On July 20, 2023, the United States Food and Drug Administration (FDA) approved colchicine 0.5 mg daily as the first anti-inflammatory drug labeled specifically for reducing the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular events.1

Notably, inflammation has long been known to play a key role in the development and progression of atherosclerotic vascular disease.2 More specifically, the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 inflammasome, and ensuing production of Interleukin1β (IL-1β) have been demonstrated within atherosclerotic plaques in response to cholesterol crystal formation, and considered responsible for the initiation and progression of endothelial dysfunction, impaired vasodilation, leukocyte homing and activation, and promoting a prothrombotic milieu.3 The ultimate result is atherosclerotic plaque growth and eventually destabilization with thrombosis superimposition and the clinical manifestation of obstructive coronary artery disease (CAD). It is therefore clear how modulating inflammation, and more specifically the inflammasome-IL-1β axis, is an attractive therapeutic target for atherosclerosis.

Preclinical and clinical studies have shown that hydroxymethylglutaryl-coenzyme A reductase inhibitors, also known as statins–the mainstay of atherosclerosis prevention and treatment, possess powerful anti-inflammatory effects, on top of lowering cholesterol associated with low-density lipoproteins.4 Targeting specifically IL-1β with canakinumab, a monoclonal antibody, also reduces cardiovascular events in patients with prior MI and evidence of systemic inflammation, independent of any lipid-lower effect.5

Colchicine is a natural alkaloid extract from plants of the genus Colchium (autumn crocus). From a pharmacologic point of view, colchicine binds in a poorly reversible manner to tubulin and prevents microtubule formation, and it has been known to interfere with organelle trafficking, intercellular adhesion, and cellular migration.6 Interestingly, colchicine at therapeutic concentration was shown to inhibit the nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 inflammasome and hence inhibit the release of IL-1β, and IL-18, and to reduce the surface expression and downstream signaling of a large number of secondary mediators, including IL-6.6,7 The net effect is a potent anti-inflammatory action that is leveraged for the treatment of acute and chronic inflammatory disease like gouty arthritis, acute and recurrent pericarditis, familial Mediterranean fever, and others. These broad anti-inflammatory effects are particularly attractive in the setting of prevention of atherosclerosis complications.

Three large randomized-controlled clinical trials have tested the hypothesis that colchicine can be beneficial in the setting of atherosclerotic cardiovascular disease (ASCVD). In the Low-Dose Colchicine for secondary prevention in cardiovascular disease (LODOCO), 532 patients with angiographically proven CAD were randomized to receive 0.5 mg or no adjunctive treatment on top of standard of care.8 Primary endpoint was a composite of acute coronary syndrome, out of hospital cardiac arrest, and noncardioembolic ischemic stroke. Median follow-up was 3 years. At follow-up, the primary endpoint occurred in 15/282 (5.3%) patients in the colchicine arm and in 40/250 (16.0%) patients in the standard of care arm, resulting in a hazard ratio (HR) of 0.33 [95% confidence interval (CI), 0.18–0.59; P < 0.001] and a number needed to treat 11.8 These promising results led to the design and execution of the subsequent Low-Dose Colchicine for secondary prevention in the cardiovascular disease-2 (LODOCO-2) trial.9 In the LODOCO-2 trial, 5522 subjects with CAD detected on invasive coronary angiography or computed tomography angiography or a coronary-artery calcium score of at least 400 Agatston units on a coronary-artery calcium scan were randomized 1:1 to receive colchicine 0.5 mg daily or matching placebo. Primary endpoint was the composite of cardiovascular death, nonfatal MI, ischemia-driven coronary revascularization, and ischemic stroke. After a median follow-up of 28 months, the active treatment arm experienced significantly less events [187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group—HR 0.69; 95% CI, 0.57 to 0.83; P < 0.001], resulting in a number needed to treat of 36. Every component of the primary endpoint had lower incidence in the colchicine group compared with the placebo group. However, the authors reported a trend toward a higher risk of noncardiovascular death among patients receiving colchicine (0.7 vs 0.5 events per 100 patient/years, HR 1.51, 95% CI, 0.99–2.31).9 Finally, the Colchicine Cardiovascular Outcome Trial (COLCOT) randomized 4745 subjects who had an acute MI in the previous 30 days to receive colchicine 0.5 mg daily or matched placebo.10 Primary endpoint was a composite of death from cardiovascular causes, recurrent acute MI, resuscitated cardiac arrest, ischemic stroke, or urgent hospitalization for angina. At a median follow-up of 22.6 months, the active treatment arm experienced a significantly lower incidence of the primary endpoint (5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group HR 0.77, 95% CI, 0.61–0.96, P = 0.02, number needed to treat of 62), which was mainly driven by a reduction of urgent revascularizations and ischemic stroke. Notably, the colchicine group experienced a significantly increased incidence of pneumonia over the study period (0.9% vs 0.4%, P = 0.03).10Table 1 summarizes the trial findings. A pooled analysis including >10,000 patients from 5 studies confirmed the beneficial effect on the incidence of MI [HR 0.78 (0.64–0.94)] and repeat revascularization [HR 0.77 (0.66–0.90)], with an HR of 0.82 [0.55–1.23] for cardiovascular death, an HR of 1.38 (0.99–1.92) for noncardiovascular death, and an HR of 1.08 (0.71–1.52) for all-cause death.11

