N Engl J Med. 2009 Feb 19;360(8):753-64. doi: 10.1056/NEJMoa0809329.

Estimation of the warfarin dose with clinical and pharmacogenetic data.

International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA.

Collaborators (96)

Lee MT, Chen YT, Wen MS, Lee MT, Caraco Y, Achache I, Blotnick S, Muszkat M, Shin JG, Kim HS, Suarez-Kurtz G, Perini JA, Silva-Assunção E, Anderson JL, Horne BD, Carlquist JF, Caldwell MD, Berg RL, Burmester JK, Goh BC, Lee SC, Kamali F, Sconce E, Daly AK, Limdi NA, Wu AH, Johnson JA, Langaee TY, Feng H, Cavallari L, Momary K, Pirmohamed M, Jorgensen A, Toh CH, Williamson P, McLeod H, Evans JP, Weck KE, Kimmel SE, Brensinger C, Nakamura Y, Mushiroda T, Veenstra D, Meckley L, Rieder MJ, Rettie AE, Wadelius M, Eriksson N, Melhus H, Stein CM, Roden DM, Schwartz U, Kurnik D, Gage BF, Deych E, Lenzini P, Eby C, Chen LY, Deloukas P, Limdi NA, Caldwell MD, Motsinger-Reif A, Altman RB, Sagreiya H, Klein TE, Srinivasan BS, Eriksson N, Wu AH, Wagner MJ, Johnson JA, Kimmel SE, Page D, Lantz E, Chang T, Ritchie M, Gage BF, Deych E, Lee MT, Lu LS, Shin JG, Caldwell MD, Klein TE, Altman RB, Srinivasan BS, Limdi NA, Johnson JA, Kimmel SE, Wagner MJ, Page D, Gage BF, Ritchie M, Klein TE, Altman RB, Srinivasan BS, Wagner MJ, Deych E.

Erratum in

N Engl J Med. 2009 Oct 15;361(16):1613. Dosage error in article text.

Abstract

BACKGROUND:

Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

METHODS:

Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

RESULTS:

In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).

CONCLUSIONS:

The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

2009 Massachusetts Medical Society