Colchicine treats a wide array of autoimmune and inflammatory conditions by inhibiting the NOD-like receptor protein 3 (NLRP3) inflammasome and key pro-inflammatory cytokines. In recent years, it has gained ground as an attenuator of vascular inflammation and a driver of atherosclerosis and cardiovascular disease (CVD). The recent Food and Drug Administration (FDA) approval of colchicine for cardiovascular risk reduction heralds a new era of its use in coronary artery disease (CAD). This paper reviews the evidence from completed and ongoing clinical trials on the therapeutic impact of colchicine on major adverse cardiovascular events (MACE) and atherosclerotic burden, including its mechanism of action on inflammatory pathways and cellular processes. We examine outcome trials on cardiovascular event reduction and novel imaging studies assessing atherosclerosis progression. In conclusion, this analysis aims to provide clinicians with a clearer understanding of the role of colchicine in cardiovascular health, including its potential therapeutic indications and limitations.
Clinical perspective
Colchicine is a promising, low-cost, and well-tolerated adjunct therapy for CAD. Extensive trials and imaging studies demonstrate that it reduces MACE significantly and stabilizes atherosclerotic plaques. Integrating colchicine for primary and secondary prevention may offer additional risk reduction beyond standard CAD management. This review examines multiple trials to assess the therapeutic benefits of colchicine and to inform clinical understanding of its role in CVD. Despite the promising findings with colchicine, a more nuanced understanding of its therapeutic indications, optimal therapeutic window, and population-specific efficacy remains necessary. This review clarifies the evolving evidence base, identifies gaps in current knowledge, and highlights future research directions and clinical applications of colchicine in CVD.
Introduction
Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of morbidity and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) has traditionally been regarded as the primary driver of CVD and a pivotal target for addressing MACE. However, an overlooked residual risk persists—namely, chronic vascular inflammation associated with atherosclerotic disease.
In 2017, the Canakinumab Therapy for Atherosclerotic Disease (CANTOS) trial enrolled patients with prior myocardial infarction (MI) and C-reactive protein (CRP) ≥ 2 mg/L. It demonstrated that anti-inflammatory therapy significantly lowered the rate of recurrent cardiovascular events. The CANTOS trial raised the question of whether ASCVD therapy should target both LDL-C and vascular inflammation. While monoclonal antibody therapy against IL-1β (Canakinumab) has shown promise, the high cost and limited accessibility highlight the need for a widely available, inexpensive, and orally administered alternative. Colchicine, a well-known anti-inflammatory agent, emerged as a promising therapeutic candidate. Originally an alkaloid extract derived from the autumn crocus plant, colchicine has long been used for its anti-inflammatory effects in conditions such as gout and familial Mediterranean fever. In 2023, the FDA approved low-dose colchicine (0.5 mg daily) for reducing cardiovascular risk in the context of secondary prevention. This landmark development marked the entry of colchicine into the cardiovascular therapeutic landscape. It is worth noting that the initial therapeutic dose of colchicine ranges from 1 to 2 mg daily; however, clinical evidence from many placebo-controlled pharmacodynamic studies has found that a low dose of 0.5 mg daily can be just as effective while having a better safety profile in preventing gout and CVD.
This emerging role spurred a wave of clinical trials investigating new therapeutic indications and outcomes. As colchicine offers a novel therapeutic approach to CVD management, a comprehensive review of current evidence is warranted. This paper aims to synthesize clinical trial data to inform present and future clinical practice regarding the use of colchicine in cardiovascular care. Special emphasis is placed on new outcome-based studies as well as advanced imaging trials that offer unique insights into how clinicians should approach this therapy. The paper will begin by discussing the mechanism of action of colchicine, providing a simplified framework for understanding its anti-inflammatory effect (including its impact on inflammatory mediators like CRP). It then reviews major clinical trials evaluating the outcomes of colchicine in CAD management. This is followed by an examination of imaging studies that offer unique insight into the role of colchicine on atherosclerotic plaque stability and disease progression. Finally, future and ongoing trials are discussed.
Mechanisms of Action of Colchicine
The anti-inflammatory effects of colchicine stem from its ability to disrupt a cascade of molecular processes and suppress the innate immune response. Microtubules are essential for leukocyte activation and migration to sites of inflammation; colchicine acts by binding the β-tubulin subunit of microtubules and destabilizing the entire structure. Additionally, it reduces E-selectin expression on endothelial cells as well as L-selectin on neutrophils. As a result, colchicine suppresses leukocyte activation and migration, thereby reducing the release of pro-inflammatory mediators.
