Author + information
- Received November 22, 2019
- Revision received February 4, 2020
- Accepted February 17, 2020
- Published online May 25, 2020.
- João Pedro Ferreira, MD, PhDa,b,
- Pardeep S. Jhund, MB BCh, PhDa,
- Kévin Duarte, PhDb,
- Brian L. Claggett, PhDc,
- Scott D. Solomon, MDc,
- Stuart Pocock, PhDd,
- Mark C. Petrie, MB ChBa,
- Faiez Zannad, MD, PhDb,c and
- John J.V. McMurray, MDa,∗ ()
- aBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- bNational Institute of Health and Medical Research, Center for Clinical Multidisciplinary Research, INSERM U1116, University of Lorraine, Regional University Hospital of Nancy, French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France
- cCardiovascular Division, Brigham and Women’s Hospital Boston, Massachusetts
- dDepartment of Biostatistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
- ↵∗Address for correspondence:
Prof. John J.V. McMurray, British Heart Foundation, Cardiovascular Research Centre, University of Glasgow 126 University Place, Glasgow G12 8TA, United Kingdom.
Objectives The purpose of this study was to compare the win ratio (WR) with the corresponding hazard ratios (HRs) and 1/HR.
Background The primary outcome in many cardiovascular trials is a composite that includes nonfatal and fatal events. The time-to-first event analysis gives equal statistical weighting to each component event. The WR, which takes into account the clinical importance and timing of the outcomes, has been suggested as an alternative approach.
Methods Cox proportional hazards models and WR.
Results In the these trials (n = 16) the WR and HR differed only slightly. For example, in the PARADIGM-HF (sacubitril/valsartan vs. enalapril), the primary outcome of time to first heart failure hospitalization (HFH) or cardiovascular death (CVD) and use of the Cox model gave a 1/HR of 1.25 (95% confidence interval [CI]: 1.12 to 1. 41; z-score = 4.8). Using WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.27 (95% CI: 1.15 to 1.39; z-score = 4.7), reflecting an effect similar to that of sacubitril/valsartan therapy on CVD and HFH. In the DIG (digoxin vs. placebo) trial, the outcome of time-to-first HFH or CVD using Cox gave a 1/HR of 1.18 (95% CI: 1.10 to 1.27; z-score = 4.5). Using the WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.14 (95% CI: 1.05 to 1.20; z-score = 3.1), reflecting a larger effect of digoxin on HFH than on CVD. Several other trials and endpoints including patient-reported measurements were studied.
Conclusions In 16 large cardiovascular outcome trials, HR and WR provided similar estimates of treatment effects. The WR allows prioritization of fatal outcomes and the hierarchical testing of broader composite endpoints including patient-reported outcomes. In this way, the WR allows for the incorporation of patient-centered and other outcomes, while prioritizing the competing risk of death and hospital admission.
Dr. Jhund's employer, the University of Glasgow, has been remunerated by Novartis for work on the PARADIGM-HF and PARAGON trials and by AstraZeneca for his time working on the DAPA-HF and DELIVER trials; and has received consulting fees from Novartis and Cytokinetics and research support from Boehringer Ingelheim. Dr. Claggett is a consultant for Amgen, Novartis, Myokardia, and AO Biome. Dr. Solomon has received research support from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, U.S. National Institutes of Health/National Heart Lung Blood Institute, Novartis, Sanofi, Pasteur, and Theracos; and is a consultant for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squib, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Pocock has received honoraria for Data Safety and Monitoring Boards for trials sponsored by Pfizer, Novartis, and AstraZeneca. Dr. Petrie has received research support from Novartis and Boehringer Ingelheim; and is a consultant for NovoNordisk, Boehringer Ingelheim, Novartis, Takeda, Napp, and Corvia. Dr. McMurray is a consultant for and/or has received compensation from Abbott, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardurion, Cyclerion Therapeutics, DalCor, GlaxoSmithKline, Merck, Novartis, Theracos, and Vifor-Fresenius with all fees paid to his employer, Glasgow University. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.
- Received November 22, 2019.
- Revision received February 4, 2020.
- Accepted February 17, 2020.
- 2020 American College of Cardiology Foundation
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