULN increase, 1.13; 95% CI, 1.05-1.21; p=0.0013). CONCLUSIONS: We used a methodology that differentiated post-PCI cTn (re)elevation from that of presenting MI in more than half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implication for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.

    View details for DOI 10.1016/j.jacc.2013.04.043

    View details for Web of Science ID 000321695500011

    View details for PubMedID 23684676

  • Angiographic Outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes) JACC-CARDIOVASCULAR INTERVENTIONS Kunadian, V., James, S. K., Wojdyla, D. M., Zorkun, C., Wu, J., Storey, R. F., Steg, P. G., Katus, H., Emanuelsson, H., Horrow, J., Maya, J., Wallentin, L., Harrington, R. A., Gibson, M. 2013; 6 (7): 671-683

    Abstract

    The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome.Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment.The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI.In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]).Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jcin.2013.03.014

    View details for Web of Science ID 000322129400007

    View details for PubMedID 23866179

  • Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA.CER) trial EUROPEAN HEART JOURNAL Leonardi, S., Tricoci, P., White, H. D., Armstrong, P. W., Huang, Z., Wallentin, L., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Providencia, L., Nordrehaug, J. E., Held, C., Strony, J., Rorick, T. L., Harrington, R. A., Mahaffey, K. W. 2013; 34 (23): 1723-1731

    Abstract

    AimsThe TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).Methods and resultsA blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077).ConclusionThe PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

    View details for DOI 10.1093/eurheartj/eht104

    View details for Web of Science ID 000320408500009

    View details for PubMedID 23530022

  • Heart Failure Complicating Non-ST-Segment Elevation Acute Coronary Syndrome Timing, Predictors, and Clinical Outcomes JACC-HEART FAILURE Bahit, M. C., Lopes, R. D., Clare, R. M., Newby, L. K., Pieper, K. S., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Diaz, R., Ohman, E. M., White, H. D., James, S., Granger, C. B. 2013; 1 (3): 223-229
  • Heart Failure Complicating Non-ST-Segment Elevation Acute Coronary Syndrome: Timing, Predictors, and Clinical Outcomes. JACC. Heart failure Bahit, M. C., Lopes, R. D., Clare, R. M., Newby, L. K., Pieper, K. S., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Diaz, R., Ohman, E. M., White, H. D., James, S., Granger, C. B. 2013; 1 (3): 223-229

    Abstract

    This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).Little is known about HF-complicating NSTE-ACS.Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.

    View details for DOI 10.1016/j.jchf.2013.02.007

    View details for PubMedID 24621874

  • Rescuing clinical trials in the United States and beyond: A call for action AMERICAN HEART JOURNAL Eapen, Z. J., Vavalle, J. P., Granger, C. B., Harrington, R. A., Peterson, E. D., Califf, R. M. 2013; 165 (6): 837-847

    Abstract

    Numerous challenges-financial, regulatory, and cultural-are hindering US participation and performance in multinational clinical trials. Consequently, it is increasingly unclear how the results of these trials should be applied to American patients, practice patterns, and systems of care. Both incremental and transformative changes are needed to revitalize US participation as well as the broader clinical trial enterprise. To promote consensus around the solutions needed to address the adverse trends in clinical research, the Duke Clinical Research Institute convenedstakeholders from academia, industry, and government. article summarizes the proceedings of this meeting and addresses: (1) adverse trends in the United States and multinational clinical trials, (2) the key issues that underlie these adverse trends, and (3) potential solutions to these problems.

    View details for DOI 10.1016/j.ahj.2013.02.003

    View details for Web of Science ID 000319439900004

    View details for PubMedID 23708153

  • A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: Design of the RENEW study AMERICAN HEART JOURNAL Povsic, T. J., Junge, C., Nada, A., Schatz, R. A., Harrington, R. A., Davidson, C. J., Fortuin, F. D., Kereiakes, D. J., Mendelsohn, F. O., Sherman, W., Schaer, G. L., White, C. J., Stewart, D., Story, K., Losordo, D. W., Henry, T. D. 2013; 165 (6): 854-?

    Abstract

    Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.

    View details for DOI 10.1016/j.ahj.2013.03.003

    View details for Web of Science ID 000319439900006

    View details for PubMedID 23708155

  • Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Giraldez, R. R., Clare, R. M., Lopes, R. D., Dalby, A. J., Prabhakaran, D., Brogan, G. X., Giugliano, R. P., James, S. K., Tanguay, J., Pollack, C. V., Harrington, R. A., Braunwald, E., Newby, L. K. 2013; 165 (6): 918-?

    Abstract

    We examined the prevalence of undiagnosed diabetes or prediabetes and associations with ischemic outcomes among non-ST-segment elevation acute coronary syndrome (ACS) patients.We categorized 8795 EARLY ACS trial patients into one of the following groups: "known diabetes" (n = 2860 [32.5%]; reported on the case report form), "undiagnosed diabetes" (n = 1069 [12.2%]; no diabetes history and fasting glucose ≥126 mg/dL or hemoglobin A1c ≥6.5%), "prediabetes" (n = 947 [10.8%]; fasting glucose ≥110 to <126 mg/dL, or "normal" (n = 3919 [44.5%]). Adjusted associations of known diabetes, undiagnosed diabetes, and prediabetes (versus normal) with 30-day and 1-year outcomes were determined.Undiagnosed diabetes was associated with greater 30-day death or myocardial infarction (MI) (ORadj 1.28, 95% CI 1.05-1.57), driven primarily by greater 30-day mortality (ORadj 1.65, 95% CI 1.09-2.48). Known diabetic patients had 30-day death or MI outcomes similar to those of normal patients, but 30-day mortality was higher (ORadj 1.40, 95% CI 1.01-1.93). Prediabetic patients had 30-day death or MI outcomes similar to those of normal patients. One-year mortality was greater among known diabetic patients (HRadj 1.38, 95% CI 1.13-1.67) but not among those with undiagnosed diabetes or prediabetes.Undiagnosed diabetes and prediabetes were common among high-risk non-ST-segment elevation ACS patients. Routine screening for undiagnosed diabetes may be useful since these patients seem to have worse short-term outcomes and deserve consideration of alternative management strategies.

    View details for DOI 10.1016/j.ahj.2013.01.005

    View details for Web of Science ID 000319439900013

    View details for PubMedID 23708162

  • Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Price, M. J., Leonardi, S., Gallup, D., Bramucci, E., Radke, P. W., Widimsky, P., Tousek, F., Tauth, J., Spriggs, D., McLaurin, B. T., Angiolillo, D. J., Genereux, P., Liu, T., Prats, J., Todd, M., Skerjanec, S., White, H. D., Harrington, R. A. 2013; 368 (14): 1303-1313

    Abstract

    The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects.In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

    View details for DOI 10.1056/NEJMoa1300815

    View details for Web of Science ID 000316989900007

    View details for PubMedID 23473369

  • Left Bundle Branch Block in Non-ST-Segment Elevation Acute Coronary Syndromes Incidence, Angiographic Characteristics, and Clinical Outcomes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rose, J. J., Newby, L. K., Broderick, S., Chiswell, K., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Ohman, E. M., Giugliano, R. P., Goodman, S. G., White, H. D., Califf, R. M., Granger, C. B., Lopes, R. D. 2013; 61 (13): 1461-1463

    View details for DOI 10.1016/j.jacc.2012.12.032

    View details for Web of Science ID 000317191200017

    View details for PubMedID 23500249

  • Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting JOURNAL OF THROMBOSIS AND HAEMOSTASIS Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Buller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2013; 11 (4): 778-782

    View details for DOI 10.1111/jth.4900

    View details for Web of Science ID 000317615500027

    View details for PubMedID 23578178

  • Radial versus femoral access, bleeding and ischemic events in patients with non-ST-segment elevation acute coronary syndrome managed with an invasive strategy AMERICAN HEART JOURNAL Klutstein, M. W., Westerhout, C. M., Armstrong, P. W., Giugliano, R. P., Lewis, B. S., Gibson, C. M., Lutchmedial, S., Widimsky, P., Steg, P. G., Dalby, A., Zeymer, U., Van de Werf, F., Harrington, R. A., Newby, L. K., Rao, S. V. 2013; 165 (4): 583-?

    Abstract

    Bleeding is a major limitation of antithrombotic therapy among invasively managed non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients; therefore, we examined the use of radial access and its association with outcomes among NSTE-ACS patients.Clinical characteristics and geographic variation in radial access were examined, as well as its association with bleeding, red blood cell transfusion and ischemic outcomes (96-hour death/myocardial infarction/recurrent ischemic/thrombotic bailout; 30-day death/myocardial infarction; 1-year death) in the EARLY versus delayed, provisional eptifibatide in acute coronary syndromes trial.Of 9126 patients, 13.5% underwent radial-access catheterization. Female sex, age, weight, and prior revascularization were inversely associated with radial access, and its use varied widely by country (2%-97%). There were fewer GUSTO severe/moderate bleeds and red blood cell transfusions in the radial access group; however, it was attenuated after adjustment (odds ratio 0.73, 95% confidence intervals [CI] [0.50-1.06], P = .094 and 1.00 [0.71-1.40] P = .991). Ischemic outcomes did not differ by access site.In this post hoc analysis of a large clinical trial, there was significant international variation in use of radial access for NSTE-ACS patients undergoing invasive management, and it was preferentially used in those at lower risk for bleeding. Radial approach was not associated with a significant reduction in either bleeding or ischemic outcomes. Further study is needed to determine whether wider application of radial approach to acute coronary syndrome patients at high risk for bleeding improves overall outcomes.

    View details for DOI 10.1016/j.ahj.2013.01.009

    View details for Web of Science ID 000317184300021

    View details for PubMedID 23537976

  • ACP Journal Club. PCI using drug-eluting stents had higher mortality than CABG in diabetes and multivessel CAD. Annals of internal medicine Harrington, R. A. 2013; 158 (6): JC8-?
  • 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Circulation Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 127 (9): 1052-1089

    View details for DOI 10.1161/CIR.0b013e3182831a11

    View details for PubMedID 23357718

  • 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on clinical data standards (writing committee to develop acute coronary syndromes and coronary artery disease clinical data standards). Journal of the American College of Cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 61 (9): 992-1025

    View details for DOI 10.1016/j.jacc.2012.10.005

    View details for PubMedID 23369353

  • Response to letter regarding article, “sustained ventricular tachycardia and ventricular fibrillation complicating non–ST-segment elevation acute coronary syndromes”. Circulation Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Califf, R. M., Harrington, R. A., Newby, L. K., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P. 2013; 127 (20): e634

    View details for PubMedID 23833786

  • Response to letter regarding article, "ticagrelor in patients with acute coronary syndromes and stroke: interpretation of subgroups in clinical trials". Stroke; a journal of cerebral circulation James, S. K., Storey, R. F., Pieper, K. S., Cannon, C. P., Becker, R. C., Steg, P. G., Wallentin, L., Harrington, R. A. 2013; 44 (8): e95–6

    View details for DOI 10.1161/STROKEAHA.113.002069

    View details for PubMedID 23800556

  • 2013 ACCF/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Acute Coronary Syndromes and Coronary Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Critical pathways in cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 12 (2): 65–105

    View details for DOI 10.1097/HPC.0b013e3182846e16

    View details for PubMedID 23680811

  • Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting. Journal of thrombosis and thrombolysis Williams, J. B., Lopes, R. D., Hafley, G. E., Bruce Ferguson, T., Mack, M. J., Michael Gibson, C., Harrington, R. A., Peterson, E. D., Smith, P. K., Mehta, R. H., Alexander, J. H. 2013

    Abstract

    Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.

    View details for DOI 10.1007/s11239-013-0904-1

    View details for PubMedID 23543398

  • Platelet inhibition with cangrelor during PCI. The New England journal of medicine Bhatt, D. L., Harrington, R. A. 2013; 369 (4): 393–94

    View details for DOI 10.1056/NEJMc1305978

    View details for PubMedID 23883387

  • ACP Journal Club. Intraaortic balloon counterpulsation did not reduce mortality in acute MI with cardiogenic shock. Annals of internal medicine Harrington, R. A. 2012; 157 (12): JC6-11
  • Conversion of Cardiovascular Conference Abstracts to Publications CIRCULATION Fosbol, E. L., Fosbol, P. L., Harrington, R. A., Eapen, Z. J., Peterson, E. D. 2012; 126 (24): 2819-?

    Abstract

    The transition of scientific knowledge from discovery into practice is less than ideal. A key step in this translation occurs when presentations from major meetings are published in peer-reviewed literature, yet the completeness and speed of this process are not known. We performed a systematic and automated evaluation of rates, timing, and correlates of publication from scientific abstracts presented at 3 major cardiovascular conferences.Using an automated computer algorithm, we searched the ISI Web of Science to identify peer-reviewed publications of abstracts presented at the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC) scientific sessions from 2006 to 2008. We compared abstract publication rates and journal impact factor between the 3 meetings using multivariable logistic regression modeling. From 2006 to 2008, 11 365, 5005, and 10 838 abstracts were presented at the AHA, ACC, and ESC meetings, respectively. Overall, 30.6% of presented abstracts were published within 2 years of the conference; ranging from 34.5% for AHA to 29.5% for ACC to 27.0% for ESC (P<0.0001). Five years after conference presentation in 2005, these rates had risen slightly to 49.7% for AHA, 42.6% for ACC, and 37.6% for ESC (P<0.0001). After adjustment for abstract characteristics and contributing countries, abstracts presented at the AHA meeting remained more likely for publication relative to the ESC (adjusted odds ratio, 1.24; 95% confidence interval, 1.16-1.34) and the ACC (adjusted odds ratio, 1.20; 95% confidence interval, 1.11-1.29). Median impact factors for subsequent publications varied from 4.8 (interquartile range, 3.8-10.1) for AHA to 4.0 (interquartile range, 3.1-7.5) for ACC and 3.9 (quartile 1-3, 2.5-5.8) for ESC (P for difference between groups <0.01). Clinical science and population science were less likely to be published compared with basic science.One third of abstracts were translated into publications by 2 years after presentation and less than one half by 5 years after presentation. Our findings suggest that efforts to understand the barriers to publication and to facilitate the rapid dissemination of new knowledge are needed to speed up the transition of scientific discovery into clinical practice.

    View details for DOI 10.1161/CIRCULATIONAHA.112.120535

    View details for Web of Science ID 000312275600010

    View details for PubMedID 23124031

  • Are Central Institutional Review Boards the Solution? The National Heart, Lung, and Blood Institute Working Group's Report on Optimizing the IRB Process ACADEMIC MEDICINE Mascette, A. M., Bernard, G. R., DiMichele, D., Goldner, J. A., Harrington, R., Harris, P. A., Leeds, H. S., Pearson, T. A., Ramsey, B., Wagner, T. H. 2012; 87 (12): 1710-1714

    Abstract

    The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.

    View details for DOI 10.1097/ACM.0b013e3182720859

    View details for Web of Science ID 000311836800021

    View details for PubMedID 23095928

  • Transforming Clinical Trials in Cardiovascular Disease Mission Critical for Health and Economic Well-being JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R. A. 2012; 308 (17): 1743-1744

    View details for Web of Science ID 000310726500017

    View details for PubMedID 23117771

  • Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: An analysis from ACT34-CMI AMERICAN HEART JOURNAL Povsic, T. J., Losordo, D. W., Story, K., Junge, C. E., Schatz, R. A., Harrington, R. A., Henry, T. D. 2012; 164 (5): 689-U86

    Abstract

    Cell therapy is a promising therapeutic for a variety of cardiovascular conditions including refractory angina. Elevation of cardiac biomarkers during cell delivery has been frequently described, but the clinical implications have never been studied.ACT34-CMI was a randomized double-blind study assessing the use of intramyocardial delivery of autologous CD34(+) cells for the treatment of refractory angina. Patients (n = 167) underwent G-CSF-mediated (5 μg/[kg day] × 5 days) stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5)/kg or 5 × 10(5)/kg CD34(+) cells or placebo. Troponin and creatinine kinase MB were assessed at baseline (n = 161), after cell mobilization and apheresis (n = 153 and 143, respectively), and post-intramyocardial injection (n = 155 and 141, respectively). Major adverse cardiac events (MACE) included death, myocardial infarction, acute congestive heart failure, urgent revascularization, or sustained ventricular arrhythmia.Seven (4.3%) subjects had troponin above the upper limits of normal (ULN) at baseline. Thirty-four (22.2%) and 11 (7.2%) subjects had troponin levels > ULN or >3× ULN after cell mobilization and apheresis, whereas 72 (46.1%) and 39 (25.2%) subjects had troponin elevations > ULN or >3× ULN, respectively, after intramyocardial injections. Age, but no other preprocedural factors, was predictive of troponin elevation. Periprocedural troponin elevation was not associated with an increased risk of MACE during 1 year, especially in cell therapy-treated patients.Troponin elevation is common during stem cell harvesting and intramyocardial administration, is usually asymptomatic, and does not appear to be associated with long-term MACE in subjects undergoing stem cell mobilization and intramyocardial injection.

    View details for DOI 10.1016/j.ahj.2012.06.022

    View details for Web of Science ID 000310783100011

    View details for PubMedID 23137499

  • Road mapping ATLAS ACS 2: are we there yet? EUROPEAN HEART JOURNAL Armstrong, P. W., Harrington, R. A. 2012; 33 (20): 2510-2512

    View details for DOI 10.1093/eurheartj/ehs015

    View details for Web of Science ID 000310167200007

    View details for PubMedID 22297122

  • Association Between Angiographic Complications and Clinical Outcomes Among Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention An EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) Angiographic Substudy JACC-CARDIOVASCULAR INTERVENTIONS Pride, Y. B., Mohanavelu, S., Zorkun, C., Kunadian, V., Giugliano, R. P., Newby, L. K., Braunwald, E., Califf, R. M., Harrington, R. A., Gibson, C. M. 2012; 5 (9): 927-935

    Abstract

    The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized.The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients.Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant.Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion. (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-segment Elevation Acute Coronary Syndrome [EARLY ACS]; NCT00089895).

    View details for DOI 10.1016/j.jcin.2012.05.007

    View details for Web of Science ID 000309351600007

    View details for PubMedID 22995880

  • 2012 American College of Cardiology Foundation/Society for Cardiovascular Angiography and Interventions expert consensus document on cardiac catheterization laboratory standards update: American College of Cardiology Foundation Task Force on expert consensus documents Society of Thoracic Surgeons Society for Vascular Medicine. Catheterization and cardiovascular interventions Bashore, T. M., Balter, S., Barac, A., Byrne, J. G., Cavendish, J. J., Chambers, C. E., Hermiller, J. B., Kinlay, S., Landzberg, J. S., Laskey, W. K., McKay, C. R., Miller, J. M., Moliterno, D. J., Moore, J. W., Oliver-McNeil, S. M., Popma, J. J., Gardner 2012; 80 (3): E37-49

    View details for DOI 10.1002/ccd.24466

    View details for PubMedID 22570114

  • Edifoligide and long-term outcomes after coronary artery bypass grafting: PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) 5-year results AMERICAN HEART JOURNAL Lopes, R. D., Williams, J. B., Mehta, R. H., Reyes, E. M., Hafley, G. E., Allen, K. B., Mack, M. J., Peterson, E. D., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Lorenz, T. J., Alexander, J. H. 2012; 164 (3): 379-U284

    Abstract

    Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes.A total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.Five-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 [95% CI 0.89-1.18], P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure.Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG.

    View details for DOI 10.1016/j.ahj.2012.05.019

    View details for Web of Science ID 000308690100015

    View details for PubMedID 22980305

  • Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial AMERICAN HEART JOURNAL Cornel, J. H., Becker, R. C., Goodman, S. G., Husted, S., Katus, H., Santoso, A., Steg, G., Storey, R. F., Vintila, M., Sun, J. L., Horrow, J., Wallentin, L., Harrington, R., James, S. 2012; 164 (3): 334-U239

    Abstract

    Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

    View details for DOI 10.1016/j.ahj.2012.06.005

    View details for Web of Science ID 000308690100009

    View details for PubMedID 22980299

  • 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. journal of thoracic and cardiovascular surgery Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 144 (3): e29-84

    View details for DOI 10.1016/j.jtcvs.2012.03.001

    View details for PubMedID 22898522

  • Lecture Halls without Lectures NEW ENGLAND JOURNAL OF MEDICINE Eapen, Z. J., Vavalle, J. P., Harrington, R. A. 2012; 367 (7): 678-678

    View details for Web of Science ID 000307496600025

    View details for PubMedID 22894591

  • Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting The RED-CABG Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Newman, M. F., Ferguson, T. B., White, J. A., Ambrosio, G., Koglin, J., Nussmeier, N. A., Pearl, R. G., Pitt, B., Wechsler, A. S., Weisel, R. D., Reece, T. L., Lira, A., Harrington, R. A. 2012; 308 (2): 157-164

    Abstract

    Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery.To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days.The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010.Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction.Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28.Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured.In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD.clinicaltrials.gov Identifier: NCT00872001.

    View details for Web of Science ID 000306219500029

    View details for PubMedID 22782417

  • Usefulness of Medical Conferences JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R., Tomaselli, G. 2012; 308 (1): 31-32

    View details for DOI 10.1001/jama.2012.6368

    View details for Web of Science ID 000306183000015

    View details for PubMedID 22760283

  • Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non-ST-Segment-Elevation Acute Coronary Syndromes CIRCULATION Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P., Califf, R. M., Harrington, R. A., Newby, L. K. 2012; 126 (1): 41-49

    Abstract

    Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non-ST-segment-elevation (NSTE) ACS populations are not well described.We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n=141); 0.6% (n=55) had VT/VF ≤48 hours after enrollment, and 0.9% (n=86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (≤48 versus >48 hours). Patients with VT/VF ≤48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF ≤48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68-16.9). The increased risk of death associated with VT/VF ≤48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF >48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39-27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60-12.08; P=0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%).Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

    View details for DOI 10.1161/CIRCULATIONAHA.111.071860

    View details for Web of Science ID 000306977100022

    View details for PubMedID 22645292

  • Highlights from the IV International Symposium of Thrombosis and Anticoagulation (ISTA), October 20-21, 2011, Salvador, Bahia, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Granger, C. B., Crowther, M., Wang, T., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa, G. S., Ribeiro, J. P., Darze, E., Kalil, R. A., Andrande, M., Boas, F. V., Andrade, J., Rocha, A. T., Harrington, R. A., Lopes, A. C., Garcia, D. A. 2012; 34 (1): 143-163

    Abstract

    To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-012-0700-3

    View details for Web of Science ID 000305523300023

    View details for PubMedID 22427055

  • Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Schneider, D. J., Bhatt, D. L., French, W. J., Price, M. J., Saucedo, J. F., Shaburishvili, T., Huber, K., Prats, J., Liu, T., Harrington, R. A., Becker, R. C. 2012; 34 (1): 44-55

    Abstract

    Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

    View details for DOI 10.1007/s11239-012-0737-3

    View details for Web of Science ID 000305523300007

    View details for PubMedID 22569899

  • 2012 ACCF/AATS/SCAI/STS Expert Consensus Document on Transcatheter Aortic Valve Replacement Developed in collaboration with the American Heart Association, American Society of Echocardiography, European Association for CardioThoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 79 (7): 1023-1082

    View details for DOI 10.1002/ccd.24351

    View details for Web of Science ID 000304753500001

    View details for PubMedID 22294439

  • Pharmacokinetic and Pharmacodynamic Effects of Elinogrel Results of the Platelet Function Substudy From the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI) Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Angiolillo, D. J., Welsh, R. C., Trenk, D., Neumann, F., Conley, P. B., McClure, M. W., Stephens, G., Kochman, J., Jennings, L. K., Gurbel, P. A., Wojcik, J., Dabrowski, M., Saucedo, J. F., Stumpf, J., Buerke, M., Broderick, S., Harrington, R. A., Rao, S. V. 2012; 5 (3): 347-356

    Abstract

    Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations.This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

    View details for DOI 10.1161/CIRCINTERVENTIONS.111.965608

    View details for Web of Science ID 000311707000012

    View details for PubMedID 22619259

  • A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y(12) Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention The INNOVATE-PCI Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Welsh, R. C., Rao, S. V., Zeymer, U., Thompson, V. P., Huber, K., Kochman, J., McClure, M. W., Gretler, D. D., Bhatt, D. L., Gibson, C. M., Angiolillo, D. J., Gurbel, P. A., Berdan, L. G., Paynter, G., Leonardi, S., Madan, M., French, W. J., Harrington, R. A. 2012; 5 (3): 336-346

    Abstract

    We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention.In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure.In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

    View details for DOI 10.1161/CIRCINTERVENTIONS.111.964197

    View details for Web of Science ID 000311707000011

    View details for PubMedID 22647518

  • Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial AMERICAN HEART JOURNAL Leonardi, S., Mahaffey, K. W., White, H. D., Gibson, C. M., Stone, G. W., Steg, P. G., Hamm, C. W., Price, M. J., Todd, M., Dietrich, M., Gallup, D., Liu, T., Skerjanec, S., Harrington, R. A., Bhatt, D. L. 2012; 163 (5): 768-?

    Abstract

    Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI.The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales.The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2012.02.018

    View details for Web of Science ID 000304261000011

    View details for PubMedID 22607853

  • Regional Patterns of Use of a Medical Management Strategy for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Insights From the EARLY ACS Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Roe, M. T., White, J. A., Kaul, P., Tricoci, P., Lokhnygina, Y., Miller, C. D., Van'T Hof, A. W., Montalescot, G., James, S. K., Saucedo, J., Ohman, E. M., Pollack, C. V., Hochman, J. S., Armstrong, P. W., Giugliano, R. P., Harrington, R. A., Van de Werf, F., Califf, R. M., Newby, L. K. 2012; 5 (2): 205-213

    Abstract

    Regional differences in the profile and prognosis of non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients treated with medical management after angiography remain uncertain.Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%) underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted hazard ratio, 1.46; 95% CI, 1.21-1.76), with no significant interaction by region (interaction probability value=0.42).Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients.

    View details for DOI 10.1161/CIRCOUTCOMES.111.962332

    View details for Web of Science ID 000302120300014

    View details for PubMedID 22373905

  • Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial CIRCULATION Goodman, S. G., Clare, R., Pieper, K. S., Nicolau, J. C., Storey, R. F., Cantor, W. J., Mahaffey, K. W., Angiolillo, D. J., Husted, S., Cannon, C. P., James, S. K., Kilhamn, J., Steg, P. G., Harrington, R. A., Wallentin, L. 2012; 125 (8): 978-986

    Abstract

    The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear.We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49).The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.032912

    View details for Web of Science ID 000300951700013

    View details for PubMedID 22261200

  • Relationship Between Vein Graft Failure and Subsequent Clinical Outcomes After Coronary Artery Bypass Surgery CIRCULATION Lopes, R. D., Mehta, R. H., Hafley, G. E., Williams, J. B., Mack, M. J., Peterson, E. D., Allen, K. B., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Alexander, J. H. 2012; 125 (6): 749-756

    Abstract

    Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes.Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21-2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71-1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.53; P=0.65).VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

    View details for DOI 10.1161/CIRCULATIONAHA.111.040311

    View details for Web of Science ID 000300605200012

    View details for PubMedID 22238227

  • Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction AMERICAN HEART JOURNAL White, H. D., Chew, D. P., Dauerman, H. L., Mahaffey, K. W., Gibson, C. M., Stone, G. W., Gruberg, L., Harrington, R. A., Bhatt, D. L. 2012; 163 (2): 182-U275

    Abstract

    There is a clinical need for an intravenous P2Y(12) inhibitor in patients with acute coronary syndromes (ACS) for patients who are unable to take oral medications or might benefit from a rapidly reversible compound. As the time from admission to percutaneous coronary intervention (PCI) shortens, establishing the benefit of novel therapies impacting ischemic events is increasingly challenging. Cangrelor, an intravenous potent rapidly acting P2Y(12) inhibitor, bolus 30 μg/Kg plus infusion of 4 μg/Kg/min, was compared to a 600-mg loading dose of clopidogrel either before or early after PCI in patients with ACS undergoing PCI in The CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON) PLATFORM and PCI studies.As both CHAMPION studies used similar inclusion/exclusion criteria and death, myocardial infarction, or ischemia-driven revascularization (including stent thrombosis) at 48 hours as their primary end points, the studies were pooled. The clinical events committee adjudicated myocardial infarction. The universal definition was used to define myocardial infarction.A total of 13 049 patients were included. Cangrelor had no effect on the primary end point with the original MI definition (P = .646). With the use of the universal definition, the primary end point was decreased with cangrelor (odds ratio 0.82, 95% confidence interval 0.68-0.99, P = .037). Stent thrombosis was reduced from 0.4% to 0.2% (odds ratio 0.44, 95% confidence interval 0.22-0.87, P = .018). Thrombolysis in Myocardial Infarction major bleeding and transfusions were not increased with cangrelor.With the use of the universal definition of myocardial infarction, cangrelor was associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non-ST-elevation ACS undergoing PCI.

    View details for DOI 10.1016/j.ahj.2011.11.001

    View details for Web of Science ID 000300226600009

    View details for PubMedID 22305835

  • ST-Elevation Acute Coronary Syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) Trial Insights From the ECG Substudy CIRCULATION Armstrong, P. W., Siha, H., Fu, Y., Westerhout, C. M., Steg, P. G., James, S. K., Storey, R. F., Horrow, J., Katus, H., Clemmensen, P., Harrington, R. A., Wallentin, L. 2012; 125 (3): 514-U131

    Abstract

    Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge.ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ≥50% ΣST-deviation (ΣST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), P=0.003). The extent of ΣST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ΣST-dev (P(interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ≤3 hours, 3 to 6 hours, >6 hours, the extent of baseline ΣST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (P=0.175).Ticagrelor did not modify ΣST-dev resolution at discharge nor was its benefit affected by the extent of baseline ΣST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047530

    View details for Web of Science ID 000300252800019

    View details for PubMedID 22179530

  • Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Tricoci, P., Huang, Z., Held, C., Moliterno, D. J., Armstrong, P. W., Van de Werf, F., White, H. D., Aylward, P. E., Wallentin, L., Chen, E., Lokhnygina, Y., Pei, J., Leonardi, S., Rorick, T. L., Kilian, A. M., Jennings, L. H., Ambrosio, G., Bode, C., Cequier, A., Cornel, J. H., Diaz, R., Erkan, A., Huber, K., Hudson, M. P., Jiang, L., Jukema, J. W., Lewis, B. S., Lincoff, A. M., Montalescot, G., Nicolau, J. C., Ogawa, H., Pfisterer, M., Carlos Prieto, J., Ruzyllo, W., Sinnaeve, P. R., Storey, R. F., Valgimigli, M., Whellan, D. J., Widimsky, P., Strony, J., Harrington, R. A., Mahaffey, K. W. 2012; 366 (1): 20-33

    Abstract

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

    View details for DOI 10.1056/NEJMoa1109719

    View details for Web of Science ID 000299968800004

    View details for PubMedID 22077816

  • Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? proceedings of an ad hoc working group meeting. Journal of thrombosis and haemostasis : JTH Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Büller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2012

    Abstract

    Physicians and patients consider the balance between benefits and risks of treatment when making decisions about the use of anticoagulants for the prevention of venous thromboembolism (VTE). The results of early trials demonstrating the efficacy of heparin compared with placebo or no thromboprophylaxis for the prevention of fatal pulmonary embolism (PE) led to adoption of routine anticoagulant prophylaxis in patients considered to be at increased risk of VTE. More recent trials comparing new anticoagulants with heparin have most commonly used the composite outcome, asymptomatic (or "silent") deep vein thrombosis (DVT), detected by screening venography, and symptomatic (or "patient-important") VTE, as the primary measure of efficacy [1-3]. © 2012 International Society on Thrombosis and Haemostasis.

    View details for DOI 10.1111/j.1538-7836.2012.04900.x

    View details for PubMedID 22906159

  • Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial EUROPEAN HEART JOURNAL Becker, R. C., Bassand, J. P., Budaj, A., Wojdyla, D. M., James, S. K., Cornel, J. H., French, J., Held, C., Horrow, J., Husted, S., Lopez-Sendon, J., Lassila, R., Mahaffey, K. W., Storey, R. F., Harrington, R. A., Wallentin, L. 2011; 32 (23): 2933-2944

    Abstract

    AIMS More intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study. METHODS AND RESULTS PLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ≥75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose. CONCLUSION Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.

    View details for DOI 10.1093/eurheartj/ehr422

    View details for Web of Science ID 000297647400008

    View details for PubMedID 22090660

  • Pulmonary Function in Patients With Acute Coronary Syndrome Treated With Ticagrelor or Clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] Pulmonary Function Substudy) AMERICAN JOURNAL OF CARDIOLOGY Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Lim, S. T., Cannon, C. P., Katus, H. A., Wallentin, L. 2011; 108 (11): 1542-1546

    Abstract

    The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a β(2) agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before β(2) agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel.

    View details for DOI 10.1016/j.amjcard.2011.07.015

    View details for Web of Science ID 000297880000004

    View details for PubMedID 21890085

  • Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes EUROPEAN HEART JOURNAL Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Cooper, A., Cairns, R., Cannon, C. P., Wallentin, L. 2011; 32 (23): 2945-2953

    Abstract

    AIMS To describe the incidence of dyspnoea and its associations with demographic characteristics and clinical outcomes in patients with acute coronary syndromes (ACS) treated with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) study. METHODS AND RESULTS In the PLATO study, 18 624 patients were randomized to receive either clopidogrel [300-600 mg loading dose (LD), 75 mg daily] or ticagrelor (180 mg LD, 90 mg b.i.d.). The occurrence of reported dyspnoea adverse events (AEs) was analysed in the 18 421 patients who received at least one dose of study medication in relation to demographic characteristics, clinical outcomes and other associations of patients with and without dyspnoea. A total of 1339 ticagrelor-treated patients (14.5%) and 798 clopidogrel-treated patients (8.7%) had a dyspnoea AE following randomization, with respectively 39 (0.4%) and 24 (0.3%) classified as severe in intensity. Excluding dyspnoea AEs occurring after the secondary endpoint of myocardial infarction (MI), the yearly rates of the efficacy endpoints in dyspnoea AE patients in the ticagrelor and clopidogrel groups were: for the primary composite of CV death, MI, and stroke, 8.8 and 10.4% (unadjusted P = 0.25; adjusted P = 0.54); for CV death, 3.1 and 4.8% (unadjusted P = 0.024; adjusted P = 0.18); and for total death 3.7 and 6.2% (unadjusted P = 0.004; adjusted P = 0.06), respectively. CONCLUSIONS Ticagrelor-related dyspnoea is usually mild or moderate in intensity and does not appear to be associated with differences concerning any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS patients.

    View details for DOI 10.1093/eurheartj/ehr231

    View details for Web of Science ID 000297647400009

    View details for PubMedID 21804104

  • Safety and efficacy of adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function AMERICAN HEART JOURNAL Melloni, C., James, S. K., White, J. A., Giugliano, R. P., Harrington, R. A., Huber, K., Tricoci, P., Armstrong, P. W., Van de Werf, F., Montalescot, G., Califf, R. M., Newby, L. K. 2011; 162 (5)

    Abstract

    Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy.Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 μg/kg/min; estimated creatinine clearance [eCrCl] ≥50 ml/min), adjusted dose (1 μg/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 μg/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI).Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy.Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency.

    View details for DOI 10.1016/j.ahj.2011.08.020

    View details for Web of Science ID 000297247800014

    View details for PubMedID 22093205

  • Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Alexander, J. H., Lopes, R. D., James, S., Kilaru, R., He, Y., Mohan, P., Bhatt, D. L., Goodman, S., Verheugt, F. W., Flather, M., Huber, K., Liaw, D., Husted, S. E., Lopez-Sendon, J., De Caterina, R., Jansky, P., Darius, H., Vinereanu, D., Cornel, J. H., Cools, F., Atar, D., Luis Leiva-Pons, J., Keltai, M., Ogawa, H., Pais, P., Parkhomenko, A., Ruzyllo, W., Diaz, R., White, H., Ruda, M., Geraldes, M., Lawrence, J., Harrington, R. A., Wallentin, L. 2011; 365 (8): 699-708

    Abstract

    Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

    View details for DOI 10.1056/NEJMoa1105819

    View details for Web of Science ID 000294205300005

    View details for PubMedID 21780946

  • Biomedical Innovation: A Risky Business at Risk SCIENCE TRANSLATIONAL MEDICINE Stack, R. S., Harrington, R. A. 2011; 3 (96)

    Abstract

    Regulatory and financial challenges conspire to stall the development and market approval of breakthrough medical products. Inconsistent parameters are used to assess the safety and efficacy of drugs, biologics, and devices; this glitch in the system introduces uncertainty, slows or blocks product approvals, and increases the costs of product development. Here, we consider how to balance the benefits and risks to the public in the assessment of innovative medical products. We also discuss the Institute of Medicine's recent report on the medical device approval process.

