https://orcid.org/0000-0002-6906-2643
Inflammation has long been known to be integral to the onset and progression of atherosclerotic disease. Effective treatment with anti-inflammatory drugs to prevent cardiovascular events remained elusive until 2017 when the placebo-controlled Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) demonstrated a positive effect of the selective inhibition of interleukin-1β with canakinumab, in patients with a history of myocardial infarction and elevated baseline C-reactive protein (CRP).1 Shortly after, data on colchicine in cardiovascular outcomes came available.
Colchicine re-purposed again
Colchicine, originally extracted from the autumn crocus (Colchicum autumnale), has been re-purposed multiple times. Historically, it was used to treat gout and other rheumatic conditions. In the 1970s, colchicine 0.6–1.2 mg daily proved effective and safe in the long-term treatment of patients with familial Mediterranean fever. The drug’s effect for treatment of pericarditis became evidence-based during the 2000s after the Colchicine for Acute Pericarditis (COPE) and Investigation for Colchicine for Acute Pericarditis (ICAP) trials. In recent years, the drug has gained new interest for its role in atherosclerosis with the results of the Colchicine Cardiovascular Outcomes Trial (COLCOT) and the second Low-Dose Colchicine (LoDoCo2) trial.2,3 Finally this year, the drug again emerged as a potential treatment of coronavirus disease 2019 (COVID-19), when the promising open-label randomized GRECCO-19 trial showed a reduction in the rate of clinical deterioration in 105 patients hospitalized patients with COVID-19.4 Larger trials of colchicine in COVID-19 are underway (COLCORONA, clinicaltrials.gov NCT04322682 and COLHEART-19, clinicaltrials.gov NCT04355143).
Colchicine in coronary disease
COLCOT randomized 4745 patients within 30 days of myocardial infarction to colchicine 0.5 mg or placebo once daily. The trial observed a 23% relative risk reduction (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.61–0.96; P = 0.02) for the composite end point of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization, compared with placebo.2
In our trial, LoDoCo2, we randomized 5522 patients with chronic coronary disease to 0.5 mg colchicine or placebo and observed a 31% relative risk reduction (HR 0.69, 95% CI 0.57–0.83; P < 0.001) for the composite end point of cardiovascular death, myocardial infarction, ischaemic stroke, or ischaemia-driven revascularization.3 A smaller trial in patients with recent acute coronary syndrome showed results consistent with COLCOT and LoDoCo2 but was underpowered to show a statistically significant effect.5
Clinical considerations
When evaluating the role of colchicine as an adjuvant in secondary prevention of coronary disease, the following important clinical considerations on the available evidence should be taken into account.
In COLCOT as well as in LoDoCo2, the benefits of colchicine appeared soon after initiation and continued to accrue over time. Both trials recruited participants irrespective of inflammatory status but excluded patients with severe heart or renal failure. The majority of patients were treated according to optimal secondary prevention strategies, with high levels of lipid-lowering drugs and antiplatelet therapy. Explorative analyses revealed no interaction of treatment with relevant clinical subgroups such as diabetes or gender.
Colchicine is known to cause a gastro-intestinal upset in some patients. In the LoDoCo2 trial, 9.4% of patients perceived side effects during the open-label run-in period. However, intolerance rates between the drug and placebo did not differ in the COLCOT trial.
Median follow-up for both trials was 23–29 months and major safety signals were investigated in an explorative manner. An increased incidence of hospitalizations for pneumonia was observed in COLCOT but not confirmed in LoDoCo2. Based on the frequent use of high dose statins, myotoxicity was investigated closely. Incidence was however low and without apparent relation to the drug.
In both trials, no difference in the occurrence of all-cause mortality was observed. The decreased number of cardiovascular deaths in LoDoCo2 was counterbalanced by an increase in non-cardiovascular deaths. Incidence of non-cardiovascular was low (0.7 and 0.5 events per 100 person-years for colchicine and placebo, respectively), limiting interpretation. Nevertheless, this signal needs attention in order to weigh the net clinical benefit of the drug. Ongoing trials involving patients with cardio- and cerebrovascular diseases will undoubtedly provide more insight on this matter.(CONVINCE, clinicaltrials.gov NCT02898610; CLEAR SYNERGY, clinicaltrials.gov NCT0304882; COLCARDIO-ACS, anzctr.org.au ACTRN12616000400460).
