Patients with coronary disease have a life-long increased risk of developing new major adverse cardiovascular events. Depending on co-morbidities and atherosclerotic burden, patients have a 5-year risk of up to 20% for MI, ischemic stroke, or death.^1,2 A proportion of this risk is attributable to the inflammatory drivers in atherosclerosis, often referred to as the residual inflammatory risk.³

CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) confirmed that modulating the inflammatory response by selective cytokine inhibition using the molecular antibody canakinumab can translate to clinical benefit.⁴ Shortly after CANTOS, two major clinical trials reported on the efficacy of the broad-acting anti-inflammatory drug colchicine in both acute and chronic coronary disease. COLCOT (Colchicine Cardiovascular Outcomes Trial) recruited patients within 30 days of MI. A total of 4,745 patients was randomized to colchicine 0.5 mg or placebo once daily. The trial showed a 23% relative risk reduction for the occurrence of the primary endpoint (the composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization).⁵ The LoDoCo2 (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2) trial recruited patients with chronic coronary disease. The trial randomized 5,522 patients to 0.5 mg colchicine or placebo once daily and demonstrated a 31% relative risk reduction for its primary endpoint (the composite of cardiovascular death, MI, ischemic stroke, or ischemia-driven revascularization) compared to placebo.⁶

When pooled, the results of the low-dose colchicine studies show a relative risk reduction of 25% (relative risk 0.75; 95% confidence interval [CI], 0.61-0.91) for major adverse cardiovascular events, with consistent effects on the individual components and in various clinical subgroups.⁷

Colchicine, originally extracted from the autumn crocus (Colchicum autumnale), is a widely available drug that is commonly used to treat gout, familial Mediterranean fever, and pericarditis. The mechanisms of action of the drug are broad and relate strongly to the inhibition of microtubule self-assembly. Microtubules are structural components that form the cytoskeleton, contribute to the shape and movement of cells, and facilitate trafficking of components within the cell. Relevant effects in the pathogenesis of atherosclerosis are the ability of colchicine to diminish neutrophil recruitment and adhesion and to inhibit nucleotide-binding oligomerisation domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 inflammasome activity.^8,9 Concentration of colchicine in leucocytes reaches its maximum within 48 hours of a single dose, and chemokine inhibitory effects occur within 6-24 hours after administration in patients with ACS.^10,11 Colchicine inhibits neutrophil degranulation proteins and is associated with a 30-40% reduction in high-sensitivity C-Reactive protein levels and a 16% reduction in interleukin‑6 levels in patients with chronic coronary disease.^12,13

Colchicine has a clear dose-response effect for side effects.⁸ High-dose colchicine (0.5 mg bi-daily or more) is used in gout, pericarditis, and in familial Mediterranean fever. It is also investigated in clinical studies of coronary interventions, post-thoracotomy syndromes, and ablation in atrial fibrillation. The incidence of any adverse side effect is at least twofold higher in studies using high-dose colchicine than the incidence that was observed in the low-dose colchicine studies in coronary disease.¹⁴ However, these adverse effects are often benign and most often concern gastrointestinal upset. Whether the 20% difference in dosage commonly used in the United States (0.6 mg once daily) versus the dosage used in studies so far (0.5 mg once daily) will translate to a clinically relevant increase in adverse events in patients with coronary disease is not known but seems unlikely.

Data on colchicine 0.6 mg and adverse events in coronary disease are scarce. Indirectly inferring a dose effect from current or future studies using 0.6 mg once daily will be challenging because variation in patient populations and run-in schemes also contribute to differences in incidence of side effects. Data on bioavailability of the two dose regimes are also limited. Determining a difference in side effects between 0.5 mg and 0.6 mg once daily would necessitate extrapolating bioavailability data, designing head-to-head comparisons of the two regimes, or using phase IV observational studies comparing the two dosages. The latter two methods need large study sizes to detect the probably subtle difference, if present.

