title: Refining clinical trial composite outcomes: an application to the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial.
abstract: BACKGROUND
  Traditional time-to-event analysis assigns equal weight to the first event in the composite end point. This is counterintuitive to many stakeholders.
  
  
  METHODS
  We constructed weights for components of a composite efficacy end point and a net clinical outcome by including metrics of safety and efficacy and compared the weighted with the traditional approach. Through an externally validated, clinician-investigator Delphi panel, the relative severity of individual components of a composite end point (30-day death, recurrent myocardial infarction, cardiogenic shock, and congestive heart failure) was determined. The net clinical outcome was assessed through the incorporation of risk thresholds for safety events (intracranial hemorrhage and major systemic bleeding). These weights were then applied to a modified analysis of the ASSENT-3 trial.
  
  
  RESULTS
  The weights for the efficacy composite were as follows: death, 1.0; shock, 0.5; congestive heart failure, 0.3; and recurrent myocardial infarction, 0.2. The traditional time-to-first-event approach demonstrated a comparable advantage for both enoxaparin (enox) and abciximab (abx) over unfractionated heparin (P = .05), whereas the weighted efficacy analysis suggested an advantage for enox and similar outcomes between unfractionated heparin and abx (P = .2). The apparent advantage of enox was attenuated when the net clinical outcome was examined; the apparent efficacy of abx combination therapy was also diminished by an elevated major systemic bleeding rate (P < .001).
  
  
  CONCLUSIONS
  This novel approach adds an alternative dimension to treatment evaluation by more efficiently incorporating the differential value of all events in each patient. Further development and application of this approach to future trial design and analysis are warranted.
authors.affiliation: University of Alberta, Edmonton, Canada. paul.armstrong@ualberta.ca
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Westerhout
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
authors.forename: Robert C
authors.initials: RC
authors.lastname: Welsh
authors.forename: Robert G
authors.initials: RG
authors.lastname: Wilcox
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bakal
mesh_terms: D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy*; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment / Q000379:methods*; D015912:Thrombolytic Therapy / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents