Colchicine and the heart

Abstract

Colchicine is a unique, sophisticated anti-inflammatory agent that has been used for decades for the prevention of acute inflammatory flares in gout and familial Mediterranean fever. In recent years, clinical trials have demonstrated its potential in a range of cardiovascular (CV) conditions. Colchicine is avidly taken up by leucocytes, and its ability to bind to tubulin and interfere with microtubular function affects the expression of cytokines and interleukins, and the ability of neutrophils to marginate, ingress, aggregate, express superoxide, release neutrophil extracellular traps, and interact with platelets. In patients with acute and recurrent pericarditis, clinical trials in >1600 patients have consistently shown that colchicine halves the risk of recurrence [relative risk (RR) 0.50, 95% confidence interval (CI) 0.42-0.60]. In patients with acute and chronic coronary syndromes, multicentre randomized controlled trials in >11 000 patients followed for up to 5 years demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic stroke and ischaemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49-0.81). The use of colchicine at doses of 0.5-1.0 mg daily in CV trials has proved safe. Early gastrointestinal intolerance limits its use in ∼10% of patients; however, ∼90% of patients tolerate it well over the long term. Despite isolated case reports, clinically relevant drug interactions with moderate to strong CYP3A4 inhibitors/competitors or P-glycoprotein inhibitors/competitors are rare if this dosage of colchicine is used in the absence of advanced renal or liver disease. The aim of this review is to summarize the contemporary data supporting the efficacy and safety of colchicine in patients with CV disease.

Keywords: Acute coronary syndrome; Atrial fibrillation; Chronic coronary syndrome; Colchicine; Coronary artery disease; Heart failure; Inflammasome; Pericarditis.

The central mechanism of the anti-inflammatory action of colchicine is the inhibition of microtubule function leading to the inhibition of granulocyte function, interference with selectin expression and neutrophil–platelet interactions, and non-specific inhibition of the assembly of the inflammasome in inflammatory cells. These actions could exert therapeutic effects in different cardiovascular diseases (e.g. pericarditis, acute and chronic coronary syndromes, atrial fibrillation, and heart failure).

Figure 1

Colchicine is the active principle derived from Colchicum autumnale plants. The drug has been cited as medical remedy for the first time in the ancient Ebers papyrus (1500 BC). The name ‘colchicine’ is after the ancient and legendary kingdom of Colchis, where Colchicum autumnale plants were widespread.

Figure 2

Colchicine anti-inflammatory actions start with the interference with microtubule assembly and function and its capability to concentrate in inflammatory cells with limited expression of P-glycoprotein (e.g. granulocytes). Anti-inflammatory effects of colchicine are derived from a combination of different actions: (i) inhibition of granulocytes, (ii) interference with qualitative and quantitative expression of selectins on endothelial and inflammatory cells and platelet aggregation stimulated by inflammation, and (iii) non-specific inhibition of the inflammasome by interference with the assembly of its components when inflammation is stimulated.

Figure 3

Colchicine uptake occurs in the ileum and jejunum. The drug is metabolized by the liver through cytochrome P450 3A4 (CYP3A4) and excreted into the bile and urine through P-glycoprotein. Colchicine can also cross the placenta and enters breast milk by P-glycoprotein.

Figure 4

Anti-inflammatory actions of colchicine have been studied for different cardiovascular indications: pericarditis (well-established and recommended by guidelines), acute and chronic coronary syndromes (emerging indication), prevention of post-operative atrial fibrillation and atrial fibrillation after ablation, and heart failure (still ongoing and to be well-defined).

Figure 5

Risk of pericarditis in patients treated with or without colchicine in different settings (acute, recurrent pericarditis, and prevention of the post-pericardiotomy syndrome). CI, confidence interval; M-H, Mantel-Haenszel.

Figure 6

Forest plot of the primary clinical efficacy endpoint derived from main randomized controlled trials in acute and chronic coronary syndromes (A for the primary composite endpoint and B for the single components of the primary composite endpoint). CI, confidence interval; M-H, Mantel-Haenszel.