Cardiovascular disease patients are at an elevated lifetime risk of experiencing new, life-threatening cardiovascular events. Patients have a 5-year risk of MI, ischaemic stroke, or mortality of up to 20% depending on co-morbidities and atherosclerotic load. The residual inflammatory risk, which is a term used to describe this component of the risk, is caused in part by the inflammatory drivers of atherosclerosis. Colchicine, an anti-inflammatory medication offers some benefits, however, there is still not enough clarity on when to begin this in patients. Now a few studies provide answers.

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CANTOS study

The clinical benefit may be obtained by utilising the molecular antibody canakinumab to modulate the inflammatory response by selective cytokine suppression, according to the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study).

Colchicine, a broad-acting anti-inflammatory medication, was shown to be effective in both acute and chronic coronary artery disease shortly after CANTOS. Within 30 days after MI, participants were included in the COLCOT trial (Colchicine Cardiovascular Outcomes Trial). Colchicine 0.5 mg or a placebo was given to 4,745 patients in total.

The study found a 23% decrease in the likelihood of the main endpoint occurring (the composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalisation for angina leading to coronary revascularisation).

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LoDoCo2 study

Chronic coronary disease patients were recruited for the LoDoCo2 (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2) study. Trial participants were randomly assigned to receive either 0.5 mg of colchicine or a placebo once daily, and the results showed a 31% reduction in the primary endpoint's (the composite of cardiovascular death, MI, ischaemic stroke, or ischaemia-driven revascularization) relative risk compared to placebo.

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Colchicine, a widely accessible medication used to treat gout, familial Mediterranean fever, and pericarditis, was initially derived from the autumn crocus (Colchicum autumnale). Microtubule self-assembly inhibition has been linked to a variety of pharmacological modes of action. The cytoskeleton is made up of microtubules, which are important for cell structure and mobility. Microtubules also help components move throughout the cell.

Colchicine's capacity to reduce neutrophil recruitment and adhesion as well as to decrease protein 3 inflammasome activity with nucleotide-binding oligomerisation domains, leucine-rich repeats, and pyrin domains is relevant in the development of atherosclerosis.

A single dosage of colchicine causes a peak in leucocyte concentration in 48 hours, and chemokine inhibitory effects appear 6-24 hours after treatment in individuals with acute coronary syndromes (ACS). Chronic coronary disease patients with high levels of high-sensitivity C-reactive protein or interleukin-6 may benefit from taking colchicine, which inhibits neutrophil degranulation proteins and lowers these levels by 30-40 per cent.

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Side effects

When it comes to side effects, there is a definite dosage response with colchicine. 0.5 mg bi-daily or more of high-dose colchicine is used for gout, pericarditis, and familial Mediterranean fever. Studies on coronary interventions, post-thoracotomy symptoms, and atrial fibrillation ablation use it as a research tool, as well.

Trials employing high doses of colchicine had a two-fold increase in the incidence of any side event compared to studies using low doses of colchicine in patients with coronary artery disease. However, these side effects are usually minor and are related to digestive problems. To what extent the 20 per cent variation in typical US dose (0.6 mg once daily) vs the dosage used in trials to date (0.5 mg once daily) would lead to an increase in adverse events in patients with coronary disease is unknown; although it seems improbable.

One of the most important issues is when to begin treatment after a MI, based on the results of benefit in coronary disease. More recent auxiliary studies have shed light on this.

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COLCOT study

All of COLCOT's patients had an MI in the past. Study medication was started within one week after MI in 40% of participants. Early-treated patients tended to be younger, heavier smokers, and to be on beta-blocking medications. A stratified post hoc Cox regression analysis looked at the time to treatment as an impact modifier for the main and secondary endpoints.

1. Patients who began therapy within three days after MI had the largest effect magnitude (hazard ratio [HR] 0.52; 95 per cent CI, 0.32-0.84).
2. Those patients who began treatment at least eight days following their MI fell into a category that was more than twice as big. Though lower and less statistically significant, the impact estimate was nonetheless directionally consistent in this particular subgroup (HR 0.82; 95 per cent CI, 0.61-1.11).

The authors failed to mention whether or whether there were statistically significant variations in observed effect sizes across strata.

When it came to measuring the relationship between treatment effect size and time since treatment start, the authors went above and above by treating the latter as a continuous variable. Despite the fact that this study proved that treatment beginning was beneficial early on, it also showed that it was difficult to detect any signal in patients who began therapy more than eight days after MI. For whatever reason, patients who began therapy more than 21 days after their first infarction had a higher relative risk decrease.

Not all unequally distributed variables were utilised in adjusting these estimators, which is an essential caution to remember. Secondly, these data do not allow us to tell whether the parabolic relationship between treatment start and impact magnitude — with larger effects being observed at both early (3 days) and late (>21 days) points to distinct biologic processes of the medication or is a result of chance. Colchicine's ability to reduce ischaemia-reperfusion damage may be the basis for early benefits.

Colchicine 0.5 mg twice day for five days reduced infarct sizes by magnetic resonance imaging, troponin-T, and creatine kinase-MB levels in patients with ST-segment elevation MI.

Patients with heart failure and renal impairment were omitted from the research, and only a small number of octogenarians were included for drawing general conclusions from the colchicine trials. In patients with chronic coronary artery disease, however, comorbidities were common, as was concurrent medication usage, with almost all of them using rigorous lipid-lowering treatment, beta-blockers, and antiplatelet or anticoagulant medicines simultaneously.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.