Key result
Among stable patients treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles had significantly less bleeding than non-carriers (36.1% vs 42.5%; HR 0.80; 95% CI 0.69-0.93; P=0.003).
Why the study?
Do CYP2C19 polymorphisms affect ischaemic and bleeding outcomes in stable outpatients treated with clopidogrel?
RCT (n=4,819)
randomized
Do CYP2C19 polymorphisms affect ischaemic and bleeding outcomes in stable outpatients treated with clopidogrel?
In stable outpatients, CYP2C19 loss-of-function alleles are associated with reduced bleeding complications but no difference in ischaemic outcomes when treated with clopidogrel.
Answers are grounded in this paper and cite their sources.
Should not alter clopidogrel use by CYP2C19 status in stable outpatients; leaves open need for randomized confirmation.
AIMS: Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. METHODS AND RESULTS: A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. CONCLUSION: No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817.
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Bhatt et al. (2012) conducted an RCT in Cardiovascular disease or multiple risk factors (n=4,819). Clopidogrel in CYP2C19 loss-of-function carriers vs. Clopidogrel in non-carriers was evaluated on any bleeding (HR 0.80, 95% CI 0.69-0.93, p=0.003). Among stable patients treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles had significantly less bleeding than non-carriers (36.1% vs 42.5%; HR 0.80; 95% CI 0.69-0.93; P=0.003).
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