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Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review
  1. Jeroen Jaspers Focks1,
  2. Marc A Brouwer1,
  3. Martijn G H van Oijen2,3,
  4. Angel Lanas4,
  5. Deepak L Bhatt5,
  6. Freek W A Verheugt1
  1. 1Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  2. 2Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
  3. 3Department of Gastroenterology and Hepatology, University of California Los Angeles Medical School, Los Angeles, California, USA
  4. 4Department of Gastroenterology, Hospital Clínico, Universidad de Zaragoza, CIBERehd, Zaragoza, Spain
  5. 5Department of Cardiology, VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Jeroen Jaspers Focks, Radboud University Nijmegen Medical Center, Department of Cardiology 670, PO Box 9101, 6500 HB Nijmegen, The Netherlands; j.jaspersfocks{at}


Background Clopidogrel as an adjunct to aspirin has improved outcomes after acute coronary syndromes, but laboratory studies suggest a reduced antiplatelet effect when proton pump inhibitors (PPIs) are co-administered. Despite corroborating data from retrospective studies, new clinical data fuel the controversy on this issue.

Purpose Systematic review of the impact of the addition of PPIs to clopidogrel on platelet function and cardiovascular outcome.

Data sources PubMed, Web-of-Science, Cochrane Database and reference lists of related articles.

Study selection Published articles on controlled studies addressing the addition of PPIs to clopidogrel. Platelet function studies describe patients as well as healthy volunteers. Clinical studies concern patients using clopidogrel for acute coronary syndromes or because of stent implantation for stable coronary disease.

Data extraction Two investigators independently reviewed the identified articles for eligibility, and one author extracted the data.

Data synthesis In 70% (7/10) of the laboratory studies examining healthy volunteers on clopidogrel, addition of PPIs resulted in a significant reduction in platelet inhibition. For patients, this was observed in 11/18 (61%) studies. The 33 clinical studies showed significant heterogeneity in observed outcomes, with risk ratios for major adverse cardiovascular events varying from 0.64 to 4.58 in the case of PPI use, which was randomly allocated in only two studies. Consequently, imbalances between prognosticators at baseline and PPI prescription bias markedly contributed to the variability in results.

Conclusions Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. With the accumulating evidence from better designed, prospective clinical studies, an adverse effect of PPI use on clinical outcome in patients on clopidogrel cannot be substantiated. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomised data.

  • Review
  • proton pump inhibitors
  • clopidogrel
  • interaction
  • platelet function
  • cardiovascular events
  • allied specialities
  • haematology
  • neurology
  • stroke
  • arrhythmias
  • atrial fibrillation
  • pharmacology
  • anticoagulation
  • antiplatelet treatment
  • myocardial ischaemia and infarction (IHD)
  • acute coronary syndrome
  • resuscitation
  • acute myocardial infarction

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  • Competing interests MGHvO has served as a consultant for and has received unrestricted grant support from AstraZeneca, Nycomed and Pfizer; AL has served as a consultant for AstraZeneca, Pfizer and Bayer AG; DLB discloses the following relationships - Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Other: Senior Associate Editor, Journal of Invasive Cardiology; Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda, and Chair of the COGENT study. FWAV has received educational and research grants from Bayer AG, Roche, Eli Lilly and Boehringer Ingelheim and has received honoraria for consultancies from Daiichi Sankyo, Eli Lilly, Merck, The Medicines Company and Bayer AG.

  • Provenance and peer review Not commissioned; externally peer reviewed.