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.
To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation
and bleeding events during warfarin therapy.
Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle,
Wash.
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.
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.
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, chi(2)(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
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).
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.