Pharmacogenetics of clopidogrel in patients with acute coronary syndromes

Abstract

Background:

The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndromes, and is therefore one of the most frequently prescribed drugs worldwide. Accumulating data suggest that the response to clopidogrel is characterised by significant inter-patient variability in the degree of platelet inhibition and the risk of cardiovascular events. Recent research findings have highlighted the role of genetic variations in determining antiplatelet response variability, and this has aroused interest in genotyping all thienopyridine-eligible patients in order to identify those who would be at increased risk of harm if treated with clopidogrel. This study tested the hypothesis that selecting antiplatelet therapy for patients with acute coronary syndromes (ACS) on the basis of a combination of genetic and clinical characteristics would lead to better clinical outcomes in comparison with the standard of care which bases the selection on clinical characteristics alone. Methods: Consecutive patients hospitalised for ACS were randomly assigned to the standard or the pharmacogenomic arm, which included the genotyping of ABCB1, CYP2C19*2 and CYP2C19*17 by means of an ST Q3 system. In the pharmacogenomic group, clopidogrel, prasugrel or ticagrelor were selected on the basis of an algorithm that considered clinical variables and genetic findings made available within 70 minutes at each patient’s bedside. All of the patients were followed-up for 12 ± 1 months for the occurrence of the primary composite end-point of cardiovascular death and the first occurrence of non-fatal myocardial infarction, non-fatal stroke and BARC 3 to 5-defined major bleeding. Results: After the enrolment of 888 patients, the study was prematurely stopped. Clopidogrel was used more frequently in the standard arm (50.7% vs 43.3%), ticagrelor more frequently in the pharmacogenomic arm (42.6% vs 32.7%; P=0.02), whereas prasugrel was equally used in both arms. The primary end-point occurred in 71 patients (15.9%) in the pharmacogenomic arm and in 114 (25.9%) in the standard of care arm (HR 0.58; 95% CI 0.43 to 0.78; P<0.001). Conclusion: A personalised approach to the selection of antiplatelet therapy for ACS patients leads to a clinically meaningful reduction in the composite end-point of ischemic and bleeding events. The trial has been registered at www.clinicaltrials.gov with the identifier NCT03347435 “Pharmacogenetics of clopidogrel in patients with acute coronary syndromes”.