title: Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial.
abstract: OBJECTIVE
  Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side.
  
  
  RESULTS
  The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events.
  
  
  CONCLUSIONS
  This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common.
  
  
  BACKGROUND
  NCT00699998.
authors.affiliation: Division of Cardiology, University of Alberta and the Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB, Canada T6G 2E1.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bakal
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine and the Duke Clinical Research Institute, Duke University, Durham, NC, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Roe
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine and the Duke Clinical Research Institute, Duke University, Durham, NC, USA.
authors.forename: E Magnus
authors.initials: EM
authors.lastname: Ohman
authors.affiliation: Division of Cardiology, University of Alberta and the Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB, Canada T6G 2E1 Division of Cardiology, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada.
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.affiliation: British Heart Foundation Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: Division of Cardiology, University of Alberta and the Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB, Canada T6G 2E1.
authors.forename: Yinggan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Cardiology, University of Alberta and the Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB, Canada T6G 2E1.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Westerhout
authors.affiliation: Cardiovascular Clinical Research Center, Leon H. Charney Division of Cardiology, New York University School of Medicine and NYU Langone Medical Center, New York, NY, USA.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Hochman
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine and the Duke Clinical Research Institute, Duke University, Durham, NC, USA.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Eileen B
authors.initials: EB
authors.lastname: Brown
authors.affiliation: Division of Cardiology, University of Alberta and the Canadian VIGOUR Centre, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB, Canada T6G 2E1 paul.armstrong@ualberta.ca.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
mesh_terms: D000368:Aged; D000789:Angina, Unstable / Q000188:drug therapy* / Q000401:mortality; D000077144:Clopidogrel; D023381:Endpoint Determination; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride / Q000627:therapeutic use*; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D012008:Recurrence; D020521:Stroke / Q000209:etiology / Q000401:mortality; D016019:Survival Analysis; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
keywords: Acute coronary syndromes; Clinical trial; Composite endpoints