Colchicine’s Role in Cardiovascular Disease Management

Abstract

Colchicine, an anti-inflammatory alkaloid, has assumed an important role in the management of cardiovascular inflammation nearly 3,500 years after its first medicinal use in ancient Egypt. Primarily used in extremely high-doses for the treatment of acute gout flares during the 20^th century, research in the early 21^st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can even add to secondary prevention of major adverse cardiovascular events. As the first FDA-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine’s safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.

Graphical Abstract

Introduction

Colchicine has long seen use as an anti-inflammatory treatment for gout and Familial Mediterranean Fever.^1,2 Beginning in the 20^th century, randomized clinical trials established low-dose colchicine as an effective treatment for pericarditis and atherosclerotic cardiovascular disease, two conditions driven by the NLRP3 inflammasome and interleukin-1.^3–5 The mechanisms through which colchicine exerts its beneficial anti-inflammatory and cardiovascular effects remain an area of vigorous investigation.⁶ When prescribing colchicine, clinicians must consider drug-drug interactions, impaired kidney and liver function, and adverse effect monitoring.⁷

This Brief Review follows colchicine’s journey from an herbal medicine used to treat joint swelling and pain through its contemporary use in cardiovascular disease. We discuss colchicine’s effects on immune cells, highlight landmark clinical trials, and consider the practical aspects of colchicine use.

A Brief History of Colchicine

Hartung published an authoritative review of colchicine’s history based upon careful examination of several dozen historical documents.⁸ The earliest medical use of colchicine possibly dates to 1,500 BCE based on writings that describe the use of a plant likely containing colchicine for the treatment of pain and swelling (Figure 1). In the 550s CE, Alexander of Tralles, a physician in the Byzantine Empire, described the use of hermodactyl, a plant resembling the Autumn crocus, for the treatment of gout as well as the botanical’s adverse gastrointestinal effects. Baron Anton Stork provided an early description of the use of colchicine for pericarditis in the 18^th century. Around the same time, Nicolas Husson developed the first commercial colchicine preparation: “Eau Medicinale”.

Figure 1. Notable historical moments related to colchicine use since 1500 BCE.

The figure displays approximate geographical locations of historical mentions of colchicine according to Hartung’s comprehensive history on the subject (Hartung EF. Arthritis Rheum. 1961;4:18–26.). Present-day names of the locations are used. All dates are approximate. Recruitment locations for landmark ASCVD clinical trials are indicated as blue circles. Map image downloaded from: https://www.vecteezy.com/free-vector/world-map-outline. ASCVD = atherosclerotic cardiovascular disease; BCE = before common era; CE = common era

Case reports and clinical trials established colchicine’s efficacy in Familial Mediterranean Fever, an inherited auto-inflammatory disorder, in the late 20^th century (Figure 1).^2,9–14 These studies then inspired testing of colchicine for pericarditis, which demonstrated that this agent reduced the risk of recurrent pericarditis by up to 50%.¹⁵ Colchicine remains a mainstay treatment for acute gout attacks, although the traditional strategy of administration until limited by gastrointestinal tolerance has given way to a regimen of 1.8 mg loading dose and 0.6 mg once or twice daily.¹

Treatment of Cardiovascular Disease with Colchicine

Coronary Artery Disease

The NLRP3 inflammasome activates the inflammatory cytokines interleukin-1 and interleukin-18 in response to molecular danger signals.¹⁶ Both interleukin-1 and interleukin-18 contribute to the genesis and progression of coronary atherosclerosis.¹⁷ The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) validated the role of inflammation and interleukin-1 in atherosclerosis by demonstrating that blocking interleukin-1β with a monoclonal antibody reduced major adverse cardiovascular events without altering blood lipid levels.¹⁸

