Benefit–risk of colchicine and spironolactone in acute myocardial infarction: a prespecified generalised pairwise comparisons analysis of the CLEAR trial
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".