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N Engl J Med. 2013 Dec 12;369(24):2283-93. doi: 10.1056/NEJMoa1310669. Epub 2013 Nov 19.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

Collaborators (198)

McBane RD, Metzger K, Lexvold N, Streichert-Blair A, Wysokinski W, Ransone T, Randolph J, Black J, O'Kane D, Christiansen P, Abdel-Rahman SZ, Clark CA, Snow LE, vonMarrensdorff H, Anderson KE, Nekhayeva I, Hallberg CK, Garcia C, Albright KJ, Mitchell C, Stevens SM, Woller SC, Peterson CP, Butler AR, Carlquist JF, Yale S, Kohnhorst D, Strey SK, Burmester JK, Schmelzer J, Caldwell M, Mazza JJ, Bhupathi S, Johnson JA, Lopez L, Zumberg M, Langaee T, Elewa H, Shahin M, Mohamed M, Chang SS, Mohler ER 3rd, Medenilla E, Rivera G, van Deerlin V, Fang MC, Magan Y, Shin J, Yglecias L, Wu A, Shah V, Kaatz S, Ellsworth S, Gikas H, Chitale D, Horenstein RB, Zhao RY, Shuldiner AR, Marron J, Fred-Omojole O, Kiser K, Sturpe D, Lee M, Limdi NA, Brown TM, Alexander J, Messiaen LM, Hill R, Dudley A, Muldowney JA 3rd, Neal T, Freehardt D, Vnencak-Jones C, Gujral J, Sharma G, Smith C, Best P, Elewa H, Deremer CE, Keller KJ, Liu S, Wang CY, Delafontaine P, Irimpen A, Ali G, Arain S, O'Meallie L, Martin-Schild SB, McDuffie R, Japa S, Asafu-Adjaye NO, Bowers S, Eloby-Childress S, Morrison E, Desnick RJ, Halperin JL, van der Zee S, Rothlauf E, Cohen I, Doheny DO, Blanchard L, Scott S, Ortel TL, Gleim MA, Sexton PA, Hall S, Jordan L, Billett HH, Naeem RC, Maala-Gentolia C, Gage BF, Do E, Venker B, Pendleton RC, Napoli L, Rondina M, McMillin G, Califf RM, Abdel-Rahman SZ, Anderson JL, Billett HH, Bookman E, Caldwell MD, Delafontaine P, Desnick RJ, Eby CS, Ellenberg JH, Fang MC, French B, Gage BF, Geller NL, Goldberg S, Goldhaber SZ, Gujral J, Hart RG, Hindorff LA, Horenstein RB, Johnson JA, Kimmel SE, Limdi NA, McBane RD, Manolio TA, Mohler ER 3rd, Muldowney JA 3rd, Ortel T, Pendleton RC, Rosenberg YD, Shah V, Stevens SM, Xu D, Yale S, Califf RM, Anderson JL, Gage BF, Johnson JA, Kimmel SE, Rosenberg YD, Wyse D, Ansell J, Crowther M, Deverka P, Richardson D, Tracy R, Kimmel SE, Ellenberg JH, French B, Kasner SE, Baldwin DA, Ballard S, Brensinger C, Cifelli D, Durborow M, Durborow S, Glick HA, Helker C, Jaskowiak J, Madigan RA, Rockwell K Jr, Wang X, Wang Y, Rosenberg YD, Goldberg S, Geller NL, Bursie Y, Hasan A, Iturriaga E, Xu D, Bookman E, Hindoff LA, Manolio TA, Eby CS, Porche-Sorbet R, King C, Kasner SE, Messé S, Goldhaber SZ, Halperin JL, Stevens SM.

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The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.


We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.


At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.


Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG number, NCT00839657.).

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