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. 2025 Sep 11:heartjnl-2025-326218.
doi: 10.1136/heartjnl-2025-326218. Online ahead of print.

Benefit-risk of colchicine and spironolactone in acute myocardial infarction: a prespecified generalised pairwise comparisons analysis of the CLEAR trial

Marc-André d'Entremont  1   2   3 , Sanjit S Jolly  4   2 , Faisal Alharthi  2 , Binita Shah  5 , David Austin  6 , Quilong Yi  7 , Robert F Storey  8   9 , Matthias Bossard  10 , Jan Cornel  11 , Jeroen Jaspers Focks  11 , Sasko Kedev  12 , Valon Asani  13 , Goran Stankovic  14 , Michael Tsang  2 , Nicholas Valettas  2 , Jessica Tyrwhitt  4 , Jackie Betz  4 , Shun Fu Lee  4 , Rajibul Mian  4 , Johanne Silvain  15   16 , Farzin Beygui  17 , Andrew Czarnecki  18 , Payam Dehghani  19 , Warren Cantor  20 , Shahar Lavi  21 , James C Spratt  22 , Emilie P Belley-Côté  4   2 , John W Eikelboom  4   2
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Free article

Benefit-risk of colchicine and spironolactone in acute myocardial infarction: a prespecified generalised pairwise comparisons analysis of the CLEAR trial

Marc-André d'Entremont et al. Heart. .
Free article

Abstract

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.

Keywords: Myocardial Infarction.

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Conflict of interest statement

Competing interests: M-Ad’E is a Canadian Institutes of Health Research Canada Graduate Scholarship awardee. SSJ reports receiving grants or contracts from Boston Scientific and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Penumbra, Teleflex and Abiomed. BS reports grant funding from the NIH NHLBI and the VA Office of Research and Development. DA reports receiving speaker fees from Philips Volcano, Astra Zeneca, Pfizer and research grants from Newcastle University, TA Sciences, Kanecra and Astra Zeneca. RFS reports research grants and personal fees from AstraZeneca and Cytosorbents, and personal fees from Abbott, Afortiori Development/Thrombolytic Science, Alfasigma, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb/Johnson & Johnson, Chiesi, Daiichi Sankyo, Idorsia, Novartis, Novo Nordisk, Pfizer, PhaseBio and Tabuk. JS reports consulting fees from Biotronik, Sanofi Aventis, CLS Behring, proctoring fees from Abbott, Occlutech, SMT and travel support fees from Abbott, Biotronik, Medtronic, Novo Nordisk. AC reports speaking honoraria from Abbott. JWE discloses honoraria, fees or research grants from Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Idorsia, Janssen, Merck, Pfizer and Servier. The other authors have no relevant disclosures.

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