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Primary percutaneous coronary intervention (PCI) is a standard treatment in patients with acute coronary syndrome. Studies have shown that proton pump inhibitors (PPIs) can potentially attenuate the antiplatelet effects of P2Y12 inhibitors with associated adverse cardiovascular outcomes.Medline was searched using Pubmed from inception to 8 November 2017 for randomized control trials studying the effect of PPIs on coronary artery disease with concomitant use of dual antiplatelet therapy (DAPT). Overall, 692 studies were identified of which five randomized control trials were included. Statistical analysis was done using RevMan, version 5.3.Five studies with 6239 patients (3113 on PPI with DAPT and 3126 with only DAPT) were included. Our analysis showed that PPI significantly reduced the incidence of gastrointestinal (GI) bleed [22 vs. 66, odds ratio (OR)=0.37, confidence interval (CI)=0.23–0.61, P≤0.0001, I2=0%], GI ulcers and GI erosions (7 vs. 18, OR=0.39, CI=0.16–0.94, P=0.04, I2=0%), and the incidence of post-PCI unstable angina in patients treated with PPI and P2Y12 agents (46 vs. 67, OR=0.67, CI=0.45–0.99, P=0.05, I2=0%). There was an insignificant difference in myocardial infarction, stroke, and cardiovascular cause of mortality. A trend toward decreased all-cause mortality with PPIs was noted. Heterogeneity was calculated using I2.Concomitantly administered PPIs with P2Y12 inhibitors have a protective effect on the GI events. It also decreases the post-PCI angina without increased adverse cardiovascular outcomes.