Table 2.

Overview of important clinical studies on the proton pump inhibitor-clopidogrel interaction

Study	PPIs used	Procedures to minimize bias	Population	Primary outcome	Results
Bhatt et al[25] (randomized, controlled, double-blind trial)	Omeprazole		3873 patients with ACS or undergoing PCI	Mean 133 d- composite safety endpoint of cardiovascular death, MI, coronary revascularisation	No difference between PPI and placebo group (HR with omeprazole 0.99, 95% CI: 0.68-1.44)
O’Donaghue et al[26] (post-hoc analysis of a RCT)	Pantoprazole omeprazole esomeprazole lansoprazole rabeprazole	Propensity score matching; multivariable and sensitivity analysis	13 608 patients undergoing planned PCI for ACS	Composite endpoint of cardiovascular death, MI or stroke after 6-15 mo	No difference between PPI and clopidogrel alone group (HR 0.94, 95% CI: 0.80-1.11)
Dunn et al[65] (post-hoc analysis of a RCT)	Not specified	Multivariable analysis	2116 patients undergoing PCI	28 d death, MI, urgent target vessel revas-cularisation 1 yr death, MI or stroke	Increased risk for adverse cardiovascular outcome regardless of clopidogrel use (clopidogrel/PPI: OR 1.63, 95% CI: 1.02-2.63 vs placebo/PPI: OR 1.55, 95% CI: 1.03-2.34)
Charlot et al[28] (retrospective cohort study)	Esomeprazole pantoprazole lansoprazole omeprazole rabeprazole	Propensity score matching; multivariable and sensitivity analysis	56 406 patients discharged with first-time myocardial infarction	1 yr composite end point of MI, stroke or cardiovascular death	Increased risk for adverse cardiovascular outcomes in PPI users regardless of clopidogrel use (HR for PPI/clopidogrel: 1.35, 95% CI: 1.22-1.50 vs HR for PPI alone: 1.43, 95% CI: 1.34-1.53)
Banerjee et al[32] (retrospective cohort study)	Predominantly omeprazole (88,9%)	Propensity score matching; multivariable and sensitivity analysis	23 200 post PCI patients	6-yr MACE	No increased risk for MACE in PPI users (HR 0,97, 95% CI: 0.65-1.44)
Ray et al[27] (retrospective cohort study)	Pantoprazole lansoprazole esomeprazole omeprazole rabeprazole	Propensity score matching; multivariable and sensitivity analysis	20 596 patients discharged after PCI or ACS	1 yr composite end point of ACS, stroke or cardiovascular death	No increased risk for serious cardiovascular disease in PPI users (HR 0.99, 95% CI: 0.82-1.19)
Rassen et al[31] (retrospective cohort study)	Pantoprazole omeprazole rabeprazole lansoprazole esomeprazole	Propensity score matching;	18 565 patients discharged after PCI or ACS (age > 65 yr)	180 d composite end point of hospitalization for MI and PCI or death of any cause	Trend towards a higher risk of composite end point in PPI users (RR 1.26, 95% CI: 0.97-1.63)
Simon et al[30] (retrospective cohort study)	Omeprazole esomeprazole pantoprazole lansoprazole	Propensity score matching; multivariable and sensitivity analysis	2744 clopidogrel and PPI-naive patients with definite MI	In hospital and 1-yr death, reinfarction or stroke	No increased risk of cardiovascular events and mortality in PPI users (HR 0.98, 95% CI: 0.90-1.08)
Harjai et al[29] (retrospective cohort study)	Omeprazole esomeprazole	Propensity score matching; multivariable and sensitivity analysis	2651 patients discharged after PCI for stable and unstable CAD	6-mo MACE	No increased risk for MACE in PPI users (HR 0.89, 95% CI: 0.63-1.27)
van Boxel et al[14] (retrospective cohort study)	Pantoprazole omeprazole rabeprazole lansoprazole	Multivariable analysis	18 139 clopidogrel users	2 yr composite endpoint of ACS, stroke and any cause death	Increased risk of composite endpoint (HR 1.75, 95% CI: 1.58-1.94), myocardial infarction (HR 1.93, 95% CI: 1.40-2.65) and unstable angina pectoris (HR 1.79, 95% CI: 1.60-2.03)
Juurlink et al[16] (population-based nested case-control study)	Omeprazole rabeprazole lansoprazole pantoprazole	Nested case –control; multivariable and sensitivity analysis	13 636 patients discharged after ACS (age > 65 yr)	90-d readmission for acute MI	Increased risk of reinfarction (OR 1.27, 95% CI: 1.03-1.57) in PPI users except pantoprazole
Ho et al[15] (retrospective cohort study)	Omeprazole rabeprazole lansoprazole pantoprazole	Multivariable and sensitivity analysis	8205 patients discharged after ACS	3 yr death or rehospitalization for ACS	Increased risk for death or rehospitalization in PPI users (OR 1.25, 95% CI: 1.11-1.41)

ACS: Acute coronary syndrome; PPI: Proton pump inhibitor; OR: Odds ratio; CI: Confidence interval; MI: Myocardial infaction; PCI: Percutaneous coronary intervention; RR: Relative risk; HR: Hazard ratio; MACE: Major adverse cardiovascular event; RCT: Randomized controlled trial.