Proton-Pump Inhibitors and Increased Cardiovascular Risk: Hype or Harm?

June 17, 2015

Proton-Pump Inhibitors and Increased Cardiovascular Risk: Hype or Harm?

  1. David A. Johnson, MD

New findings do not merit changes in PPI prescribing practices for cardiovascular risks alone.

  1. David A. Johnson, MD

The suggestion of an association between proton-pump inhibitor (PPI) use and cardiovascular harm has been shown previously in retrospective analyses in which cardiovascular risk was not the primary endpoint. Based on their own previous animal-study findings supporting a biological mechanism, researchers evaluated the association between PPI use and myocardial infarction (MI) in a data-mining pharmacovigilance study using two large electronic medical record databases. Their data-mining approach had a diagnostic accuracy of 89% and a positive-predictive value of 81%.

Code-based extractions with adjustment for age, gender, race, length of observation, and other drugs used (as proxies for health status) showed a 1.16-fold increased risk (95% confidence interval, 1.09–1.24) for MI. In a separate survival analysis in a prospective cohort, PPI use was associated with a twofold increased risk for cardiac mortality (hazard ratio, 2.00; 95% CI, 1.07–3.78), which was independent of clopidogrel use.


Even if we assume that these findings are valid as reported, 4000 patients would need to take a PPI to cause MI in one patient. However, this database analysis is subject to significant risk for stratification bias: Without accounting for comorbid diseases associated with gastroesophageal reflux disease (e.g., obesity, related metabolic diseases) that are also well established as risk factors for cardiovascular disease, the data could be skewed toward suggesting a harmful effect. Moreover, although the authors cite a 1996 study suggesting that PPIs reduce the effect of clopidogrel, they ignore level-one evidence showing that PPIs did not alter relevant cardiovascular endpoints and clearly reduced gastrointestinal complications (N Engl J Med 2010; 363:1909). Finally, recent findings from the same group show negative findings for an association between PPI use and endovascular endothelial function, contrary to their original animal-study findings (Vasc Med 2015 Apr 2; [e-pub]). Although healthcare providers should be aware of these findings, the data do not suggest that PPI use should be stopped for cardiovascular concerns alone.

Editor Disclosures at Time of Publication

  • Disclosures for David A. Johnson, MD at time of publication Consultant / Advisory board Medscape; Pfizer; CRH Medical Corporation; Covidien; Janssen; American Board of Internal Medicine; American College of Gastroenterology; WebMD Equity CRH Medical Corporation; Bovie Medical Corporation Editorial boards ACG Education Universe; Medscape Gastroenterology Leadership positions in professional societies American Board of Internal Medicine (Gastroenterology Examination Board); ACG Education Universe (Co-editor)


Reader Comments (1)

Victor Kantariya Physician, Family Medicine/General Practice

PPIs and Cardiovascular Risk, that is the question. Use PPIs with clopidogrel was not associated with risk of ischemic stroke( Stroke 2015). PPIs have remained the first-line protecion from stress-related mucosal injury and gastrointestinal bleeding.However, acid reduction reduced microbial diversity, predicted development of infections.Bacterial infections are common cause of morbidity and mortality in critically ill patients with stroke, MI, cirrhosis( Aliment Pharmacol Ther 2015).Future work is needed to identify benefits and harms PPI therapy .Victor Kantariya, MD

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