Colchicine and spironolactone after myocardial infarction: the factorial trial, the pooled evidence and the guideline's timing

The 2025 ACC/AHA/ACEP/NAEMSP/SCAI acute coronary syndrome (ACS) guideline was published online in February 2025 in both the Journal of the American College of Cardiology and Circulation ^[1][2]. Two reports from one factorial trial, published online in November 2024, found that neither colchicine nor spironolactone, given after myocardial infarction (MI), lowered the trial's primary composite outcomes ^[3][4].

What does the 2025 guideline cover, and when did its search end?

The guideline's literature search ran from July 2023 to April 2024 across MEDLINE, EMBASE, the Cochrane Library and the Agency for Healthcare Research and Quality ^[1]. That search ended before those trial reports appeared ^[1][3]. The guideline makes three points about scope and status ^[1]:

• Predecessors — it incorporates evidence since the 2013 ST-elevation MI guideline, the 2014 non-ST-elevation ACS guideline and the 2015 focused update on primary percutaneous coronary intervention ^[1].
• Dual antiplatelet duration — together with the 2021 revascularization guideline, it retires and replaces the 2016 focused update on the duration of dual antiplatelet therapy ^[1].
• Recommendations — many earlier recommendations were updated and new ones created where data supported them ^[1].

What did the factorial trial show?

Colchicine. The colchicine report randomized 7,062 patients to colchicine or placebo and to spironolactone or placebo ^[3]. The design paper specifies enrollment within 72 hours of percutaneous coronary intervention for MI ^[5]. In the colchicine report, the composite of cardiovascular death, recurrent MI, stroke or ischemia-driven revascularization occurred in 9.1% of the colchicine group and 9.3% of the placebo group over a median of 3 years (hazard ratio 0.99; 95% CI 0.85 to 1.16) ^[3]. The same report found diarrhea in 10.2% with colchicine versus 6.6% with placebo and no difference in serious infections ^[3].

Spironolactone. The spironolactone report notes that mineralocorticoid receptor antagonists reduced mortality after MI in patients with congestive heart failure ^[4]. In that report, cardiovascular death or new or worsening heart failure occurred at 1.7 per 100 patient-years with spironolactone versus 2.1 with placebo (hazard ratio 0.91; 95% CI 0.69 to 1.21) ^[4]. The report's second primary composite, the first occurrence of MI, stroke, new or worsening heart failure or cardiovascular death, occurred in 7.9% with spironolactone versus 8.3% with placebo (hazard ratio 0.96; 95% CI 0.81 to 1.13) ^[4].

Do the pooled data and the trial agree on colchicine?

Pooled colchicine data. The November 2025 Cochrane review pooled 12 randomized trials (22,983 participants) of low-dose colchicine for at least six months versus control ^[6]. They enrolled adults with stable cardiovascular disease, previous MI or stroke, not only recent MI ^[6]. The review rated as high certainty fewer myocardial infarctions (risk ratio 0.74; 95% CI 0.57 to 0.96), about 9 fewer per 1,000 patients (95% CI 16 fewer to 2 fewer) from a control-group rate of about 36 per 1,000 ^[6]. It also rated as high certainty fewer strokes (risk ratio 0.67; 95% CI 0.47 to 0.95), about 8 fewer per 1,000 (95% CI 12 fewer to 1 fewer) from a control-group rate of about 22 per 1,000 ^[6]. The review found moderate-certainty evidence of little to no difference in all-cause mortality (risk ratio 1.01; 95% CI 0.84 to 1.21) ^[6]. It found more gastrointestinal adverse events with colchicine (risk ratio 1.68; 95% CI 1.11 to 2.57) ^[6].

Divergent trials. A 2026 comparative review of three large colchicine trials notes relative risk reductions in major adverse cardiovascular events of 23% in a trial in recent MI and 31% in chronic coronary syndrome, against a neutral result in the factorial trial ^[7]. The review's authors conclude that differences in design, populations and timing do not explain the divergence definitively ^[7].

At the point of care: what to check

• Whether the patient resembles the trial population: MI treated with percutaneous coronary intervention, enrolled within 72 hours ^[3][5].
• Whether the patient resembles the Cochrane population: stable cardiovascular disease, previous MI or stroke ^[6].
• Diarrhea and other gastrointestinal symptoms: diarrhea was more frequent with colchicine in the colchicine report, gastrointestinal adverse events in the Cochrane review ^[3][6].
• Whether heart failure is present, since the spironolactone report places the earlier mortality evidence for mineralocorticoid receptor antagonists in that group ^[4].