Colchicine lowers high-sensitivity C-reactive protein (hsCRP) and may decrease coronary artery plaque volume.^19,20 In an open-label, randomized clinical trial of colchicine versus no colchicine (LoDoCo), colchicine lowered the risk of the composite of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke by 67% in people with stable coronary artery disease.²¹

More definitive evidence of the benefits of colchicine on atherosclerotic cardiovascular disease events comes from the LoDoCo2 (Low-Dose Colchicine-2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) studies.^4,5 LoDoCo2 and COLCOT each compared the effects of adding either low-dose colchicine (0.5 mg once daily) or placebo to background guideline-directed medical therapy, including antiplatelet and statin therapy, on major adverse cardiovascular events in approximately 5,000 participants per trial over 2-years of follow-up. COLCOT enrolled individuals within 30 days of a myocardial infarction while LoDoCo2 enrolled individuals with chronic coronary artery disease (at least 6 months following an acute coronary syndrome [ACS]). In both studies, low-dose colchicine lowered the risk of major adverse cardiovascular events by more than 30% compared to placebo (Figure 2).

Figure 2. Effects of colchicine on major adverse cardiovascular events.

The LoDoCo2 and COLCOT studies demonstrated the efficacy of colchicine in lowering the risk of major adverse cardiovascular events in people with stable coronary artery disease (LoDoCo2) and recent myocardial infarction (COLCOT). The primary endpoints were the composite of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven revascularization in LoDoCo2 and the composite of cardiovascular death, myocardial infarction, stroke, urgent hospitalization for angina leading to revascularization, and resuscitated cardiac arrest in COLCOT. The secondary endpoints shown are the composite of cardiovascular death, myocardial infarction and stroke for LoDoCo2 and the composite of cardiovascular death, myocardial infarction, stroke and resuscitated cardiac arrest in COLCOT (resuscitated cardiac arrest occurred in 0.2% of COLCOT participants and did not contribute meaningfully to the endpoint). CI = confidence interval; COLCOT = Colchicine Cardiovascular Outcomes Trial; HR = hazard ratio; LoDoCo2 = Low-Dose Colchicine-2

In LoDoCo2, the benefit derived from a reduction in myocardial infarction whereas in COLCOT the benefit derived from reductions in stroke and revascularization. The differential effects of colchicine on revascularization and myocardial infarction in LoDoCo2 and COLCOT mirror the effects of statins, which also primarily lower the risk of revascularization when initiated soon after an acute coronary syndrome, and the effects of colchicine in the Colchicine in Patients with Acute Coronary Syndrome (COPS) trial (discussed below), in which colchicine demonstrated more favorable effects on revascularization than on recurrent myocardial infarction.^22,23 In LoDoCo2, colchicine lowered the risk of major adverse cardiovascular events in people with or without a history of ACS, although 85% of participants did have a prior ACS. Adding colchicine to statin, antiplatelet and modern revascularization therapy did not lower the risk of all-cause death or cardiovascular death in LoDoCo2 or COLCOT. Similarly, clinical trials of adding ezetimibe, a PCSK9 inhibitor, bempedoic acid, or canakinumab (anti-interleukin-1β antibody) to contemporary medical therapy lowered the risk of major adverse cardiovascular events, but not cardiovascular or all-cause death over the study timespan.^18,24–27

Two clinical trials have evaluated the effects of colchicine, started urgently after an acute coronary syndrome, on major adverse cardiovascular events. Lack of sufficient power and other issues limited interpretation of these studies. COPS randomized 795 individuals with an ACS to colchicine 0.5 mg twice daily for 30 days followed by 0.5 mg once daily for 11 months or placebo.²⁸ The study design intended an enrollment of 1,009 participants to provide 80% power to detect a 53% reduction in the primary composite outcome of all-cause death, acute coronary syndrome, stroke or urgent revascularization assuming a control event rate of 7.2%. The steering committee stopped the trial early due to slow enrollment. Numerically fewer primary composite events occurred in the colchicine arm at 365 days (24 [6%] vs. 38 [10%]; hazard ratio [95% confidence interval]: 0.65 [0.38–1.09]). Colchicine did lower the risk of a post-hoc composite outcome of cardiovascular death, acute coronary syndrome, stroke, or urgent revascularization (similar to the outcome in COLCOT and LoDoCo2) (5% vs. 10%; hazard ratio [95% confidence interval]: 0.51 [0.29–0.89]). In 2-year follow-up, the risk of the primary outcome was significantly lower in the colchicine arm (32 [8%] vs. 54 [14%]; log-rank P-value = 0.02).²⁹ All-cause mortality was higher in the colchicine arm, a finding that we discuss below in greater detail.

