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Front. Physiol. | doi: 10.3389/fphys.2018.01550

PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel – A Systematic Review and Meta-analysis

  • 1Department of Pediatrics and Pediatric Health Centre, University of Szeged, Hungary
  • 2Institute for Translational Medicine and Division of Gastroenterology, First Department of Internal Medicine, University of Pécs, Hungary

Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis.
Methods: The PubMed, Embase and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies (randomized controlled trials (RCTs) and observational studies) using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316).
Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR=1.22, 95% CI=1.06–1.396, p=0.004) and MI (RR=1.43, 95% CI=1.24–1.66, p<0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR=0.99, 95% CI=0.76–1.28, p=0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR=1.21, 95% CI=0.97–1.50, p=0.09).
Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.

Keywords: Proton pump inhibitors (PPIs), clopidogrel, cardiovascular risk (CV risk), Drug Interaction, cytochrome P450, Meta-analysis

Received: 31 Jul 2018; Accepted: 16 Oct 2018.

Edited by:

Stephen J. Pandol, Cedars-Sinai Medical Center, United States

Reviewed by:

Giovanni Esposito, Università degli Studi di Napoli Federico II, Italy
Atsushi Yonezawa, Kyoto University, Japan  

Copyright: © 2018 Demcsák, Lantos, Bálint, Hartmann, Vincze, Bajor, Czopf, Alizadeh, Gyöngyi, Márta, Mikó, Szakács, Pécsi, Hegyi and Szabó. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD, PhD. Peter Hegyi, University of Szeged, Department of Pediatrics and Pediatric Health Centre, Szeged, 6720, Hungary,
MD, PhD. Imre L. Szabó, University of Pécs, Institute for Translational Medicine and Division of Gastroenterology, First Department of Internal Medicine, Pécs, 7622, Hungary,