Over a century, the process of atherosclerosis has been associated with the phenomenon of subendothelial accumulation of cholesterol, and the corresponding formation of atherosclerotic plaque [1]. Not much time later, in the mid-1800, Virchow described the inflammatory phenomenon associated with this process suggesting inflammation as the causal factor in atherosclerosis [2]. As decades went by, scientific evidence confirmed the causal role played by cholesterol (specifically low-density lipoprotein or LDL cholesterol) in the process of atherosclerosis and the inflammatory theory was eventually pushed into the background. Therefore, most therapeutic actions focused on changing the lipidic component associated with the subendothelial accumulation of cholesterol. This dissociation and its corresponding time gap narrowed over the last few years, and inflammation has become important an important player again in the pathophysiology of the formation of atherosclerotic plaque. As a matter of fact, different pharmacological strategies have been suggested to attenuate this process and control the so-called inflammatory residual risk in the context of secondary prevention of cardiovascular events [3].

The randomized, double-blind CANTOS trial (Canakinumab anti-inflammatory thrombosis outcome study) conducted in stable patients with a past medical history of acute myocardial infarction with persistent proinflammatory response defined by ultrasensitive C-reactive protein (CRP) levels > 2 mg per liter assessed whether canakinumab, a fully human anti IL-1β monoclonal antibody, could prevent the recurrence of vascular events. We should mention that canakinumab did not reduce the lipid levels compared to the baseline values. At the 3.7-year follow-up, the yearly rate of primary endpoint occurrence was 4.5% in the placebo group, an annual 3.9% in the group on 150 mg [HR, 0.93; 95%CI, 0.74-0.98; P = .021]. The all-cause mortality rate was not lower while certain limitations made generalization not very feasible [4].

Afterwards, the CIRT (Cardiovascular inflammation reduction trial) clinical trial on the use of methotrexate (a nonspecific anti-inflammatory therapy used to treat rheumatoid arthritis and other autoimmune diseases) did not confirm any benefits in patients with previous cardiovascular diseases [HR, 1.01; 95%CI, 0.82-1.25; P = .91] [5].

Colchicine, a thousand-year-old drug first described in Egyptian papyruses 1500 years before Christ for the management of pain and inflammation [6] was later assessed. Extracted from the Colchicum autumnale plant this alkaloid is indicated to treat acute episodes of gout, Familial Mediterranean fever, Behçet’s disease, vasculitis, and acute pericarditis. [7]

The multiple effects and properties attributed to colchicine include, at cellular level, how it impacts the binding of microtubule polymerization to tubulin and eventually changes the cytoskeleton and cellular processes requiring polymerization (division and cell migration, secretion, and traffic of proteins). On the other hand, anti-inflammatory and immunomodulatory effects are described through multiple pathways: reduced function and migration of neutrophils, NLRP-3 inflammasome inhibition affecting the production of different cytokines, adhesion molecules, and mediators such as IL1β, IL 6, and MCP-1, among other. [8]

Over the last few years, 3 landmark trials have assessed colchicine in the context of secondary prevention and atherosclerotic residual risk.

The LoDoCo (Low dose colchicine for secondary prevention of cardiovascular disease) controlled, open-label clinical trial included 532 patients on a 0.5 mg/day dose of colchicine, and a mean course of therapy around 3 years. Benefits were confirmed with the use of colchicine [HR, 0.33; 95%CI, 0.18-0.59; P < .001]. Its main limitations were its open-label nature (without a placebo group), its small sample size, and its ‘too positive to be biologically acceptable’ outcomes [9]. However, this trial was useful as a hypothesis-generator trial and prompted 2 different larger clinical trials: the COLCOT [10] and the LoDoCo2 [11].

The COLCOT (Colchicine cardiovascular outcomes trial) clinical trial blindly randomized 4745 patients to receive colchicine (0.5 mg/day) vs placebo within the next 30 days after suffering an acute coronary syndrome. Also, this trial assessed a composite endpoint of cardiovascular death, resuscitation post-cardiac arrest, nonfatal acute myocardial infarction, ischemic stroke, and need for myocardial revascularization. After a relatively short follow-up of nearly 2 years, it confirmed a statistically significant difference (HR, 0.77; 95%CI, 0.61–0.96; P = .02).

