Clinical evidence of interaction between clopidogrel and proton pump inhibitors

Table 1 Clinical evidences support the interaction between clopidogrel and proton pump inhibitors

Study design	Follow-up	Number of patients on clopidogrel with/without PPI	End point	Results	Ref.
Population-based study	6 yr	PPI: 572; no PPI: 2706	Rehospitalization (due to AMI or angina); mortality	Rehospitalization in PPI vs no PPI groups: HR: 1.23 (95% CI: 1.07-1.41, P = 0.003); mortality: HR: 1.65 (95% CI: 1.35-2.01, P < 0.001)	Huang et al[20]
Retrospective cohort study	1 yr	Low PPI: 712; high PPI: 5.03%(?); without PPI: 4800	MI	Acute MI rate: non-PPI: 1.38% (66/4800); low PPI exposure: 3.08% (22/712); high PPI exposure: 5.03% (?) (P < 0.05 for high vs no PPI use)	Pezalla et al[21]
Retrospective nested case-control	3 mo	Cases: 734 (PPI: 194); controls: 2057 (PPI: 424)	Death or readmitted for MI	Readmission for acute MI, adjusted OR 1.27 (95% CI: 1.03-1.57); pantoprazole OR: 1.02 (95% CI: 0.70-1.47); other PPIs (omeprazole, lansoprazole and rabeprazole) OR: 1.40 (95% CI: 1.10-1.77)	Juurlink et al[23]
Retrospective cohort study	October 2003 and January 2006	PPI: 5244; without PPI: 2961	Death or rehospitalization for MI or unstable angina	Death or rehospitalization: non-PPI vs PPI groups: 20.8% vs 29.8% OR: 1.25 (95% CI: 1.11-1.41); omeprazole OR: 1.24 (95% CI: 1.08-1.41); rabeprazole OR: 2.83 (95% CI: 1.96-4.09)	Ho et al[24]
Retrospective cohort study using the National Medco Integrated Database	1 yr	PPI: 6828; without PPI: 9862	Stroke or TIA, ACS, CV death, coronary revascularization	MACE rate in the PPI vs non-PPI groups: 25.1% vs 17.8% (adjusted HR of 1.57, 95% CI: 1.39-1.64); Omeprazole: 25.1% HR: 1.39 (95% CI: 1.22-1.57), esomeprazole: 24.9% HR: 1.57 (95% CI: 1.40-1.76), lansoprazole: 24.3% HR: 1.39 (95% CI: 1.16-1.67) and pantoprazole: 29.2% HR: 1.61 (95% CI: 1.44-1.81)	Kreutz et al[25]
Retrospective cohort within RCT	28 d and 1 yr	PPI: 366; without PPI: 1750	Death, MI, stroke at 1 yr; Death, MI, UTVR at 28 d	Death, MI, stroke at 1 yr: HR: 1.55, 95% CI: 1.031-2.341, P = 0.035; Death, MI, UTVR at 28 d, HR: 1.63, 95% CI: 1.015-2.627, P = 0.043	Dunn et al[46]
Retrospective cohort study	1 yr	PPI: 318; without PPI: 502	CV death, Q-wave MI, coronary revascularization and stent thrombosis	Major MACE event rate in the PPI vs non-PPI groups: 13.8% vs 8% (P = 0.008); HR of MACE: 1.8 (95% CI: 1.1-2.7, P = 0.01); overall mortality: 4.7% vs 1.8% (P = 0.02)	Gaglia et al[48]
Retrospective observational study (FRENA registry)	15 mo	PPI: 519; no PPI: 703	MI, stroke, critical limb ischemia, death	Incidence of events of PPI vs no PPI groups: MI: 4.4% vs 2.1%, HR: 2.5 (95% CI: 1.3-4.8, P = 0.003); stroke: 3.7% vs 2.3%, HR: 1.9 (95% CI: 1.03-3.7, P = 0.039); critical limb ischemia: 4.7% vs 3.4%; HR: 1.6 (95% CI: 0.95-2.8, P = 0.077); death: 7.5% vs 3.3%, HR: 2.2 (95% CI: 1.3-3.7, P = 0.003)	Muñoz-Torrero et al[49]

PPI: Proton pump inhibitor; TIA: Transient ischemic attack; MI: Myocardial infarction; AMI: Acute MI; ACS: Acute coronary syndrome; CV: Cardiovascular.

Table 2 Clinical evidences against interaction between clopidogrel and proton pump inhibitors

Study design	Follow-up	Number of patients on clopidogrel with/without PPI	End point	Results	Ref.
Cohort study	12 yr	PPI: 83; no PPI: 176	MI, CV death, urgent revascularization	No significant effect of use of PPIs	Collet et al[43]
Retrospective cohort study	180 d	PPI: 3996; no PPI: 14 569	MI, death or coronary revascularization	Adjusted RR for MI or death: 1.22 (95% CI: 0.99-1.51); for revascularization, 0.97 (95% CI: 0.79-1.21)	Rassen et al[47]
Retrospective cohort study	1-yr	PPI: 397; no PPI: 138	MI, death, CABG or repeat PCI	Death, MI events with PPI vs non-PPI groups: 6.7% vs 9.6% (P = 0.32); CABG with PPI vs non-PPI groups: 3.1% vs 4.1% (P = 0.53); revascularization with PPI vs non-PPI groups: 15.8% vs 14.2% (P = 0.65)	Ramirez et al[51]
Prospective, double-blind placebo- controlled multicentre RCT	Median of 133 d	PPI: 1801; no PPI: 1826	Cardiovascular events (death, non-fatal MI, CABG or PCI, or ischemic stroke)	Cardiovascular events: HR: 1.02, 95% CI: 0.70-1.51	Bhatt et al[53]
Double-blind randomized trial	6 mo	PPI: 2257; no PPI: 4538	MACE (CV death, MI, stroke)	MACE in PPI vs no PPI groups after adjustment for potential confounders: 11.8% vs 12.2%, adjusted HR: 0.94 (95% CI: 0.80-1.11, P = 0.46)	O’Donoghue et al[26]
Retrospective cohort study (FAST-MI Registry)	1 yr	PPI: 1453; no PPI: 900	Death, MI, or stroke	No in-hospital difference in death, reinfarction, or major bleeding in PPI vs no PPI groups; Death, MI, or stroke at 1 yr in PPI. no PPI groups: 12% vs 14% (P = 0.72), adjusted OR: 0.98 (95% CI: 0.90-1.08)	Simon et al[54]

PPI: Proton pump inhibitor; PCI: Percutaneous coronary intervention; MI: Myocardial infarction; RR: Relative risk; CV: Cardiovascular.