Heart (British Cardiac Society) · 2026
Benefit-risk of colchicine and spironolactone in acute myocardial infarction: a prespecified generalised pairwise comparisons analysis of the CLEAR trial.
СтатьяРандомизированное исследованиеМногоцентровое исследованиеСравнительное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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d'Entremont Marc-André, Jolly Sanjit S, Alharthi Faisal, Shah Binita, Austin David, Yi Quilong, Storey Robert F, Bossard Matthias, Cornel Jan, Jaspers Focks Jeroen, Kedev Sasko, Asani Valon, Stankovic Goran, Tsang Michael, Valettas Nicholas, Tyrwhitt Jessica, Betz Jackie, Lee Shun Fu, Mian Rajibul, Silvain Johanne, Beygui Farzin, Czarnecki Andrew, Dehghani Payam, Cantor Warren, Lavi Shahar, Spratt James C, Belley-Côté Emilie P, Eikelboom John W
Аннотация
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.
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.