The second colchicine ACS trial randomized 361 people with an acute coronary syndrome to colchicine 0.5 mg daily or placebo for 6 months and used a different primary composite outcome (all-cause death, hospital admission due to typical chest pain [acute myocardial infarction or unstable angina], non-cardioembolic stroke, urgent revascularization or decompensated heart failure) that was not adjudicated by an independent committee.³⁰ In this trial, colchicine significantly lowered the risk of the primary composite outcome, driven primarily by a reduction in unstable angina, as only 13 myocardial infarction events occurred in both arms.

Other Cardiovascular Conditions

Colchicine may have beneficial effects on infarct size and ischemia-reperfusion injury when given before revascularization in ACS, in people with diabetes undergoing percutaneous coronary intervention with a bare-metal stent and in people undergoing coronary artery bypass grafting surgery.^31–36 One clinical trial did not demonstrate decreased infarct size with colchicine in ACS using cardiac magnetic resonance imaging, but colchicine showed no effect on neutrophil count at 24-hours and only a trend towards lower hsCRP levels at 24-hours.³⁷

Several trials have evaluated the effect of colchicine on the risk of post-pericardiotomy syndrome^38–42 and atrial fibrillation^43–45 after cardiac surgery and atrial fibrillation ablation. The role of colchicine after cardiac procedures remains under investigation. In people with acute cerebrovascular accident, colchicine starting 24 hours after symptom onset may lower indices of inflammation.⁴⁶

Low-dose colchicine 0.5 mg daily had no effect on severely elevated albuminuria or major adverse kidney events in 160 people with type 2 diabetes and moderately elevated albuminuria.⁴⁷ In a trial of 279 individuals with stable heart failure and reduced ejection fraction, colchicine 0.5 mg twice daily did not achieve the primary endpoint of a one-grade improvement in New York Heart Association functional class at 6-months, but did associate with greater reductions in left ventricular end-diastolic and end-systolic diameters.⁴⁸ In the colchicine arm on-treatment hsCRP levels of 5.5 mg/L suggests the need for more potent anti-inflammatory effects in this setting.⁴⁸

Mechanisms of Colchicine’s Anti-Inflammatory Effects

Colchicine binds tubulin, which interferes with microtubule-dependent cellular processes in rapidly dividing cells.⁴⁹ Colchicine decreases interleukin-1β secretion by blocking the colocalization of the NLRP3 inflammasome components ASC and NLRP3 (but not the NLRC4 or AIM2 inflammasomes).^50,51 These experiments suggest that colchicine can inhibit the systemic inflammatory response related to molecular patterns that can trigger NLRP3 while leaving other host defense mechanisms intact.

