Major Finding: Cardiovascular death, myocardial infarction, or stroke occurred in 13% of patients homozygous for the C3435T genotype who received clopidogrel. The rate was 8% in patients on clopidogrel with either of two other genotype profiles (homozygous for C3435C or heterozygous with one copy of each genotype).
Data Source: TRITON-TIMI 38 multicenter study that randomized acute coronary syndrome patients to treatment with clopidogrel or prasugrel and included 2,943 patients with DNA available for pharmacogenetic analysis.
Disclosures: TRITON-TIMI 38 was supported by grants from Daiichi-Sankyo and Eli Lilly. Dr. Mega disclosed financial ties to Bayer Healthcare, Bristol-Myers Squibb, Eli Lilly, Schering-Plough, Johnson & Johnson, and Daiichi Sankyo.
ATLANTA — A second, newly recognized type of metabolic polymorphism has been found to reduce the clinical efficacy of the antiplatelet drug clopidogrel in patients with coronary disease.
In contrast, a similar antiplatelet drug, prasugrel, does not require metabolic conversion to its active form and was not associated with a change in its clinical activity related to this polymorphism, Dr. Jessica L. Mega and her associates reported in a poster at the annual meeting of the American College of Cardiology.
Clopidogrel's activity was previously shown to be affected by a polymorphism in the liver enzyme cytochrome P 2C19, estimated to occur in 2%-14% of the population. This finding formed the basis of a boxed warning imposed by the Food and Drug Administration on clopidogrel's labeling on March 12.
The newly found polymorphism also limits clopidogrel's activity and affects a cell membrane protein that controls drug efflux out of intestinal enterocytes. The homozygous polymorphism enhances efflux, thus interfering with metabolic conversion of clopidogrel. The polymorphism occurred in 27% of more than 2,900 patients with acute coronary syndrome (ACS) enrolled in a recent drug study, said Dr. Mega, a cardiologist at Brigham and Women's Hospital in Boston.
Patients with ACS who are homozygous for the polymorphism, a genotype known as C3435T, “have less platelet inhibition [from clopidogrel] and are at significantly increased risk of recurrent ischemic events in the setting of treatment with clopidogrel,” the researchers said.
The analysis used data collected in the TRITON-TIMI 38 study, which compared clopidogrel and prasugrel in a randomized trial of more than 13,000 patients with ACS treated with either drug for 15 months after percutaneous coronary intervention (N. Engl. J. Med. 2007;357:2001-15). Dr. Mega and her associates focused on the 2,943 patients who had provided DNA specimens that allowed pharmacogenetic analysis. Their mean age was 60 years, and slightly more than 25% were women.
The incidence of the primary end point—cardiovascular death, myocardial infarction, or stroke—occurred in 13% of patients homozygous for the C3435T genotype who received clopidogrel, compared with incidence rates of 8% in patients on clopidogrel with either of the other two genotype profiles (homozygous for C3435C, or heterozygous with one copy of each genotype).
In a hazard ratio analysis, patients homozygous for C3435T and on clopidogrel had a 72% increased risk for the combined cardiovascular disease end point. These patients had no significant difference in bleeding rates, compared with other patients. Among TRITON-TIMI 38 patients treated with prasugrel who had DNA specimens available, variations in the C3435 genotype had no significant effect on primary end point rates.
Dr. Mega and her associates also studied 287 healthy people who had participated in other clopidogrel and prasugrel studies. A quarter tested homozygous for C3435T, and when they received clopidogrel, their reduction in platelet aggregation underwent an absolute 7% blunting compared with heterozygote people, a significant difference. In this study, too, the homozygous C3435T genotype had no significant impact on the platelet effects of prasugrel.