Definition and pathophysiology
Atherosclerosis and acute coronary syndromes have important inflammatory components. Inflammation contributes to atherothrombosis through activation of innate immune pathways, cytokine signalling and recruitment of inflammatory cells to vascular lesions. The interleukin-1β pathway, with downstream effects involving interleukin-6 and C-reactive protein, has been a major therapeutic target.
This concept is clinically relevant because cardiovascular risk may persist despite appropriate lipid-lowering and other guideline-directed therapies. Anti-inflammatory treatment seeks to reduce this residual risk without necessarily altering lipid concentrations, blood pressure or other conventional risk factors.
Colchicine is an established anti-inflammatory drug that may inhibit inflammasome activity, reduce interleukin-1β and interleukin-6 signalling, lower C-reactive protein, and impair neutrophil chemotaxis toward inflammatory sites. Its cardiovascular effects therefore appear to reflect modulation of vascular inflammation rather than lipid lowering.
Other anti-inflammatory strategies have produced less favourable results. Canakinumab, a monoclonal antibody directed against interleukin-1β, provided proof of concept but was not developed for routine coronary prevention because of fatal infections and high cost. Low-dose methotrexate did not reduce cardiovascular outcomes, and several other agents, including pexelizumab, losmapimod and darapladib, failed to demonstrate clinical benefit in the settings studied.
Clinical application and patient populations
The evidence for anti-inflammatory treatment in coronary disease has principally involved two populations:
Patients recently recovering from myocardial infarction or acute coronary syndrome.
Patients with stable or chronic atherosclerotic coronary disease, many of whom have a previous acute coronary syndrome.
The available evidence supports consideration of low-dose colchicine as an adjunct to, rather than a replacement for, established secondary-prevention treatment. Its potential role is greatest when cardiovascular risk remains high despite optimal or maximally tolerated guideline-directed therapy, or when recurrent cardiovascular events occur despite such treatment.
The trials did not establish a mortality benefit. Consequently, the decision to prescribe colchicine requires attention to the balance between reduction in ischaemic events and possible infectious or other non-cardiovascular adverse outcomes.
Mechanisms of action
Colchicine
Colchicine appears to exert several anti-inflammatory effects relevant to coronary disease:
Reduction of inflammasome activation.
Inhibition of interleukin-1β-related inflammatory signalling.
Reduction of interleukin-6 and C-reactive protein.
Inhibition of neutrophil migration toward inflammatory foci.
These effects are mechanistically distinct from the lipid-lowering action of statins. Nevertheless, statins and some cardiometabolic therapies may also have anti-inflammatory or pleiotropic effects, and colchicine has been studied as an additional therapy alongside standard treatment.
Interleukin-1β inhibition
Canakinumab reduced inflammatory biomarkers without affecting lipids or other major coronary risk factors. In patients with previous myocardial infarction and residual inflammation, defined by hsCRP ≥2 mg/L, it produced a modest reduction in a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The clinical development of canakinumab for this indication did not continue because of safety concerns, particularly fatal infections, and because of cost.
Evidence in acute coronary syndromes and recent myocardial infarction
COLCOT
The COLCOT trial enrolled 4745 patients within 30 days of myocardial infarction. Participants received colchicine 0.5 mg once daily or placebo.
The primary composite outcome included cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke and urgent coronary revascularization. Over a median follow-up of approximately 2.3 years, the event rate was 5.5% with colchicine compared with 7.1% with placebo. The hazard ratio was 0.77, with a 95% confidence interval of 0.61–0.96.
The trial did not demonstrate a difference in all-cause mortality. Pneumonia occurred more frequently in patients receiving colchicine, although it remained uncommon. Diarrhoea was reported in 9.7% of colchicine-treated patients and 8.9% of placebo-treated patients, without a statistically significant difference.
The observed benefit was seen across a broad population of recently infarcted patients and did not require selection according to baseline C-reactive protein values.
Other acute coronary syndrome evidence
A smaller study involving 795 patients with acute coronary syndrome did not meet its primary endpoint, which comprised all-cause mortality, acute coronary syndrome, ischaemia-driven urgent revascularization or ischaemic stroke. This result indicates that the evidence in acute coronary syndromes is not uniform, although the larger COLCOT trial provides the principal supportive evidence for post-myocardial infarction treatment.
Evidence in chronic coronary disease
LoDoCo2
The LoDoCo2 trial enrolled approximately 5500–5522 patients with stable atherosclerotic coronary disease who had been clinically stable for at least six months. Approximately 84% had a previous acute coronary syndrome. Patients were randomized to colchicine 0.5 mg orally once daily or placebo.
The primary composite outcome comprised cardiovascular death, spontaneous myocardial infarction, ischaemic stroke or ischaemia-driven coronary revascularization. Over a median follow-up of approximately 2.4 years, the primary endpoint occurred in 6.8% of patients receiving colchicine and 9.6% receiving placebo. The hazard ratio was 0.69, with a 95% confidence interval of 0.57–0.83.
The secondary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke was also reduced: 4.2% versus 5.7%, corresponding to a hazard ratio of 0.72 with a 95% confidence interval of 0.57–0.92.
There was no significant difference in pneumonia or gastrointestinal disorders in this trial. However, non-cardiovascular death was numerically higher with colchicine, at approximately 0.7 versus 0.5 events per 100 person-years; the hazard ratio was 1.51, with a 95% confidence interval of 0.99–2.31. This signal requires consideration when applying the findings to routine practice.
