What evidence supports the use of colchicine for the secondary prevention of cardiovascular events?

Background
Atherosclerotic cardiovascular disease (ASCVD) is a prevalent, chronic inflammatory condition marked by the narrowing and stiffening of arteries due to plaque accumulation.1 Broadly, ASCVD encompasses various conditions including acute coronary syndrome, coronary artery disease, peripheral artery disease, and cerebrovascular disease.2 Secondary prevention plays a crucial role in patients with ASCVD to lower the likelihood of further cardiovascular (CV) events including myocardial infarction (MI), stroke, and/or other complications.

Current treatments aimed at reducing ASCVD risk primarily target low-density lipoprotein cholesterol (LDL-C) to prevent its buildup in the arteries.3 However, recent findings indicate that inflammation also plays a significant role in ASCVD, independent of cholesterol levels.4 Inflammation in the arterial endothelium leads to the migration, adhesion, and activation of leukocytes, particularly neutrophils.5 This activation results in a downstream cascade involving the upregulation of inflammatory biomarkers such as high sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6; these biomarkers have been linked to an increased risk of CV events.4 Notably, the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial confirmed the role of inflammation in atherosclerosis by demonstrating that blockade of IL-1β with canakinumab lowered the incidence of major adverse cardiovascular events (MACE) independently of any changes in blood lipid levels.6 Specifically, canakinumab reduced hs-CRP and IL-6, independent of LDL-C.

A better understanding of the role of inflammation in ASCVD has prompted numerous studies investigating whether other anti-inflammatory therapies could improve CV outcomes.7 In particular, the anti-inflammatory effects of colchicine has recently been harnessed for secondary prevention of CV disease. Colchicine, a lipophilic tricyclic alkaloid derived from the Colchicum autumnale plant, is an anti-inflammatory drug that has been in use for over a millennium.8 Colchicine was initially approved by the US Food and Drug Administration (FDA) in 1961 for the treatment of gout.9 In 2009, Colcrys® (colchicine 0.6 mg tablets) was approved for the prophylaxis and treatment of gout flares, and treatment of familial Mediterranean fever.10,11 In 2023, the FDA approved a new formulation, Lodoco® (colchicine 0.5 mg tablets) to reduce the risk of MI, stroke, coronary revascularization, and CV death in adults with established atherosclerotic disease or with multiple risk factors for CV disease.12 For this indication, the recommended dosage of colchicine is 0.5 mg orally once daily.

Colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils.12 Colchicine may also interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of IL-1β; colchicine also reduces hs-CRP. These anti-inflammatory effects may help prevent major CV events; however, the precise mechanism of action of colchicine for CV secondary prevention is not fully elucidated.

Guideline recommendations
Despite effective secondary prevention strategies, including lifestyle changes and risk factor reduction, patients with stable coronary artery disease are at continued risk for major ASCVD events.13 The 2023 American Heart Association guideline for the management of patients with chronic coronary disease states that the addition of colchicine (0.5 mg daily) may be considered to reduce recurrent ASCVD events. Given the narrow therapeutic index of colchicine, its potential for drug interactions, and risk for adverse events, a highly individualized approach is recommended. The use of colchicine should be limited to patients who remain at very high risk despite maximum-tolerated, guideline-directed medical therapy (i.e., antiplatelet agent, statin, renin-angiotensin system inhibitor, and beta-blocker) until further data become available.

Literature review
Key clinical trials on low-dose colchicine (0.5 mg daily) for secondary prevention of ASCVD events are summarized in Table 1.14-16 The open-label LoDoCo (Low-Dose Colchicine) trial was the first study to demonstrate the efficacy of colchicine 0.5 mg daily on top of optimal medical therapy (ie, aspirin and/or clopidogrel, statin) for the prevention of CV events in patients with stable coronary disease.14 Stronger evidence supporting the benefits of colchicine in reducing ASCVD events came from the LoDoCo2 and COLCOT (Colchicine Cardiovascular Outcomes Trial) randomized controlled trials.15,16 Both trials evaluated the impact of adding either colchicine or placebo to standard guideline-directed therapy (ie, antiplatelet agent, statin, renin-angiotensin system inhibitor, and beta-blocker) on MACE in approximately 5000 patients over a 2-year period. COLCOT enrolled patients who had experienced an MI within the previous 30 days, while LoDoCo2 enrolled patients with stable coronary artery disease (≥6 months post an acute coronary syndrome). In both trials, low-dose colchicine reduced the incidence of MACE by over 30% compared to placebo. The FDA approval of Lodoco® was based principally on the results of the LoDoCo2 trial.12

Table 1. Key randomized studies on low-dose colchicine for secondary prevention.14-16
Study DesignSubjectsInterventionsResults

