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Front Physiol. 2018 Nov 19;9:1550. doi: 10.3389/fphys.2018.01550. eCollection 2018.

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

Author information

1
Department of Pediatrics and Pediatric Health Centre, University of Szeged, Szeged, Hungary.
2
Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
3
First Department of Internal Medicine, University of Szeged, Szeged, Hungary.
4
Institute of Surgical Research, University of Szeged, Szeged, Hungary.
5
Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary.
6
Division of Cardiology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary.
7
Division of Hematology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary.
8
Department of Public Health Medicine, University of Pécs Medical School, Pécs, Hungary.
9
Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary.
10
János Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
11
Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary.

Abstract

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:

cardiovascular risk; clopidogrel; cytochrome P450; drug interaction; meta-analysis; proton pump inhibitors

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