Clopidogrel and proton pump inhibitors - where do we stand in 2012?

Table 1 Overview of important pharmacodynamic studies on the clopidogrel-proton pump inhibitor interaction

Study	PPIs used	Population	Primary outcome	Author’s conclusions
Gilard et al[7] OCLA study (double-blind, placebo-controled, randomized)	Omeprazole	124 patients undergoing elective coronary stent implantation	VASP-PRI on 7 d	Omeprazole significantly decreases clopidogrel inhibitory effect
Cuisset et al[11] PACA study (prospective, randomized)	Omeprazole vs Pantoprazole	104 NSTE-ACS patients undergoing coronary stenting	VASP-PRI/ADP-Ag after 1 mo	Significantly better platelet response under pantoprazole (VASP-PRI), no difference for ADP-Ag
O’Donoghue et al[26] PRINCIPLE-TIMI 44 (post hoc analysis of a RCT)	Not specified	201 patients undergoing planned PCI	ADP Ag	Mean inhibition of platelet aggregation significantly lower for patients on PPI
Siller-Matula et al[8] (prospective observational)	Pantoprazole esomeprazole	300 patients with CAD undergoing PCI	VASP-PRI/ADP-Ag in the catheter laboratory	No association of PPIs with impaired response to clopidogrel
Neubauer et al[13] (prospective observational)	Pantoprazole omeprazole esomeprazole	336 patients undergoing coronary stent implantation	ADP Ag	Pantoprazole does not diminish the antiplatelet effectiveness of clopidogrel
Angiolillo et al[12] (placebo controlled, randomized, cross-over)	Omeprazole pantoprazole	282 healthy subjects	Clopi H4 ADP Ag VASP-PRI after 5 d	Presence of a metabolic drug-drug interaction between clopidogrel and omeprazole but not for pantoprazole

VASP-PRI: Vasodilator-stimulated phosphoprotein platelet reactivity index; NSTE-ACS: Non-ST-elevation acute coronary syndrome; ADP Ag: Adenosine DiPhospate induced platelet aggregation; CAD: Coronary artery disease; PCI: Percutaneous coronary intervention; PPI: Proton pump inhibitor; OCLA: Omeprazole Clopidogrel Aspirine; PACA: PPI and clopidogrel association; PRINCIPLE-TIMI: Prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-TIMI.

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.

Table 3 Summary of studies reporting on adverse bleeding events

Study	Observed adverse event	Ascertainment	Results
Bhatt et al[25]	Composite of upper gastrointestinal bleeding (of known and unknown origin): overt bleeding, ulcers, symptomatic erosions, obstruction, perforation or decrease in hemoglobin of 2 g/dL	Endoscopic and radiologic confirmation (in known origin subgroup)	Significative reduction of upper gastrointestinal bleeding in the omeprazole treated group (1.1% against 2.9% under placebo; HR 0.34, 95% CI: 0.18-0.63)
Ray et al[27]	Hospitalization for bleeding at a gastroduodenal site (excluding angiodysplasia) or other gastrointestinal and non-gastrointestinal sites	Validated diagnostic codes with PPV of 91%	Adjusted 50% reduction of hospitalization in the PPI treated group (HR 0.50, 95% CI: 0.39-0.65), no significant difference concerning bleeding at other sites
van Boxel et al[14]	Occurence of complicated or non complicated peptic ulcer disease	ICD-9 diagnostic codes	Low incidence (0.7% with PPI against 0.2%) but significant increase of peptic ulcer disease in the PPI treated group even after multivariable adjusting (HR 4.76, 95% CI: 1.18-19.17)
Charlot et al[28]	Hospitalization for gastrointestinal bleeding	ICD-9 diagnostic codes	No reduction between the clopidogrel with PPI and clopidogrel alone group
Harjai et al[29]	TIMI major bleeding: intracranial hemorrage or a ≥ 5 g/dL decrease in hemoglobine TIMI minor bleeding: observed blood loss with decrease ≥ 3 g/dL in hemoglobine	Guthrie Health System database	No significant difference between the clopidogrel with PPI and clopidogrel alone group
Simon et al[30]	In-hospital major bleeding (not specified) or need for blood transfusion	FAST-MI registry	No significant difference between the clopidogrel with PPI and clopidogrel alone group

HR: Hazard ratio; CI: Confidence interval; PPV: Positive predictive value; PPI: Proton pump inhibitor; ICD-9: International classification of disease-9th revision; FAST-MI: French registry of acute-ST-elevation and non-ST-elevation myocardial infarction.