Nidorf 201314

LoDoCo		Prospective, randomized, observer-blinded, open-label studyN=532 patients with stable CADRandomized to receive colchicine 0.5 mg daily or no colchicine

Median follow-up of 3 years		Composite incidence of ACS, out-of-hospital cardiac arrest, non-cardioembolic ischemic stroke; colchicine versus no colchicine: 5.3% versus 16% (HR, 0.33; 95% CI, 0.18 to 0.59; p<0.001)

Tardif 201915

COLCOT		Randomized, double-blind, placebo-controlled trialN=4745 adults recruited within 30 days after an MI and completed any planned percutaneous revascularization proceduresRandomized to receive colchicine 0.5 mg daily or placebo

Median follow-up of 22.6 months		Composite of death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to revascularization; colchicine versus placebo: 5.5% versus 7.1% (HR, 0.77; 95% CI, 0.61 to 0.96; p=0.02)

Nidorf 202016

LoDoCo2		Randomized, double-blind, placebo-controlled trialN=5522 adults with chronic CADRandomized to receive colchicine 0.5 mg daily or placebo

Median follow-up of 28.6 months		Composite of death from CV causes, nonfatal MI, nonfatal stroke, or coronary revascularization in a time-to-first-event analysis; colchicine versus placebo: 6.8% versus 9.6% (HR, 0.69; 95% CI, 0.79 to 0.96; p<0.001)
Abbreviations: ACS=acute coronary syndrome; CAD=coronary artery disease; CI=confidence interval; COLCOT= Colchicine Cardiovascular Outcomes Trial; CV=cardiovascular; HR=hazard ratio; LoDoCo=low-dose colchicine; MI=myocardial infraction.

Several meta-analyses (Table 2) have recently been published on colchicine for secondary prevention.17-23 These meta-analyses have included the LoDoCo/LoDoCo2 and COLCOT trials in addition to other studies. Overall, the meta-analyses have shown benefit of colchicine in various populations for secondary prevention of ASCVD events; some studies have also found an increased risk of gastrointestinal (GI) adverse events.

Table 2. Key meta-analyses on colchicine for secondary prevention.17-23
Study DesignPopulationMain results

Zhu 202517		SR and MA of 13 RCTs measuring the efficacy of colchicine versus placebo for stroke preventionN=24900 patients with established ASCVD

5 studies evaluated colchicine doses >0.5 mg daily; all other studies used 0.5 mg daily		Colchicine decreased the risk of ischemic stroke (RR, 0.85; 95% CI, 0.72 to 0.99; I2=2.92%).

Colchicine was more effective versus placebo when:
  • prescribed as 0.5 mg/day (RR, 0.86; 95% CI, 0.75 to 0.99)
  • prescribed for >30 days (RR, 0.86; 95% CI, 0.75 to 1.00)
  • prescribed for >90 days (RR, 0.65; 95% CI, 0.46 to 0.92)
  • administered to patients with ACS (RR, 0.46; 95% CI, 0.23 to 0.92).

Shaikh 202518		SR and MA of 9 studies evaluating colchicine for secondary preventionN=7260 patients with ACS receiving standard medical therapy

Mean age, 60.1 years; 19.3% females: mean follow-up duration of 8.5 months

1 study evaluated low-dose colchicine (0.5 mg daily)		Patients who received colchicine had a reduced risk of re-hospitalizations:
OR, 0.52; 95% CI, 0.34 to 0.81; I2=0%

GI events were increased compared to placebo:
OR, 2.10; 95%, 1.20 to 3.68; I2=79%

Noll 202520		SR and MA of 32 RCTs comparing colchicine to usual care or placebo for stroke preventionPatients with various high-risk conditions including stable CAD, ACS, and recent MI (total N not reported)

Colchicine doses ranged from 0.5 mg daily to 0.6 mg twice daily across studies, with some studies using a loading dose of 1.8 to 2 mg		Colchicine reduced stroke recurrence compared to usual care or placebo:
  • RR, 0.46; 95 % CI, 0.41 to 0.52; p<0.0001; I²=0 %
  • OR, 0.44, 95 % CI, 0.36 to 0.55; p<0.0001; I²=0 %

GI adverse events were increased compared to usual care or placebo:
  • RR, 1.54; 95% CI, 1.33 to 1.79; p<0.0001; I²=63%;
  • OR, 1.60; 95% CI, 1.08 to 2.38; p=0.0007; I²=82%
LJaiswal 202521SR and MA of 16 RCTs comparing colchicine to placebo for prevention of stroke or adverse CV eventsN= 24,967 adults with CAD

Various colchicine doses were evaluated including 0.5 mg daily (7 studies)		Compared to placebo, colchicine reduced the risk of incidence of:
  • CV events by 33% (OR, 0.67; 95% CI, 0.54 to 0.82; p<0.001)
  • MI by 21% (OR, 0.79; 95% CI, 0.65 to 0.95, p=0.01)

