Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis

Abstract

Background: Dual antiplatelet therapy is the standard of care after coronary stent placement but increases the bleeding risk. The effects of proton pump inhibitors (PPIs) on clopidogrel metabolism have been described, but the clinical significance is not yet definitive. We aimed to do an updated meta-analysis comparing outcomes in patients receiving clopidogrel with and without PPIs.

Methods: We systematically searched PubMed, Scopus and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) and controlled observational studies in patients taking clopidogrel stratified by concomitant PPI use. Heterogeneity was examined with the Cochran Q test and I(2) statistics; p values inferior to 0.10 and I(2) >25% were considered significant for heterogeneity.

Results: We included 39 studies with a total of 214 851 patients, of whom 73 731 (34.3%) received the combination of clopidogrel and a PPI. In pooled analysis, all-cause mortality, myocardial infarction, stent thrombosis and cerebrovascular accidents were more common in patients receiving both drugs. However, among 23 552 patients from eight RCTs and propensity-matched studies, there were no significant differences in mortality or ischaemic events between groups. The use of PPIs in patients taking clopidogrel was associated with a significant reduction in the risk of gastrointestinal bleeding.

Conclusions: The results of our meta-analysis suggest that PPIs are a marker of increased cardiovascular risk in patients taking clopidogrel, rather than a direct cause of worse outcomes. The pharmacodynamic interaction between PPIs and clopidogrel most likely has no clinical significance. Furthermore, PPIs have the potential to decrease gastrointestinal bleeding in clopidogrel users.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of study selection.

Figure 2

Forest plot of studies examining outcomes between patients taking proton pump inhibitor ( PPIs) with clopidogrel and those taking only clopidogrel: (A) overall mortality; (B) myocardial infarction.

Figure 3

Forest plot of studies examining outcomes between patients taking proton pump inhibitor (PPIs) with clopidogrel and those taking only clopidogrel: (A) definite stent thrombosis; (B) need for revascularisation; (C) cerebrovascular accidents; (D) acute coronary syndromes.

Figure 4

Forest plot of studies examining gastrointestinal bleeding between patients taking proton pump inhibitor (PPI) with clopidogrel and those taking only clopidogrel.

Figure 5

Forest plots of randomised controlled trials and propensity score matched studies examining outcomes between patients taking proton pump inhibitor (PPIs) with clopidogrel and those taking only clopidogrel: (A) overall mortality; (B) acute coronary syndromes; (C) myocardial infarction; (D) need for revascularisation; (E) cerebrovascular accidents; (F) gastrointestinal bleeding.