The Effect of Rabeprazole on the Antiplatelet Efficacy of Clopidogrel: A Systematic Review

Introduction: Clopidogrel is a P2Y12 receptor antagonist given to patients with coronary heart disease, usually in combination with aspirin. It is metabolized to its active component through the cytochrome P450 2C19 (CYP2C19) isoenzyme. Proton pump inhibitors (PPI) are commonly used in patients who are receiving clopidogrel, especially those at high-risk for gastrointestinal bleeding. However, certain PPIs are likewise metabolized through the CYP2C19 isoenzyme. Co-administration of the two classes of drugs may lead to lower levels of clopidogrel, leading to lower antiplatelet efficacy and lower effects on cardiovascular disease prevention of the drug. Objective: To determine the effects of rabeprazole on platelet activity, major adverse cardiovascular outcomes and gastrointestinal bleeding among patients receiving clopidogrel Methodology: We performed this meta-analysis that included all types of studies (randomized controlled trials, case control studies, prospective and retrospective cohort studies) that investigated rabeprazole versus no rabeprazole or placebo. The population consisted of patients who received clopidogrel for any indication with concomitant administration of rabeprazole versus clopidogrel alone. Randomized trials were assessed using Cochrane’s Collaboration tool for assessment of risk of bias. For non randomized studies, Newcastle-Ottawa Quality Assessment Scale for cohort studies was used. Dichotomous data were analyzed using risk ratio and 95% confidence interval, while continuous variables were analyzed using mean differences and standard deviation. Heterogeneity was tested using chi-square test and I2 statistics. Results: There were no statistically significant differences noted in the outcomes of maximal platelet aggregation (mean difference 0.75, 95% CI -3.85 to 5.35), platelet reactivity index (mean difference -0.75, 95% CI -5.11 to 3.61), total cardiovascular events (RR 2.64, 95% CI 0.65 to 10.75) and gastrointestinal bleeding (RR 0.72, 95% CI 0.34 to 1.55) between clopidogrel-treated patients on rabeprazole compared to those without.. Data were not heterogenous, except on the outcome of total cardiovascular events. An influence analysis showed that removal of one trial made the outcome non-heterogenous, but the outcome difference was still not statistically significant (RR 1.25, 95% CI 0.66 to 2.37). Conclusion: Rabeprazole in addition to clopidogrel did not significantly affect maximal platelet aggregation, platelet reactivity index, gastrointestinal bleeding and cardiovascular outcomes.