Patients with a certain genetic variation who received the antiplatelet drug clopidogrel had a decreased platelet response to treatment and among those who had percutaneous coronary intervention (procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries) had an increased risk of having a cardiovascular event in the following year than patients who did not have this variant, according to a study in the August 26 issue of JAMA.
"Dual antiplatelet therapy, including clopidogrel and aspirin, inhibits platelet function, preventing ischemic events and improving outcomes following acute coronary syndromes [such as heart attack or unstable angina] and percutaneous coronary intervention (PCI)," the authors write as background information in the article. Clopidogrel therapy improves outcomes by inhibiting adenosine diphosphate (ADP; a nucleotide)-stimulated platelet activation. However, variability in response to clopidogrel is well established, with nonresponsiveness related to recurrent ischemic events. Some research has suggested that genetic variations may affect clopidogrel response, specifically the gene variant CYP2C19*2.
Alan R. Shuldiner, M.D., of the University of Maryland School of Medicine, Baltimore, and colleagues performed a genome-wide association study of ADP-stimulated platelet aggregation to identify genes associated with variation in clopidogrel response. In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), the researchers administered clopidogrel for 7 days to 429 healthy Amish persons and measured platelet response. The population in this study (Old Order Amish) are a relatively homogeneous group in which confounding variables (factors that can influence outcomes), including medication usage and lifestyle, are minimized. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant. Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention.