No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: Meta-analysis
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.
References (44)
- et al.
Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study
J Am Coll Cardiol
(2009) - et al.
Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes
Am J Cardiol
(2010) - et al.
Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials
Lancet
(2009) - et al.
The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting
Can J Cardiol
(2010) - et al.
The influencing factors for clopidogrel-mediated platelet inhibition are assay-dependent
Thromb Res
(2011) - et al.
Clopidogrel and proton pump inhibitors: Influence of pharmacological interactions on clinical outcomes and mechanistic explanations
JACC Cardiovasc Interv
(2011) - et al.
Pantoprazole does not influence the antiplatelet effect of clopidogrel-A whole blood aggregometry study after coronary stenting
J Cardiovasc Pharmacol
(2010) Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC)
- et al.
A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
CMAJ
(2009) - et al.
Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: A nationwide cohort study
Ann Intern Med
(2010)