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Cytochrome p-450 polymorphisms and response to clopidogrel
Jessica L Mega1, Sandra L Close, Stephen D Wiviott
1Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. jmega@partners.org
The New England Journal of Medicine
|December 25, 2008
Summary
Reduced-function CYP2C19 alleles significantly lower clopidogrel
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Drug Metabolism
Background:
- Clopidogrel's antiplatelet effect relies on activation by cytochrome P-450 (CYP) enzymes.
- Genetic variations in CYP enzymes, particularly CYP2C19, can impair clopidogrel activation.
- Polymorphisms in CYP genes are common and may affect drug efficacy.
Purpose of the Study:
- To investigate the association between CYP gene functional variants and clopidogrel's active metabolite levels.
- To assess the impact of these genetic variants on platelet inhibition and cardiovascular outcomes in patients treated with clopidogrel.
Main Methods:
- Genotyping for functional CYP variants in 162 healthy subjects and 1477 acute coronary syndrome patients.
- Measurement of plasma clopidogrel active metabolite concentrations and platelet aggregation.
- Analysis of cardiovascular outcomes (death, MI, stroke, stent thrombosis) in the TRITON-TIMI 38 trial.
Main Results:
- CYP2C19 reduced-function allele carriers (30% of population) showed a 32.4% decrease in active metabolite levels and 9% less platelet inhibition.
- In the TRITON-TIMI 38 cohort, carriers had a 53% increased risk of major adverse cardiovascular events (death, MI, stroke).
- Carriers experienced a threefold higher risk of stent thrombosis compared to non-carriers.
Conclusions:
- Reduced-function CYP2C19 alleles are linked to lower clopidogrel active metabolite levels and diminished platelet inhibition.
- Individuals with these alleles face a significantly higher risk of adverse cardiovascular events, including stent thrombosis.
- Genetic testing for CYP2C19 variants may inform clopidogrel therapy decisions.
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