    View details for DOI 10.1126/scitranslmed.3002459

    View details for Web of Science ID 000293953100002

    View details for PubMedID 21849662

  • American Industry and the U.S. Cardiovascular Clinical Research Enterprise An Appropriate Analogy? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Califf, R. M., Harrington, R. A. 2011; 58 (7): 677-680

    View details for DOI 10.1016/j.jacc.2011.03.048

    View details for Web of Science ID 000293455300004

    View details for PubMedID 21816302

  • Intramyocardial, Autologous CD34+Cell Therapy for Refractory Angina CIRCULATION RESEARCH Losordo, D. W., Henry, T. D., Davidson, C., Lee, J. S., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Traverse, J. H., Amrani, D., Ewenstein, B. M., Riedel, N., Story, K., Barker, K., Povsic, T. J., Harrington, R. A., Schatz, R. A. 2011; 109 (4): 428-U235

    Abstract

    A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

    View details for DOI 10.1161/CIRCRESAHA.111.245993

    View details for Web of Science ID 000293504100011

    View details for PubMedID 21737787

  • Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Mahaffey, K. W., Wojdyla, D. M., Carroll, K., Becker, R. C., Storey, R. F., Angiolillo, D. J., Held, C., Cannon, C. P., James, S., Pieper, K. S., Horrow, J., Harrington, R. A., Wallentin, L. 2011; 124 (5): 544-U78

    Abstract

    In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world.Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort.The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047498

    View details for Web of Science ID 000293338400014

    View details for PubMedID 21709065

  • Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Alexander, J. H., Armstrong, P. W., Califf, R. M., Chan, M. Y., Crowther, M., Granger, C. B., Harrington, R. A., Hylek, E. M., James, S. K., Jolicoeur, E. M., Mahaffey, K. W., Newby, L. K., Peterson, E. D., Pieper, K. S., Van de Werf, F., Wallentin, L., White, H. D., Carvalho, A. C., Giraldez, R. R., Guimaraes, H. P., Nader, H. B., Kalil, R. A., Bizzachi, J. M., Lopes, A. C., Garcia, D. A. 2011; 32 (2): 242-266

    Abstract

    To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in São Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-011-0592-7

    View details for Web of Science ID 000292833000017

    View details for PubMedID 21547405

  • Saphenous Vein Grafts With Multiple Versus Single Distal Targets in Patients Undergoing Coronary Artery Bypass Surgery One-Year Graft Failure and Five-Year Outcomes From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial CIRCULATION Mehta, R. H., Ferguson, T. B., Lopes, R. D., Hafley, G. E., Mack, M. J., Kouchoukos, N. T., Gibson, C. M., Harrington, R. A., Califf, R. M., Peterson, E. D., Alexander, J. H. 2011; 124 (3): 280-288

    Abstract

    Limited information exists on the intermediate-term graft patency and 5-year clinical outcomes of patients receiving saphenous vein grafts with multiple (m-SVG) versus single distal targets (s-SVG) during coronary artery bypass graft (CABG) surgery in the current era.We studied the association of the use of m-SVG versus s-SVG conduits with 1-year SVG failure (defined as ≥75% angiographic stenosis) and 5-year clinical events (death; death or myocardial infarction [MI]; and death, MI, or revascularization) in 3014 patients undergoing their first CABG surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV. Of 3014 patients enrolled in PREVENT IV, 1045 (34.7%) had ≥1 m-SVGs during CABG. Vein graft failure at 1-year was higher for m-SVG compared with s-SVG (adjusted odds ratio 1.24, 95% confidence interval 1.03 to 1.48). At 5 years, the adjusted composite of death, MI (including perioperative MI), or revascularization (hazard ratio 1.15, 95% confidence interval 1.00 to 1.31) and death or MI (hazard ratio 1.21, 95% confidence interval 1.03 to 1.43) were significantly higher in patients receiving m-SVGs.In patients undergoing first CABG surgery, the use of m-SVG was associated with a higher 1-year vein graft failure rate and trends toward worse clinical outcomes. Additional studies are needed to better understand the most appropriate conduit to improve long-term graft patency and clinical outcomes of patients undergoing CABG surgery. In the meantime, these data should encourage the use of s-SVG over m-SVG when feasible.

    View details for DOI 10.1161/CIRCULATIONAHA.110.991299

    View details for Web of Science ID 000292819300010

    View details for PubMedID 21709060

  • Dose Selection for a Direct and Selective Factor IXa Inhibitor and its Complementary Reversal Agent: Translating Pharmacokinetic and Pharmacodynamic Properties of the REG1 System to Clinical Trial Design JOURNAL OF THROMBOSIS AND THROMBOLYSIS Povsic, T. J., Cohen, M. G., Chan, M. Y., Zelenkofske, S. L., WARGIN, W. A., Harrington, R. A., Alexander, J. H., Rusconi, C. P., Becker, R. C. 2011; 32 (1): 21-31

    Abstract

    We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 μg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

    View details for DOI 10.1007/s11239-011-0588-3

    View details for Web of Science ID 000292832800003

    View details for PubMedID 21503856

  • Upstream Use of Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes A Systematic Overview of Randomized Clinical Trials CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Tricoci, P., Newby, L. K., Hasselblad, V., Kong, D. F., Giugliano, R. P., White, H. D., Theroux, P., Stone, G. W., Moliterno, D. J., Van de Werf, F., Armstrong, P. W., Prabhakaran, D., Rasoul, S., Bolognese, L., durand, e., Braunwald, E., Califf, R. M., Harrington, R. A. 2011; 4 (4): 448-458

    Abstract

    The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non-ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials.Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63).In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.

    View details for DOI 10.1161/CIRCOUTCOMES.110.960294

    View details for Web of Science ID 000292872500012

    View details for PubMedID 21712522

  • Dueling Registries? An Alternative Perspective and the Case for Competitive Collaboration CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Harrington, R. A. 2011; 4 (4): 486-487
  • ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents Developed in Collaboration With the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A., Bates, E. R., Bhatt, D. L., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Gilson, M. F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Mukherjee, D., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. 2011; 5 (4): 259-352

    View details for DOI 10.1016/j.jash.2011.06.001

    View details for Web of Science ID 000293866000007

    View details for PubMedID 21771565

  • Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial BRITISH MEDICAL JOURNAL James, S. K., Roe, M. T., Cannon, C. P., Cornel, J. H., Horrow, J., Husted, S., Katus, H., Morais, J., Steg, P. G., Storey, R. F., Stevens, S., Wallentin, L., Harrington, R. A. 2011; 342

    Abstract

    To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.862 centres in 43 countries.5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.Clinical trials NCT00391872.

    View details for DOI 10.1136/bmj.d3527

    View details for Web of Science ID 000291933200003

    View details for PubMedID 21685437

  • ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents CIRCULATION Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A., Bates, E. R., Bhatt, D. L., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Gilson, M. F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Mukherjee, D., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. 2011; 123 (21): 2434-2506
  • Intravenous Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction REVEAL: A Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Najjar, S. S., Rao, S. V., Melloni, C., Raman, S. V., Povsic, T. J., Melton, L., Barsness, G. W., Prather, K., Heitner, J. F., Kilaru, R., Gruberg, L., Hasselblad, V., Greenbaum, A. B., Patel, M., Kim, R. J., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Harrington, R. A. 2011; 305 (18): 1863-1872

    Abstract

    Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.clinicaltrials.gov Identifier: NCT00378352.

    View details for Web of Science ID 000290438800023

    View details for PubMedID 21558517

  • The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial Results of the Continuous Electrocardiographic Assessment Substudy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Scirica, B. M., Cannon, C. P., Emanuelsson, H., Michelson, E. L., Harrington, R. A., Husted, S., James, S., Katus, H., Pais, P., Raev, D., Spinar, J., Steg, P. G., Storey, R. F., Wallentin, L. 2011; 57 (19): 1908-1916

    Abstract

    The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes.Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes.Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days).A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest.In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2010.11.056

    View details for Web of Science ID 000290210100010

    View details for PubMedID 21545948

  • The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome. Editorial on Serebruany. "Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified" (Thromb Haemost 2011; 105.5). Thrombosis and haemostasis Wallentin, L., Becker, R. C., James, S. K., Harrington, R. A. 2011; 105 (5): 760-762

    View details for DOI 10.1160/TH11-03-0162

    View details for PubMedID 21394383

  • Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial CIRCULATION Wang, T. Y., White, J. A., Tricoci, P., Giugliano, R. P., Zeymer, U., Harrington, R. A., Montalescot, G., James, S. K., Van de Werf, F., Armstrong, P. W., Braunwald, E., Califf, R. M., Newby, L. K. 2011; 123 (7): 722-730

    Abstract

    In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use.In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata.Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

    View details for DOI 10.1161/CIRCULATIONAHA.110.958041

    View details for Web of Science ID 000287588000011

    View details for PubMedID 21300952

  • Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Held, C., Asenblad, N., Bassand, J. P., Becker, R. C., Cannon, C. P., Claeys, M. J., Harrington, R. A., Horrow, J., Husted, S., James, S. K., Mahaffey, K. W., Nicolau, J. C., Scirica, B. M., Storey, R. F., Vintila, M., Ycas, J., Wallentin, L. 2011; 57 (6): 672-684

    Abstract

    The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy.Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial.In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end.In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments.In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.

    View details for DOI 10.1016/j.jacc.2010.10.029

    View details for Web of Science ID 000286880100006

    View details for PubMedID 21194870

  • Impact of Recovery of Renal Function on Long-Term Mortality After Coronary Artery Bypass Grafting AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Honeycutt, E., Patel, U. D., Lopes, R. D., Shaw, L. K., Glower, D. D., Harrington, R. A., Califf, R. M., Sketch, M. H. 2010; 106 (12): 1728-1734

    Abstract

    Whether prognosis differs in acute renal failure (ARF) after coronary artery bypass grafting (CABG) in patients with and without recovery of renal function is not known. We studied patients who had CABG at Duke University Medical Center (1995 to 2008). ARF was defined as an increase in peak creatinine ≥50% after CABG or ≥0.7 mg/dl above baseline or need for new dialysis. Patients were categorized into 3 groups: (1) no ARF after CABG, (2) ARF after CABG and completely recovered renal function at day 7 (return of creatinine to no higher than baseline and no dialysis), or (3) ARF after CABG with no recovery of renal function at day 7 (creatinine no higher than baseline or new dialysis). Main outcome measurement was risk-adjusted long-term mortality (excluding death ≤7 days). ARF after CABG occurred in 2,083 of 10,415 patients (20%) and completely recovered in 703 (33.7%). Risk-adjusted mortality was highest in patients with ARF without recovery of renal function (hazard ratios 1.47, 95% confidence interval 1.34 to 1.62) and intermediate in those with ARF but completely recovered renal function (hazard ratios 1.21, 95% confidence interval 1.07 to 1.37, referent no-ARF group). Mortality was lower in patients with ARF compared to those without complete recovery of renal function (p = 0.0083). In conclusion, in patients with ARF after CABG, complete recovery of renal function was associated with significantly lower long-term mortality compared to those without such recovery, although this was significantly higher than in those without ARF. Thus, major emphasis should be on prevention of ARF in patients undergoing CABG.

    View details for DOI 10.1016/j.amjcard.2010.07.045

    View details for Web of Science ID 000285735000010

    View details for PubMedID 21126617

  • Patterns of discharge antiplatelet therapy and late outcomes among 8,582 patients with bleeding during acute coronary syndrome: A pooled analysis from PURSUIT, PARAGON-A, PARAGON-B, and SYNERGY AMERICAN HEART JOURNAL Chan, M. Y., Sun, J. L., Wang, T. Y., Lopes, R. D., Jolicoeur, M. E., Pieper, K. S., Rao, S. V., Newby, L. K., Mahaffey, K. W., Harrington, R. A., Peterson, E. D. 2010; 160 (6): 1056-U95

    Abstract

    Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain.We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT.Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03).Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes.

    View details for DOI 10.1016/j.ahj.2010.09.001

    View details for Web of Science ID 000285187600015

    View details for PubMedID 21146658

  • Randomized, Double-Blind, Placebo-Controlled Trial of Autologous CD34+Cell Therapy for Refractory Angina: 2-Year Safety Analysis Losordo, D. W., Henry, T. D., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G. L., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Raval, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Ewenstein, B., Story, K. O., Barker, K. B., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2010
  • ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. Journal of the American College of Cardiology Taylor, A. J., Cerqueira, M., Hodgson, J. M., Mark, D., Min, J., O'Gara, P., Rubin, G. D., Kramer, C. M., Berman, D., Brown, A., Chaudhry, F. A., Cury, R. C., Desai, M. Y., Einstein, A. J., Gomes, A. S., Harrington, R., Hoffmann, U., Khare, R., Lesser, J., McGann, C., Rosenberg, A., Schwartz, R., Shelton, M., Smetana, G. W., Smith, S. C. 2010; 56 (22): 1864-1894

    Abstract

    The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance (CMR) appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria (1). The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease (CAD) was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography (CT) for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research.

    View details for DOI 10.1016/j.jacc.2010.07.005

    View details for PubMedID 21087721

  • Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reperfusion With Primary Percutaneous Coronary Intervention A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis CIRCULATION Steg, P. G., James, S., Harrington, R. A., Ardissino, D., Becker, R. C., Cannon, C. P., Emanuelsson, H., Finkelstein, A., Husted, S., Katus, H., Kilhamn, J., Olofsson, S., Storey, R. F., Weaver, D., Wallentin, L. 2010; 122 (21): 2131-2141

    Abstract

    Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention.Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76).In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.109.927582

    View details for Web of Science ID 000284471800013

    View details for PubMedID 21060072

  • Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial AMERICAN HEART JOURNAL Melloni, C., Rao, S. V., Povsic, T. J., Melton, L., Kim, R. J., Kilaru, R., Patel, M. R., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Najjar, S. S., Harrington, R. A. 2010; 160 (5): 795-U39

    Abstract

    Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells.REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin α on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin α dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin α or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling.The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin α in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

    View details for DOI 10.1016/j.ahj.2010.09.007

    View details for Web of Science ID 000284458700004

    View details for PubMedID 21095264

  • Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome THROMBOSIS AND HAEMOSTASIS Becker, R. C., Alexander, J. H., Newby, L. K., Yang, H., Barrett, Y., Mohan, P., Wang, J., Harrington, R. A., Wallentin, L. C. 2010; 104 (5): 976-983

    Abstract

    Apixaban is an oral, direct factor Xa inhibitor under development for secondary prevention in acute coronary syndrome (ACS). Apixaban's effect on D-dimer and prothrombin fragment 1.2 (F1.2) (coagulation activity biomarkers ) was determined in a randomised, double-blinded, placebo-controlled, phase 2 study. Patients (n=1,715) with either ST- segment elevation or non-ST-segment elevation ACS received either placebo or apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily or 20 mg once daily for six months. Samples were obtained at baseline (before study drug administration), week 3 and week 26. Apixaban plasma concentrations were measured directly by liquid chromatography/mass spectometry, and anti-Xa activity was determined using apixaban as a reference standard. D-dimer and F 1.2 were measured using ELISA-based methods. Most patients had elevated D-dimer and F1.2 levels at baseline. Both coagulation activity biomarkers decreased by week 3 in all treatment groups, but to a greater degree with apixaban than placebo (p<0.001). In a multivariable analysis, apixaban was independently associated with a change in biomarkers over time (p<0.0001). While the overall decrease did not differ significantly among the three highest apixaban doses, F1.2 was suppressed more rapidly by the 10 mg once daily than the 2.5 mg twice daily dose (p<0.05). There was a strong and direct relationship between apixaban plasma concentrations and anti-Xa-apixaban levels, and an inverse relationship for both measures with coagulation activity biomarkers. In conclusion, the oral direct factor Xa inhibitor apixaban significantly reduced coagulation activity biomarkers among patients with ACS. The 10 mg once daily dose reduced thrombin generation (F 1.2) and fibrin formation (D-dimer) more rapidly and robustly than the 2.5 mg twice daily dose. The effect on both D-dimer and F 1.2 was apixaban concentration-and factor Xa inhibition dependent, durable and provided general guidance for dose selection in phase 3 investigation.

    View details for DOI 10.1160/TH10.04.0247

    View details for Web of Science ID 000284522600016

    View details for PubMedID 20806117

  • Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease AMERICAN HEART JOURNAL White, H., Held, C., Stewart, R., Watson, D., Harrington, R., Budaj, A., Steg, P. G., Cannon, C. P., Krug-Gourley, S., Wittes, J., Trivedi, T., Tarka, E., Wallentin, L. 2010; 160 (4): 655-U289

    Abstract

    Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies.STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo.The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years.STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

    View details for DOI 10.1016/j.ahj.2010.07.006

    View details for Web of Science ID 000282677300015

    View details for PubMedID 20934559

  • Relationship between renal function and outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes: Results from SYNERGY INTERNATIONAL JOURNAL OF CARDIOLOGY Spinler, S. A., Mahaffey, K. W., Gallup, D., Levine, G. N., Ferguson, J. J., Rao, S. V., Gallo, R., Ducas, J., Goodman, S. G., Antman, E., White, H. D., Biasucci, L., Becker, R. C., Col, J. J., Cohen, M., Harrington, R. A., Califf, R. M. 2010; 144 (1): 36-41

    Abstract

    Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial.Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI.Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11).Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.

    View details for DOI 10.1016/j.ijcard.2009.03.119

    View details for Web of Science ID 000282679000013

    View details for PubMedID 19406493

  • Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes in Relation to Renal Function Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION James, S., Budaj, A., Aylward, P., Buck, K. K., Cannon, C. P., Cornel, J. H., Harrington, R. A., Horrow, J., Katus, H., Keltai, M., Lewis, B. S., Parikh, K., Storey, R. F., Szummer, K., Wojdyla, D., Wallentin, L. 2010; 122 (11): 1056-1067

    Abstract

    Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates.Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant.In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding.URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.109.933796

    View details for Web of Science ID 000281877800002

    View details for PubMedID 20805430

  • President's page: the ACC reconfirms commitment to transparent relationships with industry. Journal of the American College of Cardiology Brindis, R., Harrington, R. 2010; 56 (11): 900-902

    View details for DOI 10.1016/j.jacc.2010.08.001

    View details for PubMedID 20813288

  • First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention CIRCULATION Cohen, M. G., Purdy, D. A., Rossi, J. S., Grinfeld, L. R., Myles, S. K., Aberle, L. H., Greenbaum, A. B., Fry, E., Chan, M. Y., Tonkens, R. M., Zelenkofske, S., Alexander, J. H., Harrington, R. A., Rusconi, C. P., Becker, R. C. 2010; 122 (6): 614-622

    Abstract

    The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007.This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal.This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

    View details for DOI 10.1161/CIRCULATIONAHA.109.927756

    View details for Web of Science ID 000280757300008

    View details for PubMedID 20660806

  • Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI) AMERICAN HEART JOURNAL Leonardi, S., Rao, S. V., Harrington, R. A., Bhatt, D. L., Gibson, C. M., Roe, M. T., Kochman, J., Huber, K., Zeymer, U., Madan, M., Gretler, D. D., McClure, M. W., Paynter, G. E., Thompson, V., Welsh, R. C. 2010; 160 (1): 65-72

    Abstract

    Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

    View details for DOI 10.1016/j.ahj.2010.04.008

    View details for Web of Science ID 000279440400011

    View details for PubMedID 20598974

  • Randomized Evaluation of efficacy and safety of ferric carboxymaltose in Patients with iron deficiency Anaemia and Impaired Renal function (REPAIR-IDA): rationale and study design NEPHROLOGY DIALYSIS TRANSPLANTATION Szczech, L. A., Bregman, D. B., Harrington, R. A., Morris, D., Butcher, A., Koch, T. A., Goodnough, L. T., Wolf, M., Onken, J. E. 2010; 25 (7): 2368-2375

    Abstract

    Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose).The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD. REPAIR-IDA is a multi-centre, randomized, active-controlled, open-label study. Eligible patients must have haemoglobin (Hgb) < or = 11.5 g/dL and CKD defined as (1) GFR < 60 mL/min/1.73 m(2) on two occasions or (2) GFR < 90 mL/min/1.73 m(2) and either evidence of renal injury by urinalysis or elevated Framingham cardiovascular risk score. Two thousand and five hundred patients will be randomized to FCM or Venofer(R) in a 1:1 ratio. The primary efficacy endpoint is mean change in Hgb from baseline to the highest observed Hgb between baseline and Day 56. The primary safety endpoint is the proportion of subjects experiencing at least one of the following events: death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization or medical intervention, arrhythmias, hypertension or hypotension during the 120 days following randomization.REPAIR-IDA will assess the efficacy and safety of two 750-mg infusions of FCM compared to an FDA-approved IV iron regimen in patients with NDD-CKD at increased risk for cardiovascular disease.

    View details for DOI 10.1093/ndt/gfq218

    View details for Web of Science ID 000279189400051

    View details for PubMedID 20466657

  • There Is a Role for Industry-Sponsored Education in Cardiology CIRCULATION Harrington, R. A., Califf, R. M. 2010; 121 (20): 2221-2227
  • An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design AMERICAN HEART JOURNAL Califf, R. M., Lokhnygina, Y., Cannon, C. P., Stepanavage, M. E., McCabe, C. H., Musliner, T. A., Pasternak, R. C., Blazing, M. A., Giugliano, R. P., Harrington, R. A., Braunwald, E. 2010; 159 (5): 705-709

    View details for DOI 10.1016/j.ahj.2010.03.004

    View details for Web of Science ID 000277243300001

    View details for PubMedID 20435175

  • Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel CLINICAL CARDIOLOGY Husted, S., Storey, R. F., Harrington, R. A., Emanuelsson, H., Cannon, C. P. 2010; 33 (4): 206-212

    Abstract

    Inflammation is a key factor in the development of atherosclerotic disease and acute coronary syndromes (ACS). The P2Y(12) receptor antagonists ticagrelor (AZD6140) and clopidogrel may have anti-inflammatory effects. The objective of this analysis from the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial was to compare ticagrelor and clopidogrel for effects on the inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), myeloperoxidase (MPO), and soluble CD40 ligand (sCD40L).Ticagrelor inhibits the P2Y(12) receptor and inflammation to a greater extent than clopidogrel in nonST-segment elevation ACS (NSTE-ACS) patients.In a double-blind, double-dummy, multicenter trial, 990 patients who had been hospitalized within the previous 48 hours with NSTE-ACS were randomized to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300 mg initially and then 75 mg once daily. Within the ticagrelor groups, patients were also randomized to receive or not receive a loading dose of ticagrelor 270 mg initially. All patients received standard treatment for ACS, which included 325 mg aspirin initially and 75 to 100 mg aspirin each day subsequently. Inflammatory biomarkers were measured at baseline, upon hospital discharge, and after 4 weeks.Inflammatory biomarker measurements were not significantly different among treatment groups at baseline, discharge, and 4 weeks.Ticagrelor and clopidogrel appeared not to differ in this study with respect to the inflammatory biomarkers CRP, IL-6, MPO, and sCD40L in patients with NSTE-ACS.

    View details for DOI 10.1002/clc.20732

    View details for Web of Science ID 000277113300004

    View details for PubMedID 20394040

  • Towards a new order in cardiovascular medicine: re-engineering through global collaboration EUROPEAN HEART JOURNAL Califf, R. M., Armstrong, P. W., Granger, C. B., Harrington, R. A., Lee, K., Simess, R. J., Van de Werf, F., Wallentin, L., White, H. D. 2010; 31 (8): 911-917

    View details for DOI 10.1093/eurheartj/ehp550

    View details for Web of Science ID 000277278900010

    View details for PubMedID 20130014

  • Metabolic Syndrome Is Not Associated With Increased Mortality or Cardiovascular Risk in Nondiabetic Patients With a New Diagnosis of Coronary Artery Disease CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Petersen, J. L., Yow, E., Aljaroudi, W., Shaw, L. K., Goyal, A., McGuire, D. K., Peterson, E. D., Harrington, R. A. 2010; 3 (2): 165-172

    Abstract

    Metabolic syndrome (MetSyn) is associated with increased cardiovascular risk in the general population. Its prognostic implications are less well defined in patients with coronary artery disease.We analyzed patients in the Duke Database for Cardiovascular Disease with a diagnosis of incident obstructive coronary artery disease. Diabetes mellitus (DM) was classified as a clinical history of DM, use of hypoglycemic drugs, or fasting glucose of >or=126 mg/dL. MetSyn was defined as having 3 of 5 characteristics: fasting glucose >or=100 and <126 mg/dL, low high-density lipoprotein cholesterol (men, <40 mg/dL; women, <50 mg/dL), triglycerides >150 mg/dL, blood pressure >or=130/85 mm Hg, or use of antihypertensive therapy, or body mass index >or=27. Death, myocardial infarction, or stroke was assessed at 6 months, 1 year, then annually. Cox proportional hazards models were generated to compare mortality and cardiovascular events between groups. The primary cohort consisted of 5744 patients; 1831 (31.9%) had DM, 2491 (43.4%) had MetSyn, and 1422 (24.7%) had no DM/MetSyn. Median follow-up was 5 years. Compared with no DM/MetSyn patients, DM patients had a higher adjusted risk for mortality (hazard ratio, 1.47; 95% CI, 1.28 to 1.69) but MetSyn patients did not (hazard ratio, 0.94; 95% CI, 0.81 to 1.08). Similar results were found for the combined end points of death or myocardial infarction, and death, myocardial infarction, or stroke.In a population of consecutive patients with a new diagnosis of coronary artery disease by angiography, MetSyn without DM was not an independent predictor of mortality or cardiovascular events.

    View details for DOI 10.1161/CIRCOUTCOMES.109.864447

    View details for Web of Science ID 000276080200010

    View details for PubMedID 20179266

  • Warfarin Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes AMERICAN JOURNAL OF MEDICINE Lopes, R. D., Starr, A., Pieper, C. F., Al-Khatib, S. M., Newby, L. K., Mehta, R. H., Van de Werf, F., Mahaffey, K. W., Armstrong, P. W., Harrington, R. A., White, H. D., Wallentin, L., Granger, C. B. 2010; 123 (2): 134-140

    Abstract

    We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation.Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge.Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS(2)) scores (0, 13%; 1, 14%; > or = 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98).Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS(2) score or bleeding risk.

    View details for DOI 10.1016/j.amjmed.2009.09.015

    View details for Web of Science ID 000274346200011

    View details for PubMedID 20103022

  • Comparison of ticagrelor with clopidogrel in patients with planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study LANCET Cannon, C. P., Harrington, R. A., James, S., Ardissino, D., Becker, R. C., Emanuelsson, H., Husted, S., Katus, H., Keltai, M., Khurmi, N. S., Kontny, F., Lewis, B. S., Steg, P. G., Storey, R. F., Wojdyla, D., Wallentin, L. 2010; 375 (9711): 283-293

    Abstract

    Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients.At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872.6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785).Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.

    View details for DOI 10.1016/S0140-6736(09)62191-7

    View details for Web of Science ID 000274069300029

    View details for PubMedID 20079528

  • Intravenous Platelet Blockade with Cangrelor during PCI. NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Lincoff, A. M., Gibson, C. M., Stone, G. W., McNulty, S., Montalescot, G., Kleiman, N. S., Goodman, S. G., White, H. D., Mahaffey, K. W., Pollack, C. V., Manoukian, S. V., Widimsky, P., Chew, D. P., Cura, F., Manukov, I., Tousek, F., Jafar, M. Z., Arneja, J., Skerjanec, S., Harrington, R. A. 2009; 361 (24): 2330-2341

    Abstract

    Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI).In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

    View details for DOI 10.1056/NEJMoa0908629

    View details for Web of Science ID 000272547600007

    View details for PubMedID 19915222

  • Platelet Inhibition with Cangrelor in Patients Undergoing PCI. NEW ENGLAND JOURNAL OF MEDICINE Harrington, R. A., Stone, G. W., McNulty, S., White, H. D., Lincoff, A. M., Gibson, C. M., Pollack, C. V., Montalescot, G., Mahaffey, K. W., Kleiman, N. S., Goodman, S. G., Amine, M., Angiolillo, D. J., Becker, R. C., Chew, D. P., French, W. J., Leisch, F., Parikh, K. H., Skerjanec, S., Bhatt, D. L. 2009; 361 (24): 2318-2329

    Abstract

    Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition.We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours.We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14).Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)

    View details for DOI 10.1056/NEJMoa0908628

    View details for Web of Science ID 000272547600006

    View details for PubMedID 19915221

  • Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial AMERICAN HEART JOURNAL Berger, J. S., Roe, M. T., Gibson, C. M., Kilaru, R., Green, C. L., Melton, L., Blankenship, J. D., Metzger, D. C., Granger, C. B., Gretler, D. D., Grines, C. L., Huber, K., Zeymer, U., Buszman, P., Harrington, R. A., Armstrong, P. W. 2009; 158 (6): 998-U145

    Abstract

    Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI.The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated.Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo.With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI.

    View details for DOI 10.1016/j.ahj.2009.10.010

    View details for Web of Science ID 000273051100016

    View details for PubMedID 19958867

  • Standardized reporting of bleeding complications for clinical investigations in acute coronary syndromes: A proposal from the Academic Bleeding Consensus (ABC) Multidisciplinary Working Group AMERICAN HEART JOURNAL Rao, S. V., Eikelboom, J., Steg, P. G., Lincoff, A. M., Weintraub, W. S., Bassand, J., Rao, A. K., Gibson, C. M., Petersen, J. L., Mehran, R., Manoukian, S. V., Charnigo, R., Lee, K. L., Moscucci, M., Harrington, R. A. 2009; 158 (6): 881-U16

    Abstract

    Clinical trials of antithrombotic agents for the treatment of ACS routinely assess bleeding as a safety endpoint, but variation in bleeding definitions makes comparison of the relative safety of these agents difficult.The ABC Multidisciplinary Working Group, an informal working group comprising clinical researchers and representatives from the US Food and Drug Administration, the National Institutes of Health, and the pharmaceutical industry, sought to develop a consensus approach to measuring the incidence and severity of bleeding complications during clinical trials of acute coronary syndromes (ACS). A meeting of the ABC was convened in April 2008 in Washington, DC, with the goal of developing a consensus approach to measuring the incidence and severity of hemorrhagic complications during clinical trials of ACS. Relevant literature on bleeding was reviewed through a series of short lectures and intensive group discussion.Using existing evidence on bleeding and outcomes as well as clinical judgment, criteria for the assessment of bleeding were developed through expert consensus. This consensus statement divides bleeding-related data elements into three categories: essential, recommended, and optional.The ABC Group recommendations for collection and reporting of bleeding complications provide a framework for consistency in the collection of information on hemorrhagic complications in trials of ACS. Widespread adoption of the statement recommendations will facilitate understanding of the mechanisms of adverse outcomes after bleeding and comparisons of the relative safety of antithrombotic agents, as well as the interpretation of safety results from future studies.

    View details for DOI 10.1016/j.ahj.2009.10.008

    View details for Web of Science ID 000273051100001

    View details for PubMedID 19958852

  • Comparison of Site-Reported and Core Laboratory-Reported Creatine Kinase-MB Values in Non-ST-Segment Elevation Acute Coronary Syndrome (from the International Trial SYNERGY) AMERICAN JOURNAL OF CARDIOLOGY Linefsky, J. P., Lin, M., Pieper, K. S., Reist, C. J., Berdan, L. G., Antman, E. M., Goodman, S. G., French, J. K., Guneri, S., Roe, M. T., Newby, L. K., Harrington, R. A., Ferguson, J. J., Califf, R. M., Mahaffey, K. W. 2009; 104 (10): 1330-1335

    Abstract

    The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (>or=2 times the ULN) by the core laboratory but normal (<2 times the ULN) by local standards in 708 instances (15%). There were 162 MI end points according to the core laboratory values versus 91 MI end points using the site-reported CK-MB data (kappa statistic 0.48). Compared with patients with no MI by the core or site laboratory values, patients with MI, as determined by both the core and the site laboratories, had significantly lower unadjusted 1-year survival rates (80.6% vs 93.5%, p <0.0001). Patients with MI, as determined by the core laboratory but not by the site laboratory, showed a trend toward a lower 1-year survival rate (89.8% vs 93.5%, p = 0.20). In conclusion, a substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial. More MI outcomes were identified by the core laboratory, and patients with MI as defined by core laboratory data had lower 1-year survival, making these events potentially clinically important.

    View details for DOI 10.1016/j.amjcard.2009.06.056

    View details for Web of Science ID 000271998500003

    View details for PubMedID 19892046

  • Autologous CD34+Cell Therapy for Refractory Angina: 12 Month Results of the Phase II ACT34-CMI Study 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Losordo, D. W., Henry, T., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G., Niederman, A., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Rava, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Adams, P. X., Harrington, R. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1132–S1132
  • Enoxaparin Versus Unfractionated Heparin in Elective Percutaneous Coronary Intervention 1-Year Results From the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) Trial JACC-CARDIOVASCULAR INTERVENTIONS Montalescot, G., Gallo, R., White, H. D., Cohen, M., Steg, G., Aylward, P. E., Bode, C., Chiariello, M., King, S. B., Harrington, R. A., Desmet, W. J., Macaya, C., Steinhubl, S. R. 2009; 2 (11): 1083-1091

    Abstract

    Our purpose was to evaluate long-term mortality and identify factors associated with 1-year mortality in patients who underwent elective percutaneous coronary intervention (PCI).While long-term outcomes in PCI patients have been reported previously, limited data are currently available regarding the comparative long-term outcomes in PCI patients who receive enoxaparin versus intravenous unfractionated heparin (UFH).We conducted a follow-up analysis of clinical outcomes at 1 year in patients enrolled in the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) trial of 3,528 patients undergoing elective PCI. Patients were randomized to receive either intravenous 0.50-mg/kg or 0.75-mg/kg enoxaparin or intravenous UFH during elective PCI procedures. All-cause mortality at 1 year after index PCI was the main outcome measure.Mortality rates were 1.4%, 2.0%, and 1.5% from 1 month to 1 year, and 2.3%, 2.2%, and 1.9% from randomization to 1 year, after index PCI in patients receiving 0.50 mg/kg enoxaparin, 0.75 mg/kg enoxaparin, and UFH, respectively. Multivariate analysis identified nonfatal myocardial infarction and/or urgent target vessel revascularization up to 30 days after index PCI (hazard ratio: 3.5, 95% confidence interval: 1.7 to 7.3; p < 0.001), and major bleeding within 48 h (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.5; p = 0.04) as the strongest independent risk factors for 1-year mortality.The 1-year mortality rates were low and comparable between patients receiving enoxaparin and UFH during elective PCI. Periprocedural ischemic or bleeding events were the strongest independent predictors of 1-year mortality. (The STEEPLE Trial; NCT00077844).

    View details for DOI 10.1016/j.jcin.2009.08.016

    View details for Web of Science ID 000275913800008

    View details for PubMedID 19926048

  • Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: Results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial AMERICAN HEART JOURNAL Al-Khatib, S. M., Hafley, G., Harrington, R. A., Mack, M. J., Ferguson, T. B., Peterson, E. D., Califf, R. M., Kouchoukos, N. T., Alexander, J. H. 2009; 158 (5): 792-798

    Abstract

    Current practice related to the management of atrial fibrillation (AF) complicating coronary artery bypass grafting (CABG) is uncertain.We examined management of post-CABG AF in the PREVENT-IV trial, and we explored patterns of use of postoperative rhythm versus rate control and anticoagulation for AF by geographic region and type of site. We also compared outcomes of patients who developed post-CABG AF (663) with those who did not (2,131).The incidence of AF was 24%. Post-CABG AF was treated with a rhythm control strategy in 81% of patients and with warfarin in 23% of patients. Although there were significant variations across sites in the management of post-CABG AF, patterns of use of postoperative rhythm versus rate control and anticoagulation did not differ by geographic region or by whether or not the enrolling site was an academic institution. Mortality was higher in patients with post-CABG AF than patients without AF at 30 days (1.5% vs 0.7%, P = .01) but not at 3 years (6.9% vs 4.9%, P = .41). There was a trend toward a higher risk of mortality or stroke at 30 days in patients with AF (2.4% vs 1.9%, P = .08).Although a rhythm control strategy was used in most of the patients in this trial and the overall rate of use of warfarin was low, the significance of these findings is uncertain because of the lack of data from randomized clinical trials. The substantial variations in the management of post-CABG AF across sites are likely because of definitive data on the most effective therapies, highlighting the need for clinical trials on rate versus rhythm control and on anticoagulation for AF in this setting.

