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The Relationship Between CYP2C19 Polymorphisms and Ischaemic and Bleeding Outcomes in Stable Outpatients: The CHARISMA Genetics Study
Study Questions:
What is the impact of CYP2C19 polymorphisms on ischemic and bleeding events?
Methods:
A subset of patients from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who consented to genotyping was analyzed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischemic and bleeding events were compared between carriers and noncarriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel versus placebo. Cox proportional hazards models and Kaplan–Meier survival analysis were used to evaluate the effect of CYP2C19 genotype on the time to primary or secondary efficacy events.
Results:
A total of 4,819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers (36.1% [240/665] vs. 42.5% [681/1,601] in noncarriers; hazard ratio, 0.80; 95% confidence interval, 0.69-0.93; p = 0.003 [genotype/treatment interaction, p value = 0.023}). The CYP2C19 gain-of-function alleles did not affect ischemic or bleeding endpoints.
Conclusions:
The authors concluded that no relationship was seen between CYP2C19 status and ischemic outcomes in stable patients treated with clopidogrel.
Perspective:
This study reports no relationship between CYP2C19 genotype status and ischemic outcomes in a subset of patients from a large trial with a stable, diverse pattern of atherosclerotic disease or for being at risk for atherothrombotic disease. These results differ from several previous studies of stented patients showing an adverse association with loss-of-function alleles. In the present analysis, gain-of-function carriers did not have more bleeding than noncarriers with clopidogrel treatment. However, loss-of-function carriers did have significantly less overall bleeding than noncarriers with clopidogrel therapy, suggesting less antiplatelet response. This may become more of an issue in patients who have undergone recent stenting procedures or those with acute coronary syndrome.
Keywords: Acute Coronary Syndrome, Polymorphism, Genetic, Platelet Aggregation Inhibitors, Cardiology, Composite Resins, Cardiovascular Diseases, Risk Factors, Ticlopidine, Genotype, Hemorrhage
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