Meta-Analyses of the Association Between Cytochrome CYP2C19 Loss- and Gain-of-Function Polymorphisms and Cardiovascular Outcomes in Patients With Coronary Artery Disease Treated With Clopidogrel

Study Questions:

What is the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel?

Methods:

A comprehensive literature search was conducted. A random-effects model was used to summarize the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity. The investigators calculated the overall hazard ratio (HR), 95% confidence interval (CI), and two-sided p value under a random-effects model (RE; DerSimonian and Laird).

Results:

Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event (HR, 1.23; 95% CI, 0.97-1.55). Substantial heterogeneity was observed between studies (I2 = 35.6), which was partially explained by the study sample size; the pooled HR was higher among studies with a sample size <500 patients (HR, 3.55; 95% CI, 1.66-7.56), and lower among studies with a sample size ≥500 (HR, 1.06; 95% CI, 0.89-1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR, 2.24; 95% CI, 1.52-3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR, 0.75; 95% CI, 0.66-0.87), and a higher risk of major bleeding (HR, 1.26; 95% CI, 1.05-1.50).

Conclusions:

The authors concluded that not only CYP2C19 loss-of-function, but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel.

Perspective:

This meta-analysis suggests significant heterogeneity between studies, analyzing the relationship between CYP2C19 loss-of-function alleles and major cardiovascular outcomes. This heterogeneity was partially related to study sample size: smaller studies reported a significant association between the loss-of-function alleles and a higher risk of cardiovascular outcomes, whereas no significant effect was observed in the pooled analysis of studies with a sample size >500 patients. Loss-of-function alleles were associated with a higher risk of stent thrombosis, and the presence of a CYP2C19 gain-of-function allele was associated with a lower risk of major cardiovascular recurrences and a higher risk of major bleeding. Overall, these results indicate that not only CYP2C19 loss-of-function, but also gain-of-function alleles should be considered to define the response to clopidogrel.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease

Keywords: Incidence, Coronary Artery Disease, Recurrence, Biological Markers, Thrombosis, Cardiology, Angioplasty, Hemorrhage, Stents


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