    View details for DOI 10.1016/j.ahj.2009.09.003

    View details for Web of Science ID 000271275400016

    View details for PubMedID 19853700

  • Catheter thrombosis and percutaneous coronary intervention: fundamental perspectives on blood, artificial surfaces and antithrombotic drugs JOURNAL OF THROMBOSIS AND THROMBOLYSIS Chan, M. Y., Weitz, J. I., Merhi, Y., Harrington, R. A., Becker, R. C. 2009; 28 (3): 366-380

    Abstract

    Recent reports of catheter thrombosis among patients undergoing percutaneous coronary intervention (PCI) have had a significant impact on the development of new antithrombotic therapies. The overall incidence of this complication is unknown, mainly because of underreporting in contemporary clinical trials of coronary intervention. The etiology and pathophysiology of catheter thrombosis is also poorly understood. Introduction of a catheter or guidewire may not provoke the intense thrombotic response that follows angioplasty or stenting, but factors such as catheter materials and device size, equipment surface properties, flow conditions, procedural time and complexity, as well as the antiplatelet and anticoagulant drugs administered during the procedure influence the likelihood, rate and clinical impact of thrombosis. The crucial role of cellular interactions involving tissue-factor bearing cells and platelets in the process of thrombosis also needs to be critically explored when considering blood contact with an exogenous material. Focusing on the inherently prothrombotic environment of percutaneous coronary intervention, we review the physiologic underpinnings of catheter and guidewire thrombosis, and explore the effect of antithrombotic drugs at the interface between blood and material surfaces. We also propose a clinical classification for the diagnosis and investigation of catheter thrombosis in clinical trials of anticoagulant therapy and PCI.

    View details for DOI 10.1007/s11239-009-0375-6

    View details for Web of Science ID 000269860600021

    View details for PubMedID 19597766

  • Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., Horrow, J., Husted, S., James, S., Katus, H., Mahaffey, K. W., Scirica, B. M., Skene, A., Steg, P. G., Storey, R. F., Harrington, R. A. 2009; 361 (11): 1045-1057

    Abstract

    Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

    View details for DOI 10.1056/NEJMoa0904327

    View details for Web of Science ID 000269659400007

    View details for PubMedID 19717846

  • Antithrombotics in Acute Coronary Syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Bonaca, M. P., Steg, P. G., Feldman, L. J., Canales, J. F., Ferguson, J. J., Wallentin, L., Califf, R. M., Harrington, R. A., Giugliano, R. P. 2009; 54 (11): 969-984

    Abstract

    Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

    View details for DOI 10.1016/j.jacc.2009.03.083

    View details for Web of Science ID 000269477500001

    View details for PubMedID 19729112

  • The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale AMERICAN HEART JOURNAL Harrington, R. A., Van de Werf, F., Armstrong, P. W., Aylward, P., Veltri, E., Mahaffey, K. W., Moliterno, D. J., Strony, J., Wallentin, L., White, H. D., Diaz, R., Huber, K., Nicolau, J. C., Carlos Prieto, J., Isaza, D., Widimsky, P., Grande, P., Nieminen, M., Montalescot, G., Bode, C., Wong, L., Ofner, P., Lewis, B. S., Ambrosio, G., Valgimigli, M., Ogawa, H., Yamaguchi, J., Jukema, J. W., Cornel, J. H., Nordrehaug, J. E., Ruzyllo, W., Providencia, L., Tan, H., Dalby, A., Seung-Jung, P., Betriu, A., Cequier, A., Held, C., Pfisterer, M., Ming-Fong, C., Timurkaynak, T., Storey, R. F., Chen, E., Hudson, M. P., Lincoff, A. M., Morrow, D. A., Tricoci, P., Whellan, D. 2009; 158 (3): 327-U5

    Abstract

    The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features.TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention.TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2009.07.001

    View details for Web of Science ID 000269641200002

    View details for PubMedID 19699853

  • Sex Differences in Mortality Following Acute Coronary Syndromes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Berger, J. S., Elliott, L., Gallup, D., Roe, M., Granger, C. B., Armstrong, P. W., Simes, R. J., White, H. D., Van de Werf, F., Topol, E. J., Hochman, J. S., Newby, L. K., Harrington, R. A., Califf, R. M., Becker, R. C., Douglas, P. S. 2009; 302 (8): 874-882

    Abstract

    Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS).To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina.Thirty-day mortality following ACS.Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70).Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease.

    View details for Web of Science ID 000269260100021

    View details for PubMedID 19706861

  • Premature Release of Data from Clinical Trials of Ezetimibe NEW ENGLAND JOURNAL OF MEDICINE Califf, R. M., Harrington, R. A., Blazing, M. A. 2009; 361 (7): 712-717

    View details for Web of Science ID 000268884100015

    View details for PubMedID 19675335

  • Endoscopic versus Open Vein-Graft Harvesting in Coronary-Artery Bypass Surgery NEW ENGLAND JOURNAL OF MEDICINE Lopes, R. D., Hafley, G. E., Allen, K. B., Ferguson, T. B., Peterson, E. D., Harrington, R. A., Mehta, R. H., Gibson, C. M., Mack, M. J., Kouchoukos, N. T., Califf, R. M., Alexander, J. H. 2009; 361 (3): 235-244

    Abstract

    Vein-graft harvesting with the use of endoscopy (endoscopic harvesting) is a technique that is widely used to reduce postoperative wound complications after coronary-artery bypass grafting (CABG), but the long-term effects on the rate of vein-graft failure and on clinical outcomes are unknown.We studied the outcomes in patients who underwent endoscopic harvesting (1753 patients) as compared with those who underwent graft harvesting under direct vision, termed open harvesting (1247 patients), in a secondary analysis of 3000 patients undergoing CABG. The method of graft harvesting was determined by the surgeon. Vein-graft failure was defined as stenosis of at least 75% of the diameter of the graft on angiography 12 to 18 months after surgery (data were available in an angiographic subgroup of 1817 patients and 4290 grafts). Clinical outcomes included death, myocardial infarction, and repeat revascularization. Generalized estimating equations were used to adjust for baseline covariates associated with vein-graft failure and to account for the potential correlation between grafts within a patient. Cox proportional-hazards modeling was used to assess long-term clinical outcomes.The baseline characteristics were similar between patients who underwent endoscopic harvesting and those who underwent open harvesting. Patients who underwent endoscopic harvesting had higher rates of vein-graft failure at 12 to 18 months than patients who underwent open harvesting (46.7% vs. 38.0%, P<0.001). At 3 years, endoscopic harvesting was also associated with higher rates of death, myocardial infarction, or repeat revascularization (20.2% vs. 17.4%; adjusted hazard ratio, 1.22; 95% confidence interval [CI], 1.01 to 1.47; P=0.04), death or myocardial infarction (9.3% vs. 7.6%; adjusted hazard ratio, 1.38; 95% CI, 1.07 to 1.77; P=0.01), and death (7.4% vs. 5.8%; adjusted hazard ratio, 1.52; 95% CI, 1.13 to 2.04; P=0.005).Endoscopic vein-graft harvesting is independently associated with vein-graft failure and adverse clinical outcomes. Randomized clinical trials are needed to further evaluate the safety and effectiveness of this harvesting technique.

    View details for Web of Science ID 000267976100004

    View details for PubMedID 19605828

  • A new generation of antiplatelet agents CURRENT OPINION IN CARDIOLOGY Sellers, M. B., Tricoci, P., Harrington, R. A. 2009; 24 (4): 307-312

    Abstract

    Since the development and market entry of clopidogrel, a platelet ADP blocker, physicians have had few new antiplatelet options available to them for the treatment of acute and chronic coronary disease, specifically in the setting of acute coronary syndromes, percutaneous coronary intervention, and chronic stent management. Over the years, limitations of current antiplatelet regimens have emerged, establishing a need for novel antiplatelet drugs. This article discusses potential new targets for platelet inhibition and reviews innovative antiplatelet therapies under investigation.There are five main categories of antiplatelet therapies currently undergoing clinical study, consisting of the thienopyridines (P2Y12 receptor antagonists), cyclopentyltriazolopyrimidines (P2Y12 receptor antagonists), anti-von Willebrand factor aptamers, thrombin receptor (protease-activated receptor-1) antagonists, and thromboxane receptor antagonists. Early studies of these agents are discussed.Each of these new antiplatelet therapies has a unique profile that is aimed at improving clinical response with hopes of incremental efficacy and decreased complications, specifically bleeding.

    View details for DOI 10.1097/HCO.0b013e32832e2b44

    View details for Web of Science ID 000267279500006

    View details for PubMedID 19509485

  • Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial CIRCULATION Alexander, J. H., Becker, R. C., Bhatt, D. L., Cools, F., Crea, F., Dellborg, M., Fox, K. A., Goodman, S. G., Harrington, R. A., Huber, K., Husted, S., Lewis, B. S., Lopez-Sendon, J., Mohan, P., Montalescot, G., Ruda, M., Ruzyllo, W., Verheugt, F., Wallentin, L., Darius, H., Simoons, M., Boersma, E., DeLemos, J., Spencer, F. 2009; 119 (22): 2877-U39

    Abstract

    After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding.Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.

    View details for DOI 10.1161/CIRCULATIONAHA.108.832139

    View details for Web of Science ID 000266777900004

    View details for PubMedID 19470889

  • Careers for Clinician Investigators CIRCULATION Harrington, R. A., Califf, R. M., Hodgson, P. K., Peterson, E. D., Roe, M. T., Mark, D. B. 2009; 119 (22): 2945-2950
  • Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Giugliano, R. P., White, J. A., Bode, C., Armstrong, P. W., Montalescot, G., Lewis, B. S., van't Hof, A., Berdan, L. G., Lee, K. L., Strony, J. T., Hildemann, S., Veltri, E., Van de Werf, F., Braunwald, E., Harrington, R. A., Califf, R. M., Newby, L. K. 2009; 360 (21): 2176-2190

    Abstract

    Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is unknown.We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 microg per kilogram of body weight, administered 10 minutes apart, and a standard infusion > or = 12 hours before angiography) or a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). The primary efficacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment ("thrombotic bailout") at 96 hours. The key secondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization.The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events.In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non-life-threatening bleeding and need for transfusion. (ClinicalTrials.gov number, NCT00089895.)

    View details for DOI 10.1056/NEJMoa0901316

    View details for Web of Science ID 000266206000005

    View details for PubMedID 19332455

  • Prior polyvascular disease: risk factor for adverse ischaemic outcomes in acute coronary syndromes EUROPEAN HEART JOURNAL Bhatt, D. L., Peterson, E. D., Harrington, R. A., Ou, F., Cannon, C. P., Gibson, C. M., Kleiman, N. S., Brindis, R. G., Peacock, W. F., Brener, S. J., Menon, V., Smith, S. C., Pollack, C. V., Gibler, W. B., Ohman, E. M., Roe, M. T. 2009; 30 (10): 1195-1202

    Abstract

    The presence of peripheral arterial disease (PAD) or cerebrovascular disease (CVD) is associated with higher likelihood of significant coronary artery disease (CAD). We sought to assess the prevalence of PAD, CVD, prior CAD, or pre-existent disease in multiple arterial territories ('polyvascular' disease) in patients presenting with non-ST-segment elevation acute coronary syndrome and its impact on adverse events.Data from 95 749 patients enrolled from February 2003 to September 2006 at 484 sites in the CRUSADE registry were analysed. Patients were categorized as having prior 0, 1, 2, or 3 affected arterial beds. The rates of in-hospital mortality, myocardial infarction, stroke, and congestive heart failure were analysed, as were the rates of non-bypass surgery-related red blood cell transfusion and major bleeding. On presentation, 11,345 (11.9%) patients had established PAD, 9973 (10.4%) had documented CVD, and 41,404 (43.2%) had prior CAD. In this cohort, 0, 1, 2, and 3 arterial bed disease before presentation was present in 46 814 (48.9%, 95% CI 48.6-49.2%), 36 704 (38.3%, 95% CI 37.8-39.0%), 10 675 (11.2%, 95% CI 10.9-11.9%), and 1556 (1.6%, 95% CI 1.5-1.8%) patients, respectively. The rates of ischaemic events increased with the number of affected vascular beds. The adjusted odds ratio for the composite of in-hospital ischaemic events for pre-existent disease in 1, 2, or 3 arterial beds (compared with 0 arterial bed involvement) increased from 1.07 to 1.26 to 1.31 (P < 0.001). Similarly, the adjusted odds ratio for transfusion increased with greater disease burden from 1.11 to 1.28 to 1.30 (P < 0.001), although the adjusted rates of protocol-defined non-bypass surgery-related major bleeding did not.Prior polyvascular disease increases the risk of in-hospital adverse events, including mortality. Identification of these patients in clinical trial and real world populations may provide an opportunity to reduce their excess risk with intensive secondary prevention efforts.

    View details for DOI 10.1093/eurheartj/ehp099

    View details for Web of Science ID 000266115200009

    View details for PubMedID 19339264

  • Incidence, distribution, and prognostic impact of occluded culprit arteries among patients with non-ST-elevation acute coronary syndromes undergoing diagnostic angiography AMERICAN HEART JOURNAL Wang, T. Y., Zhang, M., Fu, Y., Armstrong, P. W., Newby, L. K., Gibson, C. M., Moliterno, D. J., de Werf, F. V., White, H. D., Harrington, R. A., Roe, M. T. 2009; 157 (4): 716-723

    Abstract

    Because acute occlusion of coronary arteries supplying the inferolateral myocardium frequently eludes standard 12-lead electrocardiogram (ECG) diagnosis, these patients may present as non-ST-segment elevation acute coronary syndromes (NSTE-ACS).We examined culprit artery occlusion among 1,957 NSTE-ACS patients in the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial who underwent diagnostic coronary angiography. We compared baseline characteristics, electrocardiographic findings, in-hospital treatment, and long-term outcomes between patients with and without occluded culprit arteries.The culprit artery was occluded in 528 (27%) patients. Culprit lesions were more frequently identified in the inferolateral territory among patients with an occluded culprit artery (63%) compared with those with a nonoccluded artery (45%, P < .0001). Patients with an occluded culprit artery were younger, more often male, and more likely to have had a prior myocardial infarction. Despite similar in-hospital treatment, patients with an occluded culprit artery had larger infarcts (median peak creatine kinase-MB 4.3 vs 2.1 x upper limit of normal, P < .0001) and higher risk-adjusted 6-month mortality (hazard ratio 1.72, 95% CI 1.07-2.79).More than 25% of NSTE-ACS patients had an occluded culprit artery on angiography. These patients may represent ST-segment elevation myocardial infarction equivalents; thus, improved early risk stratification techniques would help more rapidly triage these high-risk patients to an early invasive management strategy.

    View details for DOI 10.1016/j.ahj.2009.01.004

    View details for Web of Science ID 000265110100020

    View details for PubMedID 19332201

  • Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial AMERICAN HEART JOURNAL James, S., Akerblom, A., Cannon, C. P., Emanuelsson, H., Husted, S., Katus, H., Skene, A., Steg, P. G., Storey, R. F., Harrington, R., Becker, R., Wallentin, L. 2009; 157 (4): 599-605

    Abstract

    Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y(12) receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate-receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS.PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non-ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life.The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.

    View details for DOI 10.1016/j.ahj.2009.01.003

    View details for Web of Science ID 000265110100002

    View details for PubMedID 19332184

  • Bleeding risk with AZD6140, a reversible P2Y(12) receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Husted, S., Harrington, R. A., Cannon, C. P., Storey, R. F., Mitchell, P., Emanuelsson, H. 2009; 63 (4): 667-670

    Abstract

    AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

    View details for DOI 10.1111/j.1742-1241.2009.02030.x

    View details for Web of Science ID 000264241100020

    View details for PubMedID 19335707

  • Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study LANCET Becker, R. C., Moliterno, D. J., Jennings, L. K., Pieper, K. S., Pei, J., Niederman, A., Ziada, K. M., Berman, G., Strony, J., Joseph, D., Mahaffey, K. W., Van de Werf, F., Veltri, E., Harrington, R. A. 2009; 373 (9667): 919-928

    Abstract

    An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist.We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912.257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561).Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

    View details for Web of Science ID 000264158700033

    View details for PubMedID 19286091

  • Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial) AMERICAN JOURNAL OF CARDIOLOGY Aronow, H. D., Califf, R. M., Harrington, R. A., Vallee, M., Graffagnino, C., Shuaib, A., Fitzgerald, D. J., Easton, J. D., Van de Werf, F., Diener, H., Ferguson, J., Koudstaal, P. J., Amarenco, P., Theroux, P., Davis, S., Topol, E. J. 2008; 102 (10): 1285-1290

    Abstract

    Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs > or =162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of > or =162 mg/day may be more beneficial than those <162 mg/day at preventing death.

    View details for DOI 10.1016/j.amjcard.2008.07.019

    View details for Web of Science ID 000261194000001

    View details for PubMedID 18993142

  • Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes AMERICAN HEART JOURNAL Cannon, C. P., Giugliano, R. P., Blazing, M. A., Harrington, R. A., Peterson, J. L., Sisk, C. M., Strony, J., Musliner, T. A., McCabe, C. H., Veltri, E., Braunwald, E., Califf, R. M. 2008; 156 (5): 826-832

    Abstract

    Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS.The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg. Follow-up visits are at 1 and 4 months, and every 4 months thereafter. If consecutive measures of LDL-C are >79 mg/dL at follow-up visits, the simvastatin dose will be increased to 80 mg in a double-blind manner. The primary end point is the first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke. Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point.IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further.

    View details for DOI 10.1016/j.ahj.2008.07.023

    View details for Web of Science ID 000260700100007

    View details for PubMedID 19061694

  • Relation Between Previous Lipid-Lowering Therapy and Infaret Size (Creatine Kinase-MB Level) in Patients Presenting With Acute Myocardial Infarction AMERICAN JOURNAL OF CARDIOLOGY Aronow, H. D., Lincoff, A. M., Quinn, M. J., McRae, A. T., Gurm, H. S., Houghtaling, P. L., Granger, C. B., Harrington, R. A., de Werf, F. V., Topol, E. J., Lauer, M. S. 2008; 102 (9): 1119-1124

    Abstract

    Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p <0.0001). Similarly, in an unadjusted model, patients on previous lipid-lowering therapy were less likely to have a peak CK-MB >3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p <0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p <0.0001). In a covariate- and propensity-adjusted multivariable model, the association between pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk for CK-MB >3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.

    View details for DOI 10.1016/j.amjcard.2008.06.032

    View details for Web of Science ID 000261007500001

    View details for PubMedID 18940276

  • Influence of preoperative renal dysfunction on one-year bypass graft patency and two-year outcomes in patients undergoing coronary artery bypass surgery JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Mehta, R. H., Hafley, G. E., Gibson, M., Harrington, R. A., Peterson, E. D., Mack, M. J., Kouchoukos, N. T., Califf, R. M., Ferguson, T. B., Alexander, J. H. 2008; 136 (5): 1149-1155

    Abstract

    Limited information exists on the impact of preoperative renal dysfunction on internal thoracic artery and saphenous vein graft failure and 2-year clinical outcomes in patients undergoing coronary artery bypass surgery.We studied the impact of preoperative renal dysfunction (creatinine clearance < 60 mL/min) on 1-year internal thoracic artery and saphenous vein graft failure (defined as > or = 75% angiographic stenosis) and 2-year clinical events (death; death or myocardial infarction; and death, myocardial infarction, or revascularization) in 3014 patients undergoing coronary artery bypass surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection-IV study.Of 2973 patients (98.6%) with preoperative measurement of renal function, 440 (14.8%) had renal dysfunction. Most baseline comorbidities were higher in these patients. Two-year clinical events were higher in patients with preoperative renal dysfunction (adjusted death, myocardial infarction, or revascularization, hazard ratio 1.21, 95% confidence interval 0.97-1.50; adjusted death or myocardial infarction, hazard ratio 1.35, 95% confidence interval 1.05-1.74; adjusted death, hazard ratio 1.47, 95% confidence interval 0.98-2.21). However, saphenous vein graft (odds ratio 1.02, 95% confidence interval 0.79-1.33) and internal thoracic artery (odds ratio 0.76, 95% confidence interval 0.40-1.44) failure were similar in the 2 groups.Although the risk of adverse clinical events is higher in patients with preoperative renal dysfunction, that of internal thoracic artery and saphenous vein graft failure is not. This suggests that factors other than graft failure account for the worse clinical outcomes in this high-risk cohort. Further studies are needed to identify other mechanisms of these worse outcomes so that appropriate measures can be developed to improve long-term outcomes in patients with renal dysfunction undergoing coronary artery bypass surgery.

    View details for DOI 10.1016/j.jtcvs.2008.02.085

    View details for Web of Science ID 000261162400006

    View details for PubMedID 19026795

  • Impact of perioperative myocardial infarction on angiographic and clinical outcomes following coronary artery bypass grafting (from PRoject of Ex-vivo Vein Graft ENgineering via Transfection [PREVENT] IV) AMERICAN JOURNAL OF CARDIOLOGY Yau, J. M., Alexander, J. H., Hafley, G., Mahaffey, K. W., Mack, M. J., Kouchoukos, N., Goyal, A., Peterson, E. D., Gibson, C. M., Califf, R. M., Harrington, R. A., Ferguson, T. B. 2008; 102 (5): 546-551

    Abstract

    Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase >or=10 times the upper limit of normal or >or=5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.

    View details for DOI 10.1016/j.amjcard.2008.04.069

    View details for Web of Science ID 000258784500008

    View details for PubMedID 18721510

  • Smoking status and antithrombin therapy in patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Leung, S., Gallup, D., Mahaffey, K. W., Cohen, M., Antman, E. M., Goodman, S. G., Harrington, R. A., Langer, A., Aylward, P., Ferguson, J. J., Califf, R. M. 2008; 156 (1): 177-184

    Abstract

    Smoking remains a major public health issue. We investigated the incidence of smoking and outcomes in high-risk patients with acute coronary syndromes. Differences in treatment effect of antithrombin therapies were also investigated.Using data from SYNERGY, patients were categorized by their self-reported smoking status. They were followed at 30 days and 6 months for death, nonfatal myocardial infarction (MI), revascularization procedures, stroke, and need for rehospitalization, and at 1 year for occurrences of death.Overall, 9,971 patients were evaluated, of whom 2,404 (24%) were current smokers, 3,491 (35%) were former smokers, and 4076 (41%) had never smoked. Current smokers were younger (median age 61 years, interquartile range [IQR] 52-67) than former smokers (median age 69 years, IQR 63-75) and never smokers (median age 70 years, IQR 64-77) and had fewer additional coronary artery disease risk factors (hypertension, diabetes, hypercholesterolemia). The 30-day death/MI rate was similar for former versus never smokers (15% vs 13.6%, P = .079) and for current versus never smokers (14% vs 13.6%, P = .585). Adjusted odds ratios for 30-day death/MI in patients receiving enoxaparin compared with those receiving unfractionated heparin were 1.065 (95% CI 0.883-1.283, P = .51) in never smokers, 1.034 (95% CI 0.853-1.254, P = .733) in former smokers, and 0.742 (95% CI 0.582-0.948, P = .017) in current smokers. A significant interaction for treatment and smoking status was found at 30 days (P = .0215), but not at 6 months (P = .1381) or 1 year (P = .1054). One-year unadjusted mortality rates were higher for former versus never smokers (9.1% vs 6.7%, P = .0002) but were similar for current versus never smokers (6.5% vs 6.7%, P = .7226). On follow-up at 30 days, 62.3% (n =1397) of current smokers reported not smoking.Smokers with non-ST-segment elevation acute coronary syndrome are generally younger and have fewer cardiac risk factors. A significant interaction of smoking and enoxaparin was seen at 30 days, but not sustained at 6 months and 1 year. More than 60% of smokers quit within 30 days of their cardiac event. There was little difference in outcomes from 30 days to 1 year for these smokers who quit versus those who did not.

    View details for DOI 10.1016/j.ahj.2008.02.002

    View details for Web of Science ID 000257329900025

    View details for PubMedID 18585514

  • Short- and long-term outcomes following atrial fibrillation in patients with acute coronary syndromes with or without ST-segment elevation HEART Lopes, R. D., Pieper, K. S., Horton, J. R., Al-Khatib, S. M., Newby, L. K., Mehta, R. H., De Werf, F. V., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Ohman, E. M., White, H. D., Wallentin, L., Granger, C. B. 2008; 94 (7): 867-873

    Abstract

    To assess variables associated with the occurrence of atrial fibrillation (AF) and the relation of AF with short- and long-term outcomes and with other in-hospital complications in patients with acute coronary syndromes (ACS) with and without ST-segment elevation.Pooled database of 120 566 patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation (NSTE) ACS enrolled in 10 clinical trials. Multivariable logistic regression and Cox proportional hazards modelling were used to identify factors associated with AF and its relation with clinical outcomes.ACS complicated by AF.120,566 patients with STEMI and NSTE-ACS in 10 clinical trials.None evaluated.Short- and long-term mortality.Occurrence of AF was 7.5% in the overall population (STEMI 8.0% (n = 84 161); NSTE-ACS = 6.4% (n = 36,405)). Seven-day mortality was higher for patients with AF (5.1%) than for those without (1.6%). After adjusting for confounders, association of AF with 7-day mortality was present in STEMI (hazards ratio (HR) = 1.65; 95% CI 1.44 to 1.90) and NSTE-ACS (HR = 2.30; 95% CI 1.83 to 2.90; p interaction = 0.015). Risk of long-term mortality (day 8 to 1 year) was also higher in STEMI (HR = 2.37; 95% CI 1.79 to 3.15) and NSTE-ACS (HR = 1.67; 95% CI 1.41 to 1.99). AF had a larger impact in NSTE-ACS on risk of short-term mortality (p<0.001), stroke (p<0.001), ischaemic stroke (p<0.001) and moderate or severe bleeding (p<0.001).AF is more common in patients with STEMI. An association of AF with short- and long-term mortality among patients with STEMI and NSTE-ACS was found. Understanding these findings may lead to better care of patients with this common arrhythmia.

    View details for DOI 10.1136/hrt.2007.134486

    View details for Web of Science ID 000256721000013

    View details for PubMedID 18332062

  • Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease CIRCULATION Chan, M. Y., Cohen, M. G., Dyke, C. K., Myles, S. K., Aberle, L. G., Lin, M., Walder, J., Steinhubl, S. R., Gilchrist, I. C., Kleiman, N. S., Vorchheimer, D. A., Chronos, N., Melloni, C., Alexander, J. H., Harrington, R. A., Tonkens, R. M., Becker, R. C., Rusconi, C. P. 2008; 117 (22): 2865-2874

    Abstract

    Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity.We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred.This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

    View details for DOI 10.1161/CIRCULATIONAHA.107.745687

    View details for Web of Science ID 000256376200005

    View details for PubMedID 18506005

  • Acute pharmacological conversion of atrial fibrillation to sinus rhythm - Is short-term symptomatic therapy worth it? A report from the December 2007 meeting of the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration CIRCULATION Hiatt, W. R., Lincoff, A. M., Harrington, R. A. 2008; 117 (22): 2956-2957
  • Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schünemann, H. J. 2008; 133 (6): 71S-109S

    View details for DOI 10.1378/chest.08-0693

    View details for PubMedID 18574259

  • Antithrombotic and thrombolytic therapy CHEST Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schunemann, H. J. 2008; 133 (6): 110S-112S
  • American College of Chest Physicians evidence-based clinical practice guidelines (8th edition) CHEST Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schunemann, H. J. 2008; 133 (6): 71S-109S
  • Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schünemann, H. J., American College of Chest Physician 2008; 133 (6): 110S-112S

    Abstract

    Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process. We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally. The grading system for the recommendations was adopted in 2006 by the ACCP for all its guidelines, is similar to the increasingly widely used Grades of Recommendation, Assessment, Development, and Evaluation approach, and is described in detail in one of the introductory chapters. While most of the evidence on which recommendations are made remains low quality in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have resulted in new and strong evidence-based recommendations for many indications.

    View details for DOI 10.1378/chest.08-0652

    View details for PubMedID 18574260

  • Acute ST-segment elevation myocardial infarction CHEST Goodman, S. G., Menon, V., Cannon, C. P., Steg, G., Ohman, E. M., Harrington, R. A. 2008; 133 (6): 708S-775S

    Abstract

    This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration < or = 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

    View details for DOI 10.1378/chest.08-0665

    View details for Web of Science ID 000257151800019

    View details for PubMedID 18574277

  • The primary and secondary prevention of coronary artery disease CHEST Becker, R. C., Meade, T. W., Berger, P. B., Ezekowitz, M., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H., Mark, D. B., Harrington, R. A. 2008; 133 (6): 776S-814S

    Abstract

    The following chapter devoted to antithrombotic therapy for chronic coronary artery disease (CAD) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation" chapter by Guyatt et al in this supplement, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS) we recommend daily oral aspirin (75-100 mg) [Grade 1A]. For patients with an aspirin allergy, we recommend clopidogrel, 75 mg/d (Grade 1A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we suggest discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI), we recommend daily aspirin (75-100 mg) as indefinite therapy (Grade 1A). We recommend clopidogrel in combination with aspirin for patients experiencing ST-segment elevation (STE) and NSTE-ACS (Grade 1A). For patients with contraindications to aspirin, we recommend clopidogrel as monotherapy (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend aspirin (75 to 100 mg/d) [Grade 1B]. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). We recommend that patients receiving drug-eluting stents (DES) receive aspirin (325 mg/d for 3 months followed by 75-100 mg/d) and clopidogrel 75 mg/d for a minimum of 12 months (Grade 2B). For primary prevention in patients with moderate risk for a coronary event, we recommend aspirin, 75-100 mg/d, over either no antithrombotic therapy or vitamin K antagonist (Grade 1A).

    View details for DOI 10.1378/chest.08-0685

    View details for Web of Science ID 000257151800020

    View details for PubMedID 18574278

  • Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes CHEST Harrington, R. A., Becker, R. C., Cannon, C. P., Gutterman, D., Lincoff, A. M., Popma, J. J., Steg, G., Guyatt, G. H., Goodman, S. G. 2008; 133 (6): 670S-707S

    Abstract

    This chapter about antithrombotic therapy for coronary artery disease is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicans Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggestions are weaker as there is uncertainty regarding the benefits, risks and costs such that individual patients' values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation for Antithrombotic Agents" chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations are the following: for all patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), without a clear allergy to aspirin, we recommend immediate aspirin (162 to 325 mg po) and then daily oral aspirin (75 to 100 mg) [Grade 1A]. For NSTE ACS patients who are at at least moderate risk for an ischemic event and who will undergo an early invasive management strategy, we recommend "upstream" treatment either with clopidogrel (300 mg po bolus, followed by 75 mg/d) or a small-molecule IV glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide or tirofiban) [Grade 1A]. For NSTE ACS patients who are at least moderate risk for an ischemic event and for whom an early conservative or a delayed invasive strategy of management is to be used, we recommend "upstream" treatment with clopidogrel (300 mg oral bolus, followed by 75 mg/d) [Grade 1A]. For NSTE ACS patients who undergo PCI, we recommend treatment with both clopidogrel and an IV GP IIb/IIIa inhibitor (Grade 1A). We recommend a loading dose of 600 mg of clopidogrel given at least 2 h prior to planned PCI followed by 75 mg/d (Grade 1B). For all patients presenting with NSTE ACS, we recommend anticoagulation with UFH or LMWH or bivalirudin or fondaparinux over no anticoagulation (Grade 1A). For NSTE ACS patients who will undergo an early invasive strategy of management, we recommend UFH (with a GP IIb/IIIa inhibitor) over either LMWH or fondaparinux (Grade 1B). For NSTE ACS patients in whom an early conservative or a delayed invasive strategy of management is to be used, we recommend fondaparinux over enoxaparin (Grade 1A) and LMWH over UFH (Grade 1B). We recommend continuing LMWH during PCI treatment of patients with NSTE ACS when it has been started as the "upstream" anticoagulant (Grade 1B). In low- to moderate-risk patients with NSTE ACS undergoing PCI, we recommend either bivalirudin with provisional ("bail-out") GP IIb/IIIa inhibitors or UFH plus a GP IIb/IIIa inhibitor over alternative antithrombotic regimens (Grade 1B).

    View details for DOI 10.1378/chest.08-0691

    View details for Web of Science ID 000257151800018

    View details for PubMedID 18574276

  • Cockcroft-Gault versus Modification of Diet in Renal Disease - Importance of glomerular filtration rate formula for classification of chronic kidney disease in patients with Non-ST-Segment elevation acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mellord, C., Peterson, E. D., Chen, A. Y., Szczech, L. A., Newby, L. K., Harrington, R. A., Gibler, W. B., Ohman, E. M., Spinler, S. A., Roe, M. T., Alexander, K. P. 2008; 51 (10): 991-996

    Abstract

    Our purpose was to compare formulae for estimating glomerular filtration rate (GFR) in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients.Assessment of GFR is important for antithrombotic dose adjustment in NSTE ACS patients.We assessed estimated glomerular filtration rate (eGFR) with Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) formulae in 46,942 NSTE ACS patients from 408 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines) hospitals. Formula agreement was shown continuously and by chronic kidney disease (CKD) stages. We determined in-hospital outcomes and the association between antithrombotic dose adjustment and bleeding for moderate CKD as determined by each formula.The median (interquartile range [IQR]) eGFR was 53.2 ml/min (34.7, 75.1 ml/min) by C-G and 65.8 ml/min (47.6, 83.5 ml/min) by MDRD. The mean eGFR was higher with MDRD (approximately 9.1 ml/min), but this difference was greater in age, weight, and gender subgroups. Chronic kidney disease classification differed in 20% of the population and altered when antithrombotic dose adjustment was required by C-G versus MDRD (eptifibatide: 45.7% vs. 27.3%; enoxaparin: 19.0% vs. 9.6%).Important CKD disagreements occur in approximately 20% of acute coronary syndrome patients, affecting dosing adjustments in those already susceptible to bleeding. Dosing based on C-G formula is preferable, particularly in the small, female, or elderly patient.

    View details for DOI 10.1016/j.jacc.2007.11.045

    View details for Web of Science ID 000253997000003

    View details for PubMedID 18325437

  • Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease CLINICAL CARDIOLOGY Metioni, C., Alexander, K. P., Milford-Beland, S., Newby, L. K., Szczech, L. A., Pollack, C. V., Kirk, J. D., Christenson, R. H., Harrington, R. A., Gibter, W. B., Ohman, E. M., Peterson, E. D., Roe, M. T. 2008; 31 (3): 125-129

    Abstract

    The prognostic value of cardiac troponins (cTn) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and chronic kidney disease (CKD) is debated.We tested the performance of cTnI and cTnT for risk stratification in patients with CKD and evaluated the prognostic significance of cTnI and cTnT elevations by their magnitude across the range of CKD severity.We examined correlations among cTn elevation, CKD, and in-hospital mortality in 31,586 high-risk patients with NSTE ACS included in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative (CRUSADE). Cardiac tropinins I and T levels were categorized as ratios of each site's upper limit of normal (ULN) for myocardial necrosis: normal (cTn ratio < or =1 x ULN), mild (cTn ratio > 1-3 x ULN), and major (cTn ratio > 3 x ULN) elevation. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Stages of CKD were categorized as normal to mild (eGFR > 60 mL/min), moderate (eGFR 30-60 mL/min), or severe (eGFR < 30 mL/min).Mortality increased more steeply across CKD stages (2.0%-12.9%) than across cTn ratio categories (2.7%-5.4%). In normal or mild CKD, mortality was low regardless of cTn elevations. In moderate CKD, mortality increased incrementally with cTnI (3.3% versus 5.4% versus 7.4%) and cTnT (3.7% versus 5.3% versus 7.3%) elevation. Among severe CKD patients, only major cTn elevations further distinguished risk (cTnI: 10.1% versus 9.7% versus 14.6%; cTnT: 7.0% versus 5.7% versus 14.0%).In patients with CKD, cTnI and cTnT perform equally in differentiating short-term prognosis following NSTE ACS; however, the prognostic impact of cTn is dependent upon the degree of CKD severity.