In people with non-ST segment-elevation ACS, colchicine pre-treatment before cardiac catheterization significantly lowered the transcoronary serum concentrations of interleukin-1β, interleukin-18 and interleukin-6 compared to no colchicine.⁵² Similarly, colchicine lowered the levels of interleukin-1β secretion from ex vivo stimulated monocytes derived from people with an ACS.⁵³ In a substudy of participants in the LoDoCo2 trial, colchicine significantly lowered NLRP3 protein levels in extracellular vesicles.⁵⁴

Colchicine reduced neutrophil extracellular trap production from neutrophils derived from people with an ACS.⁵⁵ In people with Familial Mediterranean Fever, colchicine decreased neutrophil chemotaxis.⁵⁶ Colchicine also may decrease neutrophil superoxide production.⁵⁷ Pharmacoproteomic studies suggest that colchicine alters circulating levels of several immune-related proteins, including many involved in neutrophil degranulation that associate with cardiovascular risk.^58–60 Somatic mutations in genes such as TET2 that accumulate with age enhance inflammasome activity and associate with a higher risk of cardiovascular disease.⁶¹ Colchicine decreased atherosclerosis in mice with Tet2-mutant clonal hematopoiesis.⁶²

Colchicine may possess broad effects on innate and adaptive immune cells. In a study of 35 people with obesity, colchicine 0.6 mg twice daily over 3 months significantly lowered circulating levels of classical monocytes and CD8+ cytotoxic T cells.⁶³ Colchicine also blunted the increase in natural killer cells and CD4+ effector cells observed in the placebo arm of that same study.⁶³

One experimental study suggests that colchicine exerts its anti-inflammatory effects in leukocytes indirectly through hepatic GDF-15 secretion.⁶ Colchicine’s gastrointestinal effects have been attributed to tubulin-dependent mitotic arrest, induction of apoptosis, and altered intestinal permeability that resolves upon treatment discontinuation.^64–66 Contrary to animal studies, colchicine appears to have no effect on the gut microbiome in people with metabolic syndrome.^65,67 Targeting the downstream effects of colchicine may provide safer anti-inflammatory therapies.

Practical Considerations for the Use of Colchicine in Cardiovascular Disease

Patient Selection

Clinicians have considerable flexibility regarding the timing of colchicine initiation. Studies support colchicine initiation during hospitalization for ACS, a strategy that has worked well for the implementation of guideline-directed medical therapy for heart failure.^29,30,68,69 Conversely, a LoDoCo2 post-hoc analysis found that colchicine significantly lowered the risk of major adverse cardiovascular events even in participants whose most recent ACS occurred between 2 to 7 years before randomization or more than 7 years before randomization.⁷⁰

Notably, none of the landmark colchicine cardiovascular clinical trials required an elevated hsCRP level for enrollment and the US FDA approved indication does not mention hsCRP testing. Clinicians could consider hsCRP testing to maximize the benefit-risk ratio in routine practice as the JUPITER trial demonstrated that primary prevention statin therapy among people with elevated high-sensitivity C-reactive protein (hsCRP) lowers the risk of major adverse cardiovascular events.⁷¹ Since COLCOT and LoDoCo2 enrolled participants already on background statin therapy, colchicine should be an adjunct to LDL cholesterol lowering. Altogether, the evidence from multiple clinical trials indicates that all individuals with coronary artery disease should be considered a potential candidate for colchicine therapy (Figure 3).

Figure 3. Proposed algorithm for use of low-dose colchicine in secondary atherosclerosis prevention.

This figure summarizes an approach for the use of low-dose colchicine in secondary atherosclerosis prevention. Low-dose colchicine can be initiated in people with an acute coronary syndrome during hospitalization or within the next 30 days as well as in people with stable coronary artery disease whose acute coronary syndrome occurred more than 6 months ago. Individuals should be screened for potential contraindications and precautions prior to colchicine initiation, and have optimal guideline-directed medical therapy. Measuring high-sensitivity C-reactive protein (hsCRP) can provide evidence of residual inflammatory risk, although the landmark colchicine clinical trials did not require a specific hsCRP level for inclusion. CYP = cytochrome P450; DDI = drug-drug interaction; eGFR = estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein; IBD = inflammatory bowel disease; P-gp = P-glycoprotein

