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Mitchell K. Higashi, PhD; David L. Veenstra, PharmD,PhD; L. Midori Kondo, PharmD; Ann K. Wittkowsky, PharmD; Sengkeo L. Srinouanprachanh, BS; Fred M. Farin, MD; Allan E. Rettie, PhD

JAMA. 2002;287:1690-1698.

Context  Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established.

Objective  To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy.

Design and Setting  Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash.

Participants  Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included.

Main Outcome Measures  Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events.

Results  Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, ²₅ = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P = .004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86).

Conclusions  The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

Author Affiliations: Pharmaceutical Outcomes Research and Policy Program (Drs Higashi and Veenstra), Institute for Public Health Genetics (Dr Veenstra), and Department of Pharmacy Services (Drs Kondo and Wittkowsky), University of Washington Medical Center; Molecular Biomarkers Laboratory, Center for Ecogenetics and Environmental Health (Ms Srinouanprachanh and Dr Farin); and Department of Medicinal Chemistry (Dr Rettie), University of Washington, Seattle.

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