Colchicine also exerts its effects on the innate immune system by targeting the NLRP3 inflammasome complex. The NLRP3 inflammasome activates caspase-1, which converts the inactive pro-Interleukin-1β (IL-1β) into the active form of IL-1β, a potent pro-inflammatory cytokine. Additionally, colchicine again disrupts microtubules (as described above) and prevents the formation of the NLRP3 inflammasome complex. This leads to an overall reduction of activated IL-1β, as well as downstream products such as IL-18, IL-6, and CRP levels. This overall reduction in pro-inflammatory cytokines dampens the inflammatory response of the inflammasome.
Colchicine and Its Effect on CRP
By suppressing leukocyte activation and migration as well as inhibiting NLRP3 inflammasome-mediated cytokine activation, colchicine dampens vascular inflammation associated with atherosclerotic disease. CRP is an acute-phase reactant synthesized in the liver (measured as high-sensitivity CRP (hs-CRP)) and serves as a marker of inflammation. Through the inhibition of IL-1β and its downstream effects on IL-6, colchicine indirectly reduces the hepatic synthesis of CRP. Multiple clinical trials have shown that colchicine lowers inflammatory biomarkers like hs-CRP, which are associated with CVD and mortality. Additionally, a meta-analysis of 11 trials examined the reduction of hs-CRP and IL-6 with colchicine in patients with CAD. It found that colchicine treatment was significantly associated with a reduction in hs-CRP (p = 0.003) and IL-6 (p = 0.02).
Colchicine and Outcomes in CAD Prevention
The low-dose colchicine trials
The low-dose colchicine trials (LoDoCo2) was a randomized, double-blinded, placebo-controlled study investigating the effects of low-dose colchicine on cardiovascular outcomes. The study included 5,522 patients with CAD as confirmed by angiography and/or a coronary artery calcium score (CAC) of at least 400 Agatston units. Patients were randomized into an intervention group (n = 2,762) receiving 0.5 mg of colchicine daily or a placebo group (n = 2,760). They were followed for a median of 28.6 months. The primary endpoints included death from CVD, spontaneous (nonprocedural) MI, noncardioembolic ischemic stroke, or ischemia-driven coronary revascularization.
The primary outcomes occurred in 6.8% of patients (187 patients) in the colchicine group, compared to 9.6% (264 patients) in the placebo group (incidence, 2.5 versus [vs] 3.6 events per 100 person-years; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.57 to 0.83; p < 0.001). These findings (published in 2020) built upon the earlier 2013 LoDoCo trial, a smaller trial (n = 532) that was the first to show the effects of colchicine on atherosclerotic disease. The primary reported side effect in the 2013 trial was gastrointestinal upset. In the colchicine group, 30 patients stopped the drug altogether, 32 discontinued it early, and 7 never initiated it. In the placebo group, no patients discontinued or dropped out of the study. Of note, the 2013 LoDoCo trial was unblinded, which may explain why none of the placebo patients discontinued the drug.
LoDoCo2, with its larger sample size, confirmed that adding low-dose colchicine (0.5 mg daily) to proven secondary prevention therapies (statins, antiplatelet, etc.) reduced the risk of cardiovascular events significantly in patients with stable CAD over a median follow-up of ∼29 months. Notably, the LoDoCo trials did not assess hs-CRP, an omission that paved the way for future trials to capitalize on.
The colchicine cardiovascular outcome trials
Colchicine cardiovascular outcome trials (COLCOT) evaluated the anti-inflammatory effects of low-dose colchicine (0.5 mg daily) on cardiovascular outcomes, specifically its role in mitigating post-MI complications. This was a randomized, double-blinded, placebo-controlled study of 4,745 participants enrolled within 30 days post-MI. Of these, 2,366 patients were assigned to the treatment group, receiving 0.5 mg of colchicine daily, and 2,379 to the placebo group. The primary outcome was a composite death from cardiovascular causes, stroke, urgent angina requiring revascularization, resuscitated cardiac arrest, and recurrent MI.
The primary composite outcomes occurred in 5.5% of patients in the colchicine group compared to 7.1% of patients in the placebo group (HR, 0.77; 95% CI, 0.61 to 0.96; p = 0.02). The most common adverse event with colchicine was diarrhea, which was reported in 9.7% of the patients in the colchicine group and 8.9% in the placebo group (p = 0.35). The overall drug discontinuation rate was similar between the colchicine and placebo groups (∼18% in each). This 2019 trial provided evidence that adding colchicine to the standard of care reduced MACE in the post-MI setting.
The COLCOT trial also looked at the time-to-treatment initiation (TTI), defined as the time from MI to colchicine initiation. “Early” initiation was within 3 days post-MI, and “late” initiation was beyond 3 days post-MI. The benefit of colchicine was most substantial if initiated within 3 days of MI (early initiation), emphasizing the importance of early inflammatory control in the post-MI period. This finding raises the question of whether early colchicine initiation dampens the post-MI inflammatory cascade and thereby improves outcomes. However, like the LoDoCo trials, COLCOT did not measure or correlate hs-CRP levels.
