Clopidogrel in combination with aspirin (dual antiplatelet therapy) is a cornerstone of therapy for prevention of ischaemic events and improving outcomes following acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI) with stenting . The current American College of Cardiology/American College of Gastroenterology/American Heart Association guideline recommends that patients receiving dual antiplatelet therapy with clopidogrel and aspirin receive a proton pump inhibitor (PPI) to reduce the risk of gastric side-effects . Approximately half of patients taking dual antiplatelet therapy were prescribed with a PPI in real world practice . Clopidogrel is a pro-drug that is converted by the hepatic cytochrome P450 (CYP450) system, and the active compound irreversibly inhibits the ADP P2Y12 receptor on circulating platelets. The need for in vivo bioactivation makes clopidogrel vulnerable to drug–drug interactions with other drugs, such as PPIs, metabolized by hepatic CYP450 isoenzymes.
Many mechanistic studies suggest that combined use of clopidogrel and PPIs may attenuate antiplatelet effects of clopidogrel [4–7], and the data from large scale observational studies have reported that concomitant use of clopidogrel and PPIs after hospital discharge was associated with an increased risk of adverse outcomes than use of clopidogrel without PPIs [8,9]. Based on these data, both the EMEA (European Medicines Agency) and the FDA (US Food and Drug Administration) have issued public statements on a possible adverse interaction between clopidogrel and PPIs [10,11]. However, results from the COGENT trial comparing omeprazole versus placebo in patients taking clopidogrel, has found no difference in the risk of cardiovascular events in patients taking omeprazole . To address this knowledge gap and provide a summary of the current available evidence, we undertook the present meta-analysis.