The Promise of Anti-Inflammatory Therapies for Secondary Prevention of Chronic Coronary Disease
Patients with coronary disease have a life-long risk of cardiovascular death, MI, and ischemic stroke and the need for coronary intervention due to progressive angina despite the aggressive use of lipid-lowering and antithrombotic therapy. This residual risk relates to ongoing low-grade inflammation within the arterial wall that drives the atherosclerotic process and predisposes to acute plaque rupture and atherothrombosis.¹ There is now strong evidence that spontaneous self-assembly of free cholesterol into its crystalline form can initiate and promote several inflammatory processes within atherosclerotic plaque. This paradigm suggests that agents that reduce the availability of free cholesterol in the vascular wall or inhibit aspects of cholesterol crystal-induced inflammation should slow the atherosclerotic process.^2,3

CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) proved that canakinumab, which specifically inhibits interleukin 1 beta expressed by macrophages, improves the outcome of patients with coronary disease.⁴ Over 5 years, canakinumab modestly reduced cardiovascular events but at an increased risk of life-threatening infection, neutropenia, and thrombocytopenia and at very high cost. The results raised questions as to whether additional specific inflammatory agents would be needed to obtain a greater clinical benefit and whether pursuing the concept of targeting inflammation in patients with coronary disease could be achieved safely and at reasonable cost.

The Potential of Colchicine for Secondary Prevention in Chronic Coronary Disease
Colchicine is an ancient sophisticated anti-inflammatory agent with protean cellular effects. It is most avidly taken up by leucocytes but also has actions on endothelium. Its ability to bind tubulin affects a range of cellular functions, including the production of interleukin 1 beta and several other pro-inflammatory interleukins.^5,6 Long-term use of colchicine at doses 0.5-1.2 mg daily is approved by the Food and Drug Administration for prevention of acute inflammatory flares in patients with Familial Mediterranean Fever and gout.⁷ Notably in patients with gout, the use of colchicine has been associated with a reduced risk of cardiovascular events.^8,9

The LoDoCo Trials
The rationale for the LoDoCo (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease) trials was based upon the known anti-inflammatory effects and long-term safety of low-dose colchicine. The LoDoCo pilot¹⁰ was the first study to demonstrate the efficacy, safety, and long-term tolerance of colchicine 0.5 mg once daily in patients with chronic coronary disease. It showed a striking reduction in cardiovascular events; however, it was a relatively small trial that included 532 patients and employed a prospective, randomized, open blinded endpoint design.

The LoDoCo2 trial was a much larger double-blind, placebo-controlled multicenter trial that included 5,522 patients recruited in Australia and the Netherlands.^11,12 The mean age was 66 years; the majority had a history of remote MI or coronary stenting. Patients were not selected based upon any clinical or laboratory markers of risk such as high-sensitivity C-reactive protein. All had proven tolerant to a 30-day trial of colchicine 0.5 mg daily. A significantly lower occurrence of cardiovascular events was observed in patients with chronic coronary disease receiving low-dose colchicine compared with those receiving placebo. Overall, among patients with chronic coronary disease, 0.5 mg of colchicine once daily resulted in a 31% lower relative risk of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization (the primary endpoint) than placebo, with a hazard ratio of 0.69.The benefit was mostly driven by significant reductions in the risk of MI and ischemia-driven revascularization, suggesting that colchicine was affecting the progression of atherosclerosis. The benefits were seen soon after initiating therapy, continued to accrue over time, and were achieved in patients already receiving effective secondary prevention therapies. Limitations include a lower-than-expected enrollment of women and lack of baseline data collection on blood pressure, lipid levels, or inflammatory state that may have provided additional insight.

