title: Replicated studies of two randomized trials of angiotensin-converting enzyme inhibitors: further empiric validation of the 'prior event rate ratio' to adjust for unmeasured confounding by indication.
abstract: OBJECTIVE
  Using data from the United Kingdom General Practice Research Database (GPRD) randomized controlled trials (RCTs) were replicated to determine whether identifiable study characteristics and/or analytic methods influence the validity of observational studies.
  
  
  METHODS
  This study reports GPRD replications of 2 RCTs that investigated whether angiotensin-converting enzyme inhibitors (ACEIs) improve cardiovascular outcomes in patients without congestive heart failure at high risk for cardiovascular disease (heart outcomes prevention evaluation (HOPE) and EUROPA). The GPRD studies replicated to the extent feasible all aspects of these RCTs except for randomization.
  
  
  RESULTS
  With adjustment for confounders using conventional biostatistical techniques, both GPRD studies exhibited results divergent from the RCTs. Myocardial infarction, stroke, congestive heart failure, and coronary revascularization were increased in the Exposed group of both GPRD studies; whereas these outcomes either were decreased or unchanged by ACEI therapy in both RCTs. The results also were analyzed with a new method that appears to adjust for both identified and unmeasured confounders. With this methodology that employs the ratio of event rates between the Exposed and Unexposed cohorts prior to study start time to adjust the study hazard ratio (HR), the GPRD results for myocardial infarction, stroke, and coronary revascularization were largely similar to those found in the two RCTs.
  
  
  CONCLUSIONS
  This study provides additional empiric evidence suggesting that this new analytic methodology, 'prior events rate ratio (PERR)' adjustment, is a promising solution for the vexing problem of 'unmeasured confounding' in observational studies. Additional statistical simulations are needed to fully appreciate the applicability and limitations of this method.
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. tannen@mail.med.upenn.edu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Tannen
authors.forename: Mark G
authors.initials: MG
authors.lastname: Weiner
authors.forename: Dawei
authors.initials: D
authors.lastname: Xie
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D003198:Computer Simulation; D015986:Confounding Factors, Epidemiologic; D003627:Data Interpretation, Statistical; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D006113:United Kingdom
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors