Key result
Concomitant use of PPIs and clopidogrel was associated with higher overall MACE risk (RR 1.22; 95% CI 1.06-1.396), but this association disappeared in RCTs (RR 0.99; 95% CI 0.76-1.28; P=0.93).
Why the study?
Clopidogrel and PPIs are metabolized by cytochrome P450 enzymes, and contradictory results have been reported regarding possible complications of simultaneous PPI and clopidogrel use.
Does concomitant use of PPIs increase cardiovascular risk in patients on clopidogrel?
Meta-Analysis (n=156,823)
Does concomitant use of PPIs increase cardiovascular risk in patients on clopidogrel?
Relative Risk: 1.22 (95% CI 1.06–1.396)
p-value: p=0.004
Concomitant use of PPIs and clopidogrel does not elevate cardiovascular risk based on RCT data, suggesting no need for restriction of simultaneous administration.
No increased CV risk with concomitant PPI-clopidogrel use; reinforces consensus on safety while leaving open questions from mixed RCT-observational data.
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.
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Demcsák et al. (2018) conducted a meta-analysis in Patients on clopidogrel (n=156,823). Proton pump inhibitors (PPIs) vs. No PPI treatment was evaluated on Major adverse cardiac event (MACE) (RR 1.22, 95% CI 1.06-1.396, p=0.004). Concomitant use of PPIs and clopidogrel was associated with higher overall MACE risk (RR 1.22; 95% CI 1.06-1.396), but this association disappeared in RCTs (RR 0.99; 95% CI 0.76-1.28; P=0.93).
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