title: Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis.
abstract: BACKGROUND
  Uncertainty regarding clopidogrel effectiveness attenuation because of a drug-drug interaction with proton pump inhibitors (PPI) has led to conflicting guidelines on concomitant therapy. In particular, the effect of this interaction in patients who undergo a percutaneous coronary intervention (PCI), a population known to have increased risk of adverse cardiovascular events, has not been systematically evaluated.
  
  
  OBJECTIVE
  To synthesize the evidence of the effect of clopidogrel-PPI drug interaction on adverse cardiovascular outcomes in a PCI patient population.
  
  
  METHODS
  We conducted a systematic literature review for studies reporting clinical outcomes in patients who underwent a PCI and were initiated on clopidogrel with or without a PPI. Studies were included in the analysis if they reported at least 1 of the clinical outcomes of interest (major adverse cardiovascular event [MACE], cardiovascular death, all-cause death, myocardial infarction, stroke, stent thrombosis, and bleed events). We excluded studies that were not exclusive to PCI patients or had no PCI subgroup analysis and/or did not report at least a 6-month follow-up. Statistical and clinical heterogeneity were evaluated and HRs and 95% CIs for adverse clinical events were pooled using the DerSimonian and Laird random-effects meta-analysis method.
  
  
  RESULTS
  We identified 12 studies comprising 50,277 PCI patients that met our inclusion and exclusion criteria. Our analysis included retrospective analyses of randomized controlled trials (2), health registries (3), claims databases (2), and institutional records (5); no prospective studies of PCI patients were identified. On average, patients were in their mid-60s, male, and had an array of comorbidities, including hyperlipidemia, diabetes, hypertension, and smoking history. Concomitant therapy following PCI resulted in statistically significant increases in composite MACE (HR = 1.28; 95% CI = 1.24-1.32), myocardial infarction (HR = 1.51; 95% CI = 1.40-1.62), and stroke (HR = 1.46; 95% CI = 1.15-1.86). However, concomitant therapy had no statistically significant effect on stent thrombosis, mortality measured by all-cause or cardiovascular death, or major bleeding before or after the grouping of studies that reported a major or minor bleed outcome. Only 1 study reported on gastrointestinal bleed, and pooled analysis could not be conducted. Statistical testing suggested heterogeneity among studies, but subgroup analysis did not reveal a clear source.
  
  
  CONCLUSIONS
  Based on the results from this meta-analysis of retrospective analyses of randomized controlled trials and observational studies, concomitant clopidogrel-PPI therapy following PCI appears to be significantly associated with adverse cardiovascular events. Further research on the effect of individual PPIs is needed.
  
  
  BACKGROUND
  Serbin, Guzauskas, and Veenstra were supported by the NIH Common Fund and NIA (1U01AG047109-01, Veenstra, PI) via the Personalized Medicine Economics Research (PriMER) project. The authors do not report any conflicting interests. All authors contributed to the study concept and design. Serbin took the lead in data collection; data interpretation was performed primarily by Serbin, with assistance from the other authors. The manuscript was written primarily by Serbin, along with Guzauskas, and revised by Guzauskas and Veenstra, with assistance from Serbin.
authors.affiliation: 1 Department of Pharmacy, University of Washington, Seattle.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Serbin
authors.affiliation: 1 Department of Pharmacy, University of Washington, Seattle.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Guzauskas
authors.affiliation: 1 Department of Pharmacy, University of Washington, Seattle.
authors.forename: David L
authors.initials: DL
authors.lastname: Veenstra
mesh_terms: D054058:Acute Coronary Syndrome / Q000453:epidemiology / Q000378:metabolism / Q000628:therapy*; D000077144:Clopidogrel; D003131:Combined Modality Therapy / Q000009:adverse effects; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects*; D054328:Proton Pump Inhibitors / Q000009:adverse effects* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012307:Risk Factors; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine