Topic Highlight
Copyright ©2012 Baishideng Publishing Group Co.
World J Gastroenterol. May 14, 2012; 18(18): 2161-2171
Published online May 14, 2012. doi: 10.3748/wjg.v18.i18.2161
Table 1 Overview of important pharmacodynamic studies on the clopidogrel-proton pump inhibitor interaction
StudyPPIs usedPopulationPrimary outcomeAuthor’s conclusions
Gilard et al[7] OCLA study (double-blind, placebo-controled, randomized)Omeprazole124 patients undergoing elective coronary stent implantationVASP-PRI on 7 dOmeprazole significantly decreases clopidogrel inhibitory effect
Cuisset et al[11] PACA study (prospective, randomized)Omeprazole vs Pantoprazole104 NSTE-ACS patients undergoing coronary stentingVASP-PRI/ADP-Ag after 1 moSignificantly 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 specified201 patients undergoing planned PCIADP AgMean inhibition of platelet aggregation significantly lower for patients on PPI
Siller-Matula et al[8] (prospective observational)Pantoprazole esomeprazole300 patients with CAD undergoing PCIVASP-PRI/ADP-Ag in the catheter laboratoryNo association of PPIs with impaired response to clopidogrel
Neubauer et al[13] (prospective observational)Pantoprazole omeprazole esomeprazole336 patients undergoing coronary stent implantationADP AgPantoprazole does not diminish the antiplatelet effectiveness of clopidogrel
Angiolillo et al[12] (placebo controlled, randomized, cross-over)Omeprazole pantoprazole282 healthy subjectsClopi H4 ADP Ag VASP-PRI after 5 dPresence of a metabolic drug-drug interaction between clopidogrel and omeprazole but not for pantoprazole
Table 2 Overview of important clinical studies on the proton pump inhibitor-clopidogrel interaction
StudyPPIs usedProcedures to minimize biasPopulationPrimary outcomeResults
Bhatt et al[25] (randomized, controlled, double-blind trial)Omeprazole3873 patients with ACS or undergoing PCIMean 133 d- composite safety endpoint of cardiovascular death, MI, coronary revascularisationNo 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 rabeprazolePropensity score matching; multivariable and sensitivity analysis13 608 patients undergoing planned PCI for ACSComposite endpoint of cardiovascular death, MI or stroke after 6-15 moNo 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 specifiedMultivariable analysis2116 patients undergoing PCI28 d death, MI, urgent target vessel revas-cularisation 1 yr death, MI or strokeIncreased 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 rabeprazolePropensity score matching; multivariable and sensitivity analysis56 406 patients discharged with first-time myocardial infarction1 yr composite end point of MI, stroke or cardiovascular deathIncreased 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 analysis23 200 post PCI patients6-yr MACENo 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 rabeprazolePropensity score matching; multivariable and sensitivity analysis20 596 patients discharged after PCI or ACS1 yr composite end point of ACS, stroke or cardiovascular deathNo 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 esomeprazolePropensity 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 causeTrend 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 lansoprazolePropensity score matching; multivariable and sensitivity analysis2744 clopidogrel and PPI-naive patients with definite MIIn hospital and 1-yr death, reinfarction or strokeNo 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 esomeprazolePropensity score matching; multivariable and sensitivity analysis2651 patients discharged after PCI for stable and unstable CAD6-mo MACENo 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 lansoprazoleMultivariable analysis18 139 clopidogrel users2 yr composite endpoint of ACS, stroke and any cause deathIncreased 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 pantoprazoleNested case –control; multivariable and sensitivity analysis13 636 patients discharged after ACS (age > 65 yr)90-d readmission for acute MIIncreased 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 pantoprazoleMultivariable and sensitivity analysis8205 patients discharged after ACS3 yr death or rehospitalization for ACSIncreased risk for death or rehospitalization in PPI users (OR 1.25, 95% CI: 1.11-1.41)
Table 3 Summary of studies reporting on adverse bleeding events
StudyObserved adverse eventAscertainmentResults
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/dLEndoscopic 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 sitesValidated 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 diseaseICD-9 diagnostic codesLow 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 bleedingICD-9 diagnostic codesNo 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 hemoglobineGuthrie Health System databaseNo 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 transfusionFAST-MI registryNo significant difference between the clopidogrel with PPI and clopidogrel alone group