Abstract
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.
Highlights
The literature consists of contradictory findings on the concomitant usage of clopidogrel and proton pump inhibitors (PPIs)
Our results showed that the risk of major adverse cardiac event (MACE) is significantly higher in the PPI group (RR = 1.22, 95% confidence interval (CI) = 1.06–1.39, p=0.004), with considerable heterogeneity across the studies included (I2 = 90%, p < 0.001)
The length of follow up and the age of the patients did not affect the risk for CV death based on results of the included 10 studies (follow up: SE = 0.009, 95% CI = −0.016 to 0.021, p = 0.81; age: FIGURE 2 | Forrest plots representing the estimated risk of overall major adverse cardiac events (A) and in case of taking specific proton pump inhibitors (B) CI, confidence interval; PPI, proton pump inhibitor; RCT, randomized controlled trials
Summary
The literature consists of contradictory findings on the concomitant usage of clopidogrel and proton pump inhibitors (PPIs). In vitro findings suggested that PPIs reduce the antiplatelet effect of clopidogrel (Gilard et al, 2008), followed by several clinical studies with contradictory outcomes (Pezalla et al, 2008; Ho et al, 2009; Juurlink et al, 2009; O’Donoghue et al, 2009; Rassen et al, 2009; Bhatt et al, 2010; Charlot et al, 2010; Gupta et al, 2010; Hudzik et al, 2010; Kreutz et al, 2010; Ray et al, 2010; van Boxel et al, 2010; Zairis et al, 2010; Burkard et al, 2012; Mo et al, 2015; Sherwood et al, 2015). Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis
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