Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents

Abstract

The potential association between major adverse cardiovascular events (MACE) and concomitant treatment with proton pump inhibitors (PPIs) and clopidogrel has been debated since 2009. Recent reports, however, suggest that PPIs may increase the risk of MACE independently of clopidogrel. This review evaluates epidemiological findings relevant to the association between PPIs, taken alone or concomitantly with antiplatelets, and the risk of MACE. A systematic review and meta-analysis were conducted. Relevant studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and then screened. Included studies were categorized into three groups: Group A: PPIs versus no PPIs; Group B: combined PPIs and clopidogrel versus clopidogrel alone; Group C: combined PPIs and other drugs versus other drugs. Pooled risk ratios (RRs) were calculated for each outcome of interest in each comparison group. Of the 1667 studies identified, 118 were included in the systematic review, of which 66 were included in the meta-analyses. Among Group A observational studies, RRs for MACE outcomes were statistically significant for some patient populations but not others. Pooled RRs from Group A RCTs were not statistically significant for any outcome. Pooled RRs for Group B observational studies were statistically significant for all-cause mortality and MI, but were diminished in magnitude when pooling was restricted to propensity score matched studies or post hoc analyses of RCTs. Group C studies did not demonstrate an association with MACE. Findings do not consistently support an association between MACE and PPIs when taken alone, or concomitantly with antiplatelets.

Keywords:

• Systematic review
• meta-analysis
• proton pump inhibitors
• clopidogrel
• platelet aggregation inhibitors
• cardiovascular diseases
• myocardial infarction
• drug interactions

Acknowledgements

We would like to thank Ms Lindsay Sikora from the Health Sciences Library at the University of Ottawa for her time and support in developing the literature search strategy.

Declaration of interest

The authors, whose affiliations are shown on the title page, had sole responsibility for preparation of this paper, including determining the strategy for reviewing the scientific literature summarized in this article, synthesizing the findings, and drawing conclusions. NF developed the initial study protocol and wrote the first draft of the manuscript. NF, YF, and NH screened references for inclusion in the systematic review, and abstracted key data elements from included references. All authors contributed to the development of the final study protocol, provided detailed comments on drafts of this article and participated in the formulation of the study conclusions.

N. F. was supported by Doctoral Research Awards from the Canadian Institutes of Health Research and the McLaughlin Center for Population Health Risk Assessment (www.mclaughlincentre.ca), and by an admission scholarship from the University of Ottawa (www.uottawa.ca). Y. F. was supported by doctoral training awards from the Fonds de recherche du Québec en santé (http://www.frqs.gouv.qc.ca), the University of Ottawa admission scholarship, the McLaughlin Centre for Population Health Risk Assessment and the Ontario Ministry of Advanced Education and Skills Development (https://osap.gov.on.ca). N. H. was supported by the University of Ottawa admission scholarship and the McLaughlin Centre for Population Health Risk Assessment. D. K. and N. B. are cosupervisors of NF’s doctoral thesis, with F. M., D. M., and S. W. serving as members of NF’s thesis advisory committee.

D. K. is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa, a peer reviewed university-industry research partnership program. D. K. and D. M., respectively, serve as Chief Risk Scientist and Chief Medical Officer for Risk Sciences International (RSI) (www.risksciences.com), a Canadian company established in 2006 in partnership with the University of Ottawa, to provide consulting services in risk science to both public and private sector clients. To date, RSI has not conducted work on PPIs or antiplatelet agents that are the subject of the present paper. N. F. has served as a consultant to RSI and to international clients on issues unrelated to those discussed in the present paper. N. H. is a senior epidemiologist with the Public Health Agency of Canada working on matters unrelated to the subject of the present paper.

Within the last 10 years, none of the authors have served as consultants either for a fee or pro bono to public or private sector clients regarding the pharmaceutical products reviewed in this paper, nor have any of the authors participated in legal proceedings related to these products. F. M. has consulted with Novartis in 2003, prior to their marketing of Prevacid in 2009, on matters unrelated to the subject of the present paper.

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