Colchicine for cardiovascular prevention: the dawn of a new era has finally come

Abstract

The US Food and Drug Administration (FDA) has recently approved colchicine to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular (CV) death in adult patients with established atherosclerotic disease or with multiple risk factors for CV disease. Colchicine was used for centuries to cure gouty arthritis and more recently for acute and recurrent pericarditis and auto-inflammatory diseases due to its wide anti-inflammatory action depending on (i) interference with microtubule functions; (ii) impairment of neutrophil chemotaxis, mobilization, and recruitment; (iii) impairment of neutrophil–platelet interplay; and (iv) indirect blockade of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome oligomerization through interferences on microtubules1 (Figure 1). Anti-inflammatory effects of colchicine. Colchicine owns anti-inflammatory properties mediated by effects on neutrophils and the NLRP3 inflammasome. Indeed, colchicine has been recently approved by US Food and Drug Administration to reduce cardiovascular risk, particularly tackling the residual inflammatory risk. AMI, acute myocardial infarction; NLRP3, NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 Once depicted as a mere accumulation of lipids within the vessel wall, atherosclerosis is now considered an inflammatory disease.2 Accumulation of pro-inflammatory lipoproteins in the lumen of arteries causes endothelial dysfunction and is followed by activation of the NLRP3 inflammasome and production of inflammasome-dependent cytokines, interleukin-1β (IL-1β), and IL-18.3 These events are responsible for sustaining endothelial dysfunction, impairing vasodilation, activation and homing of leukocytes, promotion of oxidative stress, and outward remodelling of the artery wall. Interleukin-1β locally stimulates coagulation factors and platelet activation, thus promoting plaque rupture and thrombosis, and systemically induces IL-6 production, that through an increase in pro-inflammatory and pro-coagulant events, fuels a vicious cycle responsible for increasing CV events.3 Modulation of the NLRP3 inflammasome/IL-1β axis has then resulted an appealing therapeutic target to reduce the burden of the atherosclerotic disease. While statins showed to possess cholesterol-lowering properties and anti-inflammatory effects, thus reducing the ‘residual cholesterol risk’, a portion of these patients reached target levels of low-density lipoprotein cholesterol but were found to be still at risk for CV events due to ‘residual inflammatory risk’.4 In the seminal Canakinumab ANtiinflammatory Thrombosis Outcome Study (CANTOS) trial showed that canakinumab—a monoclonal antibody blocking IL-1β—reduced recurrent CV events in patients with prior MI who were aggressively treated with statins and evidence of systemic inflammation (high-sensitivity C-reactive protein ≥ 2 mg/L), irrespective of any impact on lipids.5 Accordingly, it has been shown that among patients already on a statin, those with high inflammation levels—i.e. highest high-sensitivity C-reactive protein quartiles—experienced the highest risk for future CV events.6 Colchicine was also shown to reduce CV risk in three randomized clinical trials (RCTs)—Low-Dose Colchicine (LoDoCo), LoDoCo2, and COLCOT (COLchicine Cardiovascular Outcomes Trial).7–9 All these findings clearly highlight that decreasing the residual cholesterol risk with statins—drugs with cholesterol-lowering and anti-inflammatory properties—is not sufficient to reduce CV events as the residual inflammatory risk—i.e. high-sensitivity C-reactive protein ≥ 2 mg/L—is not adequately controlled. Anakinra—recombinant IL-1 receptor antagonist—has also shown to have promising effects in blunting the acute inflammatory response in acute MI and improving cardiorespiratory fitness in patients with heart failure and high-sensitivity C-reactive protein ≥ 2 mg/L.3 However, differently from colchicine, canakinumab, and anakinra, the same beneficial effects were not found with other anti-inflammatory drugs with a different mechanism of action, such as methotrexate, tumour necrosis factor inhibitors, and non-steroidal anti-inflammatory drugs. Colchicine possesses a number of properties that make this drug promising as an additional pillar in the treatment of patients with atherosclerotic CV disease together with statins and anti-platelets. Indeed, colchicine is administered orally, inexpensive, and widely available, that may favour its rapid implementation. It has a good safety profile, with a small, yet significant, increase in infections—pneumonia in particular, but not opportunistic infections. This side effect is to be awaited considering that the NLRP3 inflammasome blockade may delay the recognition of infections, yet it does not impair the response to pathogens or tissue repair, as extensively studied in patients experiencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.10 Although subject to drug–drug interactions, the most frequent side effect is diarrhoea that may lead to discontinuation in up to 20% of patients. Muscular and haematological toxicities are also possible yet were rarely described in trials testing colchicine 0.5 mg once daily. Finally, given the narrow therapeutic index, extreme attention should be paid to patients with chronic kidney disease. The dosage of colchicine used in the three RCTs of CV prevention was 0.5 mg once daily, which is the same approved by the FDA, although, in some countries, the available dosage is 0.6 mg. It is poorly plausible that a difference of 0.1 mg may provide great differences in terms of efficacy, side effects, or toxicity, although this point is yet to be clarified. On the other side, it is unknown whether higher doses (>0.5 mg daily) may portend larger benefits. In order to assign patients to the correct drug, it could be tempting to test patients for high-sensitivity C-reactive protein and treat only those with high-sensitivity C-reactive protein ≥ 2 mg/L. This is still a matter of debate, but it is not supported by findings as high-sensitivity C-reactive protein was not measured in the two largest trials with colchicine where the clinical benefit was evident across the wide spectrum of CV disease, including patients with asymptomatic coronary artery calcifications and patients with recent MI. The FDA approval of colchicine for secondary CV prevention definitely represents the dawn of a new era as it is the first approved drug tackling the residual inflammatory risk. The optimal duration of the treatment and the extension of its benefits to other inflammatory conditions, such as heart failure, certainly deserve dedicated, long-term trials in the next future. A.B. received honoraria from Effetti s.r.l. (Milan, Italy) to collaborate on the medical website www.inflammology.org. A.A. received research support from Kiniksa Pharmaceuticals Ltd., Novartis, Olatec, R-Pharm, and Serpin Pharma, served as an advisor to Abiomed, Applied Clinical Intel, Cromos Pharma, Eli Lilly, Implicit Bioscience, Janssen, and Novo-Nordisk, and has received honoraria from Effetti s.r.l. (Milan, Italy) and Kiniksa Pharmaceuticals Ltd. for educational events.

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