In translating the findings of benefit in coronary disease to regular clinical care of patients post-MI, one of the most relevant questions is when to commence therapy. Recent ancillary analyses have provided more guidance in this regard.^15,16

All patients in COLCOT had a prior MI. In 40% of patients, study medication was initiated within the first week after MI. Patients who received treatment early were generally younger, more often smokers, and more often taking beta-blockers. Time to treatment as effect modifier for the primary and secondary endpoint was investigated using a stratified post hoc Cox regression analysis. Effect size was most marked in patients who had treatment initiated within 3 days after MI (hazard ratio [HR] 0.52; 95% CI, 0.32-0.84).¹⁵ The subgroup of patients in which therapy was initiated 8 days or more after MI was twice as large. The effect estimate in this subgroup was directionally consistent, albeit smaller and not statically significant (HR 0.82; 95% CI, 0.61-1.11). The authors did not report whether the differences in observed effect size between strata were statistically significant.

The authors made a notable effort to quantify the relation of treatment effect size and time to treatment initiation by analyzing the latter as continuous factor (Figure 1). This analysis confirmed an early benefit of the treatment initiation but also came with imprecision to detect any signal in patients who started treatment more than 8 days after MI. Interestingly, relative risk reduction was greater in patients who commenced treatment more than 21 days after their index infarction. An important caveat in the interpretation of this finding is that not all unequally distributed characteristics were used in adjustment of these estimators. Second, whether this parabolic relation of treatment initiation and effect size—with greater effect size seen in both very early (<3 days) and very late (>21 days) treatment initiation—reflects separate biologic mechanisms of the drug or is a play of chance cannot be distinguished from these data. Early benefits could be based on the potential of colchicine to lower ischemia-reperfusion injury. A 5-day regimen of colchicine 0.5 mg twice daily in patients with ST-segment elevation MI led to smaller infarct sizes measured with magnetic resonance imaging and troponin-T and creatine kinase-MB levels compared to placebo.¹⁷

Figure 1: Associations Between Time to Treatment Initiation and the Risk of Occurrence of the Primary Composite Endpoint

These data suggest that early initiation of low-dose colchicine is justified in patients with MI. However, less than 25% of the COLCOT cohort had follow-up for more than 28 months. When evaluating treatment effect late after a coronary event, data from the LoDoCo2 trial becomes complementary. In contrast to COLCOT, patients from the LoDoCo2 trial were recruited from outpatient clinics, irrespective of a prior coronary event. A fifth of patients in the LoDoCo2 trial had over 4 years of follow-up. In 50% of patients with a history of prior ACS, the most recent event occurred more than 4 years prior to randomization (median time since last ACS = 4 years; interquartile range = 2-10 years). Benefit of treatment in the LoDoCo2 trial was consistently seen in all subgroups of prior ACS (Figure 2):

• For patients with an ACS 6-24 months prior to randomization (HR 0.75; 95% CI, 0.51-1.10)
• For patients with an ACS 2-7 years prior to randomization (HR 0.55; 95% CI, 0.37-0.82)
• For patients with an ACS >7 years prior to randomization (HR 0.70; 95% CI, 0.51-0.96)

Figure 2: Cumulative Incidence of the Primary Composite Endpoint Stratified per Time Since Last ACS

Although the relative risk reduction varied from 45% to 25% for these strata, differences were not statistically significant (p for interaction of treatment effect and prior ACS status = 0.590).¹⁶ Trial data on colchicine were collected in a wide range of patients, with and without prior ACS. These data and tabular meta-analyses show consistent effects of treatment, regardless of prior events.^5-7

Whether a high atherothrombotic risk is associated with greater treatment benefit of colchicine has not yet been confirmed. Although it seems likely that there are atherothrombotic and inflammatory phenotypes that would benefit more from treatment with colchicine, exploratory subgroup analyses from the trials did not yet reveal any clinical effect modifiers. These data come with the caveat that such subgroup analyses are almost always underpowered.

Post hoc sub-analyses from CANTOS did, however, show greatest benefit in those with greatest anti-inflammatory effect.¹⁸ These data are in accordance with the observation that clinical benefit of statins is proportional to their anti-inflammatory effects.¹⁹ Whether such associations also exist for colchicine is not yet known. A large clinical outcomes trial (COLCARDIO-ACS [Colchicine Cardiovascular Outcomes in Acute Coronary Syndrome]) will investigate the effect of the drug in patients with elevated high-sensitivity C-reactive protein. These data will contribute to the identification of high-responder populations. As for now, the available evidence suggests that colchicine can be used in the complete range of coronary syndromes irrespective of (recurrent) coronary events.