    View details for DOI 10.1002/clc.20210

    View details for Web of Science ID 000254128600006

    View details for PubMedID 18383049

  • Meta-analysis comparing reported frequency of atrial fibrillation after acute coronary syndromes in Asians versus whites AMERICAN JOURNAL OF CARDIOLOGY Novaro, G. M., Asher, C. R., Bhatt, D. L., Moliterno, D. J., Harrington, R. A., Lincoff, A. M., Newby, L. K., Tcheng, J. E., Hsu, A. P., Pinski, S. L. 2008; 101 (4): 506-509

    Abstract

    The development of atrial fibrillation (AF) in cardiac patients is multifactorial, including not well defined genetic factors. To determine if Asian ethnicity is associated with the development of AF in patients with coronary disease, a meta-analysis was conducted of patient-level data from 7 prospective randomized clinical trials that prospectively collected information on the development of AF: 3 trials in patients with ST-elevation myocardial infarction (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] I, GUSTO III, and GUSTO V), 3 trials in patients with non-ST-elevation acute coronary syndromes (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy [PURSUIT], Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II [IMPACT II], and Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network [PARAGON A]), and 1 trial in patients with both conditions (GUSTO IIb). A total of 94,785 patients were identified (93,050 white, 1,735 Asian). At baseline, Asian patients were younger; had lower body mass indexes; had a lower prevalence of female gender, previous angioplasty, and previous coronary artery bypass grafting; and had a greater prevalence of diabetes compared with white patients. The development of AF was lower in Asian than in white patients (4.7% vs 7.6%, p <0.001), while rates of ventricular tachycardia and fibrillation were similar in the 2 groups. In multivariate logistic regression analysis, Asian ethnicity was associated with significantly lower rates of AF (odds ratio 0.65, 95% confidence interval 0.50 to 0.84, p = 0.001) compared with white ethnicity. In conclusion, similar to previous studies showing a lower incidence of AF in non-Caucasian populations, Asians experiencing acute ischemic syndromes have a significantly lower frequency of AF compared with whites. Further study is needed to investigate the mechanisms and potential genetic underpinnings behind this association.

    View details for DOI 10.1016/j.amjcard.2007.09.098

    View details for Web of Science ID 000253173900018

    View details for PubMedID 18312767

  • Impact of saphenous vein graft radiographic markers on clinical events and angiographic parameters ANNALS OF THORACIC SURGERY Olenchock, S. A., Karmpaliotis, D., Gibson, W. J., Murphy, S. A., Southard, M. C., Ciaglo, L., Buros, J., Mack, M. J., Alexander, J. H., Harrington, R. A., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Gibson, C. M. 2008; 85 (2): 520-524

    Abstract

    Use of saphenous vein graft (SVG) radiographic markers has been associated with shorter cardiac catheterization procedure times and reduced contrast agent volume for postoperative coronary artery bypass graft (CABG) catheterizations. Use of such markers is varied and often operator-dependent, as the effect of SVG markers has not been fully evaluated. The goal of the present analysis was to evaluate the association of SVG markers with clinical outcomes and graft patency.Data were drawn from the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV trial of patients undergoing CABG at 107 hospitals across the United States. Repeat angiography was performed within 12 to 18 months after CABG. The SVG markers were used at the discretion of the surgeon and were identified on the follow-up angiogram as any device used to mark the ostium, regardless of shape.The SVG markers were present in 51.2% of evaluable patients (910 of 1,778) and 52.3% of SVGs (2,228 of 4,240). Among patients with totally occluded SVGs (n = 911), visual identification of the SVG was obtained more frequently in those with an SVG marker (90.7% vs 72.1%, p < 0.001). The SVG stenosis 70% or greater at follow-up did not differ by use of markers (25.8% with marker vs 24.4% without marker, p = not significant). These findings were also consistent in ostial lesions (n = 942). Long-term death or myocardial infarction (MI) was similar by use of marker. The perioperative CABG MI was higher in patients with SVG markers (10.1% vs 5.5%, odds ratio adjusted 1.86, p = 0.021).Saphenous vein graft radiographic markers were associated with higher rates of direct visualization of totally occluded SVGs without an adverse effect on graft patency or long-term clinical outcomes, but the association of SVG markers with increased perioperative CABG MI warrants further examination.

    View details for DOI 10.1016/j.athoracsur.2007.10.061

    View details for Web of Science ID 000252664900027

    View details for PubMedID 18222256

  • Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy CIRCULATION Berger, J. S., Stebbins, A., Granger, C. B., Ohman, E. M., Armstrong, P. W., de Werf, F. V., White, H. D., Simes, R. J., Harrington, R. A., Califf, R. M., Peterson, E. D. 2008; 117 (2): 192-199

    Abstract

    Although treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients.Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) trials (n=48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8% (P=0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment, aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). After adjustment, 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003).These data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST-elevation myocardial infarction.

    View details for DOI 10.1161/CIRCULATIONAHA.107.729558

    View details for Web of Science ID 000252601400016

    View details for PubMedID 18086929

  • International variation in the use of blood transfusion in patients with non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Rao, S. V., Chiswell, K., Sun, J., Granger, C. B., Newby, L. K., de Werf, F. V., White, H. D., Armstong, P. W., Califf, R. A., Harrington, R. A. 2008; 101 (1): 25-29

    Abstract

    The purpose of this study was to determine international patterns of blood transfusion in patients with acute coronary syndrome (ACS). Previous studies showed geographic heterogeneity in some aspects of ACS care. Data for variability in the use of blood transfusion in ACS management are limited. Pooled data from 3 international randomized trials of patients with non-ST-segment elevation ACS (n = 23,906) were analyzed to determine the association between non-United States (US) location and blood transfusion after stratifying by the use of invasive procedures. The analysis adjusted for differences in patient characteristics and was repeated using a 2-stage mixed-model approach and in patients who underwent in-hospital coronary artery bypass grafting. Compared with US patients, both unadjusted and adjusted hazards for blood transfusion were significantly lower in non-US patients who did not undergo invasive procedures (unadjusted hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.17 to 0.33; adjusted HR 0.20, 95% CI 0.14 to 0.28). This was also true in non-US patients who underwent invasive procedures (unadjusted HR 0.34, 95% CI 0.27 to 0.44; adjusted HR 0.31, 95% CI 0.23 to 0.42). Results were similar in both validation analyses. In conclusion, there was substantial international variation in blood transfusion use in patients with ACS. These results, along with the controversy regarding the appropriate use of transfusion in patients with coronary heart disease, emphasize the need for understanding the role of blood transfusion in the management of patients with ACS and factors that influence transfusion decisions.

    View details for DOI 10.1016/j.amjcard.2007.07.042

    View details for Web of Science ID 000252136400005

    View details for PubMedID 18157960

  • Time to coronary angiography and outcomes among patients with high-risk non-ST-segment-elevation acute coronary syndromes: Results from the SYNERGY trial CIRCULATION Tricoci, P., Lokhnygina, Y., Berdan, L. G., Steinhubl, S. R., Gulba, D. C., White, H. D., Kleiman, N. S., Aylward, P. E., Langer, A., Califf, R. M., Ferguson, J. J., Antman, E. M., Newby, L. K., Harrington, R. A., Goodman, S. G., Mahaffey, K. W. 2007; 116 (23): 2669-2677

    Abstract

    Optimal timing for an early invasive strategy in patients with non-ST-segment-elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non-ST-segment-elevation acute coronary syndrome who underwent angiography within 48 hours of admission.Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals.A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non-ST-segment-elevation acute coronary syndrome management.

    View details for DOI 10.1161/CIRCULATIONAHA.107.690081

    View details for Web of Science ID 000251361400005

    View details for PubMedID 18025532

  • Clinical and angiographic correlates of short- and long-term mortality in patients undergoing coronary artery bypass grafting AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Honeycutt, E., Shaw, L. K., Milano, C. A., Smith, P. K., Harrington, R. A., Sketch, M. H. 2007; 100 (10): 1538-1542

    Abstract

    Differences in the clinical and angiographic factors associated with short- and long-term outcomes in patients undergoing coronary artery bypass grafting (CABG) are less known. Accordingly, differences were examined in clinical and angiographic correlates of short- and long-term mortality after CABG in 8,229 patients undergoing initial CABG enrolled in the Duke Cardiovascular Disease Database (1995 to 2002). Logistic regression and Cox proportional hazard modeling were performed to determine independent correlates of 30-day and long-term mortality. Death occurred in 2.4% at 30 days and 17.6% beyond 30 days at a median follow-up of 6 years in patients who underwent CABG. Multivariable models identified older age, lower left ventricular ejection fraction, lower or higher body mass index, cerebrovascular disease, lack of internal mammary artery use, and lower cholesterol to be associated with increased risk of both events. Although hemodynamic status (preoperative myocardial infarction, New York Heart Association class, and cardiogenic shock), female gender, and minority race were associated with 30-day death; co-morbid conditions (serum creatinine, chronic lung disease, diabetes, previous heart failure, peripheral vascular disease, and left main disease) were associated with increased long-term (beyond 30 days) death (c indexes 0.76 and 0.79 for the short- and long-term mortality models, respectively). In conclusion, our study suggested that correlates of acute and long-term death were different in patients undergoing CABG. These differences should be kept in context when counseling patients undergoing CABG and may help facilitate targeted strategies to improve short- and long-term mortality risks after CABG.

    View details for DOI 10.1016/j.amjcard.2007.06.053

    View details for Web of Science ID 000251294500008

    View details for PubMedID 17996515

  • Safety, tolerability, and initial efficacy of AZD6140, the first reversivle oral adenosine diphosphate receptor antagonist, compared with clopidigrel, in patients with non-ST-segment elevation acute coronary syndrome - Primary results of the DISPERSE-2 trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cannon, C. P., Husted, S., Harrington, R. A., Scirica, B. M., Emanuelsson, H., Storey, R. F. 2007; 50 (19): 1844-1851
  • Inhibition of platelet aggregation by AZD6140, A reversible oral P2Y(12) receptor antagonist, compared with clopidogral in patients with acute coronary syndrome JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Storey, R. F., Husted, S., Harrington, R. A., Heptinstall, S., Wilcox, R. G., Peters, G., Wickens, M., Emanuelsson, H., Gurbel, P., Grande, P., Cannon, C. P. 2007; 50 (19): 1852-1856

    Abstract

    In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients.Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study).Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals.AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel.AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.

    View details for DOI 10.1016/j.jacc.2007.07.058

    View details for Web of Science ID 000250788300006

    View details for PubMedID 17980251

  • Complementary effects of thienopyridine pretreatment and platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention; Results from the ESPRIT trial CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Dery, J., Campbell, M. E., Mathias, J., Pieper, K. S., Harrington, R. A., Madan, M., Gibson, C. M., Tolleson, T. R., O'Shea, J. C., Tcheng, J. E. 2007; 70 (1): 43-50

    Abstract

    This analysis sought to investigate the complementary effect of thienopyridine pretreatment and platelet glycoprotein (GP) IIb/IIIa integrin blockade in coronary stent intervention.Definitive evidence supporting combined antiplatelet therapy consisting of thienopyridine pretreatment and GP IIb/IIIa receptor blockade in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is limited.We retrospectively analyzed clinical outcomes by thienopyridine use in the 2,040 patients randomized to eptifibatide or placebo who underwent PCI in the ESPRIT trial.A total of 901 patients received a loading dose of thienopyridine before PCI (group 1), 123 received thienopyridine pretreatment without a loading dose (group 2), and 1,016 were not treated with thienopyridine before PCI (group 3). The composite incidence of death or myocardial infarction at 30 days was significantly lower in group 1 than in groups 2 and 3 combined (OR, 0.71 [95%CI, 0.52-0.99]; P = 0.0417). A similar trend was seen for the composite of death, myocardial infarction, or urgent target vessel revascularization (unadjusted OR, 0.77 [0.57-1.05]; P = 0.1025). After adjusting for baseline characteristics, these differences were no longer significant. No interactions were identified with eptifibatide assignment for any of the group comparisons.Pretreatment with a loading dose of thienopyridine lowers the rate of ischemic complications regardless of treatment with a GP IIb/IIIa inhibitor. Conversely, the efficacy of eptifibatide is maintained whether or not a loading dose of a thienopyridine is administered. Optimal outcomes are achieved in patients receiving thienopyridine pretreatment along with platelet GP IIb/IIIa inhibitor therapy.

    View details for DOI 10.1002/ccd.21059

    View details for Web of Science ID 000247812400008

    View details for PubMedID 17203469

  • Timing of glycoprotein IIb/IIIa inhibitor use and outcomes among patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (Results from CRUSADE) AMERICAN JOURNAL OF CARDIOLOGY Tricoci, P., Peterson, E. D., Chen, A. Y., Newby, L. K., Harrington, R. A., Greenbaum, A. B., Cannon, C. P., Gibson, C. M., Hoekstra, J. W., Pollack, C. V., Ohman, E. M., Gibler, W. B., Roe, M. T. 2007; 99 (10): 1389-1393

    Abstract

    Although glycoprotein (GP) IIb/IIIa inhibitors are recommended for patients with unstable angina and non-ST-segment elevation myocardial infarction who undergo percutaneous coronary intervention (PCI), the American College of Cardiology/American Heart Association guidelines do not specify optimal timing for their initiation. We compared patient characteristics and clinical outcomes in 30,830 patients with non-ST-segment elevation myocardial infarction included in the CRUSADE initiative (January 2001 to December 2004) who underwent PCI with upstream (>1 hour before PCI) or periprocedural use of GP IIb/IIIa inhibitors. GP IIb/IIIa inhibitors were administered upstream in 43% of patients versus periprocedurally in 57%. Time from arrival to PCI was longer for patients who received GP IIb/IIIa inhibitors upstream (median 25.6 hours) compared with periprocedurally (18.2 hours). Unadjusted incidence of in-hospital death or reinfarction was lower with upstream GP IIb/IIIa inhibitor use (3.8% vs 4.3%, p = 0.046), but after adjusting for patient and hospital characteristics, this difference was not statistically significant. Treatment with upstream GP IIb/IIIa inhibitors was associated with a lower incidence of unadjusted death or reinfarction in patients who underwent PCI <12 hours from hospital arrival. In conclusion, in this observational analysis, overall ischemic outcomes were similar between the 2 groups, but clinical trials are needed to solve the controversy over optional timing of GP IIb/IIIa inhibitor use.

    View details for DOI 10.1016/j.amjcard.2006.12.066

    View details for Web of Science ID 000246715900009

    View details for PubMedID 17493466

  • Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes EUROPEAN HEART JOURNAL Rao, S. V., Eikelboom, J. A., Granger, C. B., Harrington, R. A., Califf, R. M., Bassand, J. 2007; 28 (10): 1193-1204

    Abstract

    Antithrombotic therapy and invasive risk stratification in selected high-risk patients have improved outcomes from non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but carry a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry), the definition used, and the use of invasive procedures, it is becoming clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death. Blood transfusion itself may carry a risk for ischaemic outcomes that is independent of bleeding. Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with NSTE-ACS. Anticoagulants studied in recent clinical trials that have focused on bleeding reduction include fondaparinux and bivalirudin. In this review, we discuss the clinical trial evidence for these agents, the association between bleeding and clinical outcomes, the biology of blood transfusion and potential mechanisms underlying its association with adverse outcomes, and propose strategies to deal with bleeding complications. Future directions for research and clinical practice are also discussed.

    View details for DOI 10.1093/eurheartj/ehm019

    View details for Web of Science ID 000247430000011

    View details for PubMedID 17456480

  • Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study EUROPEAN HEART JOURNAL Dzavik, V., Cotter, G., Reynolds, H. R., Alexander, J. H., Ramanathan, K., Stebbins, A. L., Hathaway, D., Farkouh, M. E., Ohman, E. M., Baran, D. A., Prondzinsky, R., Panza, J. A., Cantor, W. J., Vered, Z., Buller, C. E., Kleiman, N. S., Webb, J. G., Holmes, D. R., Parrilo, J. E., Hazen, S. L., Gross, S. S., Harrington, R. A., Hochman, J. S. 2007; 28 (9): 1109-1116

    Abstract

    Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of l-n-monomethyl-arginine (l-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery.Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of l-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was -4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four l-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was -0.4, 4.4, 1.8, -4.1, and 6.8 mmHg in the placebo and four l-NMMA groups, respectively (all P = NS).l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.

    View details for DOI 10.1093/eurheartj/ehm075

    View details for Web of Science ID 000247071200017

    View details for PubMedID 17459901

  • Changes in patterns of coronary revascularization strategies for patients with acute coronary syndromes (from the CRUSADE Quality Improvement Initiative) AMERICAN JOURNAL OF CARDIOLOGY Gogo, P. B., Dauerman, H. L., Mulgund, J., Ohman, E. M., Patel, M. R., Cohen, D. J., Saucedo, J. F., Harrington, R. A., Gibler, W. B., Smith, S. C., Peterson, E. D., Roe, M. T. 2007; 99 (9): 1222-1226

    Abstract

    Since the introduction of drug-eluting stents (DESs), patterns of revascularization strategies for patients with non-ST-segment elevation acute coronary syndromes have not been assessed. We studied 82,924 patients from the CRUSADE Initiative who presented with non-ST-segment elevation acute coronary syndromes and underwent coronary angiography at 365 United States hospitals that had capabilities for surgical (coronary artery bypass grafting [CABG]) and percutaneous (percutaneous coronary intervention [PCI]) revascularization from January 2002 to June 2005. Temporal trends in the use of PCI, CABG, and medical management without revascularization were analyzed with respect to the introduction of DESs. In total, 73,577 patients (89%) had >50% stenosis in > or =1 coronary artery, and there was a significant increase in the use of PCI (vs CABG or medical management without revascularization) during the study period (38.3% vs 52.5%). By quarter 2 of 2005, 80% of patients who underwent PCI received a DES. In total, 18,462 of 25,068 patients (73.6%) with 3-vessel disease (3VD) underwent revascularization and use of CABG decreased for these patients (48.9% to 39.9%, p <0.001), whereas use of PCI increased (51.1% to 60.1%, p <0.001). Factors significantly associated with use of PCI for patients with 3VD who underwent any revascularization included previous PCI, previous CABG, cardiology inpatient care, care at an academic hospital, renal insufficiency, and previous congestive heart failure. In conclusion, coinciding with the introduction of DESs, there has been a significant increase in the use of PCI and, in those patients with 3VD, a decrease in the use of CABG with a shift toward increasing use of PCI. Long-term implications of this shift remain uncertain, especially in patients with 3VD.

    View details for DOI 10.1016/j.amjcard.2006.12.037

    View details for Web of Science ID 000246168600010

    View details for PubMedID 17478146

  • Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock - The TRIUMPH randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Hochman, J. S., Alexander, J. H., Reynolds, H. R., Stebbins, A. L., Dzavik, V., Harrington, R. A., de Werf, F. V. 2007; 297 (15): 1657-1666

    Abstract

    Cardiogenic shock complicating acute myocardial infarction (MI) remains a common and lethal disorder despite aggressive use of early revascularization. Systemic inflammation, including expression of inducible nitric oxide synthase (NOS) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal function, and survival in patients with cardiogenic shock.To examine the effects of an isoform-nonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery.International, multicenter, randomized, double-blind, placebo-controlled trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock [TRIUMPH]) with planned enrollment of 658 patients at 130 centers. Participants were enrolled between January 2005 and August 2006 when the study was terminated early.Tilarginine (L-N(G)-monomethylarginine [L-NMMA]), 1-mg/kg bolus and 1-mg/kg per hour 5-hour infusion, vs matching placebo.The primary outcome was 30-day all-cause mortality among patients who received study medication. Secondary outcomes included shock resolution and duration, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality.Enrollment was terminated at 398 patients based on a prespecified futility analysis. Six-month follow-up was completed in February 2007. There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92-1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo; P = .31) and duration of shock (median, 156 [interquartile range, 78-759] hours tilarginine vs 190 [100-759] placebo; P = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; P = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo; P = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79-1.36; P = .80).Tilarginine, 1-mg/kg bolus and 5-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. Early mortality rates in this patient group are high. Further research is needed to develop effective therapies for patients with cardiogenic shock following acute MI.clinicaltrials.gov Identifier: NCT00112281

    View details for Web of Science ID 000245747400019

    View details for PubMedID 17387132

  • Outcomes associated with the use of secondary prevention medications after coronary artery bypass graft surgery ANNALS OF THORACIC SURGERY Goyal, A., Alexander, J. H., Hafley, G. E., Graham, S. H., Mehta, R. H., Mack, M. J., Wolf, R. K., Cohn, L. H., Kouchoukos, N. T., Harrington, R. A., Gennevois, D., Gibson, C. M., Califf, R. M., Ferguson, T. B., Peterson, E. D. 2007; 83 (3): 993-1001

    Abstract

    Secondary prevention medications are beneficial after acute coronary syndromes, but these benefits are less clear after coronary artery bypass graft surgery. We investigated whether greater use of secondary prevention medications after coronary artery bypass graft surgery is associated with improved clinical outcomes.Patients undergoing coronary artery bypass graft surgery in the PREVENT IV trial (n = 2970) were surveyed for use of antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and lipid-lowering agents after hospital discharge and at 1 year. Patients were categorized based on their percentage use of indicated medications after hospital discharge. Cox modeling was used to determine the association between medication use categories and rates of death or myocardial infarction through 2 years after adjustment for clinical factors, the number of indicated medications, and treatment propensity.Rates of use of antiplatelet agents and lipid-lowering agents were high at discharge and at 1 year, but use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was suboptimal. There was a stepwise association between medication use at discharge and patient outcomes (p for trend = 0.014). Patients taking 50% or less of indicated medications at discharge had a significantly higher 2-year rate of death or myocardial infarction (8.0% versus 4.2%; adjusted hazard ratio, 1.69; 95% confidence interval, 1.12 to 2.55; p = 0.013) than those taking all indicated medications.Greater use of indicated secondary prevention medications after coronary artery bypass graft surgery is associated with a lower 2-year rate of death or myocardial infarction. These data underscore the importance of appropriate secondary prevention measures to improve long-term clinical outcomes after coronary artery bypass graft surgery.

    View details for DOI 10.1016/j.athoracsur.2006.10.046

    View details for Web of Science ID 000244648100016

    View details for PubMedID 17307447

  • Creatine kinase-MB elevation after coronary artery bypass grafting surgery in patients with non-ST-segment elevation acute coronary syndromes predict worse outcomes: results from four large clinical trials EUROPEAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Kilaru, R., Alexander, J. H., Van de Werf, F., Califf, R. M., Simoons, M. L., Topol, E. J., Harrington, R. A. 2007; 28 (4): 425-432

    Abstract

    To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery.This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, >1-3, >3-5, >5-10, and>10x the upper limit of normal measured at the local lab (P<0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure.CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.

    View details for DOI 10.1093/eurheartj/ehl483

    View details for Web of Science ID 000245177000010

    View details for PubMedID 17267458

  • Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cantor, W. J., Mahaffey, K. W., Huang, Z., Das, P., Gulba, D. C., Glezer, S., Gallo, R., Ducas, J., Cohen, M., Antman, E. M., Langer, A., Kleiman, N. S., White, H. D., Chisholm, R. J., Harrington, R. A., Ferguson, J. J., Califf, R. M., Goodman, S. G. 2007; 69 (1): 73-83

    Abstract

    Our objective was to analyze the impact of arterial access site, sheath size, timing of sheath removal, and use of access site closure devices on high-risk patients with acute coronary syndromes (ACS).In the SYNERGY trial, 9,978 patients with ACS were randomly assigned to receive enoxaparin or unfractionated heparin.This analysis includes 9,404 patients for whom sheath access information was obtained for the first PCI procedure or diagnostic catheterization. Comparisons of baseline, angiographic, and procedural characteristics were carried out according to access site and sheath size.Overall, 9,404 (94%) patients underwent angiography at a median of 21 hr (25th and 75th percentiles: 5, 42) and 4,687 (50%) underwent PCI at a median of 23 hr (6,49) of enrollment. The access site was femoral for 94.9% of cases, radial for 4.4%, and brachial for 0.7%. Radial access was associated with fewer transfusions than femoral access (0.9% vs. 4.8%, P=0.007). For femoral access, the rates of noncoronary artery bypass grafting (CABG)-related TIMI major bleeding by sheath size was 1.5% for 4 or 5 French (Fr), 1.6% for 6 Fr, 3.3% for 7 Fr, and 3.8% for >or=8 Fr (P<0.0001). After adjustment for baseline characteristics, femoral access site, larger sheath size, and delayed sheath removal were independent predictors of need for transfusion.Smaller sheaths, radial access, and timely sheath removal may mitigate the bleeding risk associated with potent antithrombotic/platelet therapy and early catheterization.

    View details for DOI 10.1002/ccd.20897

    View details for Web of Science ID 000243330300015

    View details for PubMedID 17139670

  • A comparison of acute coronary syndrome care at academic and nonacademic hospitals AMERICAN JOURNAL OF MEDICINE Patel, M. R., Chen, A. Y., Roe, M. T., Ohman, E. M., Newby, L. K., Harrington, R. A., Smith, S. C., Gibler, W. B., Calvin, J. E., Peterson, E. D. 2007; 120 (1): 40-46

    Abstract

    Although adherence to guidelines recommendations is assumed to be more difficult for nonacademic community hospitals, patterns of adherence have not been evaluated by hospital type. We sought to identify hospital characteristics associated with high levels of adherence in order to gain insight into successful processes of care.From January 2001 through March 2004, we analyzed data from 86,042 patients in the CRUSADE Initiative with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) defined by positive cardiac markers or ischemic ST-segment changes. Academic sites were defined by Council of Teaching Hospital affiliation in the American Hospital Association database. Adherence was determined for each hospital based on guidelines recommendations for the use of 4 acute (<24 hrs) and 5 discharge therapies in patients without contraindications. Multivariable modeling was used to standardize hospital estimates for patient characteristics and control for clustering within centers.A total of 60,285 patients were admitted to nonacademic hospitals (n=355), and 25,757 were admitted to academic hospitals (n=125). Academic hospitals were larger (median 500 vs 268 beds, P <.001) and more often had bypass services (88% vs 60%, P <.001). Composite adherence to recommended therapies was slightly higher at academic vs. nonacademic hospitals (median 77.8% vs 73.7%, P <0.01), and variance in individual hospital performance was greater among nonacademic sites. Nonacademic hospitals accounted for 15 of the 20 highest performing sites and 19 of the 20 lowest performing sites. In-hospital clinical outcomes, including cardiogenic shock, stroke, and death were similar for patients admitted to both types of hospital.Adherence to American College of Cardiology and American Heart Association (ACC/AHA) guidelines for NSTE ACS care at academic hospitals is slightly higher than at nonacademic hospitals; however there is significant room for improvement within both systems. The larger performance variation in care among nonacademic hospitals highlights the need for continued emphasis on consistent care processes.

    View details for DOI 10.1016/j.amjmed.2006.10.008

    View details for Web of Science ID 000243309000010

    View details for PubMedID 17208078

  • Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial AMERICAN HEART JOURNAL White, H. D., Kleiman, N. S., Mahaffey, K. W., Lokhnygina, Y., Pieper, K. S., Chiswell, K., Cohen, M., Harrington, R. A., Chew, D. P., Petersen, J. L., Berdan, L. G., Aylward, P. E., Nessel, C. C., Ferguson, J. J., Califf, R. M. 2006; 152 (6): 1042-1050

    Abstract

    Enoxaparin reduces ischemic events more effectively than unfractionated heparin (UFH) in patients treated conservatively for non-ST-segment elevation acute coronary syndrome. The SYNERGY trial compared these agents in high-risk patients undergoing early invasive treatment. Enoxaparin was noninferior to UFH for the 30-day primary end point of death/myocardial infarction (MI), but modestly increased bleeding.This article compares the outcomes of the 4687 SYNERGY patients (47%) undergoing percutaneous coronary intervention, who were randomized to receive enoxaparin or UFH. Antithrombotic therapy was administered prerandomization in 78%. Crossover (usually in the catheterization laboratory) to the alternative antithrombotic occurred in 14.6% of enoxaparin patients and 2.9% of UFH-treated patients (P < .0001). Stenting was performed in 86.3%. Abrupt vessel closure occurred in 1.3% of enoxaparin patients and 1.7% of UFH-treated patients (P = .318). The rates of death/MI were similar at 30 days (13.1% with enoxaparin vs 14.2% with UFH, P = .289). GUSTO severe bleeding occurred with similar frequency in both groups (1.5% vs 1.6%, P = .688). TIMI major bleeding was more common with enoxaparin (3.7% vs 2.5% with UFH, P = .028). Transfusions were more frequent with enoxaparin than with UFH (6.8% vs 5.4%, P = .047). TIMI major bleeding increased with crossover from enoxaparin to UFH (from 3.7% to 7.8%) and from UFH to enoxaparin (from 2.5% to 8.6%). Statistical adjustment to model reasons for crossover did not affect the overall safety and efficacy outcomes.In high-risk patients undergoing early percutaneous coronary intervention for acute coronary syndrome, enoxaparin avoids the need for monitoring and achieves similar effectiveness to UFH but is associated with more bleeding.

    View details for DOI 10.1016/j.ahj.2006.08.002

    View details for Web of Science ID 000243110400008

    View details for PubMedID 17161049

  • The influence of peripheral arterial disease on outcomes - A pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Saw, J., Bhatt, D. L., Moliterno, D. J., Brener, S. J., Steinhubl, S. R., Lincoff, A. M., Tcheng, J. E., Harrington, R. A., Simoons, M., Hu, T., Sheikh, M. A., Kereiakes, D. J., Topol, E. J. 2006; 48 (8): 1567-1572

    Abstract

    We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI).A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes.We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events.In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013).The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.

    View details for DOI 10.1016/j.jacc.2006.03.067

    View details for Web of Science ID 000241414600007

    View details for PubMedID 17045889

  • Recent trends in the care of patients with non- ST-segment elevation acute coronary syndromes - Insights from the CRUSADE initiative ARCHIVES OF INTERNAL MEDICINE Mehta, R. H., Roe, M. T., Chen, A. Y., Lytle, B. L., Pollack, C. V., Brindis, R. G., Smith, S. C., Harrington, R. A., Fintel, D., Fraulo, E. S., Califf, R. M., Gibler, W. B., Ohman, E. M., Peterson, E. D. 2006; 166 (18): 2027-2034

    Abstract

    The extent to which national health quality improvement initiatives have altered reported treatment gaps among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unknown. We sought to determine recent trends in adherence to guideline-based therapies for NSTE ACS.We evaluated the treatment of patients with high-risk (positive cardiac markers and/or ischemic ST-segment changes) NSTE ACS enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA (American College of Cardiology/American Heart Association) Guidelines (CRUSADE) Quality Improvement Initiative from 2002 through 2004 (a total of 113 595 patients over 11 calendar quarters). We analyzed adherence to guideline-recommended therapies, including medications used in the acute care period (<24 hours after presentation), invasive procedures, in-hospital outcomes, and discharge therapies and interventions.The use of each class I guideline recommendation, as well as overall adherence to the guidelines, improved significantly (P<.001) during the study period. In the acute care setting, the use of antiplatelet agents increased by 5% and beta-blockers by 12%; at hospital discharge, the use of antiplatelet agents increased by 3% and beta-blockers by 8%. Heparin use in the acute care period increased by 6%, largely owing to a 9% increase in the use of low-molecular-weight heparin. Use of glycoprotein IIb/IIIa inhibitors in the acute care period also increased by more than 13%. At discharge, clopidogrel use increased by 22%, lipid-lowering agents by 11%, and angiotensin-converting enzyme inhibitors by 5%. While adherence improved, many patients still failed to receive 100% indicated treatments at the end of the study period.During the 4 years since the initial release of the ACC/AHA guidelines for NSTE ACS, adherence to class I recommendations has significantly improved among hospitals participating in CRUSADE. Still, further improvements are needed for optimal implementation of the these guidelines.

    View details for Web of Science ID 000241057300015

    View details for PubMedID 17030838

  • Clinical correlates of long-term mortality after percutaneous interventions of saphenous vein grafts AMERICAN HEART JOURNAL Mehta, R. H., Honeycutt, E., Shaw, L. K., Glower, D., Harrington, R. A., Sketch, M. H. 2006; 152 (4): 801-806

    Abstract

    Increasing number of patients undergo percutaneous intervention of saphenous vein grafts (SVGs). However, the clinical factors associated with long-term mortality after SVG interventions are currently less known. Accordingly, the goal of present study was to evaluate clinical correlates of long-term mortality and to develop a simple bedside tool for risk stratification in patients undergoing SVG interventions.We analyzed 1019 patients undergoing SVG interventions from the Duke Cardiovascular Disease Database (1986-2003). Cox proportional hazards model was used to identify baseline variables associated with long-term mortality, and the model variables were then used to construct a nomogram for survival probability at 4 years.At a median follow-up of 4 years, 24% of those undergoing SVG interventions died (interquartile range 2-7 years). Independent correlates of death at follow-up on multivariable analysis included presenting heart rate (hazard ratio [HR] 1.02, 95% CI 1.01-1.03), diabetes (HR 1.73, 95% CI 1.37-2.18), presenting heart failure (HR 1.62, 95% CI 1.27-2.06), age (per 10-year increase, HR 1.29, 95% CI 1.13-1.46), peripheral vascular disease (HR 1.59, 95% CI 1.23-2.04), renal insufficiency (HR 2.01, 95% CI 1.36-2.97), patent internal mammary graft (HR 0.67, 95% CI 0.53-0.86), body mass index < or = 25 kg/m2 (HR 0.91, 95% CI 0.85-0.97), carotid bruit (HR 1.44, 95% CI 1.12-1.85), S3 ventricular gallop (HR 1.83, 95% CI 1.11-3.03), and hypertension (HR 1.38, 95% CI 1.04-1.83) (c-index 0.83). Bootstrap validation confirmed excellent internal validity of the model (mean c-index 0.84, 95% CI 0.80-0.85).Long-term survival after SVG intervention is poor, with one fourth of patients dying at median follow-up of 4 years. The nomogram developed using the model variables provides a method for clinicians to advise patients undergoing SVG interventions regarding their long-term prognosis, thereby enhancing discharge and long-term follow-up planning and setting up of realistic expectations.

    View details for DOI 10.1016/j.ahj.2006.06.004

    View details for Web of Science ID 000241719300041

    View details for PubMedID 16996861

  • Prevalence, predictors, and outcomes of patients with non-ST-segment elevation myocardial infarction and insignificant coronary artery disease: Results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) initiative AMERICAN HEART JOURNAL Patel, M. R., Chen, A. Y., Peterson, E. D., Newby, L. K., Pollack, C. V., Brindis, R. G., Gibson, C. M., Kleiman, N. S., Saucedo, J. F., Bhatt, D. L., Gibler, W. B., Ohman, E. M., Harrington, R. A., Roe, M. T. 2006; 152 (4): 641-647

    Abstract

    Unlike ST-segment elevation myocardial infarction, the degree of stenosis and physiology of ischemia varies in patients with non-ST-segment elevation myocardial infarction (NSTEMI). The prevalence, predictors, and outcomes of patients with NSTEMI who lack significant epicardial coronary artery disease (CAD) in routine clinical practice remain poorly characterized. We sought to determine the prevalence, predictors, and outcomes of patients with NSTEMI and insignificant CAD.We analyzed 38301 patients with NSTEMI in the CRUSADE quality improvement initiative who underwent cardiac catheterization to determine the prevalence and factors associated with insignificant CAD (all coronary stenoses <50%) and inhospital outcomes for patients with and without CAD. A multivariable model was used to determine the factors associated with insignificant CAD.A total of 3306 (8.6%) of 38301 patients had insignificant CAD. The strongest multivariable predictors of insignificant CAD were female sex (odds ratio 2.8, 95% CI 2.6-3.1), younger age (odds ratio per 10-year decrease 1.5, 95% CI 1.5-1.6), and lack of current/recent smoking (odds ratio 1.9, 95% CI 1.7-2.0). Inhospital rates of death were 0.65% for patients with insignificant CAD compared with 2.36% for patients with CAD (P < .0001).Insignificant CAD is present in 9% of patients with NSTEMI and is associated with a low incidence of adverse outcomes. The strongest predictors of insignificant CAD are female sex and younger age. These findings underscore the need for research to understand the pathophysiology of myocardial infarction in this population.

