A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

作者：Kimmel, Stephen E.^*; French, Benjamin; Kasner, Scott E.; Johnson, Julie A.; Anderson, Jeffrey L.; Gage, Brian F.; Rosenberg, Yves D.; Eby, Charles S.; Madigan, Rosemary A.; McBane, Robert B.; Abdel-Rahman, Sherif Z.; Stevens, Scott M.; Yale, Steven; Mohler, Emile R., III; Fang, Margaret C.; Shah, Vinay; Horenstein, Richard B.; Limdi, Nita A.; Muldowney, James A. S., III; Gujral, Jaspal; Delafontaine, Patrice; Desnick, Robert J.; Ortel, Thomas L.; Billett, Henny H.

来源：New England Journal of Medicine, 2013, 369(24): 2283-2293.

DOI：10.1056/NEJMoa1310669

• OPTIMAL ANTICOAGULATION
• GENETICS
• TRIAL
• CLARIFICATION
• PREDICT

BackgroundThe clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. @@@ MethodsWe 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. @@@ ResultsAt 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. @@@ ConclusionsGenotype-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 ClinicalTrials.gov number, NCT00839657.) @@@ In this trial, 1015 patients were assigned to the use of either a genotype-guided algorithm or a clinically guided algorithm for warfarin dosing during the first 5 days. At 4 weeks, there was no significant difference in the percentage of time in the therapeutic INR range. The need for clinical trials before widespread adoption of genotype-guided drug dosing and selection remains widely debated.(1)-(4) Warfarin therapy has served as a model for the potential for pharmacogenetics to improve patient care.(1) Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. However, the clinical utility of starting warfarin at the maintenance dose predicted by genotype-guided algorithms has been tested only in small trials, none of which were definitive.(5)-(8) In contrast, observational studies have suggested potential benefits from genotype-guided dosing.(9),(10) In addition, previous clinical trials could not determine ...

• 出版日期2013-12-12