By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first anti-inflammatory drug to lower the risk of cardiovascular (CV) events occurring in adults with established atherosclerotic disease or with multiple risk factors.
Using colchicine dates to the ancient Greeks and Egyptians; in modern times, clinicians use colchicine to treat gout (i.e., acute gout flares and prophylaxis of gout flares) and familial Mediterranean fever. For the new indication, colchicine received a priority review. It will be distributed as Lodoco.
INDICATIONS
Colchicine can be prescribed to lower the risk of myocardial infarction (MI), stroke, coronary revascularization, and CV death for adults with established atherosclerotic disease or with multiple risk factors for CV disease.1
DOSAGE
Patients should take 0.5 mg orally once daily.1 Patients taking this medication should avoid consuming grapefruit and grapefruit juice. Colchicine is available as 0.5 mg tablets.
POTENTIAL ADVANTAGES
Colchicine appears to add benefit as secondary prevention to patients already on lipid-lowering and antiplatelet therapy.2
POTENTIAL DISADVANTAGES
Colchicine can cause myelosuppression (leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia) and neuromuscular toxicity, including rhabdomyolysis.1 It is contraindicated in patients with pre-existing blood dyscrasias, renal failure, and severe hepatic impairment.1 Concomitant administration with a strong CYP3A4 inhibitor or P-gp inhibitor also is contraindicated because of a risk of life-threatening colchicine toxicity.1 Base concomitant use with a moderate CYP3A4 inhibitor on the risk of adverse outcomes with more systemic exposure to colchicine.1 Common adverse reactions are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.1
COMMENTS
Colchicine is believed to exert its anti-inflammatory action by preventing activation, degranulation, and migration of neutrophils.1 It is associated with a reduction of high-sensitivity C-reactive protein and interleukin-6 levels.1-3 The efficacy of colchicine was demonstrated primarily from the Low-Dose Colchicine 2 (LoDoCo2) trial.1,4 This was an investigator-initiated, randomized, placebo-controlled, double-blind, event-driven trial. Subjects (85% men) presented with chronic but stable coronary disease (at least six months). Evidence of coronary disease was based on invasive coronary angiography or CT angiography or a coronary artery calcium score of at least 400 Agatston units on a coronary artery calcium scan.2
Researchers assigned 2,762 participants to colchicine and 2,760 to placebo. More than 99% were on antiplatelet drugs or anticoagulants and 97% were on lipid-lowering agents. The primary outcome was a composite of CV death, spontaneous MI, ischemic stroke, or ischemic-driven coronary revascularization. A key secondary outcome was a composite of CV death, spontaneous MI, or ischemic stroke.
After a median follow-up of 28.6 months, a primary endpoint event occurred in 187 patients in the colchicine group and in 264 patients in the placebo group, a 31% reduction (incidence, 2.5 events vs. 3.6 events per 100 person-years; HR, 0.69; 95% CI, 0.57-0.83). The difference was propelled primarily by MIs and ischemic-driven coronary revascularization. The secondary outcome was lower by 28% (HR, 0.72; 95% CI, 0.57-0.92). Death from any cause and CV deaths were not statistically significantly different. Low-dose colchicine also has lowered the rate of a composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization compared to placebo when given within 30 days after an MI.5 Neither all-cause mortality nor CV death rates were significantly different.
Another group of researchers conducted a systemic review and meta-analysis of four randomized, controlled studies (n = 11,594), which included the two papers referenced in this section. Patients with coronary artery disease or acute coronary syndrome showed a reduction in the composite endpoint occurrence rate but no reduction in CV mortality or all-cause mortality rates.6
CLINICAL IMPLICATIONS
Inflammation plays a prominent role in the development of atherosclerosis and other CV diseases.2 The mainstays of treatment have included blood pressure-lowering medication, lipid-lowering drugs, and antiplatelet/anticoagulant solutions.7 Colchicine seems to add another layer of benefit to patients, mainly men, already on the baseline medications to further reduce certain CV event rates — but not all-cause or CV mortality. Cost was not available at the time of this review.
REFERENCES
1. Agepha Pharma US. Lodoco prescribing information. June 2023.
2. Deftereos SG, Beerkens FJ, Shah B, et al. Colchicine in cardiovascular disease: In-depth review. Circulation 2022;145:61-78.
3. Pan Z, Cheng J, Yang W, et al. Effect of colchicine on inflammatory markers in patients with coronary artery disease: A meta-analysis of clinical trials. Eur J Pharmacol 2022;927:175068.
4. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838-1847.
5. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497-2505.
6. Samuel M, Tardif JC, Bouabdallaoui N, et al. Colchicine for secondary prevention of cardiovascular disease: A systematic review and meta-analysis of randomized controlled trials. Can J Cardiol 2021;37:776-785.
7. National Heart, Lung, and Blood Institute. Atherosclerosis treatment. Page last updated March 24, 2022.
The FDA has approved the first anti-inflammatory drug to lower the risk of cardiovascular events occurring in adults with established atherosclerotic disease or with multiple risk factors.
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