    View details for DOI 10.1016/j.ahj.2006.02.035

    View details for Web of Science ID 000241719300007

    View details for PubMedID 16996828

  • Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention NEW ENGLAND JOURNAL OF MEDICINE Montalescot, G., White, H. D., Gallo, R., Cohen, M., Steg, P. G., Aylward, P. E., Bode, C., Chiariello, M., King, S. B., Harrington, R. A., Desmet, W. J., Macaya, C., Steinhubl, S. R. 2006; 355 (10): 1006-1017

    Abstract

    Despite its limitations, unfractionated heparin has been the standard anticoagulant used during percutaneous coronary intervention (PCI). Several small studies have suggested that intravenous enoxaparin may be a safe and effective alternative. Our primary aim was to assess the safety of enoxaparin as compared with that of unfractionated heparin in elective PCI.In this prospective, open-label, multicenter, randomized trial, we randomly assigned 3528 patients with PCI to receive enoxaparin (0.5 or 0.75 mg per kilogram of body weight) or unfractionated heparin adjusted for activated clotting time, stratified according to the use or nonuse of glycoprotein IIb/IIIa inhibitors. The primary end point was the incidence of major or minor bleeding that was not related to coronary-artery bypass grafting. The main secondary end point was the percentage of patients in whom the target anticoagulation levels were reached.Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non-CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, -2.6; 95% confidence interval [CI], -4.7 to -0.6; P=0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, -2.0; 95% CI, -4.0 to 0.0; P=0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P<0.001).In elective PCI, a single intravenous bolus of 0.5 mg of enoxaparin per kilogram is associated with reduced rates of bleeding, and a dose of 0.75 mg per kilogram yields rates similar to those for unfractionated heparin, with more predictable anticoagulation levels. The trial was not large enough to provide a definitive comparison of efficacy in the prevention of ischemic events. (ClinicalTrials.gov number, NCT00077844 [ClinicalTrials.gov].).

    View details for Web of Science ID 000240273300006

    View details for PubMedID 16957147

  • Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Chen, A. Y., Pollack, C. V., Roe, M. T., Zalenski, R. J., Clements, E. A., Gibler, W. B., Ohman, E. M., Harrington, R. A., Peterson, E. D. 2006; 98 (5): 624-627

    Abstract

    In the case of non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), the acute use of certain antiplatelet agents is complicated by concerns about perioperative bleeding risks in patients requiring coronary artery bypass grafting (CABG) during the index hospitalization. As a result, clinicians often withhold potentially useful agents, such as clopidogrel, before determining patients' coronary anatomy. An accurate predictive model could allow for a better balance of this safety concern with the demonstrated benefits of agents such as clopidogrel. To create an accurate decision-making tool that would assess, at hospital presentation, the need for CABG in patients with NSTE-ACSs, we studied 61,974 high-risk patients with NSTE-ACS admitted to 311 CABG-capable hospitals participating in Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) from 2001 to 2003. A total of 8,395 patients (14%) underwent CABG during their initial hospital stay. A multivariate model was developed and identified 13 presenting clinical characteristics significantly associated with the likelihood of CABG (previous CABG, male gender, previous heart failure, diabetes, hyperlipidemia, renal insufficiency, ST depression and transient ST elevation, age > or = 75 years, previous percutaneous coronary intervention, family history of coronary artery disease, hypertension, trends in CABG rates, and previous stroke). This model had only modest predictive accuracy and calibration (c-index = 0.67). In conclusion, although certain presenting clinical features are associated with an increased likelihood of CABG in patients with NSTE-ACSs during the index hospitalization, it remains difficult to reliably identify, before diagnostic angiography, those who will subsequently undergo surgical revascularization.

    View details for DOI 10.1016/j.amjcard.2006.03.040

    View details for Web of Science ID 000240324300012

    View details for PubMedID 16923449

  • Provisional glycoprotein IIb/IIIa blockade in a randomized investigation of bivalirudin versus heparin plus planned glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: Predictors and outcome in the Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE)-2 trial AMERICAN HEART JOURNAL Exaire, J. E., Butman, S. M., Ebrahimi, R., Kleiman, N. S., Harrington, R. A., Schweiger, M. J., Bittl, J. A., Wolski, K., Topol, E. J., Lincoff, A. M. 2006; 152 (1): 157-162

    Abstract

    The REPLACE-2 trial demonstrated the noninferiority of bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) blockade as compared with heparin plus planned GPIIb/IIIa blockade among patients undergoing percutaneous coronary revascularization. Provisional drug was used in 374 (6%) of the 6010 patients. We sought to analyze the predictors for provisional drug use and to assess the outcomes in this cohort.Outcome among the 5.2% of patients in the heparin plus GPIIb/IIIa blockade group and the 7.2% of patients in the bivalirudin group who received provisional placebo or GPIIb/IIIa inhibitor, respectively, was compared against patients without provisional drug use and between randomized arms. Multivariate models identified predictors of provisional drug use and outcome at 30 days, 6 months, and 1 year.Myocardial infarction, repeat revascularization, and bleeding events occurred more frequently among patients who required provisional drug than those who did not, but there were no differences in 1-year mortality. Ischemic and hemorrhagic end points occurred at similar rates among patients receiving provisional drug in either the heparin plus GPIIb/IIIa group compared with the bivalirudin group. Independent predictors of provisional drug use were randomization to bivalirudin, recent infarction, multilesion intervention, impaired pretreatment coronary flow, and lesion complexity. Provisional drug use, but not randomization to bivalirudin, independently predicted 30-day and 6-month ischemic events.Provisional administration of a GPIIb/IIIa inhibitor is associated with more frequent ischemic and bleeding events, reflecting the procedural complications that led to the use of provisional drug. The proportion of bivalirudin-treated patients who will require provisional GPIIb/IIIa blockade, however, is not large enough to have a significant deleterious impact on the overall incidence of ischemic end points or to invalidate the strategy of bivalirudin plus provisional GPIIb/IIIa blockade.

    View details for DOI 10.1016/j.ahj.2005.09.004

    View details for Web of Science ID 000239060200026

    View details for PubMedID 16824849

  • Low-molecular-weight heparin compared with unfractionated heparin for patients with non-ST-segment elevation acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE initiative JOURNAL OF THROMBOSIS AND THROMBOLYSIS Singh, K. P., Roe, M. T., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., Goodman, S. G., Harrington, R. A., Smith, S. C., Gibler, W. B., Ohman, E. M., Pollack, C. V. 2006; 21 (3): 211-220

    Abstract

    Both heparin and glycoprotein (GP) IIb/IIIa inhibitor therapy and early invasive management strategies are recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the treatment of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, controversy exists about which form of heparin-unfractionated (UF) or low-molecular-weight (LMW)-is preferable. We sought to compare the efficacy and safety of these treatment strategies in a large contemporary population of patients with NSTE ACS.Using data from the CRUSADE Initiative, we evaluated LMWH and UFH in high-risk NSTE ACS patients (positive cardiac markers and/or ischemic ST-segment changes) who had received early (< 24 hours) GP IIb/IIIa inhibitor therapy and underwent early invasive management. In-hospital outcomes were compared among treatment groups.From a total of 11,358 patients treated at 407 hospitals in the US from January 2002-June 2003, 6881 (60.6%) received UFH and 4477 (39.4%) received LMWH. Patients treated with UFH were more often admitted to a cardiology inpatient service (73.6% vs. 65.5%, P < 0.0001) and more frequently underwent diagnostic catheterization (91.8% vs. 85.9%, P < 0.0001) and percutaneous coronary intervention (PCI) (69.7% vs. 56.9%, P < 0.0001) than patients treated with LMWH. The point estimate of the adjusted risk of in-hospital death or reinfarction was slightly lower among patients treated with LMWH (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.67-0.99) and the risk of red blood cell transfusion was similar (OR 1.01, 95% CI 0.89-1.15). Among patients who underwent PCI within 48 hours, adjusted rates of death (OR 1.14, 95% CI 0.71-1.85), death or reinfarction (OR 0.93, 0.67-1.31), and transfusion (OR 1.16, 0.89-1.50) were similar. Patients who underwent PCI more than 48 hours into hospitalization had reduced rates of death (OR 0.64, 0.46-0.88), death or reinfarction (OR 0.57, 0.44-0.73), and transfusion (OR 0.66, 0.52-0.84).In routine clinical practice, patients treated with GP IIb/IIIa inhibitors have slightly improved outcomes and similar bleeding risks with LMWH than with UFH. These findings are consistent with current ACC/AHA guidelines but raise important questions about the safety and effectiveness of antithrombotic therapy in real-world clinical practice. Using data from the CRUSADE Initiative, we evaluated low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in high-risk patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who received early (<24 hours) glycoprotein (GP) IIb/IIIa inhibitors and early invasive management. In-hospital outcomes were compared among treatment groups. LMWH was associated with slightly improved clinical outcomes and similar rates of transfusion compared with UFH. Our results support the current ACC/AHA guidelines recommendations but raise concerns about the safety and efficacy of UFH in the setting of background use of upstream GP IIb/IIIa inhibitors for patients with NSTE ACS in routine clinical practice.

    View details for DOI 10.1007/s11239-006-5708-0

    View details for Web of Science ID 000237437200001

    View details for PubMedID 16683212

  • Statin use and sex-specific stroke outcomes in patients with vascular disease STROKE Bushnell, C. D., Griffin, J., Newby, L. K., Goldstein, L. B., Mahaffey, K. W., Graffagnino, C. A., Harrington, R. A., White, H. D., Simes, R. J., Califf, R. M., Topol, E. J., Easton, J. D. 2006; 37 (6): 1427-1431

    Abstract

    Although statins reduce the risk of stroke in patients with coronary heart disease, possible differing effects of statins on stroke outcomes based on sex remain uncertain. We investigated the relationships between statin use and sex-specific stroke incidence, severity, and mortality.Data from 3 trials of oral glycoprotein IIb/IIIa inhibitors (first and second Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes [SYMPHONY] and Blockade of the glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion [BRAVO]) were pooled and stroke outcomes compared among 8191 baseline statin users versus 14,752 nonusers. Time-to-event data were modeled with proportional hazards regression. Stroke severity was assessed retrospectively with the Canadian Neurological Scale (CNS) based on records with scoreable neurological examinations.A total of 217 subjects had strokes (0.95%). Statin users had a lower risk of stroke in unadjusted (hazard ratio [HR], 0.69; 95% CI, 0.51 to 0.92) and risk-adjusted models (HR, 0.72; 95% CI, 0.53 to 0.97). There was no difference in stroke mortality with statin use (P=0.8). CNS scores could be assigned to 106 of the subjects, with no difference in severity among statin users and nonusers (median CNS=10.5 in users versus CNS=9.75 in nonusers; P=0.14). Women had more severe strokes than men (median CNS=10.5 in men versus 9.5 in women; Poisson regression P=0.035). Women had more severe strokes after adjustment for statin use (P=0.03) and the combination of statin use, atrial fibrillation, and age (P=0.03).In patients included in these clinical trials of oral glycoprotein IIb/IIIa inhibitors, statin use is associated with a reduced risk of stroke but not severity or mortality. Women had more severe strokes than men, a difference that was not explained by baseline characteristics or statin use.

    View details for DOI 10.1161/01.STR.0000221315.60282.ca

    View details for Web of Science ID 000237925000027

    View details for PubMedID 16645137

  • The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Roe, M. T., Peterson, E. D., Newby, L. K., Chen, A. Y., Pollack, C. V., Brindis, R. G., Harrington, R. A., Christenson, R. H., Smith, S. C., Califf, R. M., Braunwald, E., Gibler, W. B., Ohman, E. M. 2006; 151 (6): 1205-1213

    Abstract

    Practice guidelines for patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) recommend targeting evidence-based therapies for the highest-risk patients. We characterized guideline adherence for NSTE ACS by risk status.We analyzed inhospital treatments and outcomes for 77760 patients with NSTE ACS (ischemic ST-segment changes and/or positive cardiac markers) included in the CRUSADE initiative from January 2001 to September 2003 at 457 US hospitals. Compliance with the American College of Cardiology/American Heart Association Class guideline recommendations for NSTE ACS was evaluated in subgroups of eligible patients without listed contraindications at increased risk for mortality and among risk categories designated by an adapted version of the PURSUIT risk model designed to predict inhospital mortality.Inhospital mortality was increased in patients with diabetes mellitus (5.8% vs 4.3%), renal insufficiency (10.0% vs 3.9%), signs of congestive heart failure on presentation (10.6% vs 3.1%), and age > or = 75 years (8.6% vs 2.7%), compared with patients without these features. Use of guideline-recommended acute medications, invasive cardiac procedures, and discharge medications and interventions was significantly lower in patients with these high-risk features. Patients designated as high-risk for inhospital mortality were less likely to be treated with guideline-recommended therapies compared with low-risk and moderate-risk patients.Patients with NSTE ACS with the highest risk of mortality are less likely to receive guideline-recommended therapies and interventions. These findings highlight the need to clarify guideline recommendations for high-risk patients and to develop novel quality improvement approaches that target undertreated subgroups of patients with NSTE ACS.

    View details for DOI 10.1016/j.ahj.2005.08.006

    View details for Web of Science ID 000238614600010

    View details for PubMedID 16781220

  • Association between hospital process performance and outcomes among patients with acute coronary syndromes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Peterson, E. D., Roe, M. T., Mulgund, J., DeLong, E. R., Lytle, B. L., Brindis, R. G., Smith, S. C., Pollack, C. V., Newby, L. K., Harrington, R. A., Gibler, W. B., Ohman, E. M. 2006; 295 (16): 1912-1920

    Abstract

    Selected care processes are increasingly being used to measure hospital quality; however, data regarding the association between hospital process performance and outcomes are limited.To evaluate contemporary care practices consistent with the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations, to examine how hospital performance varied among centers, to identify characteristics predictive of higher guideline adherence, and to assess whether hospitals' overall composite guideline adherence was associated with observed and risk-adjusted in-hospital mortality rates.An observational analysis of hospital care in 350 academic and nonacademic US centers of 64,775 patients enrolled in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative between January 1, 2001, and September 30, 2003, presenting with chest pain and positive electrocardiographic changes or cardiac biomarkers consistent with non-ST-segment elevation acute coronary syndrome (ACS).Use of 9 ACC/AHA class I guideline-recommended treatments and the correlation among hospitals' use of individual care processes as well as overall composite adherence rates.Overall, the 9 ACC/AHA guideline-recommended treatments were adhered to in 74% of eligible instances. There was modest correlation in hospital performance among the individual ACS process metrics. However, composite adherence performance varied widely (median [interquartile range] composite adherence scores from lowest to highest hospital quartiles, 63% [59%-66%] vs 82% [80%-84%]). Composite guideline adherence rate was significantly associated with in-hospital mortality, with observed mortality rates decreasing from 6.31% for the lowest adherence quartile to 4.15% for the highest adherence quartile (P<.001). After risk adjustment, every 10% increase in composite adherence at a hospital was associated with an analogous 10% decrease in its patients' likelihood of in-hospital mortality (adjusted odds ratio, 0.90; 95% confidence interval, 0.84-0.97; P<.001).A significant association between care process and outcomes was found, supporting the use of broad, guideline-based performance metrics as a means of assessing and helping improve hospital quality.

    View details for Web of Science ID 000237059200026

    View details for PubMedID 16639050

  • Clopidogrel to treat patients with non-ST-segment elevation acute coronary syndromes after hospital discharge ARCHIVES OF INTERNAL MEDICINE Tricoci, P., Roe, M. T., Mulgund, J., Newby, L. K., Smith, S. C., Pollack, C. V., Fintel, D. J., Cannon, C. P., Bhatt, D. L., Gibler, W. B., Ohman, E. M., Peterson, E. D., Harrington, R. A. 2006; 166 (7): 806-811

    Abstract

    Clopidogrel added to aspirin improved outcomes after hospitalization in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, regardless of in-hospital treatment approach. The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for treating NSTE ACS thus recommend prescribing clopidogrel plus aspirin at discharge for all patients, not just for those undergoing percutaneous coronary intervention (PCI).We studied 61 052 patients with high-risk NSTE ACS (defined as the presence of positive cardiac markers and/or ischemic ST-segment changes) from January 2002 through December 2003 at 461 US hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative. We evaluated temporal trends of clopidogrel use at discharge since the ACC/AHA 2002 Guidelines update and examined variables associated with clopidogrel use in patients who did not undergo PCI.A total of 34 319 patients (56.2%) received clopidogrel when they were discharged from the hospital. Among patients who did not undergo PCI, variables associated with receiving clopidogrel at discharge included prior PCI, coronary artery bypass grafting (CABG), stroke, or myocardial infarction; hypercholesterolemia; elevated cardiac markers; and cardiology inpatient care. By late 2003, 96.3% of patients who underwent PCI received clopidogrel at discharge, compared with 42.8% of patients who did not undergo cardiac catheterization and 23.5% of the patients who underwent CABG, although clopidogrel prescription at discharge increased in each of these treatment groups from 2002 to 2003.Since release of the ACC/AHA Guidelines recommendations for treatment of NSTE ACS, prescription of clopidogrel at hospital discharge in patients with NSTE ACS who are treated with medical therapy alone and in those who undergo CABG has increased, but most of these patients still do not receive clopidogrel at discharge.

    View details for Web of Science ID 000236679800015

    View details for PubMedID 16606819

  • Initial experience with an intravenous P2Y(12) platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial AMERICAN HEART JOURNAL Greenbaum, A. B., Grines, C. L., Bittl, J. A., Becker, R. C., Kereiakes, D. J., Gilchrist, I. C., Clegg, J., Stankowski, J. E., Grogan, D. R., Harrington, R. A., Emanuelsson, H., Weaver, W. D. 2006; 151 (3)

    Abstract

    Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI.In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times.Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor.This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.

    View details for DOI 10.1016/j.ahj.2005.11.014

    View details for Web of Science ID 000236353900020

    View details for PubMedID 16504633

  • Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes EUROPEAN HEART JOURNAL Orlandini, A., Diaz, R., Wojdyla, D., Pieper, K., Van de Werf, F., Granger, C. B., Harrington, R. A., Boersma, E., Califf, R. M., ARMSTRONG, P., White, H., Simes, J., PAOLASSO, E. 2006; 27 (5): 527-533

    Abstract

    To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI).A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%).An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.

    View details for DOI 10.1093/eurheartj/ehi701

    View details for Web of Science ID 000235605100008

    View details for PubMedID 16410369

  • A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Mahaffey, K. W., Moliterno, D. J., Lincof, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Harrington, R. A. 2006; 47 (4): 809-816

    Abstract

    The goal of this study was to determine the association between Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding and clinical outcomes.There are limited data on the relative utility of either scale at predicting clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes (ACS).Pooled data from two randomized trials of patients with ACS (n = 15,454) were analyzed to determine the association between TIMI and GUSTO bleeding and 30-day and 6-month death/myocardial infarction (MI) using Cox proportional hazards modeling that included bleeding as a time-dependent covariate.There was a stepwise increase in the adjusted hazard of 30-day death/MI with worsening GUSTO bleeding (hazard ratio [95% confidence interval], GUSTO mild 1.20 [1.05 to 1.37]; moderate 3.28 [2.88 to 3.73]; severe 5.57 [4.33 to 7.17]), and an increased risk with all three levels of TIMI bleeding (TIMI minimal 1.84 [1.63 to 2.08]; TIMI minor 1.64 [1.31 to 2.04]; major 1.45 [1.23 to 1.70]). When both bleeding scales were included in the same model, the risk with GUSTO bleeding persisted; however, the association between TIMI bleeding and outcome was no longer significant.Both scales identify ACS patients with bleeding complications at risk for adverse outcomes. In a model that included both definitions, the risk with GUSTO bleeding persisted while the risk with TIMI bleeding did not. This suggests that bleeding assessed with clinical criteria is more important than that assessed by laboratory criteria in terms of outcomes. Future clinical trials should consider using a combination of the GUSTO bleeding scale and the need for transfusion to assess bleeding complications.

    View details for DOI 10.1016/j.jacc.2005.09.060

    View details for Web of Science ID 000235422900021

    View details for PubMedID 16487850

  • Cardiac tamponade in the fibrinolytic era: Analysis of > 100000 patients with ST-segment elevation myocardial infarction AMERICAN HEART JOURNAL Patel, M. R., Meine, T. J., Lindblad, L., Griffin, J., Granger, C. B., Becker, R. C., Van de Werf, F., White, H., Califf, R. M., Harrington, R. A. 2006; 151 (2): 316-322

    Abstract

    Cardiac tamponade is a life-threatening complication of acute myocardial infarction (MI). Data on the incidence, risk factors, and outcome of tamponade in patients with acute MI in the fibrinolytic era are limited.Data from a combined clinical trials database of ST-segment elevation MI were used to evaluate the incidence of cardiac tamponade, baseline characteristics, and outcomes in patients with and without tamponade. Univariable and multivariable analyses assessed the relationship between patient characteristics and tamponade development, and the influence of tamponade on mortality.Of 102,060 patients, 865 (0.85%) developed isolated cardiac tamponade during initial hospitalization. Patients with tamponade were older (median 71.9 vs 61.6 years, P < .001), were more likely to be female (54.0% vs 25.1%, P < .001), were more likely to have an anterior MI (61.9% vs 41.5%, P < .001), and had a longer time from symptom onset to reperfusion (median 3.5 vs 2.8 hours, P < .001) than those without tamponade. Multivariable analyses identified increasing age, anterior MI location, female sex, and increased time from symptom onset to treatment as significant independent predictors of tamponade. Patients with tamponade had an increased death rate at 30 days (hazard ratio 7.9, 95% CI 4.7-13.5).Cardiac tamponade occurs in < 1% of patients with fibrinolytic-treated acute MI and is associated with increased 30-day mortality. Time from symptom onset to treatment strongly predicted the development of tamponade, underscoring the need for continued efforts to increase speed to treatment in acute MI.

    View details for DOI 10.1016/j.ahj.2005.04.014

    View details for Web of Science ID 000235521100008

    View details for PubMedID 16442893

  • Frequency and clinical implications of discordant creatine kinase-MB and troponin measurements in acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Newby, L. K., Roe, M. T., Chen, A. Y., Ohman, E. M., Christenson, R. H., Pollack, C. V., Hoekstra, J. W., Peacock, W. F., Harrington, R. A., Jesse, R. L., Gibler, W. B., Peterson, E. D. 2006; 47 (2): 312-318

    Abstract

    We sought to evaluate the association between discordant cardiac marker results and in-hospital mortality and treatment patterns in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS).Creatine kinase-MB (CK-MB) and cardiac troponins (cTn) are often measured concurrently in patients with NSTE ACS. The significance of discordant CK-MB and cTn results is unknown.Among 29,357 ACS patients in the CRUSADE initiative who had both CK-MB and cTn measured during the first 36 hours, we examined relationships of four marker combinations (CK-MB-/cTn-, CK-MB+/cTn-, CK-MB-/cTn+, and CK-MB+/cTn+) with mortality and American College of Cardiology/American Heart Association guidelines-recommended acute care.The CK-MB and cTn results were discordant in 28% of patients (CK-MB+/cTn-, 10%; CK-MB-/cTn+, 18%). In-hospital mortality was 2.7% among CK-MB-/cTn- patients; 3.0%, CK-MB+/cTn-; 4.5%, CK-MB-/cTn+; and 5.9%, CK-MB+/cTn+. After adjustment for other presenting risk factors, patients with CK-MB+/cTn- had a mortality odds ratio (OR) of 1.02 (95% confidence interval [CI] 0.75 to 1.38), those with CK-MB-/cTn+ had an OR of 1.15 (95% CI 0.86 to 1.54), and those with CK-MB+/cTn+ had an OR of 1.53 (95% CI 1.18 to 1.98). Despite variable risk, patients with CK-MB+/cTn- and CK-MB-/cTn+ were treated similarly with early antithrombotic agents and catheter-based interventions.Among patients with NSTE ACS, an elevated troponin level identifies patients at increased acute risk regardless of CK-MB status, but an isolated CK-MB+ status has limited prognostic value. Recognition of these risk differences may contribute to more appropriate early use of antithrombotic therapy and invasive management for all cTn+ patients.

    View details for DOI 10.1016/j.jacc.2005.08.062

    View details for Web of Science ID 000234667100007

    View details for PubMedID 16412853

  • Elevated creatine kinase-MB with normal creatine kinase predicts worse outcomes in patients with acute coronary syndromes: Results from 4 large clinical trials AMERICAN HEART JOURNAL Galla, J. M., Mahaffey, K. W., Sapp, S. K., Alexander, J. H., Roe, M. T., Ohman, E. M., Granger, C. B., Armstrong, P. W., Harrington, R. A., White, H. D., Simoons, M. L., Newby, L. K., Califf, R. M., Topol, E. J. 2006; 151 (1): 16-24

    Abstract

    The degree to which elevated creatine kinase (CK)-MB in the presence of normal CK is predictive of outcome is not well understood despite having been studied for decades. This analysis examined whether normal CK with elevated CK-MB in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) is an independent predictor of worse outcomes. A concomitant goal was to contribute insight to the debate over how patients with NSTE ACS should be managed.Data for 25,960 patients from the GUSTO IIb, PARAGON A and B, and PURSUIT trials were analyzed. Of these patients, 6402 were excluded from primary analysis because of missing (unmeasured) biomarkers. Patients with complete laboratory data (n = 19,558) were grouped by CK and CK-MB results. To confirm the primary analysis results, data from patients with missing biomarkers were used in an imputation model.Patients were categorized in 1 of 4 groups: normal CK + normal CK-MB; normal CK + elevated CK-MB; elevated CK + normal CK-MB; or elevated CK + elevated CK-MB. For the primary outcome, 180-day death, or myocardial infarction, Kaplan-Meier estimates were 14.9%, 20.8%, 14.5%, and 18.2%, respectively. Regardless of total CK, elevated CK-MB was associated with a 25% to 49% increased relative risk of worse outcomes. Findings from the analyses were verified by the multivariable model.CK-MB remains a reliable marker for myocardial necrosis and a strong predictor of worse prognosis. All patients with ACS should have CK-MB measurement to search for cardiac ischemia. Patients with elevated CK-MB should receive aggressive management commensurate with their increased risks.

    View details for DOI 10.1016/j.ahj.2005.01.045

    View details for Web of Science ID 000234485100003

    View details for PubMedID 16368286

  • Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery - PREVENT IV: A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Alexander, J. H., Hafley, G., Harrington, R., Peterson, E. D., Ferguson, T. B., Lorenz, T. J., Goyal, A., Gibson, M., Mack, M. J., Gennevois, D., Califf, R. M., Kouchoukos, N. T. 2005; 294 (19): 2446-2454

    Abstract

    Coronary artery bypass graft (CABG) surgery with autologous vein grafting is commonly performed. Progressive neointimal hyperplasia, however, contributes to considerable vein graft failure. Edifoligide is an oligonucleotide decoy that binds to and inhibits E2F transcription factors and thus may prevent neointimal hyperplasia and vein graft failure.To assess the efficacy and safety of pretreating vein grafts with edifoligide for patients undergoing CABG surgery.A phase 3 randomized, double-blind, placebo-controlled trial of 3014 patients undergoing primary CABG surgery with at least 2 planned saphenous vein grafts and without concomitant valve surgery, who were enrolled between August 2002 and October 2003 at 107 US sites.Vein grafts were treated ex vivo with either edifoligide or placebo in a pressure-mediated delivery system. The first 2400 patients enrolled were scheduled for 12- to 18-month follow-up angiography.The primary efficacy end point was angiographic vein graft failure (> or =75% vein graft stenosis) occurring 12 to 18 months after CABG surgery. Other end points included other angiographic variables, adverse events through 30 days, and major adverse cardiac events.A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829). Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80-1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64-1.08]; P = .16).Failure of at least 1 vein graft is quite common within 12 to 18 months after CABG surgery. Edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to determine whether edifoligide has delayed beneficial effects, to understand the mechanisms and clinical consequences of vein graft failure, and to improve the durability of CABG surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00042081.

    View details for Web of Science ID 000233277400023

    View details for PubMedID 16287955

  • Relation of early saphenous vein graft failure to outcomes following coronary artery bypass surgery AMERICAN JOURNAL OF CARDIOLOGY Halabi, A. R., Alexander, J. H., Shaw, L. K., Lorenz, T. J., Liao, L., Kong, D. F., Milano, C. A., Harrington, R. A., Smith, P. K. 2005; 96 (9): 1254-1259

    Abstract

    Up to 20% of saphenous vein grafts (SVGs) fail within 2 years of coronary artery bypass grafting (CABG). The long-term effects of early SVG failure on major clinical events remain undefined in contemporary patient populations. We sought to examine the relation between early SVG failure and long-term outcomes after CABG. Using the Duke Cardiovascular Databank, we examined baseline clinical and angiographic characteristics and clinical outcomes among patients who underwent catheterization 1 to 18 months after their first CABG from 1986 to 2004. Patients were classified on the basis of their worst SVG stenosis as having no (<25%), noncritical (25% to 74%), critical (75% to 99%), or occlusive (100%) SVG disease. Our primary outcome measure was the composite of death, myocardial infarction, or repeat revascularization after catheterization. Of 1,243 patients included in the analysis, 27.9% had no, 11.9% had noncritical, 20.8% had critical, and 39.3% had occlusive SVG disease. At 10 years, the corresponding adjusted composite event rates were 41.2%, 56.2%, 81.2%, and 67.1%, respectively (p <0.0001). Most events occurred immediately after catheterization in patients with critical and occlusive SVG disease and were primarily repeat revascularization. On multivariate analysis, critical, nonocclusive SVG disease was the strongest predictor of the composite outcome (hazard ratio 2.36, 95% confidence interval 2.00 to 2.79, p <0.0001). In conclusion, in contemporary clinical practice, early SVG failure is associated with worse long-term outcomes after CABG.

    View details for DOI 10.1016/j.amjcard.2005.06.067

    View details for Web of Science ID 000233343500016

    View details for PubMedID 16253593

  • Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Van de Werf, F., Mahaffey, K. W., Califf, R. M., Harrington, R. A. 2005; 96 (9): 1200-1206

    Abstract

    Bleeding is a complication of current therapies for acute coronary syndrome (ACS). No studies have examined the effect of bleeding events on clinical outcomes. We analyzed pooled data from 4 multicenter, randomized clinical trials of patients who had ACS (n = 26,452) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate. The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting. Of all the patients included, 27.6% had > or =1 bleeding episode. Patients who bled were older and sicker at presentation than were those who did not bleed. Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased. There were stepwise increases in the adjusted hazards of 30-day mortality (mild bleeding, hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3 to 1.9; moderate bleeding, HR 2.7, 95% CI l 2.3 to 3.4; severe bleeding, HR 10.6, 95% CI 8.3 to 13.6) and 6-month mortality (mild bleeding, HR 1.4, 95% CI 1.2 to 1.6; moderate bleeding, HR 2.1, 95% CI 1.8 to 2.4; severe bleeding, HR 7.5, 95% CI 6.1 to 9.3) as bleeding severity increased. Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds. In conclusion, the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events. Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS.

    View details for DOI 10.1016/j.amjcard.2005.06.056

    View details for Web of Science ID 000233343500005

    View details for PubMedID 16253582

  • The PRoject of ex-vivo vein graft ENgineering via Transfection IV (PREVENT IV) trial: Study rationale, design, and baseline patient characteristics AMERICAN HEART JOURNAL Alexander, J. H., Ferguson, T. B., Joseph, D. M., Mack, M. J., Wolf, R. K., Gibson, M., Gennevois, D., Lorenz, T. J., Harrington, R. A., Peterson, E. D., Lee, K. L., Califf, R. M., Kouchoukos, N. T. 2005; 150 (4): 643-649

    Abstract

    Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia.PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days.Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005.The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.

    View details for DOI 10.1016/j.ahj.2005.05.021

    View details for Web of Science ID 000232953300004

    View details for PubMedID 16209958

  • Renal function, concomitant medication use and outcomes following acute coronary syndromes NEPHROLOGY DIALYSIS TRANSPLANTATION Reddan, D. N., Szczech, L., Bhapkar, M. V., Moliterno, D. J., Califf, R. M., Ohman, E. M., Berger, P. B., Hochman, J. S., Van de Werf, F., Harrington, R. A., Newby, L. K. 2005; 20 (10): 2105-2112

    Abstract

    Chronic kidney disease (CKD) is highly prevalent in patients with cardiovascular disease. We explored the associations of CKD with outcomes using combined data from two large acute coronary syndrome (ACS) trials. We also explored the associations of CKD with prescription patterns for common cardiovascular medications and the association of these prescription patterns with clinical outcomes.Patients were stratified by CKD stage using creatinine clearance (CrCl, ml/min) estimated by the modified MDRD equation using baseline core laboratory creatinine measures. Serum creatinine > or =1.5 mg/dl was an exclusion criterion for the SYMPHONY trials. Baseline characteristics and outcomes across CKD categories were compared and Cox proportional hazards regression was used to assess the relationship of renal insufficiency with clinical outcomes after adjusting for previously identified outcome predictors. Interactions between the use of specific medications and calculated CrCl were tested in the final Cox proportional hazards model predicting time to mortality.Of 13 707 patients analysed, 6840 had CKD stage I (CrCl > or =90 ml/min), 5909 stage II (CrCl 60-89 ml/min), 955 stage III (CrCl 30-59 ml/min) and three stage IV (CrCl <30 ml/min). Patients with more advanced CKD (III) were older, more often female, non-smokers and more likely to have co-morbid diseases including diabetes mellitus, hypertension and congestive heart failure. Cardiovascular medications were used less frequently in patients with CKD. Unadjusted survival was poorer in patients with CKD stages > or =II. In adjusted analyses, for those with CrCl < or =91, each 10 ml/min increase in CrCl was associated with a significantly decreased risk of mortality (hazards ratio 0.897, 95% confidence interval 0.815-0.986) (P = 0.024). The interaction between use of angiotensin-converting enzyme (ACE) inhibitors and CrCl was significantly associated with outcomes; the benefit of drug therapy was greater among patients with CKD.CKD is an independent predictor of risk among ACS patients, and is associated with less frequent use of proven medical therapies. More aggressive use of conventional cardiovascular therapies in patients with CKD and ACS may be warranted.

    View details for DOI 10.1093/ndt/gfh981

    View details for Web of Science ID 000232102800015

    View details for PubMedID 16030030

  • Frequency, predictors, and outcomes of drug-eluting stent utilization in patients with high-risk non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Roe, M. T., Ohman, E. M., Milford-Beland, S., Chen, A. Y., Lytle, B. L., Cohen, D. J., Smith, S. C., Harrington, R. A., Gibler, W. B., Peterson, E. D. 2005; 96 (6): 750-755

    Abstract

    Despite the established benefit of drug-eluting stents (DESs) in improving clinical and angiographic outcomes in pivotal, randomized trials, relatively little is known regarding the frequency and patterns of DES use in clinical practice. To characterize DES use in a broad, unselected high-risk non-ST-segment elevation acute coronary syndrome population, we evaluated the frequency, patterns, and predictors of DES use among patients in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) Quality Improvement Initiative who were selected to undergo percutaneous coronary intervention. Of 8,852 patients with high-risk non-ST-segment elevation acute coronary syndromes who underwent percutaneous revascularization at 262 hospitals between October 2003 and June 2004, 5,858 (66.2%) were treated with DESs and 2,994 (33.8%) were not. During a 9-month period, DES use increased considerably from 52.6% of cases in October 2003 to 78.5% in June 2004. Compared with the bare metal stent cohort, patients receiving DESs were more likely to be women and to have private insurance, but were less likely to present with positive cardiac markers or ST-segment depression. In adjusted analysis, death and recurrent infarction were significantly lower among the patients with a DES, yet early revascularization and treatment with guideline-recommended therapies were less frequent. In a multivariate model, significant (p <0.05) predictors of DES use included hyperlipidemia, elevated systolic blood pressure, private insurance, and treatment at a larger hospital. In conclusion, these findings not only identified differences in the selection and treatment of patients receiving bare metal stents versus DESs, but also demonstrated the increasing use of DESs in higher risk patients who have previously been excluded from randomized, pivotal trials.