Adverse Effect Profile

A systematic review and meta-analysis of all colchicine clinical trials regardless of indication published prior to 2020 (n studies=35; participants = 4,225 on colchicine [2,366 from COLCOT] and 3,956 on placebo [2,379 from COLCOT]) found a 1.74-times higher risk of any gastrointestinal event with colchicine (18% vs. 13%).⁷² Lower doses of colchicine appear as effective in resolving the gout flare and better tolerated¹ and colchicine-related diarrhea is self-limiting and resolves within 3 days in many cases.⁴⁵

The aforementioned landmark clinical trials also provide the largest randomized safety data for low-dose colchicine. In LoDoCo2, 437 participants (7%) dropped out during the open-label run-in phase due to gastrointestinal upset and in COLCOT nausea and flatulence occurred more frequently with colchicine than placebo in COLCOT. Yet diarrhea was not more common with colchicine than placebo in COLCOT, serious gastrointestinal events were not different between colchicine and placebo in either COLCOT or LoDoCo2 and, most important, treatment discontinuation did not differ between colchicine and placebo in either COLCOT or LoDoCo2. Nor did more serious and rarer colchicine adverse effects, such as leukopenia, thrombocytopenia, or neuropathy, differ between colchicine and placebo in COLCOT or LoDoCo2. These data indicate that low-dose colchicine possesses a tolerable gastrointestinal profile in most people with cardiovascular disease.

Two unexpected signals for a higher risk of mortality emerged from the LoDoCo2 trial (non-cardiovascular mortality hazard ratio [95% confidence interval]: 1.51 [0.99–2.31]) and the 1-year outcomes of the COPS trial (all-cause death occurred in 8 colchicine participants compared to 1 placebo participant).^5,28 In COPS, 3 of the 5 non-cardiovascular deaths in the 1-year report occurred off-treatment and one occurred due to cancer (not a known risk of colchicine therapy) (Table S1). The open-label 2-year follow-up of COPS, which included 13 deaths, showed no difference in the risk of all-cause or non-cardiovascular death between colchicine and placebo.²⁹ Furthermore, the risks of cardiovascular death or all-cause death were not significantly different between colchicine and placebo in COLCOT (all-cause death hazard ratio [95% confidence interval]: 0.98 [0.64–1.49]).⁴ A systematic review and meta-analysis of colchicine use in people with cirrhosis found no significant difference in the risk of all-cause mortality between colchicine and control.⁷³ A non-randomized study of people with gout reported a lower risk of all-cause mortality with colchicine use.⁷⁴

Pneumonia occurred more frequently in colchicine-treated participants in COLCOT (0.9% vs. 0.4%; P=0.03). Conversely, neither a systematic review and meta-analysis nor LoDoCo2 found a difference in infection outcomes between colchicine and placebo.⁷² These signals warrant further investigation.

Drug-Drug Interactions

Colchicine is metabolized by enteral and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, a xenobiotic extruder found in the intestine, biliary tract, kidney, and mononuclear immune cells (but not neutrophils). The management of a drug-drug interaction requires consideration of the relationship between drug exposure and clinical outcomes, the duration of concomitant use, the availability of monitoring parameters, and the clinical indication for the interacting drugs (Figure 4).

Figure 4. Proposed management of statin and non-statin drug-drug interactions with colchicine.

Colchicine interacts with many commonly used cardiovascular therapies, including statins. Colchicine can be used concomitantly with rosuvastatin, pitavastatin, or pravastatin without enhanced monitoring or dose adjustments. Concomitant use of colchicine with other statins requires enhanced monitoring for muscle-related adverse effects. The management of other drug-drug interactions with colchicine should consider the severity and duration of the interaction, the consequences of withholding colchicine therapy, other risk factors for colchicine adverse effects and the availability of alternative therapies or enhanced monitoring.