Mechanism of action and implications for basic science
The mechanism of action of colchicine involves multiple pathways. Colchicine is a dose-dependent inhibitor of microtubule self-assembly. Microtubules are structural components found in various static and dynamic processes of the cell. They form the cytoskeleton, and contribute to shape and movement of cells as well as intracellular trafficking. Altering microtubule structure and function has a wide gamut of effects on these processes.6
Neutrophil recruitment and adhesion
The atherosclerotic plaque is a highly inflamed site, owing to pathological stimuli such as oxidized low-density lipoprotein cholesterol, crystallization of cholesterol, blood pressure-related shear stress, and tobacco smoking-reduced nitric oxide bioavailability. The inflammatory response cascades an increasing influx of neutrophils and macrophages, that can eventually evolve to a thin capped fibroatheroma with a necrotic core. These fibroatheromata can develop structural instabilities that make them prone to erode and rupture and may lead to atherothrombosis.
Colchicine reduces mobility and deformability of neutrophils, compromising cells to move and extravasate to the injured site. In addition, colchicine induces shedding of L-selectin, which reduces neutrophil adhesion to endothelial cells. Neutrophil activity measured by protein expression is attenuated by colchicine in patients with chronic coronary disease.7 The inhibition of mobility and adhesion of neutrophils to the atherosclerotic plaque may alter plaque growth or structural integrity. This is supported by changing plaque characteristics assessed with computed tomography scanning after colchicine treatment.8
Inflammasome inhibition
The microtubule inhibitory effect of colchicine also affects the pathway of inflammasome activation. Activation of the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome leads to caspase-1 activation and subsequent interleukin-1 and interleukin-18 expression. These cytokines form an essential role in augmenting the inflammatory response. Crystalloid structures contribute importantly to NLRP3 inflammasome activation. The role of this crystal-induced inflammation in gouty arthritis is well recognized as a result of monosodium urate crystals. In the atherosclerotic plaque, crystallization of cholesterol may initiate the inflammasome activation and interleukin-1β expression.9 Colchicine reduces downstream markers of inflammasome activity such as interleukin-6 and hs-CRP in chronic coronary disease.10 The attenuating effects of colchicine on inflammasome activity and interleukin-1β in atherosclerosis have been postulated as its mechanism of action in atherosclerosis but not yet been proved unequivocally as such and merits additional research.
Conclusion
The availability and wide array of effects of colchicine has introduced this ancient drug to miscellaneous inflammatory maladies throughout history. It now lives through another renaissance with emerging data on its role in atherosclerosis. The clinical evidence in coronary disease is compelling. The residual risk of these patients, even with optimal treatment with statins and antiplatelet therapy, necessitates a drug that can modulate the inflammatory driver of the disease. Whether colchicine could play a role in this will become clear in the next few years. The distinctive properties of the drug may contribute in various ways to its atheroprotective effects, many of which still need to be elucidated.
Conflict of interest: All authors were involved as investigator in the LoDoCo2 trial.
References
Authors
Biography: Aernoud T.L. Fiolet graduated from Medicine at Utrecht University Medical School. He is cardiologist in training and PhD candidate on the subject of inflammation in coronary disease at the Netherlands Heart Institute and the University Medical Centre Utrecht. He is Clinical Epidemiology trainee at Utrecht University School of Life Sciences. He joined the Dutch Network for Cardiovascular Research in 2016 as investigator for the LoDoCo2 trial.
Biography: Peter L. Thompson graduated from Medicine and did his postgraduate degree in Medicine at the University of Western Australia. He trained in cardiology at Royal Melbourne Hospital and the Brigham and Women’s Hospital and Harvard University in Boston. He is currently Consultant Cardiologist and Head of the Heart Research Institute at Sir Charles Gairdner Hospital, and Clinical Professor of Medicine, at the University of Western Australia. He is also Deputy Director of the Harry Perkins Institute of Medical Research. He leads the Clinical trials Group in the Western Australian Heart Research Institute and has been Principal Investigator for over 130 trials. He is co-principal investigator of the LoDoCo2 trial.
Biography: Arend Mosterd graduated Medicine at Utrecht University Medical School. He obtained his PhD degree on heart failure at Erasmus University Rotterdam. He was trained in cardiology and clinical epidemiology at Erasmus Medical Centre Rotterdam and the Framingham Heart Study. He works as a cardiologist at Meander Medical Centre in Amersfoort. He served as Chair of the Board of the Dutch Network for Cardiovascular Research from 2013 through 2019. He supervised 6 PhD theses. He was national coordinator for the Paradigm HF trial and the SPIRE studies and co-principal investigator of the LoDoCo2 trial. He chairs the Scientific Advisory Board of the Netherlands Heart Foundation. He is a fellow of the European Society of Cardiology.