Risk of incidence of stroke was comparable between groups

Younas 202521		SR and MA of 11 RCTs comparing colchicine to placebo/no colchicine in patients post- MIN=7161 adults with MI with a follow-up duration of ≥1 month

1 study evaluated low-dose colchicine (0.5 mg daily)		Colchicine reduced the composite of:
  • CV events - RR, 0.75; 95% CI, 0.60 to 0.94; p=0.01, I2=47%
  • Hospitalization urgency - RR, 0.46; 95% CI, 0.31 to 0.68; p=0.0001, I2=0%

Adverse GI events were increased:
  • RR, 1.86; 95 % CI, 1.14 to 3.02; p=0.01, I2=79 %

Fiolet 202422		SR and MA of 6 RCTs evaluating colchicine versus placebo/no colchicine for secondary prevention of ischemic stroke and MACEN=14,934 patients with prior stroke or coronary disease

All studies evaluated low-dose colchicine (0.5 mg daily)		Colchicine compared with placebo or no colchicine reduced the risk for:
  • ischemic stroke by 27% (RR, 0.73; 95% CI, 0.58 to 0.90; p<0.004)
  • MACE by 27% (RR 0.73; 95% CI, 0.65 to 0.81; p<0.001).

Zhou 202323		SR and MA of 8 RCTs evaluating the effects of colchicine versus placebo/no colchicine on MACEN=5872 adults with recent acute MI

Colchicine doses ranged from 0.5 mg to 1 mg across studies		Colchicine reduced the occurrence of MACE (RR, 0.56; 95% CI, 0.48 to 0.67) with 2.99-fold increased GI adverse events.

The incidence of MACE decreased with longer follow-up duration (≥1 year) and lower dosage of colchicine (0.5mg/day).
Abbreviations: ACS=acute coronary syndrome; ASCVD=atherosclerotic cardiovascular disease; CAD=coronary artery disease; CI=confidence interval; CV=cardiovascular; GI=gastrointestinal; I2=heterogeneity measure; MA=meta-analysis; MACE=major adverse cardiovascular events; MI=myocardial infraction; OR=odds ratio; RCT=randomized controlled trial; RR=relative risk; SR=systematic review.

Since the publication of these meta-analyses, results of the CLEAR (Colchicine in Low-dose, Examines Acute Risk) trial have been published.24 In this multicenter, prospective, randomized, placebo-controlled trial with a 2-by-2 factorial design, patients (N=7062) who had an MI were randomized to receive either colchicine (0.5 mg daily) or placebo and either spironolactone or placebo. The primary efficacy outcome was a composite of death from CV causes, recurrent MI, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. Over a median follow-up period of 3 years, a primary-outcome event occurred in 9.1% of patients in the colchicine group compared to 9.3% in the placebo group (hazard ratio, 0.99; 95% confidence interval, 0.85 to 1.16; p=0.93).

Considerations for clinicians
Clinicians should be aware of the distinct indication, dosing, timing, and duration of therapy for colchicine formulations, including Lodoco®, which is indicated at a dosage of 0.5 mg once daily.12 A recent analysis using data from the National Prescription Audit quantified the volume and trends of colchicine prescriptions dispensed through U.S. retail pharmacies between 2018 and 2024.25 The study found that, despite the FDA approval of colchicine 0.5 mg tablets, clinical trials demonstrating efficacy of the agent, and its inclusion in recent clinical guidelines, the drug remains underutilized in cardiology for CV disease prevention. This suggests limited adoption for ASCVD risk reduction. Contributing factors may include clinical inertia, limited clinician awareness of the new indication and formulation, and patient-related challenges such as cost and side effects, potentially affecting adherence. Guideline-based adoption of colchicine in ASCVD prevention may be enhanced by addressing these challenges. For example, healthcare providers should inform patients about potential side effects and drug interactions related to colchicine use.

Summary and conclusion
Colchicine, an old drug with broad anti-inflammatory effects, has recently gained a new indication for ASCVD risk reduction in patients with chronic coronary disease.12 Evidence from several large RCTs (notably LoDoCo2 and COLCOT) suggests that low-dose colchicine may benefit patients with CAD, and the drug has been incorporated into recent guideline recommendations in this population.7,15,16,26 However, when prescribing colchicine, clinicians should be mindful of potential GI side effects, possible drug interactions, and the need to monitor kidney and liver function.7,12 Although further research is needed to fully define the role of colchicine in CV care, key clinical trials have laid the groundwork for its use as an approved targeted anti-inflammatory therapy for managing atherosclerotic risk.26

References

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Prepared by:
Honey Joseph, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2025

The information presented is current as of April 14, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.