COLCOT and LoDoCo2 indicated the general safety of combining statins with colchicine. Yet, case reports have described serious colchicine toxicity in people taking a statin with colchicine due to competitive inhibition of CYP3A4 and P-gp. Myalgia and myotoxic effects occurred more commonly among colchicine-treated participants (21% vs. 19%; P < 0.05) in LoDoCo2 participants enrolled in The Netherlands (muscle-related symptoms were not assessed in COLCOT or LoDoCo2 participants in Australia). In 1,775 LoDoCo2 participants with available end-of-study blood samples, colchicine was associated with higher creatine kinase levels (123 vs. 110 U/L for colchicine vs. placebo; P < 0.01), but the mean levels remains within the normal range, creatine kinase levels greater than 5-times the upper-limit-of-normal were rare (0.7% vs. 0.2% for colchicine vs. placebo) and there were no instances of levels greater than 10-times the upper-limit-of-normal. Many candidates for colchicine therapy will require concomitant treatment with a high-intensity statin. Rosuvastatin (neither a substrate nor inhibitor of CYP3A4 and P-gp) can be used with colchicine without enhanced monitoring or dose adjustment.^7,75 Atorvastatin, a weak inhibitor of CYP3A4 and a P-gp substrate, can be used as an alternative to rosuvastatin. Atorvastatin 40 mg daily (a weak CYP3A4 and P-gp inhibitor) increased the total exposure of a single colchicine 0.6 mg dose (as measured by area-under-the-concentration-time curve) by 24% (90% confidence interval: 110%–141%) in healthy volunteers, slightly above the US FDA threshold for clinical significance.^76,77 Non-fibrate therapy for triglyceride lowering should be preferred for concomitant use with colchicine.⁷⁸

Other cardiovascular medications that interact with colchicine include amiodarone, dronedarone, quinidine, and propafenone.^7,75 Concomitant use of these anti-arrhythmic agents with colchicine should involve collaborative monitoring with an electrophysiologist. Concomitant use of diltiazem and verapamil with colchicine should be avoided when possible in favor of other rate control agents like beta-blockers and more effective blood pressure-lowering agents.

Other Considerations

LoDoCo2 excluded people with eGFR less than 50 mL/min per 1.73 m², although the US FDA-approved indication for low-dose colchicine (which was a modification of the existing approval for colchicine in gout rather than a new indication review) allows for use with eGFR as low as 30 mL/min per 1.73 m².⁷⁹ Advanced age, in the absence of reduced kidney function, does not significantly augment colchicine exposure.⁸⁰ Due to its metabolism by hepatic CYP3A4, colchicine should be avoided in people with Child-Pugh Class C liver disease.

In the United States, colchicine has been available as 0.6 mg doses, whereas the rest of the world uses 0.5 mg. Since the 0.5 mg doses proved effective in large-scale cardiovascular clinical trials, the 0.5 mg dose should receive preference when available and affordable. If patients cannot access the 0.5 mg dose, judicious use of 0.6 mg furnishes an acceptable alternative to forgoing treatment with the only available anti-inflammatory therapy for atherosclerotic cardiovascular disease. Clinical observations of people with colchicine toxicity have led to estimations that the therapeutic plasma concentration lies between 0.5 and 3 ng/mL.^7,81,82 Pharmacokinetic modeling studies suggest that both the 0.5 mg and 0.6 mg doses provide therapeutic plasma concentrations, but the 0.5 mg dose should be used in people with kidney disease and those with concomitant drug-drug interactions.⁸³ Important limitations to the use of plasma colchicine concentrations for therapeutic drug monitoring include the observation that colchicine concentrations within leukocytes exceed those of plasma by several orders of magnitude and become saturated at plasma levels well below the proposed therapeutic range (Figure 5).^84,85 Additionally, people with Familial Mediterranean Fever seem to tolerate daily colchicine doses up to 3 mg daily and plasma concentrations well above 3 ng/mL (Figure S1).⁸⁶

Figure 5. Non-linear relationship between colchicine plasma concentrations and circulating leukocyte concentrations.