    View details for DOI 10.1016/j.amjcard.2005.05.015

    View details for Web of Science ID 000232096700003

    View details for PubMedID 16169352

  • Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide, monotherapy in acute Myocardial Infarction (ADVANCE MI) trial AMERICAN HEART JOURNAL Adgey, J., Ardissino, D., ARMSTRONG, P., Berger, P., Betriu, A., Beyar, R., Bode, C., Braunwald, E., Brindis, R., Brogan, G., Buller, C., Califf, R., CASTERELLA, P., Gibler, W. B., Giugliano, R., Goldstein, P., Granger, C., Guetta, V., Harrington, R., Herrmann, H., Hochman, J., Hoekstra, J., Kleiman, N., Labinaz, M., Langer, A., Montalescot, G., Ohman, E. M., O'Neill, W., Pollack, C., Roe, M., Satler, L., Schweiger, M., Simoons, M., Steg, G., Tanguay, J. F., Van de Werf, F., Wallentin, L., Zeymer, U. 2005; 150 (1): 116-122

    Abstract

    Facilitated percutaneous coronary intervention (PCI)--simultaneous administration of glycoprotein IIb/IIIa inhibitors and reduced-dose fibrinolytics before primary PCI for ST-segment elevation myocardial infarction (STEMI)--may be a promising reperfusion strategy.The ADVANCE MI trial was intended to evaluate facilitated PCI in 5640 STEMI patients but was prematurely terminated as a result of slow recruitment over 12 months at 30 centers in the United States. Patients with STEMI with planned primary PCI were randomly assigned to receive eptifibatide + 50% of standard-dose tenecteplase (which equated to 0.25 mg/kg intravenous bolus) or eptifibatide + placebo before PCI and randomized in a 2 x 2 factorial design to unfractionated heparin or enoxaparin.A total of 148 patients were randomized (74 patients in each treatment arm) and formed the "as-randomized" intention-to-treat population. However, only 69 patients actually received eptifibatide + tenecteplase, and 77 actually received eptifibatide + placebo (2 patients did not receive eptifibatide and 4 patients randomized to tenecteplase did not receive this therapy)--these 146 patients formed the "as-treated" population. Among both populations, epicardial infarct artery patency and myocardial tissue perfusion on pre-PCI angiography were improved in the tenecteplase group, but ST-segment resolution at 60 minutes was similar. The frequency of the primary end point of death or new/worsening severe heart failure at 30 days was higher among patients treated with eptifibatide + tenecteplase in the "as-treated" (10% vs 3%, P = .09) and the "as-randomized" (11% vs 1%, P = .02) populations. Bleeding complications were 2-fold higher with eptifibatide + tenecteplase. Analysis of the results by treatment with unfractionated heparin versus enoxaparin demonstrated similar findings.Although definitive conclusions cannot be made as a result of the small sample size and premature study termination, facilitated PCI with eptifibatide + reduced-dose tenecteplase was associated with improved angiographic flow patterns, increases in adverse clinical outcomes, and higher bleeding rates compared with eptifibatide + placebo administered before primary PCI for STEMI.

    View details for DOI 10.1016/j.ahj.2005.04.005

    View details for Web of Science ID 000232219900018

    View details for PubMedID 16084157

  • Use of bivalirudin during percutaneous coronary intervention in patients with diabetes mellitus - An analysis from the randomized evaluation in percutaneous coronary intervention linking angiomax to reduced clinical events (REPLACE)-2 trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gurm, H. S., Sarembock, I. J., Kereiakes, D. J., Young, J. J., Harrington, R. A., Kleiman, N., Feit, F., Wolski, K., Bittl, J. A., Wilcox, R., Topol, E. J., Lincoff, A. M. 2005; 45 (12): 1932-1938

    Abstract

    The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy.Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied.We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI.The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69).Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

    View details for DOI 10.1016/j.jacc.2005.02.074

    View details for Web of Science ID 000229848500004

    View details for PubMedID 15963389

  • Characterization of myocardial infarction as an end point in two large trials of acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Roe, M. T., Kilaru, R., French, J. K., Alexander, J. H., Berdan, L. G., Van de Werf, F., Simoons, M. L., Weaver, W. D., White, H. D., Lincoff, A. M., Kleiman, N. S., Topol, E. J., Harrington, R. A. 2005; 95 (12): 1404-1408

    Abstract

    Myocardial infarction (MI) is a key component of composite end points in trials that evaluate new therapies in non-ST-segment elevation acute coronary syndromes. Types of MI events in these trials have not been well characterized. A similar clinical-events classification process adjudicated all suspected MI end points in the PURSUIT and PARAGON B trials. All MI end points were classified as nonprocedural, related to percutaneous coronary intervention, or related to coronary artery bypass grafting. A total of 16,173 patients was enrolled in the 2 trials, and 1,802 MI end points occurred during a 30-day follow-up. Nearly 66% of MI end points were not related to percutaneous coronary intervention or coronary artery bypass grafting. Patients who had MI compared with those who did not had higher 30-day mortality rates (13.6% vs 2.3%, p <0.001) and 6-month mortality rates (18.4% vs 4.4%, p <0.001). Patients who had been randomized to glycoprotein IIb/IIIa inhibition showed trends toward fewer MI events regardless of type. Two-thirds of MI end points in 2 large trials of acute coronary syndrome were not related to procedure. All MI types were associated with worse short- and long-term outcomes. Characterization of the type of MI provides an opportunity for more informed interpretation of clinical trial results and improved planning for future trials.

    View details for DOI 10.1016/j.amjcard.2005.02.005

    View details for Web of Science ID 000229952900002

    View details for PubMedID 15950560

  • The Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial: A randomized placebo-controlled trial evaluating the clinical benefits of early front-loaded-eptifibatide in the treatment of patients with non-ST-segment elevation acute coronary syndrome - Study design and rationale AMERICAN HEART JOURNAL Giugliano, R. P., Newby, L. K., Harrington, R. A., Gibson, C. M., Van de Werf, F., ARMSTRONG, P., Montalescot, G., Gilbert, J., Strony, J. T., Califf, R. M., Braunwald, E. 2005; 149 (6): 994-1002

    Abstract

    The recent North American and European practice guidelines in patients with non-ST-segment elevation acute coronary syndrome (nSTE ACS) recommend glycoprotein IIb/IIIa (GpIIb-IIIa) inhibition in patients undergoing an early invasive treatment strategy. However, the guidelines are not explicit regarding the timing of initiation of GpIIb-IIIa antagonists, and there is marked variation in clinical practice regarding their use.The EARLY ACS trial will enroll 10,500 patients in a prospective, randomized, double blind, international, multicenter investigation of early eptifibatide compared with placebo (with provisional eptifibatide in the catheterization laboratory) in patients with high-risk nSTE ACS in whom an invasive strategy is planned no sooner than the next calendar day. The primary efficacy end point is the 96-hour composite of all-cause mortality, nonfatal myocardial infarction, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout with GpIIb-IIIa inhibitor during percutaneous coronary intervention. The key secondary end point is the composite of death or nonfatal myocardial infarction within 30 days of enrollment.The EARLY ACS trial will be the largest study to date to evaluate the utility of early GpIIb-IIIa inhibition in patients with nSTE ACS in whom an invasive approach is planned. This trial will provide important evidence regarding the benefit of initiating eptifibatide early after presentation with high-risk ACS versus delayed provisional use after coronary angiography. Furthermore, it will explore the ability of biomarkers to identify high-risk patients who may benefit from such an early aggressive approach.

    View details for DOI 10.1016/j.ahj.2005.03.029

    View details for Web of Science ID 000230622100012

    View details for PubMedID 15976780

  • Should we routinely supplement coronary patients with folate therapy to prevent in-stent restenosis? AMERICAN HEART JOURNAL Halabi, A. R., Harrington, R. A. 2005; 149 (6): 1035-1036

    View details for DOI 10.1016/j.ahj.2005.03.014

    View details for Web of Science ID 000230622100024

    View details for PubMedID 15976784

  • Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: Patient selection and associated treatment patterns ACADEMIC EMERGENCY MEDICINE Hoekstra, J. W., Roe, M. T., Peterson, E. D., Menon, V., Mulgund, J., Pollack, C. V., Miller, C., Palabrica, T., Harrington, R. A., Ohman, E. M., Gibler, B. 2005; 12 (5): 431-438

    Abstract

    The authors analyzed contemporary use of glycoprotein (GP) IIb/IIIa inhibitors in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) to determine patient selection patterns with early (<24 hours) GP IIb/IIIa inhibitor use and the relationship between GP IIb/IIIa inhibitor therapy and use of other guidelines-recommended therapies for NSTE ACS.Using the CRUSADE Quality Improvement Initiative database, patient characteristics, in-hospital treatments, and outcomes for 65,424 patients with ischemic chest pain of <24 hours' duration and either positive cardiac markers or ischemic electrocardiographic changes were analyzed. Data were collected from 443 U.S. hospitals from January 2001 to June 2003.Only 35% of eligible patients received GP IIb/IIIa inhibitors <24 hours after hospital admission. Approximately one third of patients received GP IIb/IIIa inhibitors in the emergency department, one third in the coronary care unit, and one third in the catheterization laboratory. Admission to a cardiologist's care was the most significant associated factor with early GP IIb/IIIa inhibitor use, along with elevated cardiac markers or ST-segment deviation. Patients at high risk for adverse cardiac events due to advanced age, congestive heart failure, or female gender were less likely to receive early GP IIb/IIIa inhibitor therapy. Patients who received early GP IIb/IIIa inhibitor therapy were more likely to receive other guidelines-recommended therapies.Despite the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations, early GP IIb/IIIa inhibitor therapy remains underutilized in patients with NSTE ACS and administration of early GP IIb/IIIa inhibitors is directed toward lower-risk patients. Early GP IIb/IIIa inhibitor therapy is associated with improved overall adherence to the ACC/AHA guidelines.

    View details for DOI 10.1197/j.aem.2004.11.029

    View details for Web of Science ID 000228817100008

    View details for PubMedID 15863399

  • Comparison of ST-segment resolution with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy versus fibrinolytic alone (data from four clinical trials) AMERICAN JOURNAL OF CARDIOLOGY Rebeiz, A. G., Johanson, P., Green, C. L., Crater, S. W., Roe, M. T., Langer, A., Giugliano, R. P., Lincoff, A. M., Newby, L. K., Harrington, R. A., Topol, E. J., Califf, R. M., Wagner, G. S., Krucoff, M. W. 2005; 95 (5): 611-614

    Abstract

    We compared combination fibrinolytic plus glycoprotein IIb/IIIa inhibitor therapy with stand-alone fibrinolysis with respect to speed and stability of reperfusion in patients who had acute ST-segment elevation myocardial infarction; data were obtained from 654 patients in 4 trials (Integrilin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction, Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction, Integrilin and Tenecteplase in Acute Myocardial Infarction, and the Fifth Global Use of Strategies to Open Occluded Coronary Arteries) that compared thrombolytics plus lamifiban, eptifibatide, or abciximab with standard thrombolysis. We found significantly faster and more stable ST-segment recovery with combination therapy starting at 60 minutes (56.7% vs 48.0% with >/=50% ST-segment resolution, p = 0.03) and sustained over 180 minutes after drug administration; this transient benefit may suggest a time frame when more optimal percutaneous coronary intervention can be performed.

    View details for DOI 10.1016/j.amjcard.2004.10.038

    View details for Web of Science ID 000227156400012

    View details for PubMedID 15721101

  • Outcomes, Health Policy, and Managed Care - Influence of clinical trial enrollment on the quality of care and outcomes for patients with non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Kandzari, D. E., Roe, M. T., Chen, A. Y., Lytle, B. L., Pollack, C. V., Harrington, R. A., Ohman, E. M., Gibler, W. B., Peterson, E. D. 2005; 149 (3): 474-?
  • First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS trial JOURNAL OF THROMBOSIS AND HAEMOSTASIS Alexander, J. H., Yang, H., Becker, R. C., Kodama, K., Goodman, S., Dyke, C. K., Kleiman, N. S., Hochman, J. S., Berger, P. B., Cohen, E. A., Lincoff, A. M., Burton, J. R., Bovill, E. G., Kawai, C., Armstrong, P. W., Harrington, R. A. 2005; 3 (3): 439-447

    Abstract

    Unfractionated heparin is widely used in patients with non-ST-elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed.To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX-9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non-ST-elevation acute coronary syndromes.Patients (n = 402) from the USA, Canada, and Japan were randomized to blinded, weight-adjusted heparin, low-dose DX-9065a, or high-dose DX-9065a.The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low-dose DX-9065a, and high-dose DX-9065a (P = 0.91 for heparin vs. combined DX-9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX-9065a were associated with a lower likelihood of ischemic events (P = 0.03) and a non-significant tendency toward a higher likelihood of major bleeding (P = 0.32).In this small phase II trial, there was a non-significant tendency toward a reduction in ischemic events and bleeding with DX-9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST-monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX-9065a in acute coronary syndromes or percutaneous intervention.

    View details for Web of Science ID 000227685500006

    View details for PubMedID 15748230

  • Angiographic and clinical outcomes associated with direct versus conventional stenting among patients treated with fibrinolytic therapy for ST-elevation acute myocardial infarction AMERICAN JOURNAL OF CARDIOLOGY Ly, H. Q., Kirtane, A. J., Buros, J., Giugliano, R. P., Popma, J. J., Antman, E. M., Harrington, R. A., Ohman, E. M., Gibson, C. M. 2005; 95 (3): 383-386

    Abstract

    The present study reports outcomes of direct stenting versus conventional stenting, which was performed during adjunctive/rescue percutaneous coronary intervention (n = 556) in the Integrilin and Tenecteplase in Acute Myocardial Infarction trial, the Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction-Thrombolysis in Myocardial Infarction 23 trial, and the Fibrinolytic and Aggrastat ST-Elevation Resolution trial of fibrinolytic therapy in ST-elevation myocardial infarction. Direct stenting was associated with a lower rate of death, myocardial infarction, or congestive heart failure during hospitalization and at 30 days and was independently associated with improved in-hospital outcomes (odds ratio 0.44, 95% confidence interval 0.23 to 0.85, p = 0.014).

    View details for DOI 10.1016/j.amjcard.2004.09.038

    View details for Web of Science ID 000226679800014

    View details for PubMedID 15670549

  • Outcomes of patients with acute coronary syndromes and prior percutaneous coronary intervention: a pooled analysis of three randomized clinical trials EUROPEAN HEART JOURNAL Labinaz, M., Mathias, J., Pieper, K., Granger, C. B., Lincoff, A. M., Moliterno, D. J., Van de Werf, F., Simes, J., White, H. D., Simoons, M. L., Califf, R. M., Topol, E. J., Armstrong, P. W., Harrington, R. A. 2005; 26 (2): 128-136

    Abstract

    We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS).We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation.Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI.

    View details for DOI 10.1093/eurheartj/ehi061

    View details for Web of Science ID 000228892000007

    View details for PubMedID 15618068

  • Vascular endothelial tissue factor pathway inhibitor kinetics in culture following exposure to DX-9065a - A selective and direct factor Xa inhibitor JOURNAL OF THROMBOSIS AND THROMBOLYSIS Becker, R. C., Alexander, J. H., Li, Y. F., Robertson, T., Kunitada, S., Spencer, F. A., Yang, H. Q., Harrington, R. A. 2005; 18 (3): 193-197
  • Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes - Results from the CRUSADE quality improvement initiative JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bhatt, D. L., Roe, M. T., Peterson, E. D., Li, Y., Chen, A. Y., Harrington, R. A., Greenbaum, A. B., Berger, P. B., Cannon, C. P., Cohen, D. J., Gibson, C. M., Saucedo, J. F., Kleiman, N. S., Hochman, J. S., Boden, W. E., Brindis, R. G., Peacock, W. F., Smith, S. C., Pollack, C. V., Gibler, W. B., Ohman, E. M. 2004; 292 (17): 2096-2104

    Abstract

    The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) recommend early invasive management for high-risk patients, given the benefits with this approach demonstrated in randomized clinical trials.To determine the use and predictors of early invasive management strategies (cardiac catheterization <48 hours following presentation) in high-risk patients with NSTE ACS and to examine the association of early invasive management with mortality.The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative evaluated care patterns and outcomes for 17,926 high-risk NSTE ACS patients (positive cardiac markers and/or ischemic electrocardiographic changes) based on ACC/AHA guidelines recommendations at 248 US hospitals with catheterization and revascularization facilities between March 2000 and September 2002.Use of early invasive management within 48 hours of presentation, predictors of early invasive management, and in-hospital mortality. Results Of the 17,926 patients analyzed, 8037 (44.8%) underwent early cardiac catheterization less than 48 hours following presentation. Predictors of early invasive management included cardiology care, younger age, lack of prior or current congestive heart failure, lack of renal insufficiency, ischemic electrocardiographic changes, positive cardiac markers, white race, and male sex. Patients treated with early invasive management were more likely to be treated with medications and interventions recommended by the ACC/AHA guidelines and had a lower risk of in-hospital mortality after adjusting for differences in clinical characteristics and after comparing propensity-matched pairs (2.5% vs 3.7%, P<.001). Conclusions An early invasive management strategy is not utilized in the majority of high-risk patients with NSTE ACS. This strategy appears to be reserved for patients without significant comorbidities and those cared for by cardiologists and is associated with a lower risk of in-hospital mortality.

    View details for Web of Science ID 000224921900022

    View details for PubMedID 15523070

  • Thrombolysis and adjunctive therapy in acute myocardial infarction CHEST Menon, V., Harrington, R. A., Hochman, J. S., Cannon, C. P., Goodman, S. D., Wilcox, R. G., Schunemann, H. J., Ohman, E. M. 2004; 126 (3): 549S-575S
  • Antithrombotic therapy during percutaneous coronary intervention - The seventh ACCP Conference on antithrombotic and thrombolytic therapy CHEST Popma, J. J., Berger, P., Ohman, E. M., Harrington, R. A., Grines, C., Weitz, J. I. 2004; 126 (3): 576S-599S

    Abstract

    This chapter about antithrombotic therapy during percutaneous coronary intervention (PCI) is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading, see Guyatt et al, CHEST 2004;126:179S-187S). Among the key recommendations in this chapter are the following: For patients undergoing PCI, we recommend pretreatment with aspirin, 75 to 325 mg (Grade 1A). For long-term treatment after PCI, we recommend aspirin, 75 to 162 mg/d (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend lower-dose aspirin, 75 to 100 mg/d (Grade 1C+). For patients who undergo stent placement, we recommend the combination of aspirin and a thienopyridine derivative (ticlopidine or clopidogrel) over systemic anticoagulation therapy (Grade 1A). We recommend clopidogrel over ticlopidine (Grade 1A). For all patients undergoing PCI, particularly those undergoing primary PCI, or those with refractory unstable angina or other high-risk features, we recommend use of a glycoprotein (GP) IIb-IIIa antagonist (abciximab or eptifibatide) [Grade 1A]. In patients undergoing PCI for ST-segment elevation MI, we recommend abciximab over eptifibatide (Grade 1B). In patients undergoing PCI, we recommend against the use of tirofiban as an alternative to abciximab (Grade 1A). In patients after uncomplicated PCI, we recommend against routine postprocedural infusion of heparin (Grade 1A). For patients undergoing PCI who are not treated with a GP IIb-IIIa antagonist, we recommend bivalirudin over heparin during PCI (Grade 1A). In PCI patients who are at low risk for complications, we recommend bivalirudin as an alternative to heparin as an adjunct to GP IIb-IIIa antagonists (Grade 1B). In PCI patients who are at high risk for bleeding, we recommend that bivalirudin over heparin as an adjunct to GP IIb-IIIa antagonists (Grade 1B). In patients who undergo PCI with no other indication for systemic anticoagulation therapy, we recommend against routine use of vitamin K antagonists after PCI (Grade 1A).

    View details for Web of Science ID 000224298900017

    View details for PubMedID 15383485

  • Antithrombotic therapy for coronary artery disease CHEST Harrington, R. A., Becker, R. C., Ezekowitz, A., Meade, T. W., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H. 2004; 126 (3): 513S-548S
  • Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes - A systematic overview JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Petersen, J. L., Mahaffey, K. W., Hasselblad, V., Antman, E. M., Cohen, M., Goodman, S. G., Langer, A., Blazing, M. A., Le-Moigne-Amrani, A., de Lemos, J. A., Nessel, C. C., Harrington, R. A., Ferguson, J. J., Braunwald, E., Califf, R. M. 2004; 292 (1): 89-96

    Abstract

    Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

    View details for Web of Science ID 000222448100032

    View details for PubMedID 15238596

  • Dynamic prognostication in non-ST-elevation acute coronary syndromes: Insights from GUSTO-llb and PURSUIT AMERICAN HEART JOURNAL Chang, W. C., Boersma, E., Granger, C. B., Harrington, R. A., Califf, R. M., Simoons, M. L., Kleiman, N. S., Armstrong, P. W. 2004; 148 (1): 62-71

    Abstract

    Risk assessment in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) traditionally focuses on and is limited to admission findings. The objective of the current study was to develop an approach to predicting outcome in NSTE-ACS that could account for the changing nature of risk.In 7294 of 8010 patients with NSTE-ACS and complete electrocardiographic data in the GUSTO-IIb trial, we predicted the mortality probability at days 0-2, 0-30, 3-30, 5-30, and 7-30 using multiple logistic regression. Resulting risk estimates were incorporated into a composite, dynamic model to estimate the effects of changing probabilities over time. These models were validated against an independent sample of 9461 patients from the PURSUIT trial.As time passed after admission, the risk of 30-day death declined in stable patients. This risk, which was 3.72% at baseline, declined to 1.92% in 6-day survivors, and the risk reduction was greatest for those with the highest baseline risk. Importantly, however, the development of inhospital complications modified these trends. The use of dynamic models not only allowed us to estimate early (<48 h) mortality with a high degree of accuracy (C-index of 0.87), but also to continuously update the longer-term prognosis with increasing accuracy: the C-index increased from 0.75 for the day 0-30 model to 0.81 and 0.82 for the composite and day 7-30 models, respectively.Dynamic risk assessment is feasible and reliable. This approach can improve risk assessment and provide valuable guidance for management of patients with NSTE-ACS.

    View details for DOI 10.1016/j.ahj.2003.05.004

    View details for Web of Science ID 000222357700010

    View details for PubMedID 15215793

  • Combined assessment of thrombolysis in myocardial infarction flow grade, myocardial perfusion grade, and st-segment resolution to evaluate epicardial and myocardial reperfusion AMERICAN JOURNAL OF CARDIOLOGY Giugliano, R. P., Sabatine, M. S., Gibson, C. M., Roe, M. T., Harrington, R. A., Murphy, S. A., Morrow, D. A., Antman, E. M., Braunwald, E. 2004; 93 (11): 1362-1367

    Abstract

    The restoration of epicardial and myocardial flow remains the primary goal of reperfusion therapy in patients with ST-segment elevation myocardial infarction, but the optimal method to assess this goal has not been defined. Thrombolysis In Myocardial Infarction flow grade (TFG), myocardial perfusion grade (MPG), and ST-segment resolution (STRes) were combined to formulate a new measure of successful reperfusion in 649 patients who received pharmacologic reperfusion therapy in 3 recent phase II clinical trials of ST-segment elevation myocardial infarction. Coronary angiograms and electrocardiograms were analyzed at 60 minutes (before any intervention) after the initiation of reperfusion therapy. The complete restoration of perfusion, or the "trifecta," defined as the presence of TFG 3, MPG 3, and complete (> or =70%) STRes, occurred in 117 patients (18%). The achievement of this trifecta was associated with low rates of 30-day mortality (0% vs 3.9%, p = 0.02), congestive heart failure (CHF) (0.9% vs 7.1%, p = 0.01), and the combination of death or CHF (0.9% vs 10.7%, p = 0.001). When the results were stratified with respect to subsequent percutaneous coronary intervention (PCI) from 60 to 120 minutes, attainment of the trifecta at 60 minutes remained a strong predictor of better clinical outcomes, particularly in those patients who underwent early PCI. The achievement of TFG 3, MPG 3, and complete STRes at 60 minutes after fibrinolytic therapy and before PCI occurred in only 18% of patients but was associated with very low rates of death and CHF at 30 days. This new end point is proposed to evaluate the success of reperfusion therapy in patients who undergo early angiography.

    View details for DOI 10.1016/j.amjcard.2004.02.031

    View details for Web of Science ID 000221815100006

    View details for PubMedID 15165915

  • Six-month outcomes of percutaneous coronary balloon angioplasty in acute coronary syndromes: Results from the PURSUIT trial CANADIAN JOURNAL OF CARDIOLOGY Labinaz, M., Kaul, P., Harrington, R. A., Chang, W. C., Kleiman, N. S., Simoons, M. L., Boersma, E., Akkerhuis, M., Califf, R. M., Armstrong, P. W. 2004; 20 (8): 773-778

    Abstract

    Potent inhibition of the platelet glycoprotein IIb/IIIa receptor has improved the acute outcome of patients presenting with acute coronary syndromes (ACS). For patients with ACS undergoing percutaneous balloon angioplasty without coronary stenting in the era of platelet glycoprotein IIb/IIIa blockade, the long-term prognosis is less clear.To examine the six-month outcome of patients who received eptifibatide within a randomized clinical trial and subsequently underwent balloon angioplasty.Patients included in this substudy were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized study evaluating the efficacy of eptifibatide in reducing the incidence of death or nonfatal myocardial infarction (MI) in non-ST segment elevation ACS. During the index hospitalization, 1151 (12.2%) of the PURSUIT patients underwent percutaneous balloon angioplasty without coronary stenting.Eptifibatide was associated with a significant reduction in the adjudicated composite end point of death or MI at six months after randomization in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) (P=0.037). A trend toward a beneficial effect was evident before the procedure (4.7% versus 6.9%; P=0.13) and at 30 days (12.1% versus 15.3%; P=0.12). The incidence of repeat revascularization was relatively low for patients undergoing PTCA, with no difference observed between the eptifibatide and placebo groups (16.3% versus 14.8%; P=0.51).Eptifibatide was associated with a sustained beneficial effect to six months in patients with ACS undergoing PTCA. It reduced the incidence of preprocedural MI. The rate of repeat revascularization at six months was low and was not significantly altered by eptifibatide.

    View details for Web of Science ID 000222287100005

    View details for PubMedID 15229770

  • Comparison of Bivalirudin versus heparin during percutaneous coronary intervention (the randomized evaluation of PCI linking angiomax to reduced clinical events [REPLACE]-1 trial) AMERICAN JOURNAL OF CARDIOLOGY Lincoff, A. M., Bittl, J. A., Kleiman, N. S., Sarembock, I. J., Jackman, J. D., Mehta, S., Tannenbaum, M. A., Niederman, A. L., Bachinsky, W. B., Tift-Mann, J., Parker, H. G., Kereiakes, D. J., Harrington, R. A., Feit, F., Maierson, E. S., Chew, D. P., Topol, E. J. 2004; 93 (9): 1092-1096

    Abstract

    To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.

    View details for DOI 10.1016/j.amjcard.2004.01.033

    View details for Web of Science ID 000221140100003

    View details for PubMedID 15110198

  • Association of the timing of ST-segment resolution with TIMI myocardial perfusion grade in acute myocardial infarction AMERICAN HEART JOURNAL Gibson, C. M., Karha, J., Giugliano, R. P., Roe, M. T., Murphy, S. A., Harrington, R. A., Green, C. L., Schweiger, M. J., Miklin, J. S., Baran, K. W., Palmeri, S., Braunwald, E., Krucoff, M. W. 2004; 147 (5): 847-852

    Abstract

    More complete ST-segment resolution (ST res) in acute myocardial infarction (MI) has been associated with better epicardial and myocardial reperfusion as assessed with the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and the TIMI myocardial perfusion grade (TMPG), respectively. However, no data exist comparing the speed of ST resolution on continuous electrocardiogram (ECG) monitoring with the TMPG on coronary angiography. We hypothesized that delayed ST res is associated with impaired TMPGs.Continuous 12-lead ECG recordings and 60-minute angiographic data were analyzed in 120 patients with acute MI who received tenectaplase monotherapy or combination therapy with low-dose tenectaplase and eptifibatide in the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial.More rapid ST res on continuous ECG monitoring was associated with improved TMPGs on coronary angiography performed 60 minutes after study drug administration. For TMPG 3, the median time to ST resolution was 53 minutes. For TMPG 2, 1, and 0, the corresponding times were 64 minutes, 80 minutes, and 106 minutes, respectively (P =.01 for trend). Likewise, more rapid ST res was also associated with faster epicardial flow. For TFG 3, the median time to ST resolution was 46 minutes, compared with 109 minutes for TIMI flow grades 0 to 2 (P =.001). The corresponding times for a corrected TIMI frame count < or =40 versus >40 were 52 minutes and 112 minutes, respectively (P <.001).Although the static ECG has been associated with epicardial and myocardial blood flow in the past, this study extends these observations to demonstrate that more rapid ST res on continuous ECG monitoring is associated with improved myocardial perfusion after thrombolytic administration.

    View details for DOI 10.1016/j.ahj.2003.11.015

    View details for Web of Science ID 000221479100022

    View details for PubMedID 15131541

  • Association of a pulsatile blood flow pattern on coronary arteriography and short-term clinical outcomes in acute myocardial infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gibson, C. M., Karha, J., Murphy, S. A., de Lemos, J. A., Morrow, D. A., Giugliano, R. P., Roe, M. T., Harrington, R. A., Cannon, C. P., Antman, E. M., Califf, R. M., Braunwald, E. 2004; 43 (7): 1170-1176

    Abstract

    We hypothesized that recognition of systolic flow reversal (pulsatile flow) after thrombolytic administration on coronary angiography is associated with angiographic and electrocardiogram findings reflecting impaired myocardial perfusion, as well as poorer clinical outcomes.Reversal of systolic flow on Doppler velocity wire recordings has been associated with impaired tissue perfusion on myocardial contrast echocardiography in the setting of myocardial infarction (MI).Patients (n = 1,062) with a patent infarct-related artery were drawn from the Thrombolysis In Myocardial Infarction (TIMI) 10, TIMI 14, and Integrillin and Tenecteplase acute MI trials.Pulsatile flow (systolic flow reversal with cessation of antegrade contrast-dye motion or frank reversal of contrast-dye motion during systole) at 60 min after fibrinolytic administration was present in 11.0% of patients. Pulsatile flow was associated with higher corrected TIMI frame counts (slower epicardial flow) (median 40.1 frames, IQ 30 of 63 vs. 30 frames, interquartile 22 of 42, p < 0.0001), a closed microvasculature (TIMI myocardial perfusion grades 0 of 1, 57.1% vs. 37.8%, p = 0.03) and less complete (> or =70%) ST-segment resolution (23.5% vs. 58.9%, p = 0.008). Patients with pulsatile flow had a higher risk of death or reinfarction at 30 days (10.3% vs. 5.0%, p = 0.019). After controlling for age, pulse, blood pressure, anterior MI location, epicardial flow, and creatine kinase, pulsatile flow remained associated with an increased risk of death/MI (odds ratio 3.1, p = 0.006).A pulsatile pattern of flow is associated with impaired myocardial perfusion and poorer clinical outcomes independent of the velocity of antegrade flow in the epicardial artery. This simple and easily identifiable angiographic flow pattern may be useful in clinical risk stratification.

    View details for DOI 10.1016/j.jacc.2003.11.035

    View details for Web of Science ID 000220640400007

    View details for PubMedID 15063425

  • Aspirin dose and six-month outcome after an acute coronary syndrome JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Quinn, M. J., Aronow, H. D., Calif, R. M., Bhatt, D. L., Sapp, S., Kleiman, N. S., Harrington, R. A., Kong, D. F., Kandzari, D. E., Topol, E. J. 2004; 43 (6): 972-978

    Abstract

    This study was designed to compare the efficacy of low and intermediate aspirin doses in acute coronary syndromes.Little is known of the comparative efficacy of low and intermediate aspirin doses in this setting.We compared six-month death, myocardial infarction (MI), and stroke in patients with unstable angina or acute MI discharged while receiving low (<150 mg) or intermediate (> or =150 mg) aspirin therapy in the GUSTO IIb and PURSUIT trials (n = 20,521). We used multivariable analysis and performed a propensity analysis in order to adjust for baseline imbalances between the groups.Aspirin doses <150 mg were prescribed to 29.9% (6,128) of patients. By six months, 6.4% of the patients (1,310 of 20,521) had a primary event, 6.2% of the patients receiving <150 mg and 6.6% of the patients receiving aspirin doses > or =150 mg (hazard ratio [HR] 1.06 [95% confidence interval (CI) 0.94 to 1.19], p = 0.35). After adjusting for baseline imbalances and the propensity score for discharge aspirin dose, there was no effect of aspirin dose on the composite end point at six months (HR 0.92 [95% CI 0.79 to 1.07], p = 0.28). However, the higher aspirin dose was associated with a reduction in six-month MI (HR 0.79 [95% CI 0.64 to 0.98], p = 0.03). The outcome was similar when patients were matched on the basis of the propensity score for aspirin dose (HR for death/MI/stroke 0.94 [95% CI 0.80 to 1.12], p = 0.51), although stroke occurred significantly more frequently among patients receiving the higher aspirin dose (HR 1.74 [95% CI 1.01 to 3.02] p = 0.05) and the effect on MI was no longer apparent.Although these data are non-randomized, they suggest that the aspirin dose upon discharge may influence the clinical course after unstable angina or acute MI.

    View details for DOI 10.1016/j.jacc.2003.09.059

    View details for Web of Science ID 000220212400007

    View details for PubMedID 15028352

  • Improved clinical outcomes with abciximab therapy in acute myocardial infarction: A systematic overview of randomized clinical trials AMERICAN HEART JOURNAL Kandzari, D. E., Hasselblad, V., Tcheng, J. E., Stone, G. W., Califf, R. M., Kastrati, A., Neumann, F. J., Brener, S. J., Montalescot, G., Kong, D. F., Harrington, R. A. 2004; 147 (3): 457-462

    Abstract

    Investigations of glycoprotein (GP) IIb/IIIa inhibition in primary percutaneous coronary intervention (PCI) have suggested the efficacy of abciximab in improving clinical and angiographic outcomes, but sample-size limitations and variability in trial design preclude the ability to generalize these results to a broader patient population.Meta-analytic techniques were used to evaluate clinical outcomes from randomized trials comparing GP IIb/IIIa inhibition with placebo or control therapy in primary PCI for acute myocardial infarction (MI).In 3266 patients, treatment with abciximab significantly reduced the 30-day composite end point of death, reinfarction, or ischemic or urgent target-vessel revascularization (TVR; odds ratio [OR], 0.54; 95% CI, 0.40-0.72), with trends toward reduced 30-day death and death or reinfarction. Abciximab resulted in an increased likelihood of major bleeding (OR, 1.74; 95% CI, 1.11-2.72). By 6 months, abciximab significantly reduced the occurrence of death, reinfarction, or any TVR (OR, 0.80; 95% CI, 0.67-0.97), and there were positive trends favoring a decrease in mortality alone and the composite of death or reinfarction.Treatment with abciximab significantly reduces early adverse ischemic events, a clinical benefit that is maintained at 6-month follow-up. These findings support the use of adjunctive GP IIb/IIIa inhibition in primary PCI.

