{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada",
        "Hamilton Health Sciences, Hamilton, Ontario, Canada",
        "Department of Medicine, Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"
      ],
      "name": "Marc-André d’Entremont"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada",
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "Sanjit S Jolly"
    },
    {
      "affiliations": [
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "Faisal Alharthi"
    },
    {
      "affiliations": [
        "Department of Medicine, NYU Grossman School of Medicine, New York, New York, USA"
      ],
      "name": "Binita Shah"
    },
    {
      "affiliations": [
        "Population Health Science Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "David Austin"
    },
    {
      "affiliations": [
        "University of Ottawa, Ottawa, Ontario, Canada"
      ],
      "name": "Quilong Yi"
    },
    {
      "affiliations": [
        "Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK",
        "Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK"
      ],
      "name": "Robert F Storey"
    },
    {
      "affiliations": [
        "Luzerner Kantonsspital, Lucerne, Switzerland"
      ],
      "name": "Matthias Bossard"
    },
    {
      "affiliations": [
        "Departement of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands"
      ],
      "name": "Jan Cornel"
    },
    {
      "affiliations": [
        "Departement of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands"
      ],
      "name": "Jeroen Jaspers Focks"
    },
    {
      "affiliations": [
        "University Clinic of Cardiology, Skopje, North Macedonia"
      ],
      "name": "Sasko Kedev"
    },
    {
      "affiliations": [
        "Clinical Hospital Tetovo, Tetovo, North Macedonia"
      ],
      "name": "Valon Asani"
    },
    {
      "affiliations": [
        "Department of Cardiology, Clinical Center of Serbia and Medical School of Belgrade, Belgrade, Serbia"
      ],
      "name": "Goran Stankovic"
    },
    {
      "affiliations": [
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "Michael Tsang"
    },
    {
      "affiliations": [
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "Nicholas Valettas"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada"
      ],
      "name": "Jessica Tyrwhitt"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada"
      ],
      "name": "Jackie Betz"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada"
      ],
      "name": "Shun Fu Lee"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada"
      ],
      "name": "Rajibul Mian"
    },
    {
      "affiliations": [
        "Département de Cardiologie, UPMC Faculte de Medecine, Paris, France",
        "Département de Cardiologie, Assistance Publique - Hopitaux de Paris, Paris, France"
      ],
      "name": "Johanne Silvain"
    },
    {
      "affiliations": [
        "Cardiology, Centre Hospitalier Universitaire de Caen, Caen, France"
      ],
      "name": "Farzin Beygui"
    },
    {
      "affiliations": [
        "Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada"
      ],
      "name": "Andrew Czarnecki"
    },
    {
      "affiliations": [
        "Prairie Vascular Research Inc, Regina, Saskatchewan, Canada"
      ],
      "name": "Payam Dehghani"
    },
    {
      "affiliations": [
        "Southlake Regional Health Centre, Newmarket, Ontario, Canada"
      ],
      "name": "Warren Cantor"
    },
    {
      "affiliations": [
        "Department of Medicine, London Health Sciences, London, Ontario, Canada"
      ],
      "name": "Shahar Lavi"
    },
    {
      "affiliations": [
        "St George’s Healthcare NHS Trust, London, UK"
      ],
      "name": "James C Spratt"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada",
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "Emilie P Belley-Côté"
    },
    {
      "affiliations": [
        "Population Health Research Institute, Hamilton, Ontario, Canada",
        "Hamilton Health Sciences, Hamilton, Ontario, Canada"
      ],
      "name": "John W Eikelboom"
    }
  ],
  "title": "Benefit–risk of colchicine and spironolactone in acute myocardial infarction: a prespecified generalised pairwise comparisons analysis of the CLEAR trial",
  "uid": "2380abf0-d3bc-5850-9b14-160a2690c9b6"
}