Colchicine concentrations in plasma (total bound and unbound colchicine) and in granulocytes and mononuclear cells was measured in people with Familial Mediterranean Fever who were taking colchicine 0.5 to 2.0 mg daily. Annotations indicate the approximate plasma concentration at which leukocyte concentrations plateau, estimated maximal concentrations (Cmax) observed in people according to kidney function and the estimated safe upper limit plasma concentration. Granulocyte and mononuclear cell concentrations were extrapolated visually across the higher end of the plasma concentration range. Figure was based on data from Br J Clin Pharmacol. 1994;38(1):87–9. and Am J Med. 2022;135(1):32–38. Cmax = maximal concentration

Conclusions

Colchicine exerts pleiotropic anti-inflammatory effects on assembly of the NLRP3 inflammasome and various neutrophil functions. Based on multiple, large randomized controlled trials, individuals with coronary artery disease and preserved kidney function may benefit from low-dose colchicine therapy. When prescribing colchicine, clinicians should be cognizant of gastrointestinal adverse effects, drug-drug interactions and changes in kidney and liver function. Colchicine provides an example of the long history of natural product to cardiovascular drug development (digoxin, reserpine, gliflozins). While the use of colchicine in cardiovascular disease requires much further study, landmark trials have pointed the way for its clinical adoption as an approved targeted anti-inflammatory agent in the management of atherosclerotic risk.

Table 1.

Design and participant characteristics of the COLCOT and LoDoCo2 studies CAC = coronary artery calcium; eGFR = estimated glomerular filtration rate

	COLCOT		LoDoCo2
Design features
Design	Randomized, double-blind, placebo-controlled, event-driven clinical trial		Randomized, double-blind, placebo-controlled, event-driven clinical trial (1 month open-label run-in period)
Key inclusion criteria	• Myocardial infarction within the prior 30 days • Use of guideline-directed medical therapy		• Coronary artery disease by invasive or non-invasive angiography or CAC score > 400 Agatston units • Clinically stable for 6 months
Key exclusion criteria	• Serum creatinine greater than 2-times the upper limit of normal • Inflammatory bowel disease • Progressive neuromuscular disease • Leukopenia or thrombocytopenia • Symptomatic heart failure		• Serum creatinine greater than 1.7 mg/dL (150 umol/L) or eGFR less than 50 mL/min per 1.73 m2 • Symptomatic heart failure • Peripheral neuritis, myositis or myosensitivity to statins
Colchicine regimen	0.5 mg once daily		0.5 mg once daily
Run-in period	NA		6,528 entered run-in period • 611 stopped due to side effects (9%) • 395 stopped for other reasons (6%) • 5,522 randomized
Participant characteristics
	Colchicine	Placebo	Colchicine	Placebo
Number of participants	2,366	2,379	2,762	2,760
Age, years	61	61	66	66
Women, %	20%	18%	17%	14%
White, %	73%	72%	NR	NR
Current smoking, %	30%	30%	12%	12%
Hypertension, %	50%	52%	51%	50%
Diabetes	20%	21%	23%	24%
Mean time to randomization from index MI, days	13	13	NA	NA
Most recent ACS within 24 months	NA	NA	27%	26%
Statin	99%	99%	94%	94%
Antiplatelet agent	98%	98%	90%	90%
Median follow-up duration, months	23		29
Study treatment discontinuation, %	18%	19%	11%	11%

Highlights.

• Randomized clinical trials established low-dose colchicine as an effective treatment for pericarditis and atherosclerotic cardiovascular disease

• The mechanisms through which colchicine exerts its beneficial anti-inflammatory and cardiovascular effects remain an area of vigorous investigation

• When prescribing colchicine, clinicians must consider drug-drug interactions, impaired kidney and liver function, and adverse effect monitoring

• While the use of colchicine in cardiovascular disease requires much further study, landmark trials have pointed the way for its clinical adoption as an approved targeted anti-inflammatory agent in the management of atherosclerotic risk