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Original research article
Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis
  1. Rhanderson N Cardoso1,
  2. Alexandre M Benjo2,
  3. James J DiNicolantonio3,
  4. Daniel C Garcia1,
  5. Francisco Y B Macedo4,
  6. Georges El-Hayek5,
  7. Girish N Nadkarni6,
  8. Sebastiano Gili7,
  9. Mario Iannaccone7,
  10. Ioannis Konstantinidis6 and
  11. John P Reilly2
  1. 1Department of Internal Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, USA
  2. 2Department of Cardiology, Ochsner Medical Center, New Orleans, Louisiana, USA
  3. 3Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
  4. 4Department of Cardiology, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas, USA
  5. 5St.Luke's Roosevelt Medical Center, New York, New York, USA
  6. 6Nephrology Department, Mount Sinai Hospital, New York, New York, USA
  7. 7Department of Cardiology, University of Turin, Turin, Italy
  1. Correspondence to Dr Rhanderson N Cardoso; rhmncardoso{at}


Background Dual antiplatelet therapy is the standard of care after coronary stent placement but increases the bleeding risk. The effects of proton pump inhibitors (PPIs) on clopidogrel metabolism have been described, but the clinical significance is not yet definitive. We aimed to do an updated meta-analysis comparing outcomes in patients receiving clopidogrel with and without PPIs.

Methods We systematically searched PubMed, Scopus and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) and controlled observational studies in patients taking clopidogrel stratified by concomitant PPI use. Heterogeneity was examined with the Cochran Q test and I2 statistics; p values inferior to 0.10 and I2 >25% were considered significant for heterogeneity.

Results We included 39 studies with a total of 214 851 patients, of whom 73 731 (34.3%) received the combination of clopidogrel and a PPI. In pooled analysis, all-cause mortality, myocardial infarction, stent thrombosis and cerebrovascular accidents were more common in patients receiving both drugs. However, among 23 552 patients from eight RCTs and propensity-matched studies, there were no significant differences in mortality or ischaemic events between groups. The use of PPIs in patients taking clopidogrel was associated with a significant reduction in the risk of gastrointestinal bleeding.

Conclusions The results of our meta-analysis suggest that PPIs are a marker of increased cardiovascular risk in patients taking clopidogrel, rather than a direct cause of worse outcomes. The pharmacodynamic interaction between PPIs and clopidogrel most likely has no clinical significance. Furthermore, PPIs have the potential to decrease gastrointestinal bleeding in clopidogrel users.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

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