Jeffrey A Bakal1, Matthew T Roe2, E Magnus Ohman2, Shaun G Goodman3, Keith A A Fox4, Yinggan Zheng1, Cynthia M Westerhout1, Judith S Hochman5, Yuliya Lokhnygina2, Eileen B Brown6, Paul W Armstrong7. 1. 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. 2. Division of Cardiology, Department of Medicine, Duke University School of Medicine and the Duke Clinical Research Institute, Duke University, Durham, NC, USA. 3. 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. 4. British Heart Foundation Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK. 5. 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. 6. Eli Lilly and Company, Indianapolis, IN, USA. 7. 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.
Abstract
AIMS: 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. METHODS AND 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 eitherprasugrel 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. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: NCT00699998. Published on behalf of the European Society of Cardiology. All rights reserved.
RCT Entities:
AIMS: 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. METHODS AND 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. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: NCT00699998. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Alexander C Fanaroff; Derek Cyr; Megan L Neely; Jeffery Bakal; Harvey D White; Keith A A Fox; Paul W Armstrong; Renato D Lopes; E Magnus Ohman; Matthew T Roe Journal: Circ Cardiovasc Qual Outcomes Date: 2018-12
Authors: Patrizia Natale; Suetonia C Palmer; Valeria M Saglimbene; Marinella Ruospo; Mona Razavian; Jonathan C Craig; Meg J Jardine; Angela C Webster; Giovanni Fm Strippoli Journal: Cochrane Database Syst Rev Date: 2022-02-28
Authors: Marco Valgimigli; Francesco Costa; Yuliya Lokhnygina; Robert M Clare; Lars Wallentin; David J Moliterno; Paul W Armstrong; Harvey D White; Claes Held; Philip E Aylward; Frans Van de Werf; Robert A Harrington; Kenneth W Mahaffey; Pierluigi Tricoci Journal: Eur Heart J Date: 2017-03-14 Impact factor: 29.983
Authors: Meaghan Lunney; Marinella Ruospo; Patrizia Natale; Robert R Quinn; Paul E Ronksley; Ioannis Konstantinidis; Suetonia C Palmer; Marcello Tonelli; Giovanni Fm Strippoli; Pietro Ravani Journal: Cochrane Database Syst Rev Date: 2020-02-27
Authors: Tamar Irene de Vries; Jan Westerink; Michiel L Bots; Folkert W Asselbergs; Yvo M Smulders; Frank L J Visseren Journal: BMJ Open Date: 2021-03-08 Impact factor: 2.692