Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups: integration of the TRITON-TIMI 38 trial data.
BACKGROUND
Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON-TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced-function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non-ST segment elevation myocardial infarction is currently uncertain.


RESULTS
An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38 trial. Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39-0.83]. For CYP2C19 extensive metabolizers (∼70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80-1.20).


CONCLUSIONS
Integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.
Sorich
M J
MJ
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia. michael.sorich@unisa.edu.au
Vitry
A
A
Ward
M B
MB
Horowitz
J D
JD
McKinnon
R A
RA
D000368:Aged; D000789:Angina, Unstable / Q000188:drug therapy; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077144:Clopidogrel; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy; D010597:Pharmacogenetics; D010879:Piperazines / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use; D012306:Risk; D013876:Thiophenes / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine