What is the role of colchicine in reducing the risk of cardiovascular events in adults?
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Introduction
About 1 in 3 deaths in the United States are attributed to heart disease, stroke, or other cardiovascular diseases every year. Heart disease and stroke are the first and fifth leading causes of death in the United States, respectively.1 Chronic coronary disease (CCD) refers to a heterogeneous group of conditions including obstructive and nonobstructive coronary artery disease (CAD) with or without previous myocardial infarction (MI) or revascularization, ischemic heart disease (diagnosed by noninvasive testing) and chronic angina with various underlying causes.2 Atherosclerotic cardiovascular disease (ASCVD) is caused by the buildup of plaque in the arterial walls, and includes four major areas: coronary heart disease, cerebrovascular disease, peripheral artery disease, and aortic atherosclerotic disease.3
Originally derived from the flowering plant, Autumn crocus, colchicine has been around for centuries and remains one of the oldest therapeutic agents still used today.4 It is approved for the prophylaxis of gout flares and Familial Mediterranean Fever (FMF) in adults.5 In June 2023, low-dose colchicine (0.5 mg) was approved by the Food and Drug Administration (FDA) to reduce the risk of MI, stroke, coronary revascularization, and cardiovascular death in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease.6
A 2020 FAQ summarized evidence supporting the use of colchicine for secondary prevention after an acute MI. The purpose of this review is to provide an update on data supporting the use of colchicine for its new indication.
Mechanism of Action
The mechanism of action of colchicine for the prevention of major cardiovascular events is related to its anti-inflammatory effects. Colchicine disrupts cytoskeletal functions through inhibition of beta-tubulin polymerization into microtubules, thus preventing the activation, degranulation, and migration of neutrophils. In addition, colchicine blocks the inflammasome complex in neutrophils and monocytes that mediate interleukin-1 beta activation.6 These anti-inflammatory effects are consistent with clinical data from the COLCOT and LoDoCo trials demonstrating that colchicine reduces high sensitivity C-reactive protein (hs-CRP), an inflammatory marker.7,8
Recent data suggests that inflammation assessed by hs-CRP is a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by low-density lipoprotein cholesterol (LDL-C). A 2023 analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials looked at 31,245 patients with ASCVD taking statin therapy and found that levels of hs-CRP were consistently a more powerful determinant of recurrent cardiovascular events, cardiovascular death, and all-cause mortality than was LDL-C.9 As a result, there has been increased attention focused on the role of colchicine as an agent to reduce cardiovascular risk.
Clinical Trials
There is limited data on the effectiveness of colchicine for secondary prevention and the correlation between anti-inflammatory effects and cardiovascular risk reduction. In addition to the previous review, the following published studies have assessed the use of colchicine in this role. The studies summarized below focus on clinical endpoints rather than markers of inflammation.
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| Study | Design / Duration | Population | Interventions | Outcome(s) | Limitations |
|---|---|---|---|---|---|
| Nidorf 20138 LoDoCo | Prospective, randomized, observer-blinded endpoint (PROBE) design 2 years | N=532 adults 35 to 85 years of age with coronary disease and clinically stable for ≥ 6 months before enrollment with no major comorbidities or contraindications to colchicine therapy. Patients had to be considered compliant with therapy and routine cardiology appointments. | Colchicine 0.5 mg daily (n=282) vs. control (n=250) | Primary: ACS, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke: Colchicine: 5.3% Control: 16% HR, 0.33; 95% CI, 0.18 to 0.59; p < 0.001; NNT, 11 The reduction in the primary outcome was largely driven by the reduction in patients presenting with ACS: Colchicine: 4.6% Control: 13.4% HR, 0.33; 95% CI, 0.18 to 0.63; p < 0.001 Safety: The most reported adverse events in the treatment group were GI upset (2.5%) and myalgia (0.9%). Ten patients in the control group died (5 of a presumed cardiac disease, 2 after an out-of-hospital cardiac arrest, and 2 from cardiogenic shock following acute MI); 4 patients in the colchicine group died from noncardiac causes. | PROBE trial design may lead to outcome ascertainment and reporting bias. |
| Nidorf 202010 LoDoCo2 | MC, DB, PC, RCT Median duration: 28.6 months | N=5522 adults 35 to 82 years of age with evidence of coronary disease and clinically stable for ≥ 6 months before enrollment. | Colchicine 0.5 mg daily (n=2762) Placebo (n=2760) | Primary: Cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization: Colchicine: 6.8% Placebo: 9.6% HR, 0.69; 95% CI, 0.57 to 0.83; p<0.001 Secondary: Composite of cardiovascular death, spontaneous MI, or ischemic stroke: Colchicine: 4.2% Placebo: 5.7% HR, 0.72; 95% CI, 0.57 to 0.92; p=0.007 Composite of MI or ischemia-drive coronary revascularization: Colchicine: 5.6% Placebo: 8.1% HR, 0.67; 95% CI, 0.55 to 0.83; P<0.001 Composite of cardiovascular death or MI: Colchicine: 3.6% Placebo: 5.0% HR, 0.71; 95% CI, 0.5 to 0.92; p=0.01 MI: Colchicine: 3.0% Placebo: 4.2% HR, 0.70; 95% CI, 0.53 to 0.93; p=0.01 Ischemic stroke, death from any cause, and cardiovascular death did not differ between the colchicine group and the placebo group. Safety: Noncardiovascular deaths occurred more frequently in the colchicine group than in the placebo, but results were not statistically significant (HR, 1.51; 95% CI, 0.99 to 2.31). There were similar rates between the groups in: cancer diagnosis, hospitalization for infection, pneumonia, or GI events. | Only 15.3% of participants were female BP and lipid levels were not measured during the trial. CRP was not measured at baseline, so the effects of colchicine could not be compared to the inflammatory state at baseline |
