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Lookup NU author(s): Dr David AustinORCiD
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© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group. Background: Composite outcomes in cardiovascular trials often group events of unequal clinical importance, and conventional analyses may obscure treatment trade-offs. Generalised pairwise comparisons (GPC), expressed as a win ratio (WR), allow for hierarchical ranking of events and incorporation of recurrent outcomes, providing a potentially more intuitive assessment of benefit-risk. Methods: In a prespecified exploratory analysis of the 2×2 factorial, randomised CLEAR (Colchicine and Spironolactone in Patients with Myocardial Infarction) trial (7062 patients within 72 hours of acute myocardial infarction (MI) and percutaneous coronary intervention), we applied both time-to-first and recurrent-event GPC to reassess low-dose colchicine (0.5 mg daily) and spironolactone (25 mg daily) versus placebo. For the colchicine comparison, the hierarchical benefit-risk outcome included all-cause death, stroke, recurrent MI, unplanned ischaemia-driven revascularisation, serious infection or diarrhoea. For the spironolactone comparison, the outcome included all-cause death, stroke, MI, new or worsening heart failure, significant ventricular arrhythmia, hyperkalaemia or gynaecomastia/gynaecodynia. GPC results were compared with Cox, logistic and Andersen-Gill models. Results: For colchicine, the time-to-first event GPC showed a 12% lower proportional win rate compared with placebo (WR 0.88, 95% CI 0.79 to 0.98; win difference -2.10%, 95% CI -3.84 to -0.37), driven largely by excess diarrhoea. For spironolactone, patients experienced a 14% lower win rate (WR 0.86, 95% CI 0.75 to 0.99; win difference -1.46%, 95% CI -2.84% to -0.08%), largely attributable to gynaecomastia and hyperkalaemia. Conventional statistical approaches yielded concordant results. Across both interventions, higher-order efficacy outcomes (death, MI, stroke, heart failure) showed no benefit. Conclusions: In patients with post-MI, both low-dose colchicine and spironolactone demonstrated disadvantageous benefit-risk profiles, reinforcing that neither agent should be used routinely. This prespecified application of GPC provided results consistent with traditional methods but offered a clinically intuitive framework for interpreting composite outcomes.
Author(s): D'Entremont M-A, Jolly SS, Alharthi F, Shah B, Austin D, Yi Q, Storey RF, Bossard M, Cornel J, Jaspers Focks J, Kedev S, Asani V, Stankovic G, Tsang M, Valettas N, Tyrwhitt J, Betz J, Lee SF, Mian R, Silvain J, Beygui F, Czarnecki A, Dehghani P, Cantor W, Lavi S, Spratt JC, Belley-Cote EP, Eikelboom JW
Publication type: Article
Publication status: Published
Journal: Heart
Year: 2026
Volume: 112
Issue: 6
Pages: 326-332
Print publication date: 01/03/2026
Online publication date: 04/09/2025
Acceptance date: 22/08/2025
ISSN (print): 1355-6037
ISSN (electronic): 1468-201X
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/heartjnl-2025-326218
DOI: 10.1136/heartjnl-2025-326218
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