ISCHEMIC STROKE / PREVENTION
Colchicine in stroke prevention
David Goldemund M.D.
Updated on 25/03/2024, published on 24/03/2024
Introduction
- despite the proven efficacy of antithrombotic, lipid-lowering, antihypertensive therapies, and lifestyle modification changes for ischemic stroke prevention, the risk of stroke, coronary events, and vascular death remains high
- accumulating evidence suggests that inflammation is of key importance in the pathophysiology of atherosclerotic plaque stabilization and thromboembolism, with inflammatory cells being involved in all stages of atherosclerosis development
- a multicentre cohort study of 10 499 patients with ischemic stroke/TIA, residual inflammatory risk (defined as presenting an LDL cholesterol level < 100mg/dL and high-sensitivity C-reactive protein level ≥ 3mg/L) was associated with recurrent stroke (hazard ratio, 1.18) (Li, 2022)
- therefore, anti-inflammatory therapies targeting atherosclerotic plaque inflammation may play an important role in preventing thromboembolic events
- colchicine is a safe and widely used anti-inflammatory drug that inhibits inflammation associated with vascular disease; it represents a new approach to the prevention of atherosclerotic ischemic stroke and may change current clinical practice (Castilla-Guerra, 2022)
- COLCOT trial evidenced a reduction in combined ischemic cardiovascular events, mainly due to the reduction of stroke and urgent hospitalization for angina leading to coronary revascularization in patients who suffered an acute myocardial infarction in the last 30 days. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo (Tardif, 2019)
- a meta-analysis suggests that in a population with high cardiovascular risk, the use of colchicine results in a significant reduction of stroke risk (Masson, 2020)
- however, CHANCE-3 results showed that the primary outcome of any stroke at 90 days occurred in 6.3% of the colchicine group vs 6.5% of the placebo group, a nonsignificant difference
- another meta-analysis showed that the addition of low-dose colchicine to standard medical therapy reduces the incidence of all major CV events (Samuel, 2021)
- CONVINCE trial results are awaited, as they will provide high-quality randomized data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke
- residual inflammatory risk (RIR) refers to the ongoing risk of cardiovascular events, such as heart attack or stroke, despite optimal management of traditional vascular risk factors
- this concept has led to increased interest in strategies to reduce inflammation as a means of further reducing cardiovascular risk beyond traditional approaches
- RIR is defined as LDL-C <2.6 mmol/L and hsCRP ≥3 mg/L
Mechanism of action
- via binding to α-tubulin and β-tubulin proteins, colchicine has multiple anti-inflammatory properties, including inhibition of microtubule polymerization, with inhibition of leucocyte rolling and endothelial adhesion, impaired leucocyte motility, phagocytosis, and cytokine secretion
- it inhibits crystal-induced activation of the NLRP inflammasome, thus inhibiting caspase-1 proteolysis and IL-1β secretion in monocyte–macrophages
Indications
- primarily indicated for the treatment and prevention of gout attacks
- management of familial Mediterranean fever (FMF) and pericarditis
- cardiovascular disease prevention (due to potential benefits in stroke prevention in high-risk populations)
- the 2021 guidelines of the European Society of Cardiology (ESC) recommend for the first time the use of anti-inflammatory treatment for the secondary prevention of atherosclerosis. They recommend considering low-dosed colchicine (0.5mg once daily) for the secondary prevention of cardiovascular disease when other risk factors are not sufficiently controlled or if recurrent events occur despite optimal treatment (grade IIb, LoE I) (ESC guidelines 2021 on CV disease prevention)
- stroke specialists are waiting for the results of the CONVINCE trial
Contraindications
- known hypersensitivity to the medication
- patients with severe rena/hepatic impairment (potential for increased toxicity)
- concomitant use with strong CYP3A4 inhibitors (such as clarithromycin, ketoconazole, or grapefruit juice)
- colchicine should not be administered to patients with severe gastrointestinal, cardiac, or hematological disorders, as it may exacerbate these conditions
- pregnant and breastfeeding women should avoid colchicine unless the potential benefits of taking the medication outweigh the risks
Interactions, adverse events
- gastrointestinal symptoms (diarrhea, nausea, vomiting, and abdominal pain)
- myopathy
- bone marrow suppression
- neuropathy
- closely monitor individuals with renal/hepatic impairment since colchicine’s toxicity may be increased in these cases
Dosing
- low-dose colchicine for stroke prevention: 0.5 mg once daily