TABLE 1. - Characteristics of the Three Main Trials Leading to the Approval of Low-Dose Colchicine for Secondary Prevention in Atherosclerotic Vascular Disease Trial Name LODOCO LODOCO-2 COLCOT Study design Prospective, randomized, comparative, non–placebo-controlled trial Randomized controlled, double-blind Randomized controlled, double-blind No. of patients 532 5522 4745 Study medication Colchicine 0.5 mg daily Colchicine 0.5 mg daily Colchicine 0.5 mg daily Inclusion criteria Angiography proven CAD. Angiography or CCTA proven CAD or CAC >400 Agatston unit. Acute myocardial infarction in the preceding 30 d. Primary endpoint Composite of acute coronary syndrome, out of hospital cardiac arrest, and noncardioembolic ischemic stroke. Composite of cardiovascular death, nonfatal myocardial infarction, ischemia-driven coronary revascularization and ischemic stroke. Composite of death from cardiovascular causes, recurrent acute myocardial infarction, resuscitated cardiac arrest, ischemic stroke, or urgent hospitalization for angina. Follow up duration 3 y 28 mo 22.6 mo Results HR for primary endpoint 0.33 (95% CI, 0.18–0.59, P < 0.001). NNT 11. HR for primary endpoint 0.69 (95% CI, 0.57–0.83, P < 0.001). NNT 36. HR for primary endpoint 0.77 (95% CI 0.61–0.96, P = 0.02). NNT 62. Safety endpoints 32 early dropouts in the colchicine group because of GI side effects.
30 late dropouts for mild adverse events. Trend toward higher rates of noncardiovascular death in the treatment arm (HR 1.51, 95% CI 0.99–2.31). Significantly higher incidence of pneumonia (0.9% vs 0.4%, P = 0.03).

CAC, coronary artery calcium score; CCTA, coronary computed tomography angiography; NNT, number-needed-to-treat.

Overall, the canakinumab and colchicine trials point to a consistent beneficial effect of an anti-inflammatory agent primarily targeting the inflammasome/IL-1β axis in secondary prevention. This is in stark contrast with other classes of anti-inflammatory therapies such as nonsteroidal anti-inflammatory drugs, tumor necrosis factor inhibitors, Janus kinase inhibitors, and methotrexate. Canakinumab and colchicine also show a similar safety profile associated with a small, but significant, increase in common, and not opportunistic, infections. This is consistent with the central role of the inflammasome/IL-1β in the innate immune response and early response, and limited effects on the adaptive cellular and humoral response, by which inflammasome/IL-1β blockers may delay recognition of the infection, and thus jeopardize health, but not impair the pathogen-specific response. Of note colchicine and IL-1 targeted therapies have been thoroughly studied and found beneficial in the treatment of pneumonia secondary to the coronavirus disease and other infections.12

The use of colchicine for the secondary prevention of patients with atherosclerotic CAD is appealing because it provides a novel therapeutic strategy that is distinct from existing therapies. Orally available and available at low cost, colchicine use can be rapidly implemented worldwide. Colchicine, however, accumulates in the blood in patients with severely impaired renal disease and it is subject to many drug–drug interactions,13 and it is associated with frequent gastrointestinal complaints, that lead to discontinuation in up to 20% of cases. Although colchicine can be associated with muscular and hematologic toxicity, these events were rare in the clinical trials of colchicine 0.5 mg daily.

