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The Evolving Role of Colchicine in Coronary Atherosclerosis Management: Timing May Be Everything

Apr 07, 2025   |  Anum Zehra, BA; Abhishek Gami, MD; Jaideep Patel, MD, FACC

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Quick Takes

  • Colchicine is an anti-inflammatory drug approved by the Food and Drug Administration for reduction of cardiovascular risk.
  • Low-dose colchicine has shown significant reduction in cardiovascular events in patients with chronic coronary artery disease.
  • Defining the optimal timing of colchicine initiation after a myocardial infarction may better inform its role in reducing recurrent atherosclerotic cardiovascular events.

Chronic inflammation plays a role in the pathogenesis of cardiovascular diseases, including atherosclerosis, pericarditis, stroke, and myocardial infarction (MI). The discovery of its complex interaction with other mechanisms of disease like thrombosis and dyslipidemia have introduced newer dimensions of cardiovascular disease management, including new drug targets. Colchicine, the first anti-inflammatory drug approved by the Food and Drug Administration (FDA) in 2023 for reduction of residual cardiovascular risk, is one example.1

While the exact anti-inflammatory mechanism of colchicine is still under investigation, it is known to destabilize microtubules (MT) by binding to beta-tubulin. By inhibiting MT-dependent cell signaling, colchicine impairs neutrophil function and reduces leukocytes and inflammatory cytokines (e.g., interleukin [IL]-1 beta, IL-6, and IL-18). It also reduces high-sensitivity C-reactive protein (CRP), indicating a reduction in systemic inflammation.

Recent trials have demonstrated a reduction in future atherosclerotic cardiovascular disease (ASCVD) events among those taking low-dose colchicine (Table 1).2-6 For example, in the LoDoCo (Low-Dose Colchicine) trial, colchicine significantly reduced the risk of an ASCVD event (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.18-0.59; p < 0.001), with the reduction largely driven by non–stent-related acute coronary syndrome events.2 In the LoDoCo2 (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2) trial, patients with coronary artery disease (CAD) (angiographically or coronary artery calcium score ≥400 Agatston units) randomized to 0.5 mg/day had a significantly lower composite of ASCVD events compared with placebo (HR, 0.69; 95% CI, 0.57-0.83; p < 0.001).3 In both trials, patients were clinically stable for ≥6 months at the time of enrollment.

Table 1: Summary of Colchicine Trial Outcomes

Trial
Details
Outcome
Notes
LoDoCo (2013) n = 532

Pts with stable, angiographically proven CAD who were clinically stable for ≥6 months were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy only.		 Colchicine had a lower composite outcome of ACS, OHCA, or noncardioembolic ischemic stroke vs. control (5.3% vs. 16%; HR, 0.33; 95% CI, 0.18-0.59; p < 0.001). The most common adverse effect was GI disturbance.
COLCOT (2019) n = 4,745

Pts within 30 days post MI were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy plus placebo.		 Lower incidence of MACE in the colchicine group (5.5% vs. 7.1%; HR, 0.77; 95% CI, 0.61-0.96; p = 0.02). The most common adverse effect was GI disturbance.
COPS (2020) n = 795

Pts presenting with ACS with evidence of CAD (angiographically managed with PCI or medical therapy) were randomized to receive either standard therapy plus colchicine (0.5 mg twice daily for the first month post ACS, then 0.5 mg daily for 11 months) or placebo plus standard therapy.		 No statistically significant difference between the two arms (HR, 0.65; 95% CI, 0.38-1.09; p= 0.1) in the primary outcome (i.e., a composite of all-cause mortality, ACS [STEMI/NSTEMI/UA], ischemia-driven urgent revascularization, and noncardioembolic ischemic stroke).

However, the colchicine group showed lower incidence of the primary outcome when all-cause mortality was replaced with CV mortality (5% vs. 9.5%; HR, 0.51; 95% CI, 0.29-0.89; p= 0.019).		 There was a higher incidence of non-CV death (5 vs. 0;p = 0.023) and total death (8 vs. 1; p= 0.018) in the colchicine group, not statistically significant.

The most common adverse effect was GI disturbance.
LoDoCo2 (2020) n = 5,522

Pts with stable CAD (angiographically or CAC score ≥400 AU) who were clinically stable for ≥6 months were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy plus placebo.

In total, 3,179 pts had ACS for ≥24 months before randomization.		 Colchicine had a lower incidence of CV death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization versus placebo (6.8% vs. 9.6%; HR, 0.69; 95% CI, 0.57-0.83; p < 0.001). There was a greater incidence of non-CV death in the colchicine group, not statistically significant (incidence, 0.7 vs. 0.5 events per 100 person-years; HR, 1.51; 95% CI, 0.99-2.31).
CLEAR SYNERGY (2024) n = 7,062

Pts within 72 hours post MI were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy plus placebo.		 There was no difference in MACE outcomes between the two groups (9.1% vs 9.3%; HR, 0.99; 95% CI, 0.85-1.16; p = 0.93).

There was no difference in all-cause death (4.6% vs. 5.1%; HR, 0.90; 95% CI, 0.73-1.12).		 There was a higher incidence of diarrhea in the colchicine group (6.6% vs. 10.2%; p < 0.001).

