New England Journal of Medicine AUGUST 31, 2020

Colchicine in Patients with Chronic Coronary Disease (LoDoCo2)

Stefan M. Nidorf, Aernoud T.L. Fiolet, Arend Mosterd, et al.

Bottom Line

In patients with chronic coronary disease already receiving optimal medical therapy, the addition of low-dose colchicine (0.5 mg daily) significantly reduces the risk of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization.

Key Findings

1. The primary composite endpoint occurred in 6.8% of patients in the colchicine group compared to 9.6% in the placebo group (hazard ratio, 0.69; 95% CI, 0.57 to 0.83; P<0.001).

2. The benefit was primarily driven by reductions in myocardial infarction and ischemia-driven coronary revascularization.

3. There was a numeric, non-significant signal toward higher non-cardiovascular mortality in the colchicine group (hazard ratio, 1.51; 95% CI, 0.99 to 2.31).

4. There were no significant differences observed between the treatment groups regarding cardiovascular death or all-cause mortality.

Study Design

Design

RCT

Double-Blind

Sample

5,522

Patients

Duration

28.6 mo

Median

Setting

Multicenter, Australia and Netherlands

Population Patients aged 35 to 82 years with stable chronic coronary disease who were clinically stable for at least 6 months and could tolerate colchicine.

Intervention Colchicine 0.5 mg once daily

Comparator Matching placebo

Outcome Composite of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization

Study Limitations

• The trial included a 30-day run-in phase where 15.4% of patients were excluded due to colchicine intolerance, which may lead to an underestimation of real-world adverse event rates.

• The trial did not mandate specific high-intensity statin use, leaving some potential for residual lipid-related confounding.

• There was a notable gender imbalance in the study population, with women comprising only approximately 15% of the enrolled participants.

• The signal for increased non-cardiovascular death remains a point of clinical uncertainty, although the cause was not clearly linked to common adverse effects like infections.

Clinical Significance

The study provides robust evidence that targeting residual inflammatory risk with inexpensive, low-dose colchicine is an effective strategy for secondary prevention in stable coronary artery disease, supporting its use as an adjunct to standard lipid-lowering and antiplatelet therapies.

Historical Context

The LoDoCo2 trial built upon the foundational evidence provided by the earlier LoDoCo pilot study and the COLCOT trial, which demonstrated the benefit of colchicine in the acute setting following myocardial infarction. It solidified the role of anti-inflammatory therapy in managing stable atherosclerotic cardiovascular disease.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the specific cellular mechanism by which low-dose colchicine exerts its anti-inflammatory effects in patients with chronic coronary disease, and how does this supplement traditional antiplatelet therapy?

Key Response

Colchicine inhibits microtubule polymerization by binding to tubulin, which in turn disrupts the assembly and activation of the NLRP3 inflammasome within macrophages and neutrophils. This reduces the production of interleukin-1beta and interleukin-18, targeting 'residual inflammatory risk' that antiplatelet agents (which target thrombosis) do not address.

Resident

In the context of the LoDoCo2 trial results, which patient population with stable CAD is most likely to benefit from colchicine, and what are the most common adverse effects that might lead to treatment discontinuation?

Key Response

Patients with proven chronic coronary disease who are already stable on optimal medical therapy (statins, antiplatelets) benefit significantly. However, clinicians must monitor for gastrointestinal side effects (diarrhea, nausea), which were the primary reasons for discontinuation during the trial's run-in period, and be wary of myopathy when used with high-dose statins.

Fellow

Compare the findings of LoDoCo2 with the COLCOT trial regarding the timing of intervention; does the efficacy of colchicine depend on the 'cooling' of an acute plaque rupture or is it equally effective in the quiescent phase of atherosclerosis?

Key Response

COLCOT demonstrated benefit starting shortly after an MI (acute), while LoDoCo2 showed benefit in patients who were stable for at least 6 months (chronic). Together, these trials suggest that the NLRP3-mediated inflammatory pathway is a continuous driver of MACE regardless of the clinical stage of coronary disease, justifying long-term inflammatory modulation.

Attending

How do you reconcile the 31% relative risk reduction in major cardiovascular events seen in LoDoCo2 with the observed numerical (though non-significant) increase in non-cardiovascular deaths in the colchicine group?

Key Response

The trial was not powered for mortality. While the reduction in MI and revascularization is robust, the non-CV death imbalance (1.5% vs 0.9%) requires a cautious, individualized approach, particularly in older patients or those with multi-morbidity, until further meta-analyses clarify if this is a chance finding or a true safety signal.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

LoDoCo2 utilized a 30-day open-label run-in period to ensure drug tolerance. How does this 'enrichment' design affect the internal versus external validity of the trial's hazard ratios for efficacy and safety?

Key Response

The run-in period increases internal validity by ensuring the study population can tolerate the drug, leading to higher adherence and power. However, it compromises external validity (generalizability) because the reported hazard ratios only apply to the subset of the population that can tolerate the drug, likely underestimating the true incidence of side effects in a 'real-world' unselected population.

Journal Editor

Given the 'neutral' effect on all-cause mortality despite a highly positive primary composite endpoint, what specific post-hoc analyses should be performed to ensure that the reduction in ischemic events is not being offset by a specific category of non-cardiovascular harm?

Key Response

An editor would look for a breakdown of non-CV deaths by cause (e.g., sepsis, malignancy, or respiratory failure). If the deaths are concentrated in one category, it might suggest a drug-specific toxicity (like immunosuppression leading to fatal infection) that would necessitate a warning despite the reduction in MI.

Guideline Committee

Based on the LoDoCo2 findings, should colchicine be upgraded from a Class IIb to a Class I or IIa recommendation in the next update for chronic coronary syndrome guidelines, and what contraindications should be explicitly listed?

Key Response

With two large RCTs (LoDoCo2 and COLCOT) showing consistent benefit, an upgrade to Class IIa ('should be considered') is likely. Guidelines (currently following ESC 2021 or AHA/ACC standards) must emphasize excluding patients with severe renal impairment (CrCl < 30 mL/min) or hepatic dysfunction to prevent toxic accumulation, given the narrow therapeutic window of colchicine.

Clinical Landscape

Noteworthy Related Trials

2017

CANTOS Trial

n = 10,061 · NEJM

Tested

Canakinumab (anti-IL-1beta monoclonal antibody)

Population

Patients with prior myocardial infarction and high-sensitivity C-reactive protein levels of 2 mg or more per liter

Comparator

Placebo

Endpoint

Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death

Key result: Targeting interleukin-1beta inhibition with canakinumab resulted in a lower rate of recurrent cardiovascular events than placebo.

2019

COLCOT Trial

n = 4,745 · NEJM

Tested

Colchicine 0.5 mg daily

Population

Patients with a recent myocardial infarction

Comparator

Placebo

Endpoint

Composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina

Key result: Colchicine led to a significantly lower risk of ischemic cardiovascular events than placebo in patients with a recent myocardial infarction.

2020

COPS Trial

n = 795 · Circulation

Tested

Colchicine 0.5 mg twice daily for 1 month then once daily

Population

Patients with acute coronary syndrome

Comparator

Placebo

Endpoint

All-cause mortality, urgent coronary revascularization, or stroke at 12 months

Key result: While there was a numerical trend toward benefit, the difference in the primary outcome did not reach statistical significance at 12 months.

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