Real-World Relationship Between Proton Pump Inhibitors and Cerebro-Cardiovascular Outcomes Independent of Clopidogrel A Meta-Analysis of Observational Studies

Previous studies have provided established evidence on adverse outcomes of the coadministration of proton pump inhibitors (PPIs) and clopidogrel, whereas cerebro-cardiovascular outcomes of PPI use in the absence of clopidogrel therapy remain controversial. In this study, we aimed to assess the association between PPIs and cerebro-cardiovascular outcomes independent of clopidogrel. Systematic searches were conducted in the Cochrane Library, PubMed, and Embase databases for all relevant studies up to August 2018. Odds ratios (ORs) with its 95% confidence intervals (CIs) were abstracted and pooled using the random-effects model. A total of 14 observational studies (13 cohort studies and 1 case-control study) were identified. Compared with non-PPI users, PPI users experienced higher risks of stroke (OR: 1.22, 95% CI: 1.08-1.36), myocardial infarction (MI; OR: 1.23, 95% CI: 1.14-1.32), cardiovascular death (OR: 1.83, 95% CI: 1.69-1.98), and major adverse cardiovascular events (MACEs; OR: 1.22, 95% CI: 1.05-1.40) independent of clopidogrel use, but not all-cause death (OR: 1.50, 95% CI: 0.99-2.25). In the subgroup analysis, PPI alone was associated with significant risks of new-onset MI (OR: 1.23, 95% CI: 1.13-1.35) and stroke (OR: 1.17, 95% CI: 1.05-1.30) in patients without previous MI or stoke and recurrent MI (OR: 1.24, 95% CI: 1.02-1.51) and stroke (OR: 1.36, 95% CI: 1.19-1.55) risks in patients with a previous MI. Based on current publications, PPI use seems to be associated with increased risks of stroke, MI, cardiovascular death, and MACEs independent of clopidogrel. Greater caution should be therefore exercised while considering its clinical benefits and further investigate any causal relationships.