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- Title
Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Outcomes During Warfarin Therapy.
- Authors
Higashi, Mitchell K.; Veenstra, David L.; Kondo, L. Midori; Wittkowsky, Ann K.; Srinouanprachanh, Sengkeo L.; Farin, Fred M.; Rettie, Allan E.
- Abstract
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, χ[sup 2][sub 5] = 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...
- Subjects
WARFARIN; ANTICOAGULANTS; PHARMACODYNAMICS; CLINICAL medicine
- Publication
JAMA: Journal of the American Medical Association, 2002, Vol 287, Issue 13, p1690
- ISSN
0098-7484
- Publication type
Article
- DOI
10.1001/jama.287.13.1690