title: Evaluation of early percutaneous coronary intervention vs. standard therapy after fibrinolysis for ST-segment elevation myocardial infarction: contribution of weighting the composite endpoint.
abstract: OBJECTIVE
  The selection of optimal endpoints for cardiovascular clinical trials continues to be challenging. We examined an alternative interpretation of a series of trials when the individual event severity is considered.
  
  
  RESULTS
  We analysed three contemporary myocardial infarction (MI) trials of early percutaneous coronary intervention after fibrinolysis, using a weighted composite method. This method allows the examination of the heterogeneity in the direction and magnitude of component endpoints, and multiple events (vs. first event). We incorporated a physician-assessed severity of each component endpoint in all patients for the five-item composite in the largest study, Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI), which enrolled 1059 ST-elevation MI patients. The traditional approach yielded event-free survival probabilities of 0.89 [95% confidence interval (CI) 0.86-0.91] for the early invasive arm and 0.83 (95% CI 0.79-0.86) for the standard care arm (P = 0.004). After accounting for the clinician-investigator-determined weights, the effective survival probabilities were 0.93 (95% CI 0.91-0.95) for the early invasive arm and 0.93 (95% CI 0.90-0.95) with no significant difference (P = 0.54). The same pattern was observed in the three-trial cohort using a four-item composite with an observed improvement in event-free survival outcomes (P = 0.01), which was no longer apparent after the severity weights were considered (P = 0.44).
  
  
  CONCLUSIONS
  This analysis highlights the importance of considering the relative severity and multiple events in the evaluation of a clinical trial.
authors.affiliation: Division of Cardiology, 2-132 Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bakal
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Westerhout
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Cantor
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
authors.forename: Robert C
authors.initials: RC
authors.lastname: Welsh
authors.forename: David
authors.initials: D
authors.lastname: Fitchett
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
mesh_terms: D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D023381:Endpoint Determination; D006801:Humans; D053208:Kaplan-Meier Estimate; D009203:Myocardial Infarction / Q000401:mortality / Q000628:therapy*; D062645:Percutaneous Coronary Intervention / Q000379:methods*; D015912:Thrombolytic Therapy / Q000379:methods*; D016896:Treatment Outcome