| Abbreviations: ACS=acute coronary syndrome; blood pressure; CI=confidence interval; CRP=C-reactive protein; DB, double-blind; GI, gastrointestinal; HR=hazard ratio; MC, multicenter; MI=myocardial infarction; NNT=number needed to treat; PC, placebo-controlled; PROBE=prospective, randomized, observer-blinded endpoint; RCT, randomized controlled trial. | |||||
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A 2021 analysis investigated the outcomes of the LoDoCo2 trial to determine if colchicine’s cardiovascular benefits were consistent independent of prior acute coronary syndrome (ACS) status.11 The authors discovered that 16% of the total patient population (n=864/5522) had no prior ACS, 27% had a recent ACS within 6-24 months, 29% had a remote ACS within 2-7 years, and 29% had a very remote ACS >7 years prior to randomization. The incidence of the primary outcome was independent of prior ACS status. Colchicine reduced the primary endpoint consistently compared to placebo in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; HR, 0.81; 95% CI, 0.52-1.27), as well as those with prior ACS (incidence: 2.4 vs 3.6 events per 100 person-years; HR, 0.67; 95% CI, 0.54-0.82) (P for interaction = 0.43). These results were consistent across the subgroups with recent ACS, remote ACS, and very remote ACS.
Guidelines
The 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients with Chronic Coronary Disease (CCD) recommends lifestyle modifications, management of comorbidities, lipid management, antiplatelet/anticoagulant therapy, and/or colchicine for secondary prevention of cardiovascular events in patients with CCD.2 Due to colchicine’s narrow therapeutic effect and mixed effects reported in clinical trials, these guidelines recommend limiting use at this time to individuals who remain at high risk despite maximum tolerated guideline-directed medication therapy. Specifically, the guideline states that the addition of colchicine may be considered for secondary prevention in patients with CCD to reduce recurrent ASCVD events (class of recommendation 2B, level of evidence B-R).
Conclusion
For patients with chronic coronary disease already taking guideline-directed therapy for secondary prevention, colchicine 0.5 mg daily has been shown to lower major cardiovascular events including cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-drive coronary revascularization. However, data is still limited currently, so its role in therapy is emerging. Clinicians should be mindful of safety risks associated with colchicine; its use is contraindicated with concurrent use of strong cytochrome (CYP)3A4 or P-glycoprotein inhibitors, in patients with renal failure (creatinine clearance < 15 mL/minute), severe hepatic impairment, pre-existing blood dyscrasias, or hypersensitivity to drug or inactive ingredients. In addition, colchicine can cause neuromuscular toxicity and rhabdomyolysis as well as gastrointestinal symptoms, which are usually the first sign of toxicity.2,6 While low-dose (0.5 mg) colchicine is now approved, guidelines suggest it has a limited role at this time.
References:
- Heart disease and stroke. Centers for Disease Control and Prevention. Updated September 8, 2022. Accessed January 29, 2024. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/heart-disease-stroke.htm.
- Writing Committee Members, Virani SS, Newby LK, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines [published correction appears in J Am Coll Cardiol. 2023;82(18):1808]. J Am Coll Cardiol. 2023;82(9):833-955. doi:10.1016/j.jacc.2023.04.003
- Wilson PWF. Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach. In: Gersh BJ, ed. UpToDate. UpToDate; 2024. Accessed January 29, 2024. https://www.uptodate.com/contents/atherosclerotic-cardiovascular-disease-risk-assessment-for-primary-prevention-in-adults-our-approach?search=ascvd&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.
- Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL. Colchicine: an ancient drug with novel applications. Br J Dermatol. 2018;178(2):350-356. doi: 10.1111/bjd.15896.
- Colchicine. Package insert. Piscataway, NJ: Camber Pharmaceuticals, Inc; 2021.
- Lodoco. Package insert. Parsippany, NJ: AGEPHA Pharma USA, LLC. 2023.
- Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497-2505. doi:10.1056/NEJMoa1912388
- Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404-410. doi:10.1016/j.jacc.2012.10.027
- Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401(10384):1293-1301. doi:10.1016/S0140-6736(23)00215-5
- Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838-1847. doi:10.1056/NEJMoa2021372
- Opstal TSJ, Fiolet ATL, van Broekhoven A, et al. Colchicine in patients with chronic coronary disease in relation to prior acute coronary syndrome. J Am Coll Cardiol. 2021;78(9):859-866. doi:10.1016/j.jacc.2021.06.037.
Prepared by:
Drew Saunders
PharmD Candidate Class of 2024
Edited by:
Jen Phillips, PharmD, BCPS, FCCP, FASHP
Clinical Professor
University of Illinois at Chicago College of Pharmacy
February 2024
The information presented is current as January 29, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.