A 2021 sub-study aimed to address the lack of correlation between hs-CRP data and colchicine. It included a smaller sample size of 429 patients (207 from COLCOT and 222 for LoDoCo-MI) and evaluated paired pre- and post-treatment hs-CRP. Colchicine did not significantly reduce hs-CRP as a continuous variable (β = 0.41; p = 0.429). However, notably, more patients on colchicine achieved a post-treatment hs-CRP of ≤1.0 mg/L compared to those on placebo (odds ratio [OR]: 1.64, 95% CI: 1.07 to 2.51, p = 0.024). Although limited by a small sample size, this finding suggests a potential role for colchicine in reducing hs-CRP levels in post-MI patients. Questions remain, however, as no large-scale data exist to confirm this.
The colchicine and spironolactone in patients with ST elevation MI and SYNERGY stent registry trial (CLEAR SYNERGY)
The CLEAR SYNERGY trial assessed the long-term cardiovascular effects of spironolactone and low-dose colchicine in patients with MI undergoing percutaneous coronary intervention (PCI). This multicenter, randomized, double-blinded, placebo-controlled, 2 × 2 factorial study enrolled 7,062 patients with ST-elevation MI (STEMI) or large non-ST-elevation MI (NSTEMI), all treated with PCI. For this review, only the colchicine arm is considered. Patients were randomized to either colchicine 0.5 mg daily (n = 3,528) or placebo (n = 3,534) and were followed for a median of ∼3 years. The primary endpoints were a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization. Inflammatory markers (including CRP) were also measured in both groups.
CLEAR SYNERGY showed no statistically significant difference in the composite endpoint between the colchicine and placebo groups (9.1% vs 9.3%; HR: 0.99; 95% CI: 0.85 to 1.16; p = 0.93). However, inflammatory markers were significantly lower in the colchicine group (p < 0.001). Diarrhea was the most common side effect, occurring in more patients in the colchicine group when compared to the placebo group (10.2% vs 6.6% respectively; p < 0.001). The drug discontinuation rate was similar in both groups (∼26%). CLEAR SYNERGY is the largest trial to date evaluating colchicine in MI patients undergoing PCI. Interestingly, although colchicine reduced inflammatory markers, such as CRP, it had no significant effect on MACE over a median follow-up of 3 years.
These findings contradict many prior studies (e.g., COLCOT and LoDoCo2), raising further questions about the efficacy of colchicine for secondary prevention in this patient population. It is worth noting that a higher than expected ∼26% of participants discontinued treatment, which may have influenced the results.
Other meta-analyses
In the European Heart Journal, 2 recent meta-analyses published in May 2025 further investigated the effects of colchicine on MACE. The first meta-analysis evaluated 6 randomized controlled trials (RCTs) involving 21,800 patients with stable vascular disease (CAD, stroke, and post-MI). It concluded that low-dose colchicine (0.5 mg daily) reduced the primary endpoint of MACE significantly by ∼25% compared to placebo (p < 0.05). The second meta-analysis reviewed 9 RCTs involving 20,659 patients with either prior stroke or CAD. It found that the colchicine group experienced a significant 12% relative risk reduction (RRR) in MACE compared to the control (noncolchicine) group.
The Role of Colchicine in Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention
Colchicine in patients with coronary disease who underwent coronary artery bypass surgery: a meta-analysis of randomized controlled trials
This 2024 meta-analysis of 5 RCTs aimed to evaluate the impact of colchicine on outcomes in CAD patients undergoing elective CABG. It included 953 patients: 477 received perioperative low-dose colchicine, while 476 received standard perioperative care. The primary outcome was postoperative atrial fibrillation (POAF). Secondary endpoints included all-cause mortality, postoperative stroke, MI, and length of intensive care unit stay. The dose of colchicine varied from 1 2 mg preoperatively and 0.5-1 mg postoperatively. The meta-analysis found that the incidence of POAF was significantly reduced with perioperative colchicine administration compared to placebo (21.6% vs 33.5%. RR: 0.64; 95% CI: 0.48–0.85; p = 0.002). The authors highlight a knowledge gap, calling for further investigation into the effect of colchicine on reducing arrhythmic complications in high-risk CABG patients.