ACS = acute coronary syndrome; AU = Agatston unit; CAC = coronary artery calcium; CAD = coronary artery disease; CI = confidence interval; CLEAR SYNERGY = Colchicine in Acute Myocardial Infarction; COLCOT = Colchicine Cardiovascular Outcomes Trial; COPS = Colchicine to Improve Cardiovascular Outcomes in ACS Patients; CV = cardiovascular; GI = gastrointestinal tract; HR = hazard ratio; LoDoCo = Low-Dose Colchicine; LoDoCo2 = Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2; MACE = major adverse cardiac event; MI = myocardial infarction; NSTEMI = non–ST-segment elevation myocardial infarction; OHCA = out-of-hospital cardiac arrest; PCI = percutaneous coronary intervention; Pts = patients; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.

However, data studying the use of colchicine in populations immediately post MI have yielded mixed results (Table 1). The COLCOT (Colchicine Cardiovascular Outcomes Trial) showed a significantly lower composite outcome of major adverse cardiovascular events (MACE) in patients post MI (within 30 days) randomized to 0.5 mg daily colchicine (HR, 0.77; 95% CI, 0.61-0.96; p = 0.02).4 In the CLEAR SYNERGY (Colchicine in Acute Myocardial Infarction) trial of patients post MI (within 72 hours), MACE incidence was almost identical in the placebo and colchicine groups (HR, 0.99; 95% CI, 0.85-1.13; p = 0.93) despite a significant reduction in CRP levels from baseline (2.98 vs. 4.27 mg/dL, p < 0.001).5 The COPS (Colchicine to Improve Cardiovascular Outcomes in ACS Patients) trial showed no difference (HR, 0.65; 95% CI, 0.38-1.09; p = 0.10) in its primary outcome between patients presenting with an acute coronary syndrome and CAD receiving placebo versus twice daily 0.5 mg colchicine for the first month followed by once daily 0.5 mg colchicine for 11 months. However, when all-cause mortality was replaced by cardiovascular mortality, the colchicine group had a lower incidence of the composite outcome (5.0% vs. 9.5%; HR, 0.51; 95% CI, 0.29-0.89; p= 0.019).6

Reflecting the earlier clinical trial findings, the 2024 European Society of Cardiology and the 2023 American Heart Association/American College of Cardiology guidelines recommend considering the addition of colchicine to reduce recurrent ASCVD events for those with chronic stable CAD (Class 2a, Level of Evidence [LOE] A and Class 2b, LOE B-R, respectively).7,8 Similarly, Canadian and South American national guidelines encourage using 0.5 daily colchicine to reduce atherothrombotic events in almost all patients with pre-existing coronary disease, assuming no contraindications.9,10

Despite the 23%-31% reduction in cardiovascular events seen in LoDoCo2 and COLCOT, the CLEAR SYNERGY trial, which examined patients immediately post MI, was neutral. Some have hypothesized this may be due to the trial's enrollment during the coronavirus disease 2019 pandemic; however, the proximity in timing to recent MI and higher achieved CRP levels after therapy (mean of 3 mg/dL in the colchicine arm) may provide a signal that the timing of colchicine initiation is important in determining which patients may most benefit. LoDoCo2 (stable CAD) and COLCOT (mean 13.5 days after MI) enrolled individuals further out from MI than CLEAR SYNERGY, perhaps allowing for a more favorable substrate prior to initiation of the drug. The utility of an initial high dose of colchicine followed by standard, single-day dosing in COPS may lend insights into the optimal timing of colchicine initiation. Prior to dismissing its use overall, further research is needed to determine the optimal timing of initiation in the short term after MI. In the long term, other factors such as residual inflammatory risk after achievement of low-density lipoprotein cholesterol goals, lipoprotein(a) level, apolipoprotein B100, and triglycerides may also be considered in the decision to initiate colchicine therapy.

References

  1. U.S. Food and Drug Administration. Center for Drug Evaluation and Research: Approval Package for: APPLICATION NUMBER: 215727Orig1s000 [colchicine tablets, 0.5 mg] (FDA website). 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/215727Orig1s000Approv.pdf . Accessed 03/19/2025.
  2. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10.
  3. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838-47.
  4. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497-505.
  5. Jolly SS, d'Entremont MA, Lee SF, et al.; CLEAR Investigators. Colchicine in acute myocardial infarction. N Engl J Med 2025;392:633-42.
  6. Tong DC, Quinn S, Nasis A, et al. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial. Circulation 2020;142:1890-900.
  7. Vrints C, Andreotti F, Koskinas KC, et al.; ESC Scientific Document Group. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J 2024;45:3415-537.
  8. Virani SS, Newby LK, Arnold SV, et al.; Peer Review Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2023;148:e9-e119.
  9. Institut de Cardiologie de Montréal. Approbation de la colchicine à faible dose par Santé Canada pour les maladies cardiovasculaires, basée sur l'étude COLCOT (Institut de Cardiologie de Montréal website). 2021. Available at: https://icm-mhi.org/2021/08/27/approbation-de-la-colchicine-a-faible-dose-par-sante-canada-pour-les-maladies-cardiovasculaires-basee-sur-letude-colcot/. Accessed 03/18/2025.
  10. Ponte-Negretti CI, Wyss F, Piskorz D, et al. Latin American consensus on management of residual cardiometabolic risk. A consensus paper prepared by the Latin American Academy for the Study of Lipids and Cardiometabolic Risk (ALALIP) endorsed by the Inter-American Society of Cardiology (IASC), the International Atherosclerosis Society (IAS), and the Pan-American College of Endothelium (PACE). Arch Cardiol Mex 2021;92:6601.

Resources

Clinical Topics: Acute Coronary Syndromes, Prevention

Keywords: Colchicine, Anti-Inflammatory Agents, Risk, Acute Coronary Syndrome, Myocardial Infarction