Risk of Adverse Cardiovascular Events With Proton Pump Inhibitors Independent of Clopidogrel

Systematic Review With Meta-analysis

Riley Batchelor; Radya Kumar; Julia F. M. Gilmartin-Thomas; Ingrid Hopper; William Kemp; Danny Liew


Aliment Pharmacol Ther. 2018;48(8):780-796. 

In This Article

Abstract and Introduction


Background: Clopidogrel's anti-platelet effects may be attenuated by a pharmacokinetic interaction with co-prescribed proton pump inhibitors, which inhibit oxidative pathways that convert clopidogrel into its active metabolites. Despite this, the impact of PPIs on cardiovascular risk in the absence of clopidogrel is not well defined.

Aim: To report on a systematic review and meta-analysis of the association between PPIs and cardiovascular risk, independent of clopidogrel.

Methods: The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were systematically searched in October 2017. The primary outcome was association between PPI monotherapy and any adverse cardiovascular event. The secondary outcome was association between proton pump inhibitor monotherapy and acute myocardial infarction. Studies were excluded if they reported or did not adjust for concomitant anti-platelet therapy or involved participants aged less than 18 years.

Results: A total of 22 studies were included in the systematic review. Data from 16 studies were included in the meta-analysis (involving 447 408 participants). Of these, eight were randomised controlled trials, seven were observational studies and one was a retrospective analysis of a randomised controlled trial. An increased risk of any adverse cardiovascular event with PPI monotherapy was observed using pooled data from observational studies (risk ratio 1.25, 95% CI 1.11–1.42, I 2 81%, P < 0.001), but not from randomised controlled trials (risk ratio 0.89, 95% CI 0.34–2.33, I 2 0%, P = 0.85).

Conclusion: There is no clear evidence of an association between PPI monotherapy and increased cardiovascular risk.


Proton pump inhibitors (PPIs) are among the world's most frequently prescribed medications, for which estimated sales are in excess of USD$10 billion worldwide.[1–3] However, 30%–60% of prescriptions may be inappropriate,[4,5] and although generally well tolerated, serious PPI adverse events include increased risk of community– and hospital-acquired pneumonia,[6] Clostridium difficile enterocolitis,[7] interstitial nephritis,[8] bone fracture[9] and hypomagnesemia.[10] Evidence supports the use of PPIs for gastro-oesophageal reflux disease,[11] peptic ulcer disease,[12] and for mitigating the risk of gastrointestinal (GI) bleeding associated with anti-platelet therapy.[13,14]

As PPIs significantly reduce the risk of GI bleeding associated with anti-platelet therapy, PPIs are often administered in combination with clopidogrel.[13] Clopidogrel is a first-line anti-platelet prodrug indicated for the secondary prevention of atherothrombotic cardiovascular disease.[14,15] Pharmacokinetic studies have postulated an interaction between PPIs and clopidogrel, arising from metabolism by the same hepatic isoenzyme (CYP2C19).[16–18] Inhibition of CYP2C19 by PPIs may reduce the bioavailability of the active metabolites of clopidogrel, and attenuate clopidogrel's cardiovascular benefits.[16–18] As a result, the United States Food and Drug Administration (FDA) has warned against using clopidogrel in combination with the PPIs omeprazole and esomeprazole.[19]

Observational studies and randomised controlled trials have yielded conflicting results as to whether the proposed pharmacokinetic interaction between PPIs and clopidogrel manifests as an increased clinical risk of adverse cardiovascular events.[20–24] Furthermore, it has been suggested that the observed risk of PPI use with anti-platelet therapy may be partly due to an increase in cardiovascular risk conferred by PPIs directly.[25,26] To help address this theory, a systematic review and meta-analysis was conducted to explore the association between cardiovascular risk and PPIs independent of concomitant clopidogrel therapy.