When generalizing the findings from the colchicine trials, it should be noted that patients with heart failure and renal impairment were excluded from participation, and only a very low number of octogenarians was included in the studies. However, comorbidities were typical of patients with chronic coronary disease, as was concomitant drug use, with almost all patients using intensive lipid-lowering therapy, beta-blockers, and antiplatelet or anticoagulant agents.

The insights emanating from recent large clinical outcome trials on the role of colchicine as anti-inflammatory treatment in patients with coronary disease come with new questions for regular clinical practice. Treatment with colchicine is now incorporated as a recommendation in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice.²⁰ When considering timing of treatment, the aforementioned subgroup analyses and clinical considerations contribute. Commencing treatment early after MI appears valid, as is starting therapy for patients without cardio-renal failure treated in the outpatient clinic. Current data suggest a consistent effect throughout prolonged treatment, irrespective of timing of a prior ACS.

References

1. Murchie P, Campbell NC, Ritchie LD, Simpson JA, Thain J. Secondary prevention clinics for coronary heart disease: four year follow up of a randomised controlled trial in primary care. BMJ 2003;326:84.
2. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018;379:2097-107.
3. Ridker PM. How Common Is Residual Inflammatory Risk? Circ Res 2017;120:617-9.
4. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31.
5. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med 2019;381:2497-505.
6. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020;383:1838-47.
7. Fiolet ATL, Opstal TSJ, Mosterd A, et al. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J 2021;42:2765-75.
8. Leung YY, Hui LLY, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45:341-50.
9. Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018;269:262-71.
10. Chappey ON, Niel E, Wautier JL, et al. Colchicine disposition in human leukocytes after single and multiple oral administration. Clin Pharmacol Ther 1993;54:360-7.
11. Robertson S, Payet C, Martinez GJ, et al. Abstract 13715: Colchicine Acutely Suppresses the NLRP3 Inflammasome in Acute Coronary Syndrome Patients Monocytes. Circulation 2015;132:A13715.
12. Opstal TSJ, Hoogeveen RM, Fiolet ATL, et al. Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease: A LoDoCo2 Proteomic Substudy. Circulation 2020;142:1996-8.
13. Fiolet ATL, Silvis MJM, Opstal TSJ, et al. Short-term effect of low-dose colchicine on inflammatory biomarkers, lipids, blood count and renal function in chronic coronary artery disease and elevated high-sensitivity C-reactive protein. PLoS One 2020;15:e0237665.
14. Verma S, Eikelboom JW, Nidorf SM, et al. Colchicine in cardiac disease: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2015;15:96.
15. Bouabdallaoui N, Tardif JC, Waters DD, et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J 2020;41:4092-9.
16. Opstal TSJ, Fiolet ATL, van Broekhoven A, et al. Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome. J Am Coll Cardiol 2021;78:859-66.
17. Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation 2015;132:1395-403.
18. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018;39:3499-507
19. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-8.
20. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiovascular Care Team, Noninvasive Imaging, Pericardial Disease, Prevention, ACS and Cardiac Biomarkers, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Magnetic Resonance Imaging

Keywords: Colchicum, Troponin T, Interleukin-6, Inflammasomes, C-Reactive Protein, Leucine, Colchicine, Secondary Prevention, Cardiovascular Diseases, Acute Coronary Syndrome, Atrial Fibrillation, Familial Mediterranean Fever, Cytokines, Pharmaceutical Preparations, Neutrophil Infiltration, Biological Availability, Risk, Pyrin Domain, Confidence Intervals, Thoracotomy, Brain Ischemia, Neutrophils, Time, Stroke, Myocardial Infarction, Anti-Inflammatory Agents, Atherosclerosis, Coronary Disease, Thrombosis, Magnetic Resonance Imaging, Ischemia, Pericarditis, Cytoskeleton, Microtubules, Infarction, Reperfusion Injury, Regression Analysis, Hospitalization, Renal Insufficiency, Ambulatory Care Facilities, Ischemic Stroke, Ischemic Stroke, Creatine Kinase, Heart Arrest, Nucleotides, Biological Products

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