Meta-analysis: The Effects of Proton Pump Inhibitors on Cardiovascular Events and Mortality in Patients Receiving Clopidogrel

C. S. Kwok; Y. K. Loke


Aliment Pharmacol Ther. 2010;31(8):810-823. 

In This Article

Abstract and Introduction


Background Recent studies have suggested an adverse interaction between proton pump inhibitors (PPI) and clopidogrel.
Aim To perform a meta-analysis of cardiovascular outcomes and mortality in patients taking clopidogrel, with and without concomitant PPI.
Methods We searched MEDLINE, EMBASE, Cochrane Controlled Trials Register in October 2009, and checked conference abstracts for randomized and nonrandomized studies that reported the risk of cardiovascular events and mortality with PPI exposure in patients taking clopidogrel. We performed random effects meta-analysis, stratified by study design and assessed heterogeneity using the I 2 statistic.
Results Our review included 23 studies covering 93 278 patients. There was substantial heterogeneity in the meta-analyses of major cardiovascular events (19 studies, I 2 = 79%) or myocardial infarction (12 studies, I 2 = 77%). Analysis of propensity-matched or randomized trial participants showed no associated cardiovascular risk with PPIs, whereas other observational studies generally showed a significant association. Meta-analysis of 13 studies showed no significant association between PPI use and overall mortality (RR 1.09, 95% CI: 0.94–1.26, P = 0.23, I 2 = 60%).
Conclusion As there are conflicting and inconsistent data regarding the adverse clopidogrel–PPI interaction, clinicians should focus on potential harm from ulcers/haemorrhage before deciding to omit PPIs in patients taking clopidogrel.


There is currently significant controversy regarding cardiovascular (CV) adverse events arising from a potential drug interaction with concomitant use of clopidogrel and proton pump inhibitors (PPI).[1–3] On one hand, a number of recent commentaries from experts in the field have argued that there is no evidence that this potential drug interaction carries any major clinical impact.[4,5] In contrast, the US Food and Drug Administration (FDA) recently issued an updated statement cautioning against concomitant clopidogrel and PPI use[6] and this stance appears to be shared by some other researchers who believe that there is a genuine clinical problem.[7]

Given that there has now been a rapid profusion of diverse study designs reporting widely varying results, it seems likely that different opinions may be formed depending on the selection of studies that one has access to. In this complex situation, an up-to-date systematic review of all currently available data may help clarify things. Moreover, when data from many different types of studies are available, the Cochrane Adverse Methods Group recommends that such an analysis can be usefully stratified according to type of study design.[8] This is particularly important when the risk or level of bias varies with the methods and design used in particular studies.

As such, the aim of our meta-analysis was to determine the effect of concomitant PPIs and clopidogrel use on CV outcomes and mortality, stratified by study design.