    View details for DOI 10.1016/j.ahj.2003.08.011

    View details for Web of Science ID 000220539400017

    View details for PubMedID 14999194

  • Economic impact of drug-eluting stents on hospital systems: A disease-state model AMERICAN HEART JOURNAL Kong, D. F., Eisenstein, E. L., Sketch, M. H., Zidar, J. P., RYAN, T. J., Harrington, R. A., Newman, M. F., Smith, P. K., Mark, D. B., Califf, R. M. 2004; 147 (3): 449-456

    Abstract

    Drug-eluting intracoronary stents decrease restenosis and later revascularization. The US Department of Health and Human Services (HHS), recognizing the financial and clinical impact of this technology, recently proposed accelerated reimbursement to hospitals.A disease state-transition computer model simulated the clinical and economic consequences to hospitals of drug-eluting stents over 5 years. Model parameters combined information from a longitudinal clinical database, a hospital cost-accounting system, and a survey instrument. Simulations were repeated 1000 times for each set of parameters. With 85% of stent procedures shifted to drug-eluting stents in the first year of availability, the mean number of repeat revascularizations dropped by 60.4% at year 5. With no changes in reimbursement policy, a hospital with a catheterization laboratory volume of 3112 patients yearly converted from a 2.01 million dollars (M) annual profit to an 8.10 M dollars loss in the first year (95% CI 8.09 M dollars to 8.12 M dollars) and 8.7 M dollars annual losses in later years. This represented an overall change in cash flow of 55.71 M dollars (95% CI 55.66 M dollars to 55.76 M dollars) away from the hospital over 5 years. The incremental reimbursement proposed by HHS reduced this loss to 4.75 M dollars in the first year and to 5.6 M dollars annually thereafter. In sensitivity analyses, the conversion of patients from bypass surgery to drug-eluting stents was the largest driver of overall cash flow shifts.Although Medicare has proposed to increase reimbursement to ease the impact of drug-eluting stents on hospitals, this increase will not totally offset the costs.

    View details for DOI 10.1016/j.ahj.2003.11.005

    View details for Web of Science ID 000220539400016

    View details for PubMedID 14999193

  • Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Chu, A., Brodie, B. R., Stuckey, T. A., Hermiller, J. B., Vetrovec, G. W., Hannan, K. L., Krucoff, M. W., Christenson, R. H., Gibbons, R. J., Sigmon, K. N., Garg, J., Hasselblad, V., Collins, K., Harrington, R. A., Berger, P. B., Chronos, N. A., Hochman, J. S., Califf, R. M. 2004; 93 (5): 636-639

    Abstract

    In a nonrandomized feasibility study of therapeutic hypothermia in acute myocardial infarction, 18 patients were treated with endovascular cooling (Alsius, Irvine, California) as adjunctive therapy to primary percutaneous coronary intervention to assess measures of infarct size (area under the curve creatinine kinase-MB and technetium-99m single-photon emission computed tomography sestamibi) and the quality of myocardial perfusion (continuous ST-segment monitoring). Periprocedural endovascular cooling successfully decreased core body temperature (median 33.5 degrees C) and was well tolerated, which supports the evaluation of adjunctive hypothermia in pivotal trials to limit infarct size and decrease reperfusion injury.

    View details for DOI 10.1016/j.amjcard.2003.11.038

    View details for Web of Science ID 000220075800027

    View details for PubMedID 14996598

  • Improved speed and stability of ST-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute ST-segment elevation myocardial infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Roe, M. T., Green, C. L., Giugliano, R. P., Gibson, C. M., Baran, K., Greenberg, M., Palmeri, S. T., Crater, S., Trollinger, K., Hannan, K., Harrington, R. A., Krucoff, M. W. 2004; 43 (4): 549-556

    Abstract

    This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results.Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics.We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 microg/kg) plus high-dose eptifibatide (2 boluses of 180 microg/kg separated by 10 min, 2.0 microg/kg/min infusion) was compared with full-dose tenecteplase (0.53 microg/kg).The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min.Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.

    View details for DOI 10.1016/j.jacc.2003.09.039

    View details for Web of Science ID 000188944600008

    View details for PubMedID 14975462

  • Differential treatment benefit of platelet glycoprotein IIb/IIIa inhibition with percutaneous coronary intervention versus medical therapy for acute coronary syndromes - Exploration of methods CIRCULATION Pieper, K. S., Tsiatis, A. A., Davidian, M., Hasselblad, V., Kleiman, N. S., Boersma, E., Chang, W. C., Griffin, J., Armstrong, P. W., Califf, R. M., Harrington, R. A. 2004; 109 (5): 641-646

    Abstract

    Although many believe that platelet glycoprotein IIb/IIIa inhibitors should be used only in acute coronary syndrome patients undergoing percutaneous coronary intervention, supporting data from randomized clinical trials are tenuous. The assumption that these agents are useful only in conjunction with percutaneous coronary intervention is based primarily on inappropriate subgroup analyses performed across the glycoprotein IIb/IIIa inhibitor trials.We describe the problems with these analytical techniques and demonstrate that different approaches to the question can result in opposing answers.Clinical-practice decisions and practice guidelines should be based on overall trial results and not analyses of post-randomization subgroups.

    View details for DOI 10.1161/01.CIR.0000112570.97220.89

    View details for Web of Science ID 000188836600016

    View details for PubMedID 14769687

  • Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes EUROPEAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Kilaru, R., Alexander, J. H., Akkerhuis, K. M., Simoons, M. L., Harrington, R. A., Tardiff, B. E., Granger, C. B., Ohman, E. M., Moliterno, D. J., Lincoff, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Topol, E. J. 2004; 25 (4): 313-321

    Abstract

    To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS).Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017).Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

    View details for DOI 10.1016/j.ehj.2003.12.009

    View details for Web of Science ID 000220194100007

    View details for PubMedID 14984920

  • Conflict of interest AMERICAN HEART JOURNAL Holmes, D. R., Firth, B. G., James, A., Winslow, R., Hodgson, P. K., Gamble, G. L., Popp, R. L., Harrington, R. A. 2004; 147 (2): 228-237

    Abstract

    The clinical research enterprise is increasingly scrutinized, in part because of the issue of conflict of interest. The issue is broad and its implications touch on a wide range of concerns, from the safety of patient care to the viability of a large industry. Numerous constituencies are affected by conflict of interest, and representatives of all of them convened in November 2002 for a one-and-a-half day discussion of the issues as well as possible solutions to both the perception and the actuality of such conflict. Participants included medical journal editors, news reporters, physician investigators, representatives of institutional conflict-of-interest oversight committees, representatives of the medical products industry, and Federal regulators. The resulting manuscript provides a review of the issues as well as desirable ways for each of the players to monitor themselves; each section thus contains provocative recommendations for eliminating conflict of interest to ensure that our vibrant health care system continues to foster exciting new advances to improve patient care.

    View details for DOI 10.1016/j.ahj.2003.12.001

    View details for Web of Science ID 000220253900011

    View details for PubMedID 14760318

  • Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI pilot JOURNAL OF THROMBOSIS AND HAEMOSTASIS Alexander, J. H., Dyke, C. K., Yang, H., Becker, R. C., Hasselblad, V., Zillman, L. A., Kleiman, N. S., Hochman, J. S., Berger, P. B., Cohen, E. A., Lincoff, A. M., Saint-Jacques, H., Chetcuti, S., Burton, J. R., Buergler, J. M., Spence, F. P., Shimoto, Y., Robertson, T. L., Kunitada, S., Bovill, E. G., Armstrong, P. W., Harrington, R. A. 2004; 2 (2): 234-241

    Abstract

    Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI).To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI.Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin.At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose.Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study.

    View details for Web of Science ID 000189249200006

    View details for PubMedID 14995984

  • Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Rebeiz, A. G., Roe, M. T., Alexander, J. H., Mahaffey, K. W., Granger, C. B., Peterson, E. D., Califf, R. M., Harrington, R. A. 2004; 116 (2): 119-129

    Abstract

    Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.

    View details for DOI 10.1016/j.amjmed.2003.09.028

    View details for Web of Science ID 000188246900008

    View details for PubMedID 14715326

  • GP IIb/IIIa blockade in elective percutaneous coronary intervention CURRENT PHARMACEUTICAL DESIGN Dery, J. P., Harrington, R. A., Tcheng, J. E. 2004; 10 (4): 387-398

    Abstract

    Cumulative scientific evidence gathered over the past ten years has confirmed the role of platelet GP IIb/IIIa inhibitors in reducing ischemic complications of patients undergoing percutaneous coronary intervention (PCI). Recently, mortality data available on more than 20,000 patients enrolled in randomized clinical trials suggest that GP IIb/IIIa blockade also improves short and long-term survival after PCI. Despite convincing arguments, GP IIb/IIIa inhibitors are still inconsistently administered in patients undergoing coronary intervention. The following review will discuss the scientific grounds and the principal controversies surrounding the use of these compounds in patients undergoing elective percutaneous coronary intervention.

    View details for Web of Science ID 000188439200007

    View details for PubMedID 14965200

  • Evaluating the benefits of glycoprotein, IIb/IIIa inhibitors in heart failure at baseline in acute coronary syndromes AMERICAN HEART JOURNAL Srichai, M. B., Jaber, W. A., Prior, D. L., Marso, S. P., Houghtaling, P. L., Menon, V., Simoons, M. L., Harrington, R. A., Hochman, J. S. 2004; 147 (1): 84-90

    Abstract

    We evaluated whether the use of glycoprotein IIb/IIIa receptor inhibitors, in addition to heparin and aspirin, imparts an incremental benefit in a subgroup of patients with acute coronary syndromes (ACS) who had congestive heart failure (CHF) symptoms at presentation.We analyzed patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized, double-blind, placebo-controlled study evaluating the use of eptifibatide versus placebo for patients with ACS without persistent ST-elevation. We compared the clinical characteristics and 30-day outcomes for 861 patients who had Killip class II or III CHF symptoms with those of 8558 patients who had no CHF symptoms.Odds ratios for the primary end point, 30-day death or non-fatal myocardial infarction, in the placebo group versus the eptifibatide group were similar for patients with and without CHF (odds ratio, 1.11; 95% CI, 0.8-1.5; odds ratio, 1.13; 95% CI, 1.0-1.3). However, adverse events were almost twice as frequent for patients with CHF compared with patients with no CHF (24.5% vs 14%).Although patients with non-ST-segment elevation ACS who have CHF have markedly worse outcomes than patients without CHF symptoms, we did not find an incremental benefit from the use of eptifibatide in this seriously ill subgroup.

    View details for DOI 10.1016/S0002-8703(03)00530-1

    View details for Web of Science ID 000220253800016

    View details for PubMedID 14691424

  • Changing the model of care for patients with acute coronary syndromes AMERICAN HEART JOURNAL Roe, M. T., Ohman, E. M., Pollack, C. V., Peterson, E. D., Brindis, R. G., Harrington, R. A., Christenson, R. H., Smith, S. C., Califf, R. M., Gibler, W. B. 2003; 146 (4): 605-612

    Abstract

    Acute coronary syndromes (ACS) represent a major cause of morbidity and mortality for patients with cardiovascular disease, but evidence-based therapies shown to improve outcomes for ACS are often underused in clinically eligible patients. Although clinical practice guidelines have been developed to provide standards for the diagnosis and treatment of patients with ACS and to provide physicians with a framework for clinical decision-making, multiple obstacles have hindered their implementation and questions remain about the applicability of guidelines for diverse clinical situations. Systematic reviews of quality-improvement studies have shown that multifaceted approaches using targeted educational interventions, creation of quality standards, and regular performance feedback are needed to ensure sustained improvements in care. Approaches to quality improvement thus are being redirected to focus on multidisciplinary collaborations designed to improve the entire process of care for patients with ACS. Multiple large observational registries and quality-improvement initiatives now are capturing data regarding adherence to practice guidelines and contemporary patterns of care for ACS. This comprehensive evaluation of ACS treatment will help guide efforts designed to promote evidence-based care and ultimately determine the effect of widespread implementation of practice guidelines on clinical outcomes. The shifting model of care for ACS therefore suggests that quality improvement and monitoring of adherence to practice guidelines should be considered components of optimal clinical practice.

    View details for DOI 10.1016/S0002-8703(03)00388-0

    View details for Web of Science ID 000186019200009

    View details for PubMedID 14564312

  • Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions AMERICAN JOURNAL OF CARDIOLOGY Kong, D. F., Hasselblad, V., Harrington, R. A., White, H. D., Tcheng, J. E., Kandzari, D. E., Topol, E. J., Califf, R. M. 2003; 92 (6): 651-655

    Abstract

    We performed a cumulative meta-analysis of available studies to evaluate the effect of intravenous platelet glycoprotein (GP) IIb/IIIa antagonists on survival at 30 days and 6 months after percutaneous coronary intervention (PCI). Compounds that block the GP IIb/IIIa receptor substantially reduce myocardial infarctions (MIs) and repeat revascularization. We included 12 trials, which enrolled 20,186 patients in all, in the analysis. Overall, 30-day mortality was significantly reduced with GP IIb/IIIa inhibition (odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.024). Although 10 of the 12 trials showed a beneficial effect of GP IIb/IIIa inhibitor treatment on mortality, no individual trial detected a statistically significant mortality benefit. The 30-day mortality benefit became significant at the p <0.05 level with addition of the ADMIRAL trial and was further enhanced by the CADILLAC trial. No significant heterogeneity was detected in the collection of trials. At 6 months, the odds ratio was 0.84 (95% confidence interval 0.69 to 1.03, p = 0.087). This survival benefit amounts to preventing approximately 1 of every 3 deaths that occur within 30 days after PCI, saving 2.8 lives/1,000 patients treated (number needed to treat, 357). Thus, patients who undergo PCI can expect significantly lower 30-day mortality, in addition to known reductions in nonfatal MI and repeat procedures, with GP IIb/IIa inhibition. There also is increasing evidence that mortality reductions are preserved at 6 months.

    View details for DOI 10.1016/S002-9149(03)00816-6

    View details for Web of Science ID 000185330800001

    View details for PubMedID 12972100

  • Reduction of myocardial ischemic injury following coronary intervention (The MC-1 to eliminate necrosis and damage trial) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Labinaz, M., Cantor, W. J., Madan, M., Gallup, D. S., Hasselblad, V., Joseph, D., Allen, A., Green, C., Hidinger, K. G., Krucoff, M. W., Christenson, R. H., Harrington, R. A., Tcheng, J. E. 2003; 92 (6): 660-664

    Abstract

    Myocardial ischemic injury complicating acute myocardial infarction (AMI) and coronary revascularization procedures remains an unresolved clinical dilemma. In preclinical studies, treatment with pyridoxal-5'-phosphate monohydrate (MC-1), a vitamin B6 metabolite, has demonstrated cardioprotective effects. Sixty patients scheduled for elective percutaneous coronary intervention (PCI) who had clinically high-risk characteristics for ischemic complications were randomized to treatment with MC-1 or placebo in a 2:1 double-blinded fashion. The primary end point was defined as infarct size as measured by area under the curve creatine kinase MB (CK-MB) enzymes. Secondary end points included periprocedural ischemia as assessed by continuous electrocardiographic monitoring, 30-day major adverse cardiac events, and net clinical safety, which included liver function testing. The primary end point, median periprocedural CK-MB area under the curve, was reduced from 32.9 ng/ml in the placebo group to 18.6 ng/ml with MC-1 treatment (p = 0.038), reflecting a shift in the distribution of CK-MB. By categorical classification, the occurrence of 30-day nonfatal AMI did not differ between groups. There were no deaths, and 30-day composite adverse event rates were similar (17.9% MC-1 vs 15.0% placebo, p = 1.0). There were no significant differences in ischemia parameters per continuous electrocardiographic monitoring, and no safety issues were identified. In this phase II pilot study, treatment of high-risk patients who underwent PCI with MC-1 was associated with a decrease in the total amount of CK-MB released after PCI. These results support the evaluation of MC-1 in pivotal trials of patients at risk for developing myocardial ischemia, infarction, or reperfusion injury.

    View details for DOI 10.1016/S0002-91-9149(03)00818-X

    View details for Web of Science ID 000185330800003

    View details for PubMedID 12972102

  • Association between admission white blood cell count and one-year mortality in patients with acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Yen, M. H., Bhatt, D. L., Chew, D. P., Harrington, R. A., Newby, L. K., Ardissino, D., Van de Werf, F., White, J. A., Moliterno, D. J., Topol, E. J. 2003; 115 (4): 318-321
  • Frequency of stent thrombosis after acute coronary syndromes (from the SYMPHONY and 2nd SYMPHONY trials) AMERICAN JOURNAL OF CARDIOLOGY Tolleson, T. R., Newby, L. K., Harrington, R. A., Bhapkar, M. V., Verheught, F. W., Berger, P. B., Moliterno, D. J., White, H. D., Ohman, E. M., Van de Werf, F., Topol, E. J., Califf, R. M. 2003; 92 (3): 330-333

    Abstract

    We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

    View details for DOI 10.1016/s0002-9149(03)00641-6

    View details for Web of Science ID 000184503800024

    View details for PubMedID 12888148

  • Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease CIRCULATION Topol, E. J., Easton, D., Harrington, R. A., Amarenco, P., Califf, R. M., Graffagnino, C., Davis, S., Diener, H. C., Ferguson, J., Fitzgerald, D., Granett, J., Shuaib, A., Koudstaal, P. J., Theroux, P., Van de Werf, F., Sigmon, K., Pieper, K., Vallee, M., Willerson, J. T. 2003; 108 (4): 399-406

    Abstract

    This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

    View details for DOI 10.1161/01.CIR.0000084501.48570.F6

    View details for Web of Science ID 000184409300009

    View details for PubMedID 12874182

  • Effect of revascularization on mortality associated with an elevated white blood cell count in acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Bhatt, D. L., Chew, D. P., Lincoff, A. M., Simoons, M. L., Harrington, R. A., Ommen, S. R., Jia, G., Topol, E. J. 2003; 92 (2): 136-140

    Abstract

    Inflammation is increasingly recognized as having an important role in patients with acute coronary syndromes. We sought to determine whether an elevated white blood cell (WBC) count would predict subsequent mortality and whether revascularization would have a protective effect. We analyzed data from 10,480 patients with acute coronary syndromes enrolled in the PURSUIT trial who had a WBC count measured on admission. WBC count values were stratified by quartiles, and death rates at 6 months were examined in univariate and multivariate analyses. Propensity analysis was performed to assess the effect of revascularization on the relation between WBC count and mortality. In the lowest quartile of WBC count, mortality was 4.0%; it was 5.8% in the second quartile, 6.7% in the third quartile, and 8.0% in the fourth quartile (p <0.001). In a multivariable model incorporating baseline demographic and clinical variables, an increasing WBC count was a significant predictor of death, with a hazard ratio of 1.07 per 1,000/microl increment in WBC count (p <0.001). Furthermore, the interaction term between mortality due to an elevated WBC count and benefit of in-hospital revascularization was significant (hazard ratio 0.94, p = 0.032), suggesting that the excess risk due to an elevated WBC count was attenuated by revascularization. An elevated WBC count at hospital admission, although only a crude index of inflammation, nevertheless is an independent predictor of death at 6 months in patients with acute coronary syndromes. This finding supports a pivotal role for inflammation in acute coronary syndromes. Importantly, this study suggests that in-hospital revascularization may mitigate some of the excess risk due to inflammation.

    View details for DOI 10.1016/S0002-9149(03)00527-7

    View details for Web of Science ID 000184163000004

    View details for PubMedID 12860213

  • Distance from the coronary ostium to the culprit lesion in acute ST-elevation myocardial infarction and its implications regarding the potential prevention of proximal plaque rupture JOURNAL OF THROMBOSIS AND THROMBOLYSIS Gibson, C. M., Kirtane, A. J., Murphy, S. A., Karha, J., Cannon, C. P., Giugliano, R. P., Roe, M. T., Harrington, R. A., Ohman, E. M., Antman, E. M. 2003; 15 (3): 189-196

    Abstract

    Shorter distances from the coronary ostia to culprit lesions have been associated with a higher incidence of adverse outcomes in ST elevation acute myocardial infarction (STEMI). As drug-eluting stents are associated with low rates of restenosis and formation of a stable intima, we sought to develop a mathematical model to estimate how far down the coronary artery a drug-eluting stent would have to be placed to theoretically mitigate the risk of proximal plaque rupture.Distances from the ostia to the end of the culprit lesions were planimetered in 1,914 patients from the TIMI 14, INTEGRITI, FASTER and ENTIRE/TIMI 23 trials.The first 60 mm of the coronary artery contained 75% of STEMI culprit lesions. The median distance from the vessel ostium to the end of the culprit lesion was 43 mm (mean 50 +/- 34) and the relative distance from the vessel ostium to the end of the lesion was 29% (mean 33 +/- 17%) of the total culprit artery length. Diabetes was the only baseline clinical characteristic associated with a longer absolute distance to the end of the culprit lesion (46 mm vs. 43 mm, p = 0.03) as well as relative to total artery length (31% vs. 29%, p = 0.04). Median distances from the artery ostium to the end of the culprit lesion were shortest among the left anterior descending culprits (40 mm), followed by circumflex lesions (43 mm) and then right coronary artery lesions (47 mm, 3-way p < 0.0001).The majority of culprit lesions in STEMI are contained within the proximal 30% of the major epicardial coronary arteries, but the distance varies depending upon which epicardial artery is involved. Cumulative distribution functions are presented to allow estimation of the percent of culprit lesions lying proximal to any given distance from the ostium to model the feasibility of prophylactic drug-eluting stenting to minimize the risk of subsequent proximal plaque rupture.

    View details for Web of Science ID 000187940500007

    View details for PubMedID 14739628

  • Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction - Results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Giugliano, R. P., Roe, M. T., Harrington, R. A., Gibson, M., Zeymer, U., Van de Werf, F., Baran, K. W., Hobbach, H. P., Woodlief, L. H., Hannan, K. L., Greenberg, S., Miller, J., Kitt, M. M., Strony, J., McCabe, C. H., Braunwald, E., Califf, R. M. 2003; 41 (8): 1251-1260

    Abstract

    The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI).Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established.Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min.In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively.Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

    View details for DOI 10.1016/S0735-1097(03)00123-2

    View details for Web of Science ID 000182177300003

    View details for PubMedID 12706917

  • Does the discharge ECG provide additional prognostic insight(s) in non-ST elevation ACS patients from that acquired on admission? EUROPEAN HEART JOURNAL HERSI, A., Fu, Y., Wong, B., Mahaffey, K. W., Harrington, R. A., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 24 (6): 524-533
  • Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention - REPLACE-2 Randomized Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Lincoff, A. M., Bittl, J. A., Harrington, R. A., Feit, F., Kleiman, N. S., Jackman, J. D., Sarembock, I. J., Cohen, D. J., Spriggs, D., Ebrahimi, R., Keren, G., Carr, J., Cohen, E. A., Betriu, A., Desmet, W., Kereiakes, D. J., Rutsch, W., Wilcox, R. G., de Feyter, P. J., Vahanian, A., Topol, E. J. 2003; 289 (7): 853-863

    Abstract

    The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI).To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications.The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization.Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P =.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P =.40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001).Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.

    View details for Web of Science ID 000181072200029

    View details for PubMedID 12588269

  • Troponin T and quantitative ST-segment depression offer complementary prognostic information in the risk stratification of acute coronary syndrome patients JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaul, P., Newby, L. K., Fu, Y. L., Hasselblad, V., Mahaffey, K. W., Christenson, R. H., Harrington, R. A., Ohman, E. M., Topol, E. J., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 41 (3): 371-380

    Abstract

    Our primary objective was to examine the prognostic relationship between baseline quantitative ST-segment depression (ST) and cardiac troponin T (cTnT) elevation. The secondary objectives were to: 1) examine whether ST provided additional insight into therapeutic efficacy of glycoprotein IIb/IIIa therapy similar to that demonstrated by cTnT; and 2) explore whether the time to evaluation impacted on each marker's relative prognostic utility.The relationship between the baseline electrocardiogram (ECG) and cTnT measurements in risk-stratifying patients presenting with acute coronary syndromes (ACS) has not been evaluated comprehensively.The study population consisted of 959 patients enrolled in the cTnT substudy of the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B trial. Patients were classified as having no ST (n = 387), 1 mm ST (n = 433), and ST > or =2 mm (n = 139). Forty-percent (n = 381) were classified as cTnT-positive based on a definition of > or =0.1 ng/ml.Six-month death/(re)myocardial infarction rates were 8.4% among cTnT-negative patients with no ST and 26.8% among cTnT-positive patients with ST > or =2 mm. On ECGs done after 6 h of symptom onset, ST > or =2 mm was associated with higher risk compared to its presence on ECGs done earlier (odds ratio [OR] 7.3 vs. 2.1). In contrast, the presence of elevated cTnT within 6 h of symptom was associated with a higher risk of adverse events compared with elevations after 6 h (OR 2.4 vs. 1.5).Quantitative ST and cTnT status are complementary in assessing risk among ACS patients and both should be employed to determine prognosis and assist in medical decision making.

    View details for DOI 10.1016/S0735-1097(02)02824-3

    View details for Web of Science ID 000180759800003

    View details for PubMedID 12575962

  • Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention - Observations from the ESPRIT trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tolleson, T. R., O'Shea, J. C., Bittl, J. A., Hillegass, W. B., Williams, K. A., Levine, G., Harrington, R. A., Tcheng, J. E. 2003; 41 (3): 386-393

    Abstract

    We evaluated the relationship between the degree of heparin anticoagulation and clinical efficacy and bleeding in patients undergoing contemporary percutaneous coronary intervention (PCI) with stent implantation.Despite universal acceptance of heparin anticoagulation as a standard of care in PCI, considerable controversy still exists regarding the appropriate dosing of heparin.The study population (n = 2,064) comprised all patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. The index activated clotting time (ACT) was defined as the ACT measured after the last heparin dose and before first device activation and was correlated with outcome and bleeding events.No association was observed between decreasing ACT levels and the rate of ischemic events in the treatment or placebo arms. The incidence of the primary composite end point (death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy at 48 h) was actually lowest in the lowest ACT tertile for both the placebo (10.0%) and treatment groups (6.1%). When analyzed by tertile, major bleeding rates did not increase in the lowest ACT tertile in patients given placebo (0.6%) versus those receiving eptifibatide (0.7%). Major bleeding rates increased as the ACT increased in the eptifibatide-treated patients.Ischemic end points in patients undergoing contemporary PCI with stent placement do not increase by decreasing ACT levels, at least to a level of 200 s. Bleeding events do increase with increasing ACT levels and are enhanced with eptifibatide treatment. An ACT of 200 to 250 s is reasonable in terms of efficacy and safety with the use of contemporary technology and pharmacotherapy.

    View details for DOI 10.1016/S0735-1097(02)02767-5

    View details for Web of Science ID 000180759800005

    View details for PubMedID 12575964

  • Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: The CRUSADE initiative ACADEMIC EMERGENCY MEDICINE Hoekstra, J. W., Pollack, C. V., Roe, M. T., Peterson, E. D., Brindis, R., Harrington, R. A., Christenson, R. H., Smith, S. C., Ohman, M., Gibler, W. B. 2002; 9 (11): 1146-1155

    Abstract

    Although acute coronary syndromes (ACS) represent a well-recognized source of morbidity and mortality for patients with cardiovascular disease, evidence-based therapies shown to improve outcomes for ACS are frequently underused in appropriate patients, especially in the emergency department (ED). Despite dissemination of expert recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and ED-focused recapitulation of them in the emergency medicine literature, significant barriers continue to limit the adoption of guidelines in clinical practice and appear to hinder the use of beneficial therapies and interventions in the ED. Unique and creative approaches are therefore needed to stimulate better adherence to practice guidelines and improve the quality of care for patients with non-ST-elevation myocardial infarction (NSTE) ACS. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines) quality improvement and educational initiative provides an innovative and multifaceted approach to the education of emergency physicians and cardiologists in the care of patients with NSTE ACS. The CRUSADE initiative is a multidisciplinary cooperative effort involving over 400 EDs and medical centers. It includes an ACS registry designed to characterize demographic patterns and risk stratification results in patients who meet diagnostic criteria for high-risk NSTE ACS. It also measures the use of ED treatment modalities including aspirin, heparin, beta-blockers, and platelet inhibitors as recommended in the ACC/AHA guidelines. The results of a given institution's treatment patterns will be reported back to the practitioners, with comparisons with national norms. These reports can be used as quality improvement tools to improve care at participating institutions. Beyond a static registry, these reports are coupled with educational efforts by the CRUSADE steering committee, scientific publications of risk stratification practice and success, as well as ED patterns of care, and tailored educational interventions, to reinforce compliance with the ACC/AHA guidelines. This initiative represents a truly innovative approach to improving care for ACS patients in the ED as well as on the cardiology service. This article describes the CRUSADE initiative and its implications for the practicing emergency physician. It is the intent of CRUSADE to improve patient care in the ED by tracking and encouraging compliance with evidence-based guidelines for the evaluation and management of NSTE ACS.

    View details for Web of Science ID 000179203100014

    View details for PubMedID 12414463

  • Randomized COMparison of platelet inhibition with abciximab, TiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes - The COMPARE trial CIRCULATION Batchelor, W. B., Tolleson, T. R., Huang, Y., Larsen, R. L., Mantell, R. M., Dillard, P., Davidian, M., Zhang, D. W., Cantor, W. J., Sketch, M. H., Ohman, E. M., Zidar, J. P., Gretler, D., DiBattiste, P. M., Tcheng, J. E., Califf, R. M., Harrington, R. A. 2002; 106 (12): 1470-1476
  • Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation - Incidence, predictors, and outcomes CIRCULATION Al-Khatib, S. M., Granger, C. B., Huang, Y., Lee, K. L., Califf, R. M., Simoons, M. L., Armstrong, P. W., Van de Werf, F., White, H. D., Simes, R. J., Moliterno, D. J., Topol, E. J., Harrington, R. A. 2002; 106 (3): 309-312

    Abstract

    The prognosis of ventricular arrhythmias among patients with non-ST-elevation acute coronary syndromes is unknown. We studied the incidence, predictors, and outcomes of sustained ventricular arrhythmias in 4 large randomized trials of such patients.We pooled the datasets of the Global Use of Streptokinase and tPA for Occluded Arteries (GUSTO)-IIb, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON)-A, and PARAGON-B trials (n=26 416). We identified independent predictors of ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared the 30-day and 6-month mortality rates of patients who did (n=552) and did not (n=25 864) develop these arrhythmias during the index hospitalization. Independent predictors of in-hospital VF included prior hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, and ST-segment changes at presentation. Except for hypertension, these variables also independently predicted in-hospital VT. In Cox proportional-hazards modeling, in-hospital VF and VT were independently associated with 30-day mortality (hazard ratio [HR], 23.2 [95% CI, 18.1 to 29.8] for VF and HR, 7.6 [95% CI, 5.5 to 10.4] for VT) and 6-month mortality (HR, 14.8 [95% CI, 12.1 to 18.3] for VF and HR, 5.0 [95% CI, 3.8 to 6.5] for VT). These differences remained significant after excluding patients with heart failure or cardiogenic shock and those who died <24 hours after enrollment.Despite the use of effective therapies for non-ST-elevation acute coronary syndromes, ventricular arrhythmias in this setting are associated with increased 30-day and 6-month mortality. More effective therapies are needed to improve the survival of patients with these arrhythmias.

    View details for DOI 10.1161/01.CIR.0000022692.49934.E3

    View details for Web of Science ID 000176944300009

    View details for PubMedID 12119245

  • Early angioplasty in acute coronary syndromes without persistent ST-segment elevation improves outcome but increases the need for six-month repeat revascularization - An analysis of the PURSUIT trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ronner, E., Boersma, E., Laarman, G. J., Somsen, G. A., Harrington, R. A., Deckers, J. W., Topol, E. J., Califf, R. M., Simoons, M. L. 2002; 39 (12): 1924-1929
  • First experience with direct factor Xa inhibition in patients with stable coronary disease - A pharmacokinetic and pharmacodynamic evaluation CIRCULATION Dyke, C. K., Becker, R. C., Kleiman, N. S., Hochman, J. S., Bovill, E. G., Lincoff, A. M., Gerstenblith, G., Dzavik, V., Gardner, L. H., Hasselblad, V., Zillman, L. A., Shimoto, Y., Robertson, T. L., Kunitada, S., Armstrong, P. W., Harrington, R. A. 2002; 105 (20): 2385-2391

    Abstract

    Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa.In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001).This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

    View details for DOI 10.1161/01.CIR.0000016351.12759.52

    View details for Web of Science ID 000175853600012

    View details for PubMedID 12021225

  • Minor myocardial damage and prognosis - Are spontaneous and percutaneous coronary intervention-related events different? CIRCULATION Akkerhuis, K. M., Alexander, J. H., Tardiff, B. E., Boersma, E., Harrington, R. A., Lincoff, A. M., Simoons, M. L. 2002; 105 (5): 554-556

    Abstract

    The relevance of the adverse prognostic implications of CK-MB elevation after percutaneous coronary intervention (PCI) remains controversial. Therefore, we compared the relationship between the level of postprocedural CK-MB elevation and 6-month mortality in patients undergoing PCI with the relationship between the level of spontaneous, non-PCI-related CK-MB elevation and 6-month mortality in patients with acute coronary syndromes (ACS) treated medically.In the PURSUIT trial, 5583 of 9461 patients who presented with a non-ST-elevation ACS did not undergo PCI or CABG and had at least 1 CK-MB sample collected during index-hospitalization. There was a gradual increase in 6-month mortality with higher CK-MB levels: 4.1%, 8.6%, 9.0%, 14.3%, 15.5% for CK-MB ratios 0 to 1, >1 to 3, >3 to 5, >5 to 10, and >10 times the upper limit of normal. A combined analysis in 8838 patients undergoing PCI in 5 large, clinical trials revealed a proportional relationship between postprocedural CK-MB levels (1 to 3, >3 to 5, >5 to 10, and >10, the risk of death was 1.3%, 2.0%, 2.3%, 4.3%, and 7.4%, respectively. The absolute mortality rates were lower after procedure-related infarcts compared with spontaneous infarcts. Yet, the relative increase in 6-month mortality with each increase in peak CK-MB level was similar for PCI-related myocardial necrosis and spontaneous myocardial necrosis, as all tests for heterogeneity of the odds ratios were nonsignificant.The present analysis indicates that the adverse prognostic implications of periprocedural myocardial necrosis should be considered similar to the adverse consequences of spontaneous myocardial necrosis.

    View details for Web of Science ID 000173735400019

    View details for PubMedID 11827918

  • Misreporting of myocardial infarction end points: Results of adjudication by a central clinical events committee in the PARAGON-B trial AMERICAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Dyke, C. K., Newby, L. K., Kleiman, N. S., Connolly, P., Berdan, L. G., Sparapani, R., Lee, K. L., Armstrong, P. W., Topol, E. J., Califf, R. M., Harrington, R. A. 2002; 143 (2): 242-248
  • Outcomes of patients with acute coronary syndromes and prior coronary artery bypass grafting - Results from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial CIRCULATION Labinaz, M., Kilaru, R., Pieper, K., Marso, S. P., Kitt, M. M., Simoons, M. L., Califf, R. M., Topol, E. J., Armstrong, P. W., Harrington, R. A. 2002; 105 (3): 322-327

    Abstract

    Patients with prior CABG with a subsequent non-ST-segment elevation acute coronary syndrome (ACS) pose an increasingly important clinical problem. Although GP IIb/IIIa inhibitors have improved the outcome of patients with ACS, their efficacy in patients with prior CABG has not been previously evaluated. Methods and Results- We analyzed the 30- and 180-day outcomes of patients with prior CABG enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. In this trial, which evaluated the efficacy of eptifibatide in patients with ACS, 1134 patients (12%) with prior CABG and 8321 without prior CABG were enrolled. After adjusting for differences in baseline characteristics and treatment, patients with prior CABG had a significantly higher mortality rates at 30 days (hazard ratio [HR], 1.45 [95% CI, 1.06 to 1.98]; P=0.019) and at 180 days (HR, 1.32 [95% CI, 1.04 to 1.67]; P=0.021). At 30 days, there was a similar effect on the primary end point of death or myocardial infarction in the eptifibatide group versus the placebo group in prior CABG patients (unadjusted HR, 0.90 [95% CI, 0.67 to 1.20]) and in patients without a history of CABG (unadjusted HR, 0.89 [95% CI, 0.80 to 0.99]).Patients with prior CABG with non-ST-segment elevation ACS have a significantly worse prognosis than do patients without a history of CABG. The treatment effect of eptifibatide in the prior CABG group was similar to the effect seen in patients without prior CABG.