Major adverse cardiovascular events after colchicine administration before percutaneous coronary intervention: follow-up of the colchicine-PCI trial
The original colchicine-percutaneous coronary intervention (PCI) trial was a randomized, double-blinded, placebo-controlled study evaluating whether a short-term preprocedural colchicine loading dose (1.2 mg 1 hour before PCI, followed by 0.6 mg 1 hour prior) could reduce postprocedural MI. The original study found no significant difference in postprocedural MI between both groups (57.3% vs 64.2%, p = 0.19). This was followed by a long-term outcome study investigating the role of colchicine in reducing MACE over a median follow-up period of 2 years. MACE was assessed at 30 days, 6 months, and then annually for a minimum of 2 years and a maximum of 5 years. The study population consisted of 400 patients undergoing (194 in the standard therapy arm and 206 in the colchicine arm). The primary endpoint was composite MACE, defined as all-cause mortality, nonfatal MI, stroke, or ischemia-driven target vessel revascularization. The study found that a 1-time colchicine loading dose 1-2 hours before PCI did not significantly reduce long-term MACE (32.5% vs 34.9%, HR 0.95; 95% CI: 0.68 to 1.34; p = 0.79). The researchers hypothesized that a brief 1-time dose might be insufficient and that continued daily colchicine therapy after PCI could be required to observe benefits. (Outcome trials summarized in Table 1 ).
Table 1
Primary outcome of clinical trials of colchicine in coronary artery disease
| Study | Patients (N) | Inclusion criteria (population) | Mean age; follow up | Primary endpoint(s) | Concurrent CV + colchicine therapy | Markers | Adverse events (discontinuation) | Major/key findings |
|---|---|---|---|---|---|---|---|---|
| LoDoCo2 | 5,522 chronic CAD patients | Stable CAD on angiography or CAC ≥ 400 Agatston units | 66 yrs; Median 28.6 mo | MACE (CV death, non‐procedural MI, ischemic stroke, or ischemia-driven revascularization) | >99% on antiplatelet or anticoagulant and 97% on statins. Colchicine of 0.5 mg/day. | N/A | GI: 30 completely stopped the drugs, 32 noted early discontinuation in colchicine group. No placebo dropouts. | ↓︎ MACE by 31% (HR 0.69, p < 0.001) with reduced MI and ischemia-driven revascularization |
| COLCOT | 4,745 post-MI patients | Recent myocardial infarction (≤30 days post-MI) | 61 yrs; Median 22.6 mo | MACE (CV death, resuscitated cardiac arrest, MI, stroke, or urgent angina leading to revascularization) | 93% PCI for index MI, >99% on antiplatelet therapy and 98% on statins. Colchicine of 0.5 mg/day. | N/A | GI: No significant difference (9.7% vs 8.9%; p = 0.35) | ↓︎ MACE by 23% (HR 0.77, p = 0.02) with reduced CV death, resuscitated cardiac arrest, and recurrent MI |
| CLEAR SYNERGY | 7,062 acute MI patients | Acute STEMI (PCI ≤12 hours) or high-risk NSTEMI (PCI ≤48 hours) | 60.5 yrs; Median 3.0 yrs | MACE (CV death, MI, stroke, or ischemia-driven revascularization) | 100% PCI with drug-eluting stent and DAPT in all. Colchicine of 0.5 mg/day. | hs-CRP | GI: ↑︎ colchicine group (10.2% vs 6.6%; p < 0.001). Similar discontinuation rate of ∼26% | No significant reduction in MACE (HR 0.99, p = 0.93), but colchicine ↓︎ hs-CRP (p < 0.001) |
| CABG & colchicine meta-analysis | 5 RCTs (953 patients) | CAD who underwent elective CABG | 63 yrs; ∼30 days postop | POAF incidence | Standard perioperative management. Variable colchicine dosing. | N/A | GI: ↑︎ colchicine group (15.6% vs 5.7%; p = 0.001) | ↓︎ POAF incidence (21.6% vs 33.5%, p = 0.002) |
| Colchicine-PCI follow-up | 400 patients undergoing PCI | Adults ≥18 yrs undergoing coronary angiography with PCI | 61.5 yrs; Mean 3.3 yrs | MACE (all-cause death, nonfatal MI, stroke and ischemia-driven target vessel revascularization) | All received standard PCI care. Colchicine 1.8mg loading. | N/A | N/A | No significant reduction in MACE (HR 0.95, p = 0.79) |
Abbreviations: CAD = coronary artery disease; CABG = coronary artery bypass grafting; CAC = coronary artery calcium; CV = cardiovascular; DAPT = dual antiplatelet therapy; GI = gastrointestinal; Hs-CRP = High sensitivity- C-reactive protein; MACE = major adverse cardiac events; MI = myocardial infarction; NSTEMI = non-ST-elevation myocardial infarction; PCI = percutaneous coronary intervention; POAF = postoperative atrial fibrillation; RCT = randomized controlled trial; STEMI = ST-elevation myocardial infarction.
All listed trials were randomized and placebo-controlled. All patients received standard guideline-directed medical therapy. Colchicine was given at 0.5 mg once daily in each trial, except Colchicine-PCI, which used a 1.8 mg loading dose before PCI. Primary endpoints refer to composite cardiovascular outcomes as defined in each study.
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