MedWire News: Variant forms of a cytochrome P-450 (CYP) enzyme alter a patient’s ability to metabolize clopidogrel, say US researchers who found acute coronary syndromes (ACS) patients with a reduced-function gene had a greater risk for adverse outcomes than other individuals.
The team found that patients carrying the CYP2C19 gene – found in around 30% of White, 40% of Black and 55% of East Asian individuals – had significantly poorer pharmacokinetic and pharmacodynamic responses to clopidogrel than noncarriers.
“Our results provide strong evidence linking CYP genetic variation to a reduced exposure to the active drug metabolite, less platelet inhibition, and less protection from recurrent ischemic events in persons receiving clopidogrel,” report Jessica Mega (Brigham and Women’s Hospital, Boston, Massachusetts) and co-authors.
They add: “Our findings show that in patients with ACS treated with clopidogrel, the same variants in CYP2C19 were associated with adverse clinical outcomes, including a rate of death from cardiovascular causes, myocardial infarction, or stroke that was more than 50% greater and a rate of stent thrombosis that was greater by a factor of three than the rate in noncarriers.”
The researchers examined the impact of five CYP gene variants on plasma concentration of the clopidogrel active drug metabolite and platelet inhibition in 162 healthy individuals.
They found that the 34% of participants with at least one copy of the CYP2C19 reduced-function allele had a 32.4% reduction in plasma levels of the active metabolite than participants without the variant gene. This was accompanied by a relative 25% reduction in pharmacodynamic platelet aggregation response to clopidogrel compared with noncarriers.
Meanwhile, individuals carrying the reduced-function CYP2B6 allele had a 15.7% relative reduction in plasma exposure to the clopidogrel active metabolite and a reduced platelet aggregation response to clopidogrel compared with noncarriers.
In contrast, the CYP2C9, CYP3A5, and CYP1A2 alleles had no impact on pharmacokinetic or pharmacodynamic responses to clopidogrel.
The researchers then examined the impact of the CYP2C19 allele on the outcomes of 1477 clopidogrel-treated ACS patients participanting in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38.
They found that patients carrying the CYP2C19 allele were significantly more likely than other patients to reach the primary composite outcome of death from cardiovascular causes, myocardial infarction, or stroke (12.1% vs 8.0%, hazard ratio [HR]=1.53).
CYP2C19 carriers were also significantly more likely to experience stent thrombosis than noncarriers (2.6% vs 0.8%, HR=3.09).
The study is published in the New England Journal of Medicine, accompanying a second study, also reported by MedWire News, demonstrating a increased risk for adverse outcome after myocardial infarction in CYP2C19 carriers.
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