    View details for Web of Science ID 000173466100015

    View details for PubMedID 11804987

  • Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials LANCET Boersma, E., Harrington, R. A., Moliterno, D. J., White, H., Theroux, P., Van de Werf, F., De Torbal, A., Armstrong, P. W., Wallentin, L. C., Wilcox, R. G., Simes, J., Califf, R. M., Topol, E. J., Simoons, M. L. 2002; 359 (9302): 189-198

    Abstract

    Platelet glycoprotein IIb/IIIa inhibitors have been shown to reduce cardiac complications in patients undergoing percutaneous coronary intervention. The clinical efficacy of these drugs in acute coronary syndromes, however, is still unclear. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularisation.Inclusion criteria were: randomisation of patients with acute coronary syndromes but without persistent ST elevation; comparison of a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non-recommendation of early coronary revascularisation during study-drug infusion; and enrollment of at least 1000 patients. Data on individual patients were obtained from all participants in these trials.Six trials, enrolling 31402 patients, fulfilled the inclusion criteria. 30 days after randomisation, 3530 (11.2%) patients died or developed a myocardial infarction. At 30 days, a 9% reduction in the odds of death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% [1980/18297] vs 11.8% [1550/13105] events; odds ratio 0.91 [95% CI 0.84-0.98]; p=0.015). The relative treatment benefit was similar in subgroups of patients according to important clinical baseline characteristics; hence, the absolute treatment benefit was largest in high-risk patients. An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0.81 [0.75-0.89] but not in women (1.15 [1.01-1.30]). However, once patients were stratified according to troponin concentration, there was no evidence of a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin concentrations. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2.4% [445/18297] vs 1.4% [180/13105]; p<0.0001), but intracranial bleeding was not (16 [0.09%] vs 8 [0.06%]; p=0.40).Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction in patients with acute coronary syndromes not routinely scheduled for early revascularisation. The event reduction is greatest in patients at high risk of thrombotic complications. Treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered especially in such patients early after admission, and continued until a decision about early coronary revascularisation has been made.

    View details for Web of Science ID 000173350800008

    View details for PubMedID 11812552

  • Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS) AMERICAN JOURNAL OF CARDIOLOGY O'Connor, C. M., Gattis, W. A., Hellkamp, A. S., Langer, A., Larsen, R. L., Harrington, R. A., Berkowitz, S. D., O'Gara, P. T., Kopecky, S. L., Gheorghiade, M., DALY, R., Califf, R. M., Fuster, V. 2001; 88 (5): 541-546

    Abstract

    The Coumadin Aspirin Reinfarction Study demonstrated that combination treatment with fixed dose warfarin (1 or 3 mg) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infarction for reducing nonfatal reinfarction, nonfatal stroke, and cardiovascular death. In this analysis, we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke. The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg. In the Coumadin Aspirin Reinfarction Study, 2,028 patients were randomized to aspirin 80 mg plus warfarin 1 mg, and 3,393 were randomized to aspirin 160 mg alone. A predictive model for ischemic stroke was developed using the Cox proportional-hazards model. A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups. The incidence of ischemic stroke was lower in patients treated with aspirin 160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg (0.6% vs 1.1%; p = 0.0534). Age, previous stroke or transient ischemic attack, and aspirin dose were independent predictors of ischemic stroke. In addition, the highest risk patients, those with Q-wave myocardial infarction and male patients, appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg. The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infarction patients.

    View details for Web of Science ID 000170652400015

    View details for PubMedID 11524065

  • Atrial fibrillation and mortality among patients with acute coronary syndromes without ST-segment elevation: Results from the PURSUIT trial AMERICAN JOURNAL OF CARDIOLOGY Al-Khatib, S. M., Pieper, K. S., Lee, K. L., Mahaffey, K. W., Hochman, J. S., Pepine, C. J., Kopecky, S. L., Akkerhuis, M., Stepinska, J., Simoons, M. L., Topol, E. J., Califf, R. M., Harrington, R. A. 2001; 88 (1): 76-79
  • Prognostic value of ST segment depression in acute coronary syndromes: Insights from PARAGON-A applied to GUSTO-IIb JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaul, P., Fu, Y. L., Chang, W. C., Harrington, R. A., Wagner, G. S., Goodman, S. G., Granger, C. B., Moliterno, D. J., Van de Werf, F., Califf, R. N., Topol, E. J., Armstrong, P. W. 2001; 38 (1): 64-71

    Abstract

    Our objectives were to develop a risk-stratification model addressing the importance of the magnitude and distribution of ST segment depression in predicting long-term outcomes and to validate the model in an analogous patient population.Although patients without ST segment elevation presenting with acute coronary syndromes represent an increasingly frequent population admitted to coronary care units, little attention has been paid to quantifying their ST segment abnormalities.ST segment depression was categorized into three groups: 1) no ST segment depression; 2) 1-mm ST segment depression in two contiguous leads; and 3) ST segment depression > or =2 mm in two contiguous leads. A logistic regression model was developed using Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A) data to assess the prognostic value of the extent and distribution of ST segment depression in predicting one-year mortality. The model was validated using the non-ST segment elevation population in Global Use of Strategies To Open occluded arteries in acute coronary syndromes (GUSTO-IIb).ST segment depression was the strongest predictor of one-year mortality, accounting for 35% of the model's predictive power. Patients with ST segment depression > or =2 mm were approximately 6 times (odds ratio [OR] 5.73, 95% confidence interval [CI] 2.8 to 11.6) more likely to die within one year than patients with no ST segment depression. On validation, the model showed good discriminatory power (c-index = 0.75). Patients with ST segment depression > or =2 mm in more than one region were almost 10 times more likely to die within one year than patients with no ST segment depression.These data provide new evidence supporting the powerful prognostic value of the baseline electrocardiogram and, in particular, the magnitude and distribution of ST segment depression in predicting unfavorable events.

    View details for Web of Science ID 000169625400010

    View details for PubMedID 11451297

  • Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Alexander, K. P., Newby, L. K., Hellkamp, A. S., Harrington, R. A., Peterson, E. D., Kopecky, S., Langer, A., O'Gara, P., O'Connor, C. M., Daly, R. N., Califf, R. M., Khan, S., Fuster, V. 2001; 38 (1): 1-7

    Abstract

    This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI).Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year.The Coumadin Aspirin Reinfarction Study (CARS) database contains information on HRT use and menopausal status for women with a recent MI. We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment, new users if they began HRT during the study period or never users. We assessed the incidence of cardiac events (death, MI, unstable angina [UA]) during follow-up.In our cohort, 28% (n = 524) used HRT at some point. Of these, 21% (n = 111) began HRT after their MI. New users had a higher incidence of death/MI/UA (41% vs. 28%, p = 0.001) during follow-up than never users, largely due to a higher incidence of UA (39% vs. 20%, p = 0.001). After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]).Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.

    View details for Web of Science ID 000169625400001

    View details for PubMedID 11451256

  • Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study LANCET Aronow, H. D., Topol, E. J., Roe, M. T., Houghtaling, P. L., Wolski, K. E., Lincoff, A. M., Harrington, R. A., Califf, R. M., Ohman, E. M., Kleiman, N. S., Keltai, M., Wilcox, R. G., Vahanian, A., Armstrong, P. W., Lauer, M. S. 2001; 357 (9262): 1063-1068

    Abstract

    Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors. However, the effect of lipid-lowering therapy on short-term mortality immediately after an acute coronary syndrome has not been determined. We did an observational study using data from two randomised trials to investigate this issue.We used data from the GUSTO IIb and PURSUIT trials to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n=3653) with those who were not (n=17,156). A propensity analysis was done to adjust for presumed selection biases in the prescription of lipid-lowering agents.Lipid-lowering therapy was associated with a smaller proportion of deaths at 30 days (17 [0.5%] vs 179 [1.0%], hazard ratio 0.44 [95% CI 0.27-0.73], p=0.001) and at 6 months (63 [1.7%] vs 605 [3.5%], 0.48 [0.37-0.63], p<0.0001). After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (0.67 [0.48-0.95], p=0.023).Prescription of a lipid-lowering drug at hospital discharge was independently associated with reduced short-term mortality among patients after an acute coronary syndrome.

    View details for Web of Science ID 000167996200007

    View details for PubMedID 11297956

  • Prognostic importance of concomitant heparin with eptifibatide in acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Peterson, J. G., Topol, E. J., Roe, M. T., Sapp, S. K., Lincoff, A. M., Deckers, J. W., Blackstone, E. H., Harrington, R. A., Califf, R. M., Lauer, M. S. 2001; 87 (5): 532-536

    Abstract

    Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

    View details for Web of Science ID 000167218000006

    View details for PubMedID 11230834

  • Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: Results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial AMERICAN HEART JOURNAL Cohen, M. G., Pacchiana, C. M., Corbalan, R., Perez, J. E., Ponte, C. I., Oropeza, E. S., Diaz, R., PAOLASSO, E., Izasa, D., Rodas, M. A., Urrutia, C. E., Harrington, R. A., Topol, E. J., Califf, R. M. 2001; 141 (3): 391-401

    Abstract

    Although more than 9500 patients have been enrolled in major clinical trials in Latin America, practice patterns in this region have rarely been examined. We sought to compare characteristics, resource utilization, and outcomes of patients treated for acute coronary syndromes in Latin America with those in North America.The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Theraphy Trial (PURSUIT) enrolled 10,948 patients with non-ST-segment elevation acute coronary syndromes, including 585 in Latin America and 4358 in North America. We analyzed regional differences in patient groups, treatment patterns, and outcomes and used logistic regression analysis to identify association of enrollment region and survival.For patients in Latin America, the length of hospital stay was significantly longer (10 [7, 15] days vs 6 [4, 9], P <.001). Angiograms, angioplasty, and bypass surgery were significantly less common in Latin America (46.2%, 17.6%, and 11.3% vs 79.4%, 33.6%, and 19.4%, P <.001). Thirty-day death/myocardial infarction was not significantly higher, although mortality alone was significantly higher (6.8% vs 3.1%, P <.001). After adjustment for baseline characteristics, enrollment in Latin America remained an independent predictor for death at 30 days (odds ratio [OR] [95% confidence interval (CI)] 2.42 [1.60-3.67]) and persisted at 6 months (OR [95% CI] 2.5 [1.8-3.4]).Latin American patients treated for acute coronary syndromes were managed less invasively and were twice as likely as their North American counterparts to die within 6 months. This mortality difference was not explained by imbalances in baseline risk.

    View details for DOI 10.1067/mhj.2001.113216

    View details for Web of Science ID 000167321600015

    View details for PubMedID 11231436

  • Systematic adjudication of myocardial infarction end-points in an international clinical trial CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 180-186
  • Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 187-194
  • Antithrombotic therapy in patients undergoing percutaneous coronary intervention CHEST Popma, J. J., Ohman, E. M., Weitz, J., Lincoff, M., Harrington, R. A., Berger, P. 2001; 119 (1): 321S-336S

    View details for Web of Science ID 000166812000020

    View details for PubMedID 11157657

  • Shifting the open-artery hypothesis downstream: The quest for optimal reperfusion JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Roe, M. T., Ohman, E. M., Maas, A. C., Christenson, R. H., Mahaffey, K. W., Granger, C. B., Harrington, R. A., Califf, R. M., Krucoff, M. W. 2001; 37 (1): 9-18

    Abstract

    Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.

    View details for Web of Science ID 000166238100002

    View details for PubMedID 11153779

  • Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting CIRCULATION Marso, S. P., Bhatt, D. L., Roe, M. T., Houghtaling, P. L., Labinaz, M., Kleiman, N. S., Dyke, C., Simmoons, M. L., Califf, R. M., Harrington, R. A., Topol, E. J. 2000; 102 (24): 2952-2958

    Abstract

    Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown.The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7).Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

    View details for Web of Science ID 000165813600015

    View details for PubMedID 11113045

  • Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition - Insights from the platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial CIRCULATION Lincoff, A. M., Harrington, R. A., Califf, R. M., Hochman, J. S., Guerci, A. D., Ohman, E. M., Pepine, C. J., Kopecky, S. L., Kleiman, N. S., Pacchiana, C. M., Berdan, L. G., Kitt, M. M., Simoons, M. L., Topol, E. J. 2000; 102 (10): 1093-1100

    Abstract

    A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States.Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world.Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.

    View details for Web of Science ID 000089157400006

    View details for PubMedID 10973836

  • Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation results from an international trial of 9461 patients CIRCULATION Boersma, E., Pieper, K. S., Steyerberg, E. W., Wilcox, R. G., Chang, W. C., Lee, K. L., Akkerhuis, K. M., Harrington, R. A., Deckers, J. W., Armstrong, P. W., Lincoff, A. M., Califf, R. M., Topol, E. J., Simoons, M. L. 2000; 101 (22): 2557-2567

    Abstract

    Appropriate treatment policies should include an accurate estimate of a patient's baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation.We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81).The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.

    View details for Web of Science ID 000087431100004

    View details for PubMedID 10840005

  • Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial AMERICAN HEART JOURNAL Topol, E. J., Easton, J. D., Amarenco, P., Califf, R., Harrington, R., Graffagnino, C., Davis, S., Diener, H. C., Ferguson, J., Fitzgerald, D., Shuaib, A., Koudstaal, P. J., Theroux, P., Van de Werf, F., Willerson, J. T., Chan, R., Samuels, R., Ilson, B., Granett, J. 2000; 139 (6): 927-933

    Abstract

    Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

    View details for Web of Science ID 000087467600001

    View details for PubMedID 10827369

  • Age and outcome after acute coronary syndromes without persistent ST-segment elevation AMERICAN HEART JOURNAL Hasdai, D., Holmes, D. R., Criger, D. A., Topol, E. J., Califf, R. M., Harrington, R. A. 2000; 139 (5): 858-866

    Abstract

    Although age is the most important variable associated with death among patients with persistent ST-segment elevation, its impact on outcome among patients without persistent ST-segment elevation remains unknown. Moreover, the impact of age on the efficacy of antiplatelet therapy with eptifibatide is unknown.We analyzed the impact of increased age on outcome (death or [re]infarction) among patients enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy), a prospective, randomized study comparing placebo versus eptifibatide therapy in acute coronary syndromes without persistent ST-segment elevation. The 9461 patients were divided into 10-year age groups: <50, 50-59, 60-69, 70-79, and >/=80. In addition, we examined whether age had an impact on the efficacy of eptifibatide therapy.Eptifibatide improved outcome at 30 days (P =.04). There was no interaction among age and treatment (placebo vs eptifibatide) and adjusted outcome (P =.16 for death or [re]infarction at 30 days). Despite their worse clinical profile, older patients were less likely to undergo coronary angiography at 30 days: 936 (71%), 1489 (68%), 1969 (65%), 1357 (57%), and 193 (38%) in the respective age groups. Death or (re)infarction at 30 days occurred in 121 (9%), 255 (12%), 447 (15%), 460 (19%), and 134 (26%) in the respective age groups, and at 6 months in 149 (11%), 301 (14%), 547 (18%), 575 (24%), and 162 (32%). For a 10-year difference in age group, the adjusted odds for death or (re)infarction were greater by 33% within 30 days and by 34% within 6 months. These trends persisted for patients with or without myocardial infarction on presentation.Age did not significantly affect the efficacy of eptifibatide. Older age among patients with acute coronary syndromes was associated with worse baseline characteristics, fewer invasive procedures, and worse outcome.

    View details for Web of Science ID 000086970400019

    View details for PubMedID 10783220

  • Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes - Results from PURSUIT EUROPEAN HEART JOURNAL Akkerhuis, K. M., Deckers, J. W., Boersma, E., Harrington, R. A., Stepinska, J., Mahaffey, K. W., Wilcox, R. G., Lincoff, A. M., Keltai, M., Topol, E. J., Califf, R. M., Simoons, M. L. 2000; 21 (5): 371-381

    Abstract

    Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial.In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect.Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment.The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process.

    View details for Web of Science ID 000085515100010

    View details for PubMedID 10666351

  • Cigarette smoking status and outcome among patients with acute coronary syndromes without persistent ST-segment elevation: Effect of inhibition of platelet glycoprotein IIb/IIIa with eptifibatide AMERICAN HEART JOURNAL Hasdai, D., Holmes, D. R., Criger, D. A., Topol, E. J., Califf, R. M., Wilcox, R. G., PAOLASSO, E., Simoons, M., Deckers, J., Harrington, R. A. 2000; 139 (3): 454-460

    Abstract

    Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers.The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain

    View details for Web of Science ID 000085761900014

    View details for PubMedID 10689260

  • Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes CIRCULATION Mark, D. B., Harrington, R. A., Lincoff, A. M., Califf, R. M., Nelson, C. L., Tsiatis, A. A., Buell, H., Mahaffey, K. W., Davidson-Ray, L., Topol, E. J. 2000; 101 (4): 366-371

    Abstract

    In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction).We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year.Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

    View details for Web of Science ID 000085064400011

    View details for PubMedID 10653826

  • Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial LANCET Topol, C. E., Califf, R. M., Simes, R. J., Van de Werf, F., Diaz, R., PAOLASSO, E., Aylward, P. E., KEECH, A., Klein, W., Piegas, L., Tomov, I., Armstrong, P. W., Widimsky, P., Grande, P., Halinen, M., Vahanian, A., Neuhaus, K., Dimas, A. P., Preda, I., Kristinsson, A., Tzivoni, D., Ardissino, D., White, H. D., Madsen, S., Sugrue, D., Sadowski, Z., Seabra-Gomes, R., Apetrei, E., Dalby, A., Betriu, A., Pfisterer, M., Verheugt, F., Fox, K., Bates, E. R., Gibler, W. B., Granger, C. B., Harrington, R. A., Hochman, J. S., Holmes, D. R., Kleiman, N. S., Lee, K. L., Moliterno, D. J., Newby, L. K., Ohman, E. M., Califf, R., Newby, K., Zillman, L., Lee, K., Lemons, P., McCourt, B., Campbell, C., Tardiff, B., Snapp, J., Bassett, K., Hodgson, P., Hannan, K., Kandzari, L., Hawkins, S., Hinman-Smith, E., McDougal, M., Raffetto, K., Thompson, D., Wehrle, T., Ange, C., Brown, R., Grissom, G., Heuckel, M., McCall, J., Pennachi, W., Spychala, M., Veasey, S., Pullium, M., Journey, T., Quintero, K., Mark, D., Davidson-Ray, L., Diner, L., Nelson, C., Sowers, C., Webb, G., Young, M., Bhapkar, M., Pacchiana, C., Sparapani, R., Tuttle, R., Weaver, D., Borzak, S., Douthat, L., Topol, E., Moliterno, D., Konczos, L., Baishnab, R., Baishnab, R., Bakos, A., Blashford, L., Bratsch, J., BROWN, K., Cadorini, E., Carlson, J., Clemmons, P., DELVALLE, M., Drabik, M., Fu, G., Gates, K., Gibson, Y., Heil, L., Hill, N., Klancar, R., McHale, B., Montague, E., Pasca, N., Pergi, L., Randall, R., Rosso, R., Sankovich, K., Smith, D., Wisniewski, L., Witkowski, M., Zovkic, V., Alexander, K., Bhatt, D., Brener, S., Campbell, L., Cho, L., COLE, C., Deedy, M., Foody, J., Gassler, J., Ghaffari, S., Haas, G., Kapadia, S., Lauer, M., Lauer, M. S., Lincoff, M., Lutton, S., Marso, S., Mukherjee, D., Patel, V., Penn, M., Robbins, M., Roe, M., Sila, C., Thamilarasan, M., Wagner, G., ARMSTRONG, P., Bestilny, S., Van de Werf, F., Budts, W., Graux, S., Luyten, A., Simes, J., KEECH, A., Kava, M., Bower, T., Chan, S., Crampton, L., Monro, C., Nayak, M., Parente, G., Riley, V., Wilton, D., Aylward, P., Dolan, S., Thomas, C., White, H., Scott, M., Frye, R., Alpert, J., Bertrand, M., Ryan, T., Fisher, L., Asarch, L., Smith, M., Lim, L., Bokslag, M., Chiu, P., Chung, J., Collins, S., Dougherty, C., Guimaraes, D., Hakim, Z., Mathieson, J., Montgomery, L., Novotny, B., Steiner, B., Wittke, B. 2000; 355 (9201): 337-345
  • Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Alexander, J. H., Sparapani, R. A., Mahaffey, K. W., Deckers, J. W., Newby, L. K., Ohman, E. M., Corbalan, R., Chierchia, S. L., Boland, J. B., Simoons, M. L., Califf, R. M., Topol, E. J., Harrington, R. A. 2000; 283 (3): 347-353

    Abstract

    Controversy surrounds the diagnostic and prognostic importance of slightly elevated cardiac markers in patients with acute coronary syndromes without ST-segment elevation.To investigate the relationship between peak creatine kinase (CK)-MB level and outcome and to determine whether a threshold CK-MB level exists below which risk is not increased.Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997.A total of 8250 patients with acute coronary syndromes without ST-segment elevation who had at least 1 CK-MB sample collected during their index hospitalization.Mortality at 30 days and 6 months, was assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3, >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic regression was used to determine the independent prognostic significance of peak CK-MB level after adjustment for baseline predictors of 30-day and 6-month mortality.Mortality at 30 days and 6 months increased from 1.8% and 4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2 % at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3 to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10 times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30-day and 6-month mortality (P<.001 for both).Our data show that elevation of CK-MB level is strongly related to mortality in patients with acute coronary syndromes without ST-segment elevation, and that the increased risk begins with CK-MB levels just above normal. In the appropriate clinical context, even minor CK-MB elevations should be considered indicative of myocardial infarction.

    View details for Web of Science ID 000084732400026

    View details for PubMedID 10647797

  • Redefining medical treatment in the management of unstable angina AMERICAN JOURNAL OF MEDICINE Braunwald, E., Califf, R. M., Cannon, C. P., Fox, K. A., Fuster, V., Gibler, W. B., Harrington, R. A., King, S. B., Kleiman, N. S., Theroux, P., Topol, E. J., Van de Werf, F., White, H. D., Willerson, J. T. 2000; 108 (1): 41-53

    Abstract

    In 1994, the Agency for Health Care Policy and Research sponsored the development of guidelines for diagnosing and managing patients with unstable angina. Since their publication, several important developments have occurred. The prognostic value of biochemical assays for cardiac-specific troponins T and I have been shown in many studies. The possible role for C-reactive protein in determining prognosis deserves further investigation. Substantial clinical benefits have been obtained with intravenous inhibitors of the platelet glycoprotein (GP) IIb-IIIa receptor (abciximab, eptifibatide, tirofiban) and with one of the low-molecular-weight heparins (enoxaparin). The therapeutic potential of other low-molecular-weight heparins, direct thrombin inhibitors, and oral GP IIb-IIIa inhibitors remains to be clarified. On the basis of this evidence, consideration should be given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina.

    View details for Web of Science ID 000084710800008

    View details for PubMedID 11059440

  • Recent clinical trials in acute coronary syndromes without persistent ST elevation CURRENT OPINION IN CARDIOLOGY Tolleson, T. R., Harrington, R. A. 1999; 14 (5): 403-411

    Abstract

    Acute coronary occlusion is a serious manifestation of coronary artery disease leading to significant short- and long-term morbidity and mortality. Traditionally classified as Q-wave myocardial infarction, non-Q-wave myocardial infarction, and unstable angina, these events are more appropriately termed acute coronary syndromes with and without ST-segment elevation, reflecting the diagnostic criteria used by clinicians to guide initial treatment strategies. Standard therapy with aspirin and heparin has been expanded with the low molecular weight heparin enoxaparin and the intravenous glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban. Debate continues as to whether a strategy of early intervention or initial conservative management is most appropriate. Continued clinical trials will help define optimal treatment strategies in this high-risk group of patients.

    View details for Web of Science ID 000082197900008

    View details for PubMedID 10500902

  • Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome - The platelet glycoprotein IIb IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial experience CIRCULATION McClure, M. W., Berkowitz, S. D., Sparapani, R., Tuttle, R., Kleiman, N. S., Berdan, L. G., Lincoff, A. M., Deckers, J., Diaz, R., Karsch, K. R., Gretler, D., Kitt, M., Simoons, M., Topol, E. J., Califf, R. M., Harrington, R. A. 1999; 99 (22): 2892-2900

    Abstract

    The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non-ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes.Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk.Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.

    View details for Web of Science ID 000080662900010

    View details for PubMedID 10359733

  • Use of glycoprotein IIb IIIa inhibition plus fibrinolysis in acute myocardial infarction JOURNAL OF THROMBOSIS AND THROMBOLYSIS Hudson, M. P., Greenbaum, A. B., Harrington, R. A., Ohman, E. M. 1999; 7 (3): 241-245

    Abstract

    Pharmacological reperfusion therapy for acute myocardial infarction with intravenous fibrinolytic agents improves survival yet fails to achieve early and complete coronary blood flow in nearly half of treated patients. In principle, glycoprotein (GP) IIb/IIIa inhibitors, potent antiplatelet agents, might improve the efficacy and clinical outcomes associated with fibrinolysis. Preclinical research suggests more rapid and effective reperfusion with combined platelet GP IIb/IIIa inhibition and fibrinolysis. Early clinical studies confirm improved early patency and more rapid electrocardiographic resolution, but increased bleeding complications, with the addition of GP IIb/IIIa antagonists to conventional fibrinolysis. Future studies may combine reduced-dose fibrinolytic therapy with GP IIb/IIIa inhibition to optimize efficacy and safety.

    View details for Web of Science ID 000081163600003

    View details for PubMedID 10373717

  • Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease CIRCULATION Kong, D. F., Califf, R. M., Miller, D. P., Moliterno, D. J., White, H. D., Harrington, R. A., Tcheng, J. E., Lincoff, A. M., Hasselblad, V., Topol, E. J. 1998; 98 (25): 2829-2835

    Abstract

    Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization.ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0. 51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0. 74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes).Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.

    View details for Web of Science ID 000077606900009

    View details for PubMedID 9860783

  • Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade LANCET Topol, E. J., Lincoff, A. M., Califf, R. M., Tcheng, J. E., Kleiman, N. S., Adelman, A. G., Burton, J. R., Talley, J. D., Ivanhoe, R. J., Ducas, C., Cheung, P. K., Schick, U., Badard, D., Kramer, J., Leary, J., Snyder, H., Wilson, R., Dearen, M., Caramori, P., Webber, S., Taylor, J., Ferrando, T., Cohen, E., Balleza, L., Rouse, C., Hogg, N., Kelly, T., Alston, S., Webb, J., Buller, E., Ricci, D. R., Mockman, S., Tanguay, J. F., Poitras, A. M., Timis, G., Davey, D., Coleman, P., Herrold-Runge, P., O'Neill, B. J., Foshey, K., Fitzgerald, N., Almond, D., Kostuk, W., WHITE, J., Oskalns, R., Gottlieb, R., Koren, P., Palazzo, D., Azrin, M., Barry, M. B., Blankenship, J., Demko, S. L., Kraft, P., Dvorak, L., Brown, R., Colclough, M., Stevens, K., Sarembock, I., Snyder, L., Sayre, S., Browne, K., Roy, M., Reen, B., Short, R., Thompson, M., Chiodo, V., Hoffman, D., Bass, T. A., Zenni, M., Rohman, G., Marquis, J. F., Labinaz, M., Jelley, J., French, W., Goldberg, S., Wang, S., Gradman, A., Boltey, L., Collins, J., Worley, S., Hollywood, L., Frey, L., Yakubov, S., Gilliland, C., Rodriguez, A., Potter, K., Taylor, M., Aji, J., Cleary, E., Tannenbaum, M., Hartz, A., Rund, M., Smigley, R., Lopez, J., Kunny, P., Hochman, J., Slater, J., Termey, D., Bates, E., Fox-Bruenger, P., Gonzalez, M., Jopperri, L., Runyon, J. P., Higby, N., Krucoft, M., Booth, T., Aguirre, F., Bach, R., Mechem, C., Azrin, M., Murphy, D., Cummins, F. E., Nonweiler, J., Sanz, M., COLE, C., Weston, M. W., Anderson, H. V., Weigelt, L., Larkin, T., JACKSON, B. J., Rosenberg, M. J., Tully, S., Hartman, C., Lunow, S., Lucore, C., Mishkel, G., McShane, K., Muhlestein, B., Jerman, J., Sander, G., Stevens, A., Chisholm, R., Del Core, M., Stengel, L., Cannata, R., Castle, V., DeLuca, S., Balog, C., Knuth, T., McCollough, T., Godfrey, N., Melton, J., Miller, D., Pulliam, M., Sapp, S., Sigmon, K. N., Templin, M., Montague, E., Carlson, J., Heil, L., Zovkic, V., Malone, K., Rodkey, S., Haas, G., Harrington, R., Kapadis, S., Campbell, L., Mukherjee, D., Deedy, M., Augostini, R., Alexander, J., Whellan, D., Bajzer, C., Rabbani, R., Clemons, P., Baishnab, R., Randall, R., Underwood, D., Lauer, M. A., Lauer, M. S., Roe, M., Farhy, R., Schweikert, R., Grady, T., Ellis, S., Moliterno, D., Debowey, D., Ivanc, T., Ols, L., Poliszcuk, R., Balazs, E., Witherspoon, B., Anderson, K. M., Barnathan, E., Cabot, C. F., Stoner, G. L., Weisman, H. F. 1998; 352 (9122): 87-92

    Abstract

    Coronary stenting with use of heparin, aspirin, and ticlopidine for thromboprophylaxis is performed in more than 500,000 patients per year worldwide. We did a randomised controlled trial to assess the role of platelet glycoprotein-IIb/IIIa blockade for use in elective stenting.At 63 hospitals in the USA and Canada, 2399 patients with ischaemic heart disease and suitable coronary-artery lesions were randomly assigned stenting plus placebo (n=809), stenting plus abciximab, a IIb/IIIa inhibitor (n=794), or balloon angioplasty plus abciximab (n=796). The primary endpoint was a combination of death, myocardial infarction, or need for urgent revascularisation in the first 30 days. All patients received heparin, aspirin, and standard pharmacological therapy.The primary endpoint occurred in 87 (10.8%) of 809 patients in the stent plus placebo group, 42 (5.3%) of 794 in the stent plus abciximab group (hazard ratio 0.48 [95% CI 0.33-0.69] p<0.001), and 55 (6.9%) of 796 in the balloon plus abciximab group (0.63 [0.45-0.88] p=0.007). The main outcomes that occurred less with abciximab were death and large myocardial infarction--7.8% in the placebo group, 3.0% for stent plus abciximab (p<0.001), and 4.7% for balloon angioplasty plus abciximab (p=0.01). Major bleeding complications occurred in 2.2% of patients assigned stent plus placebo, 1.5% assigned stent plus abciximab, and 1.4% assigned balloon angioplasty plus abciximab (p=0.38).Platelet glycoprotein-IIb/IIIa blockade with abciximab substantially improves the safety of coronary-stenting procedures. Balloon angioplasty with abciximab is safer than stenting without abciximab.

    View details for Web of Science ID 000074775100010

    View details for PubMedID 9672272

  • Myonecrosis after revascularization procedures JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Califf, R. M., Abdelmeguid, A. E., Kuntz, R. E., Popma, J. J., Davidson, C. J., Cohen, E. A., Kleiman, N. S., Mahaffey, K. W., Topol, E. J., Pepine, C. J., Lipicky, R. J., Granger, C. B., Harrington, R. A., Tardiff, B. E., Crenshaw, B. S., Bauman, R. P., Zuckerman, B. D., Chaitman, B. R., Bittl, J. A., Ohman, E. M. 1998; 31 (2): 241-251

    Abstract

    The detection of elevated cardiac enzyme levels and the occurrence of electrocardiographic (ECG) abnormalities after revascularization procedures have been the subject of recent controversy. This report represents an effort to achieve a consensus among a group of researchers with data on this subject. Creatine kinase (CK) or CK-MB isoenzyme (CK-MB) elevations occur in 5% to 30% of patients after a percutaneous intervention and commonly during coronary artery bypass graft surgery (CABG). Although Q wave formation is rare, other ECG changes are common. The rate of detection is highly dependent on the intensity of enzyme and ECG measurement. Because most events occur without the development of a Q wave, the ECG will not definitively diagnose them; even the ECG criteria for Q wave formation signifying an important clinical event have been variable. At least 10 studies evaluating > 10,000 patients undergoing percutaneous intervention have demonstrated that elevation of CK or CK-MB is associated not only with a higher mortality, but also with a higher risk of subsequent cardiac events and higher cost. Efforts to identify a specific cutoff value below which the prognosis is not impaired have not been successful. Rather, the risk of adverse outcomes increases with any elevation of CK or CK-MB and increases further in proportion to the level of intervention. This information complements similar previous data on CABG. Obtaining preprocedural and postprocedural ECGs and measurement of serial cardiac enzymes after revascularization are recommended. Patients with enzyme levels elevated more than threefold above the upper limit of normal or with ECG changes diagnostic for Q wave myocardial infarction (MI) should be treated as patients with an MI. Patients with more modest elevations should be observed carefully. Clinical trials should ensure systematic evaluation for myocardial necrosis, with attention paid to multivariable analysis of risk factors for poor long-term outcome, to determine the extent to which enzyme elevation is an independent risk factor after considering clinical history, coronary anatomy, left ventricular function and clinical evidence of ischemia. In addition, tracking of enzyme levels in clinical trials is needed to determine whether interventions that reduce periprocedural enzyme elevation also improve mortality.

    View details for Web of Science ID 000071796900001

    View details for PubMedID 9462562

  • IMMEDIATE AND REVERSIBLE PLATELET INHIBITION AFTER INTRAVENOUS ADMINISTRATION OF A PEPTIDE GLYCOPROTEIN IIB/IIIA INHIBITOR DURING PERCUTANEOUS CORONARY INTERVENTION AMERICAN JOURNAL OF CARDIOLOGY Harrington, R. A., Kleiman, N. S., KOTTKEMARCHANT, K., Lincoff, A. M., Tcheng, J. E., Sigmon, K. N., Joseph, D., Rios, G., Trainor, K., Rose, D., Greenberg, C. S., Kitt, M. M., Topol, E. J., Califf, R. M. 1995; 76 (17): 1222-1227

    Abstract

    We studied the pharmacokinetic and pharmacodynamic properties of integrelin, a novel platelet glycoprotein IIb/IIIa receptor inhibitor, in patients undergoing elective percutaneous coronary intervention. Patients were randomized to placebo (n = 19) or to 1 of 4 integrelin dosing regimens (total n = 54) that were studied sequentially. All patients received aspirin and heparin. Patients were followed until discharge for the occurrence of adverse clinical events: death, myocardial infarction, coronary artery bypass surgery, repeat intervention, or recurrent ischemia. Bleeding was the primary safety end point. Frequent blood sampling was performed for adenosine diphosphate-induced platelet aggregations. Simplate bleeding times were performed. Adverse clinical events occurred less often in the integrelin-treated patients, although the overall numbers were too small to make a definitive statement as to clinical efficacy. There was no significant increase in serious bleeding among integrelin-treated patients. The 2 highest integrelin boluses (180 and 135 micrograms/kg) immediately (15 minutes after the bolus) provided > 80% inhibition of adenosine diphosphate-induced platelet aggregation in > 75% of treated patients. A constant integrelin infusion of 0.75 micrograms/kg/min maintained this marked antiplatelet effect, whereas an infusion of 0.50 micrograms/kg/min allowed gradual recovery of platelet function. Elective coronary intervention was performed safely and with no significant increase in serious bleeding events using integrelin with aspirin and heparin as an antithrombotic regimen. Integrelin provided rapid, intense, and persistent ex vivo platelet inhibition during coronary intervention. This new antiplatelet agent may be beneficial in reducing platelet-mediated ischemic complications of percutaneous coronary intervention.

    View details for Web of Science ID A1995TK15100003

    View details for PubMedID 7503000

  • MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF THE PLATELET INTEGRIN GLYCOPROTEIN IIB/IIIA BLOCKER INTEGRELIN IN ELECTIVE CORONARY INTERVENTION CIRCULATION Tcheng, J. E., Harrington, R. A., KOTTKEMARCHANT, K., Kleiman, N. S., Ellis, S. G., Kereiakes, D. J., MICK, M. J., Navetta, F. I., Smith, J. E., Worley, S. J., Miller, J. A., Joseph, D. M., Sigmon, K. N., Kitt, M. M., DUMEE, C. P., Califf, R. M., Topol, E. J. 1995; 91 (8): 2151-2157