In comparison, Canakinumab is a product of biomedical engineering, FDA-approved for chronic autoinflammatory diseases, that comes at high cost and is available as an injectable. Anakinra, recombinant IL-1 receptor antagonist, and rilonacept, recombinant chimeric fusion protein functioning as an IL-1 trap, are FDA-approved for chronic autoinflammatory disease, and have been studied in acute MI, heart failure, and pericarditis.3 Ziltivekimab, an IL-6 antibody, is also being studied for the secondary prevention of atherosclerotic cardiovascular disease, and it is not FDA-approved for any indication at this time. Table 2 summarizes the main characteristics of the biological inhibitors of the IL-1/IL-6 axis studied in the setting of cardiovascular disease. Canakinumab, anakinra, and ziltivekimab are associated with injection site reaction, but they have rather limited side effects, no organ toxicities, limited drug–drug interactions, and they can be used also in patients with severe kidney disease. Table 2 summarizes the main characteristics of the above-mentioned drugs.

TABLE 2. - Inhibitors of the IL-1β Pathway Being Investigated in the Setting of Cardiovascular Disease Drug Biological Action Evidence Anakinra Recombinant IL-1 receptor antagonist Some evidence of reduction of HF events after STEMI and improved exercise tolerance in the setting of HFHF in phase II trials. Canakinumab Human monoclonal IgGk antibody targeting IL-1β Significant reduction of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke when used in phase III trial of secondary prevention for ASCVD. Improves exercise capacity in the setting of heart failure. Goflikicept Heterodimeric fusion protein capable of a high-affinity binding to human IL-1β and IL-1α Treatment and prevention of recurrences of pericarditis in a phase III trial. Rilonacept Fusion protein containing IL-11-β binding domain of IL-1 receptor and fragment-crystallizable portion of human IgG1 Treatment and prevention of recurrences of pericarditis in a phase III trial. First-line FDA-approved for the treatment of recurrent pericarditis. Ziltivekimab Human monoclonal antibody against IL-6 Reduction in CRP levels and phase II trial. Being actively investigated in the setting of secondary prevention of ASCVD among patients with CKD and HF.

CKD, chronic kidney disease; HF, heart failure; IL, interleukin; STEMI, ST-elevation myocardial infarction.

With the FDA approval of colchicine for secondary prevention of CAD, we expect an increase in its use. The formulation of colchicine used in the main studies and FDA-approved is a tablet of 0.5 mg. This is notably different from other formulations approved for other conditions, all of 0.6 mg. Whether a difference of 0.1 mg provides a benefit in side effects, toxicity, or efficacy is not known. Whether 0.6 mg or even higher doses, as those used for prevention/treatment of gouty arthritis, pericarditis, and familial Mediterranean fever, are associated with greater dose-dependent benefit is also not known.

The benefit of colchicine in clinical trials seems to be across a wide spectrum of disease, ranging from patients with asymptomatic coronary artery calcifications to patients with recent MI. Whether inflammatory biomarkers, such as high-sensitivity C reactive protein can predict not only the cardiovascular events, but also the benefit of colchicine is unknown. The optimal duration of treatment with colchicine is also not known, as in all major trials colchicine was continued long-term.

In conclusion, FDA approval of colchicine for the secondary prevention of CAD marks an important day in Cardiovascular Medicine, providing a paradigm shift by which inhibiting inflammation appears nearly as important as cholesterol lowering in patients with established CAD. Colchicine 0.5 mg should be considered in all patients with CAD, and risk/benefit and cost/benefit analyses should be performed to select the scenarios in which the benefits of colchicine outweigh the side effects and potential adverse events, and the cost of adding an additional drug in the polypharmacy of CAD. Monitoring of colchicine toxicity (gastrointestinal, renal, muscular, and hematologic) and increased awareness for infection will be necessary, especially in older patients, with comorbid conditions, on long-term therapies. Further studies may be needed to investigate whether colchicine therapy can be tailored to the individual in dosage and duration. Considering the efficacy of colchicine in acute and recurrent pericarditis,14,15 it would be interesting to determine whether it may beneficial in other nonatherosclerotic forms of cardiovascular disease, such as acute myocarditis and heart failure. Moreover, it will be important to consider how colchicine may compare with novel, targeted, anti-inflammatory therapies in the future, or when such drugs may be used as alternative to colchicine for patients who are intolerant or have contraindications.

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