Outcomes across studies
A meta-analysis including more than 12,000 patients with atherothrombotic coronary disease found that colchicine was associated with lower risks of several individual ischaemic outcomes:
| Outcome | Relative risk with colchicine |
|---|---|
| Myocardial infarction | 0.76 |
| Stroke | 0.48 |
| Unstable-angina-driven revascularization | 0.61 |
| Cardiovascular death | No significant difference |
| All-cause death | No significant difference |
| Gastrointestinal events when daily dose was ≤0.5 mg | No significant difference |
The available data therefore support a reduction in selected non-fatal ischaemic events, particularly myocardial infarction, stroke and ischaemia-driven revascularization. They do not establish a reduction in cardiovascular death or all-cause mortality.
Treatment and management
Position within secondary prevention
Colchicine should be considered only after the established components of secondary prevention have been addressed. The source material specifically describes it as an adjunct to other preventive therapies in patients who remain at high risk despite maximum tolerated guideline-directed medical treatment.
Standard coronary preventive treatment includes therapies with proven cardiovascular benefit. Aspirin and statins are also recognized to have anti-inflammatory pleiotropic effects, although their principal clinical roles extend beyond inflammation.
For patients with recent acute coronary syndrome, low-dose colchicine may be considered for long-term management, particularly in either of the following circumstances:
Other cardiovascular risk factors remain insufficiently controlled.
Recurrent cardiovascular events occur despite optimal therapy.
Dose
The cardiovascular dose supported by the outcome trials is:
| Drug | Dose |
|---|---|
| Colchicine | 0.5 mg orally once daily |
The available coronary evidence concerns low-dose treatment. The meta-analysis found no significant increase in gastrointestinal events when the daily dose did not exceed 0.5 mg.
Practical considerations
Potential benefits must be weighed against:
Increased pneumonia observed in COLCOT.
A signal for increased non-cardiovascular mortality in LoDoCo2.
The absence of demonstrated benefit in all-cause mortality.
The need to identify patients who may be particularly susceptible to infectious or other non-cardiac adverse effects.
The role of colchicine in patients with immune-mediated inflammatory diseases and high cardiovascular risk remains uncertain. Its use in routine daily practice also requires further experience and clinical study, despite the favourable results of the major trials.
Guideline recommendations
Current recommendations described in the source material support the following approach:
Low-dose colchicine 0.5 mg once daily may be considered in patients with established atherosclerotic coronary disease, particularly when other risk factors are inadequately controlled or cardiovascular events recur despite optimal treatment.
Following acute coronary syndrome, low-dose colchicine may be considered for long-term management, especially in patients with persistent high risk despite guideline-directed therapy.
Colchicine should be used as an adjunct to comprehensive secondary prevention, not as a substitute for lipid-lowering, antithrombotic or other indicated treatments.
The risk–benefit profile should be assessed individually because reductions in ischaemic events have not translated into an established reduction in all-cause mortality, and infectious or other non-cardiovascular adverse outcomes may offset part of the benefit.
Therapies not established for coronary event prevention
Canakinumab
Canakinumab reduced inflammatory biomarkers and modestly reduced a composite of cardiovascular death, myocardial infarction and stroke in patients with previous myocardial infarction and hsCRP ≥2 mg/L. Its development for coronary prevention was discontinued because of fatal infections and high cost.
Methotrexate
Low-dose methotrexate, with a target dose of 15–20 mg once weekly, did not reduce the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or unstable-angina-driven revascularization. The study was stopped early for futility, and the treatment did not produce the expected change in inflammatory biomarkers.
Other agents
Pexelizumab did not reduce infarct size or mortality in the settings studied. Losmapimod did not reduce short-term cardiovascular death, myocardial infarction or severe recurrent ischaemia after acute myocardial infarction. Darapladib did not alter the composite of cardiovascular death, myocardial infarction or stroke.
These negative findings reinforce that the presence of inflammation in atherosclerosis does not by itself establish efficacy for every anti-inflammatory agent.
Biomarkers and laboratory findings
High-sensitivity C-reactive protein has been used to identify residual inflammation, particularly in studies of canakinumab. The CANTOS population had previous myocardial infarction and hsCRP ≥2 mg/L.
Colchicine trials in recent myocardial infarction did not require elevated C-reactive protein for treatment selection. The cardiovascular benefit observed in COLCOT was therefore not restricted to a biomarker-defined inflammatory subgroup.
Inflammatory biomarkers are useful for demonstrating pharmacodynamic effects and for defining trial populations, but the source material does not establish a specific hsCRP threshold for selecting patients for colchicine in routine clinical practice.
Prognosis and follow-up
Anti-inflammatory treatment with colchicine reduces the risk of several non-fatal cardiovascular events in selected patients with recent myocardial infarction or chronic atherosclerotic coronary disease. However, neither COLCOT nor LoDoCo2 demonstrated a reduction in all-cause mortality, and LoDoCo2 raised concern about non-cardiovascular mortality.
Follow-up should therefore assess both cardiovascular efficacy and treatment safety. Particular attention is warranted for infectious complications, including pneumonia, and for other non-cardiovascular adverse outcomes. Persistent or recurrent cardiovascular events should prompt reassessment of adherence, lipid-lowering intensity, other modifiable risk factors and the overall secondary-prevention regimen before, or alongside, consideration of colchicine.
The long-term role of anti-inflammatory therapy continues to evolve. Colchicine currently has the most supportive evidence for clinical use, but further investigation is needed to identify patients most likely to benefit and those at greater risk of infectious or other non-cardiovascular complications.
