No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: Meta-analysis

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Abstract

Background

Data from pharmacokinetic and pharmacodynamic studies indicate that the adverse clopidogrelproton pump inhibitor (PPI) interaction may vary between PPIs, with pantoprazole considered relatively less problematic. We aimed to evaluate systematically whether individual PPIs differ in their risk for cardiovascular events when concomitantly administered with clopidogrel.

Methods

We searched MEDLINE, EMBASE and Cochrane Trials Register up to December 2011 for randomized and non-randomized studies that reported adverse cardiovascular events with exposure to specific PPIs in patients receiving clopidogrel. We performed random effects meta-analysis, and assessed heterogeneity using the I2 statistic.

Results

A total of 23 studies with 222,311 participants were included. Meta-analysis of major adverse cardiovascular events was mostly limited by moderate-substantial heterogeneity. Pooled estimates of cardiovascular risk were significantly elevated for individual PPIs such as omeprazole, esomeprazole, lansoprazole, and pantoprazole when used with clopidogrel. However, meta-analysis of adverse cardiovascular risk in seven observational studies reporting on PPI therapy alone (without concomitant clopidogrel) also found an elevated odds ratio of 1.28 (95% CI 1.14–1.44) compared with no clopidogrel/no PPI exposure. Meta-analysis of two randomized controlled trials did not show significant adverse cardiovascular effect from omeprazole or esomeprazole.

Conclusions

The absence of consistent evidence on differential cardiovascular risk amongst PPIs (particularly regarding safety of pantoprazole) is in direct opposition to the platelet function and pharmacokinetic data. Our findings of increased cardiovascular risk with PPIs in the absence of clopidogrel suggest that confounding and bias are strong possibilities. The clinical validity or relevance of the hypothesized PPI-clopidogrel interaction remains questionable.

Introduction

Pharmacokinetic and pharmacodynamic studies have found that the postulated adverse interaction between proton pump inhibitors (PPIs) and clopidogrel may not represent a class effect, i.e. certain PPIs (particularly omeprazole and esomeprazole) have a demonstrable interaction, while pantoprazole seems less problematic [1], [2]. The US Food and Drug Administration has directed a warning specifically against omeprazole and esomeprazole, because these specific agents are considered to have an important negative impact on the bioactivation of clopidogrel (through cytochrome P450 2 C19), whereas pantoprazole has limited effect on P450 2 C19 [3]. A population-based Canadian case–control study has also reported an increased risk of adverse cardiovascular events for all PPIs except pantoprazole [4]. Although more recent studies have yielded conflicting results [5], [6], [7], [8], [9], pantoprazole has been recommended as the preferred PPI in patients receiving clopidogrel [1], [2], [10].

Nevertheless, the evidence for a clinical recommendation in favour of pantoprazole has yet to be evaluated systematically. Our previous meta-analysis of PPIs (as a class) found marked heterogeneity regarding the cardiovascular effects of concomitant PPI-clopidogrel therapy [11], but at that time, we did not have sufficient data to separately analyse the risk with each individual PPI. Thus, the primary objective of this newer systematic review was to identify any discernable intra-class difference amongst the PPIs for the postulated clopidogrel interaction, concentrating in particular on whether pantoprazole has a lower risk of cardiovascular events than other PPIs.

Section snippets

Eligibility criteria

We included randomized controlled trials (RCTs) and controlled observational studies that reported major adverse cardiovascular events (MACE) or myocardial infarction (MI) in patients receiving clopidogrel, with and without concomitant PPI exposure. We focused specifically on studies that reported risk with specific PPIs. For RCTs, the inclusion criteria was a parallel group randomized trial of PPI versus control in clopidogrel-treated patients and with clear reporting of cardiovascular

Results

Our search yielded 23 eligible studies with 222,311 patients (Fig. 1) [4], [5], [6], [7], [8], [9], [10], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. The salient characteristics of the included studies are summarized in Table 1. These included 19 cohort studies, two post-hoc analyses of participants in clinical trials, and two prospective randomized controlled trials. The average age of participants in the 17 studies which reported this

Discussion

Despite pharmacokinetic and platelet function data to the contrary, our systematic review did not identify any discernable differences in the clinical impact of individual PPIs on clopidogrel. Each PPI had evidence of statistically significant harm from two or more studies, even though the pooled average estimates of increased risk seen with each PPI were typically limited by moderate to substantial heterogeneity. Moreover, the clinical outcome results do not correlate well with the current

Conclusions

The results from our meta-analysis of clinical outcome studies do not support the notion that individual PPIs confer differential risks for adverse cardiovascular events in patients receiving clopidogrel. Discordance with the results of pharmacokinetic-pharmacodynamic studies undermines plausibility of this hypothesized interaction. The observational data linking PPI exposure with increased adverse cardiac outcomes even in the absence of clopidogrel indicate that residual confounding is likely

Contributors

This manuscript has been read and approved by all the authors, the requirements for authorship have been met, everyone who qualifies for authorship has been listed as an author and each author believes that the manuscript represents honest work.

Competing interests

Yoon K Loke, Vinodh Jeevanantham, Buddhadeb Dawn and CS Kwok have no competing interests to declare.

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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