Low-Dose Colchicine for Secondary Prevention of CAD: Key Points

Nelson K, Fuster V, Ridker PM.
Low-Dose Colchicine for Secondary Prevention of Coronary Artery Disease: JACC Review Topic of the Week. J Am Coll Cardiol 2023;82:648-660.

The following are key points to remember from a state-of-the-art review on low-dose colchicine for secondary prevention of coronary artery disease (CAD):

  1. This JACC review article is co-authored by Dr. Kyle Nelson, a senior fellow at Mount Sinai in New York; his mentor Dr. Valentin Fuster, the Physician-in-Chief at Mt. Sinai, Editor-in-Chief of JACC, and one of the giants in health care who passionately promotes cardiovascular disease (CVD) prevention; and Dr. Paul Ridker, who with colleagues at the Brigham and Women’s Hospital, Boston, pioneered the clinical implication of inflammation in the pathobiology of atherosclerosis, particularly the predictive value of inflammation as detectable by the serum high-sensitivity C-reactive protein (hsCRP) and exploration of treatment options. Clearly, it was written to encourage: a) the use of colchicine for the secondary prevention of CAD, as approved in many countries in the world, b) approval by the Food and Drug Administration, and c) recommendation in the US guidelines. Their justification is convincing.
  2. Low-grade systemic inflammation as determined by hsCRP is a more powerful determinant of recurrent cardiovascular (CV) events, CV death, and all-cause mortality than low-density lipoprotein cholesterol (LDL-C). When hsCRP is ≥2 mg/L, the predictive value of CV events is independent of LDL-C even at low levels, suggesting it should be included when deciding risk in stable CV disease (CVD).
  3. The recent randomized trials of the interleukin-1 inhibitor canakinumab and of the microtubule polymerization inhibitor low-dose colchicine provide evidence that inflammation inhibition safely lowers CV event rates among statin-treated patients with a magnitude of effect similar to if not greater than that of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, and other adjunctive lipid-lowering agents.
  4. The clinical benefit of targeted inflammation inhibition for patients with atherosclerotic CVD (ASCVD) is particularly true for low-dose colchicine (0.5 mg po qd), which in the LoDoCo2 (Low Dose Colchicine Trial 2) study of 5,522 patients with stable coronary disease reduced ASCVD events by 31%. The benefit in stable coronary disease was regardless of history and timing of prior acute coronary ischemia and the effect was largely driven by reductions in spontaneous infarction and ischemia-driven revascularization. The number-needed-to-treat over a mean follow-up duration of 28.6 months was 35, consistent with the benefits of aspirin, statins, and antihypertensive therapy in secondary prevention.
  5. Long-term low-dose colchicine in the stable phase following acute myocardial infarction (MI) or percutaneous coronary intervention (PCI) also provides significant clinical benefit. With a median time for initiation of treatment at 14 days following hospitalization and median follow-up of 23 months, in the COLCOT (Colchicine Cardiovascular Outcomes Trial) study, patients treated with colchicine 0.5 mg daily had a 23% lower incidence of the primary composite CV endpoint. The benefit was most significant in reducing stroke (26%) and angina requiring revascularization (50%). As in LoDoCo2, all-cause mortality in COLCOT was neutral, a finding also true for contemporary trials of patients on statins including PCSK9 inhibition, ezetimibe, and bempedoic acid.
  6. In contrast to the risk reductions observed for low-dose colchicine in stable CAD and when initiated on average a few weeks after MI, in three small trials of colchicine utilized as an immediate treatment for acute coronary ischemia, there was no reduction in event rates. Large ongoing trials are designed to determine the benefit in MI with PCI and acute coronary syndrome with hsCRP ≥2 mg/L.
  7. Colchicine is excreted via the kidney and should be avoided in those with clinically significant chronic kidney disease as well as liver disease. In contrast to LoDoCo2 participants with preserved renal function where low-dose colchicine was highly effective, colchicine did not reduce vascular events among those with estimated glomerular filtration rate <60 mL/min/1.73 m2, a level at which it may be nephrotoxic. Chronic exposure to colchicine 0.5 mg daily did not adversely alter renal function.
  8. In several meta-analyses, there were no significant drug-drug interactions between colchicine and aspirin, statins, or other guideline-directed medical therapies commonly used to treat atherosclerotic disease. The safety of colchicine 0.5 mg in >10,000 statin-treated patients in the LoDoCo2 and COLCOT trials is reassuring, considering reports using higher acute doses of colchicine in the setting of significant renal or hepatic disease had previously suggested a small increase in risk for statin-associated myositis. There are no case reports of myositis when low-dose colchicine is used in the absence of kidney or liver disease and/or in the absence of concomitant strong CYP3A4 or P-glycoprotein inhibitors. Unfortunately, the latter are often used in CVD and antifungals. It is prudent to temporarily discontinue colchicine for a week or two if any of these drugs are initiated as short-term therapy.
  9. Cardiologists in the United States should consider 0.5 mg of colchicine for stable coronary disease with the caveats as described. The 0.6 mg dose that is used for gout should not be prescribed and the 0.5 mg dose should be available soon.
  10. The 2021 European Society of Cardiology guidelines for the prevention of CVD recommend that low-dose colchicine 0.5 mg po daily be considered for secondary prevention purposes, particularly among individuals with uncontrolled risk factors or recurrent events despite optimal medical therapy. National guidelines in Canada and South America endorse broad use of 0.5 mg colchicine daily for the reduction of atherothrombotic events in almost all patients with pre-existing coronary disease, assuming no contraindications.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and SIHD, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease

Keywords: Angina Pectoris, Antihypertensive Agents, Aspirin, Atherosclerosis, Cholesterol, LDL, Colchicine, Coronary Artery Disease, C-Reactive Protein, Gout, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Inflammation, Interleukin-1, Kidney Diseases, Liver Diseases, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Myositis, PCSK9, Percutaneous Coronary Intervention, Proprotein Convertase 9, Renal Insufficiency, Chronic, Risk Factors, Secondary Prevention, Stroke, Vascular Diseases

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