The LoDoCo2 (Low dose colchicine for secondary prevention of cardiovascular disease 2) is a randomized, double-blind clinical trial that studied 5522 patients with chronic ischemic heart disease; it used colchicine (0.5 mg/day) or placebo. The median follow-up was 28.6 months. The study primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, and need for myocardial revascularization was reduced significantly (HR, 0.69; 95%CI, 0.57–0.83; P < .001). We should mention that none of the studies that reviewed colchicine in cardiovascular prevention confirmed lower mortality rates; finally, colchicine proved safe, and only a higher rate of GI adverse events was reported (diarrhea).

A recent meta-analysis that assessed the effect of the administration of low-doses of colchicine in 11 816 patients in cardiovascular secondary prevention (chronic coronary artery disease, and patients with recent acute coronary syndrome) revealed significant benefits regarding a reduced composite endpoint of cardiovascular death, acute myocardial infarction, and ischemic stroke (RR, 0.75; 95%CI, 0.61–0.92; P = .005); a 22% lower rate (RR, 0.78; 95%CI, 0.64–0.94; P = .010) of acute myocardial infarctions, a 46% lower rate (RR, 0.54; 95%CI; 0.34–0.86; P = .009) of ischemic stroke (RR, 0.77; 95%CI, 0.66–0.90; P < .001), and a 23% lower rate of new myocardial revascularization; a lower rate of cardiovascular death was evident (RR, 0.82; 95%CI, 0.55–1.23; P = .34), although an excess of non-cardiovascular deaths (RR, 1.38; 95%CI, 0.99–1.92; P = .060) counterbalanced this effect and eventually established the lack of a lower all-cause mortality rate (RR, 1.08; 95%CI, 0.71–1.62; P = .73) [12].

In the current COVID-19 pandemic setting, colchicine has been evaluated in different clinical scenarios like in the double-blind, randomized COLCORONA (Colchicine for community-treated patients with COVID-19) clinical trial whose results reported no benefits whatsoever in outpatients regarding death complications or hospitalizations (OR, 0·79; 95%CI, 0.61–1.03; P = .081) [13]. On the other hand, the English RECOVERY working group did not reduce the 28-day mortality rate in hospitalized patients with COVID-19 (trial still unpublished to this date) [14]. Finally, in Argentina, the COLCOVID open-label, randomized trial of 1279 hospitalized patients is in its presentation and publication stage at the moment [15].

In conclusion, we can say that colchicine, one of the oldest drugs currently in use, with its multiple anti-inflammatory and immunomodulator properties, is a therapeutic option that has been backed by scientific evidence for patients who have been through ischemic cardiovascular events. The incoming new guidelines and recommendations still have not included it in the therapeutic arsenal for the secondary prevention of ischemic vascular events.

1. Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis, and longevity. Circulation. 1966;34(4):679–97.

2. Virchow R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI–Atheromatous affection of arteries. 1858. Nutr Rev. 1989 Jan;47(1):23–5.

3. Sardu C, Paolisso G, Marfella R. Inflammatory Related Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Targets. Curr Pharm Des. 2020;26(22):2565-2573.

4. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1aÌ€ inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-in!ammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 2011;162:597–605

5. Ridker PM. Anti-in!ammatory therapy for atherosclerosis: interpreting divergent results from the CANTOS and CIRT clinical trials. J. Intern. Med. 2019;285:503–9.

6. Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL. Colchicine: an ancient drug with novel applications. Br J Dermatol. 2018;178(2):350–6.

7. Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S. Colchicine: old and new. Am J Med. 2015 May;128(5):461-70.

8. Marques-da-Silva C, Chaves MM, Castro NG, Coutinho-Silva R, Guimaraes MZ. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: implications for its therapeutic action. Br J Pharmacol. 2011;163(5):912–26.

9. Hennessy T, Soh L, Bowman M, Kurup R, Schultz C, Patel S, et al. The Low Dose Colchicine after Myocardial Infarction (LoDoCo- MI) study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction. Am Heart J. 2019;215:62–9.

10. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–505.

11. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838–47.

12. Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, Jolly SS, Keech AC, Kelly P, Tong DC, Layland J, Nidorf SM, Thompson PL, Budgeon C, Tijssen JGP, Cornel JH. 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 Mar 26:ehab115. 

13. Tardif JC, Bouabdallaoui N, L’Allier PL, et al.; COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021 May 27:S2213-2600(21)00222-8.

14. https://www.medrxiv.org/content/10.1101/2021.05.18.21257267v1.full-text

15. https://clinicaltrials.gov/ct2/show/NCT04328480.

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Colchicine and residual inflammatory risk; two old players that meet at last

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