New analysis evaluated impact of genetic variation on response to prasugrel


A new substudy from 1,466 patients from the phase III TRITON-TIMI 38 clinical trial showed that patients who took prasugrel and had a reduced function of the CYP2C19 gene did not have an increased risk of cardiovascular death, heart attack or stroke compared with those patients who had normal function. The substudy results were published online in Circulation on 4 May 2009.

Prasugrel is a “prodrug” that requires the use of cytochrome P450 (CYP) enzymes to convert the drug into the active metabolite. Approximately 30% of Caucasians and 60% of Asians have reduced function in the CYP2C19 gene, which is part of the CYP system and encodes the enzymes that are responsible for converting prasugrel into its active form.

In the substudy, researchers examined how variation in cytochrome P450 (CYP) genes affected the response to prasugrel. In prasugrel-treated patients with acute coronary syndromes who underwent percutaneous coronary intervention, the incidence of the combined endpoint of cardiovascular death, heart attack or stroke was 8.5% (n=407) in those who carried at least one variant in the CYP2C19 gene that reduced its function versus 9.8% (n=1048) in patients without a genetic variant (p=.27). In addition, the rate of stent thrombosis in carriers of the reduced-function variant in the CYP2C19 gene compared with noncarriers treated with prasugrel was .5% vs. 1%, respectively (p=.48). The results also showed that rates on noncoronary artery bypass graft-related TIMI major or minor bleeding did not significantly differ by genetic variant among those treated with prasugrel.

“It is well documented in the medical literature that particular genetic variants in the CYP2C19 gene are associated with an increased risk of cardiovascular outcomes in patients treated with clopidogrel,” said Dr Jessica Mega, Brigham and Women’s Hospital, Boston, USA, and investigator at the TIMI Study Group. “We wanted to test if these genetic variants have a similar effect in patients who took prasugrel. Our findings showed that variation in the CYP2C19 gene did not appear to influence the rate of cardiac events in patients treated with prasugrel in this study.”
This prespecified analysis was designed to examine whether there is a genetic variation in DNA that could affect patient response to antiplatelet therapy. The pharmacogenetic analyses with prasugrel examined DNA samples from 1,466 patients from the TRITON-TIMI 38 clinical trial.

The genetic subanalysis was not powered to make efficacy comparisons between clopidogrel and prasugrel based on genetic variations.

The main TRITON-TIMI 38 clinical trial, previously published in the New England Journal of Medicine in November 2007 (Vol. 357 No.20), compared prasugrel with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. In the primary analysis of the study, prasugrel reduced the risk of the combined endpoint of cardiovascular death, heart attack, or stroke by 19% (9.9% vs. 12.1%), with an increased risk of major bleeding by 32% compared with clopidogrel (2.4% vs. 1.8%), which included life-threatening and fatal bleeding.