Variants in genes that control the cytochrome P450 pathway can reduce the beneficial effects of clopidogrel, significantly increasing the rate of cardiovascular death, heart attack, stroke, and stent thrombosis in persons who carry the polymorphisms.
The variants “were associated with adverse clinical outcomes … more than 50% greater, and a rate of stent thrombosis that was greater by a factor of 3 than the rate in noncarriers,” Dr. Jessica L. Mega and her associates reported (N. Engl. J. Med. 2009;360:354-62).
The cytochrome P450 pathway transforms clopidogrel into an active metabolite. Genetic variants that reduce the pathway's enzymatic function also decrease this transformation, thus reducing exposure to the active metabolite, wrote Dr. Mega of Brigham and Women's Hospital, Boston, and her colleagues. The reduced-function variant is common, occurring in about 30% of whites, 40% of blacks, and 55% of East Asians.
The two-pronged study analyzed the alleles' pharmacokinetic effects in healthy patients who were included in several drug studies, and its clinical effects in patients who received clopidogrel during the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel [Clopidogrel]-Thrombolysis in Myocardial Infarction 38) study.
The pharmacokinetic study measured plasma concentrations of clopidogrel's active metabolite in 162 subjects, and sorted the results according to five genes known to affect the enzymatic pathway. Carriers of at least one of the reduced-function alleles of the CYP2C19 gene had a 32% reduction in the active metabolite, compared with noncarriers, and exhibited a 9% decrease in pharmacodynamic response. The reduced response was seen after a loading dose and during maintenance therapy.
The clinical outcomes analysis included data on 1,477 patients who had been assigned to clopidogrel treatment in TRITON-TIMI 38, and who had provided DNA samples. At least one reduced-function CYP2C19 allele was present in 27% of the study population.
Overall, carriers were 50% more likely than noncarriers to experience one of the study's primary outcomes. On individual outcomes, carriers were nearly five times more likely to die from cardiovascular causes, 38% more likely to have had a nonfatal heart attack, and four times more likely to have had a nonfatal stroke.
Carriers were also three times more likely to experience stent thrombosis than were noncarriers. The CYP2C19*2 allele was present in 95% of patients who were classified as having a reduced-function allele.