Safety and Tolerance of Long-Term Colchicine 0.5 mg Once Daily
In the LoDoCo2 trial, colchicine was not associated with an increased risk of serious infection or cancer, and the incidence of myotoxicity and neutropenia were very rare and no different from the incidence in patients assigned to placebo. Further, long-term colchicine proved to be well tolerated, with 3.4% of participants in both the active and treatment arms stopping their trial medication due to perceived side-effects out to 5 years. The incidence of non-cardiovascular death was low in the active and placebo groups (0.7 vs. 0.5 events per 100 person years, respectively), and the difference was not statistically significant (hazard ratio1.51; 95% confidence interval, 0.99-2.31). However, the apparently high hazard ratio is of some concern, and additional trials are indicated to better assess risk-to-benefit ratio with colchicine. There was no evidence that therapy increased the risk of death related to cancer or sepsis.

Colchicine Did Not Reduce All-Cause Mortality in Patients With Chronic Coronary Disease
In the LoDoCo2 trial, colchicine did not reduce all-cause mortality (hazard ratio 1.21; 95% confidence interval, 0.86-1.71) despite a non-significant trend toward lower cardiovascular death (hazard ratio 0.80; 95% confidence interval, 0.44-1.44).

Effect of Therapy in Women and Other Clinically Important Subgroups
Participants in the LoDoCo2 trial were recruited from cardiology outpatient clinics and were aged up to 82 years. Despite this, the proportion of women randomized into the trial was lower than anticipated. Nonetheless, the effect of colchicine was directionally consistent in men and women and in a broad range of other subgroups including those who were younger or older than 65 years of age and those with and without a history of hypertension, diabetes, or past coronary revascularization or acute coronary syndrome. The benefits of therapy were also independent of other therapies including statins, angiotensin-converting enzyme inhibitors, and antithrombotic therapy.

Clinical Implications
The LoDoCo trials suggest that colchicine 0.5 mg daily in patients with chronic coronary disease is safe, well tolerated over the long-term, and effective in improving disease-free survival when added to lipid-lowering and antiplatelet therapy. Because the LoDoCo trials recruited patients without regard for clinical or laboratory markers of risk, the benefits of colchicine can be reasonably expected in most patients with chronic coronary disease. However, colchicine should not be used in patients with advanced renal disease (creatinine clearance <30 ml/min) or known hematologic conditions with neutropenia and should not be used concomitantly with clarithromycin or antifungal or anti-rejection therapy.

A trial of colchicine 0.5 mg once daily comes at little cost and low risk because it does not cause or aggravate bleeding or lower blood pressure; it is not pro-arrhythmic and does not cause or aggravate renal or liver dysfunction. Further, early intolerance is infrequent, usually mild and short-lived, and can be largely avoided by introducing colchicine at half of a pill before graduating to 1 pill (0.5 mg or 0.6 mg) daily. For the vast majority of patients who do not experience early intolerance, long-term use is well tolerated.

Conclusion
The cumulative data from randomized controlled trials suggest that, when used judiciously, colchicine 0.5 mg daily is safe and effectively improves disease-free survival in patients with chronic coronary disease who are already receiving lipid-lowering and antithrombotic therapy.

References

1. Libby P, Loscalzo J, Ridker PM, et al. Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol 2018;72:2071-81.
2. Düewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357-61.
3. Nidorf SM, Fiolet A, Abela GS. Viewing atherosclerosis through a crystal lens: How the evolving structure of cholesterol crystals in atherosclerotic plaque alters its stability. J Clin Lipidol 2020;Jul 11:[Epub ahead of print].
4. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31.
5. Leung YY, Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45:341-50.
6. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 1995;96:994-1002.
7. Gilbert JL. Center for Drug Evaluation and Research NDA 22-353 (FDA.gov website). November 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022353s000_MedR.pdf. Accessed October 9, 2020.
8. Solomon DH, Liu CC, Kuo IH, Zak A, Kim SC. Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims. Ann Rheum Dis 2016;75:1674-9.
9. Crittenden DB, Lehmann RA, Schneck L, et al. Colchicine Use Is Associated with Decreased Prevalence of Myocardial Infarction in Patients with Gout. J Rheumatol 2012;39:1458-64.
10. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10.
11. Nidorf SM, Fiolet AT, Eikelboom JW, et al. The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J 2019;218:46-56.
12. Nidorf SM, Fiolet AT, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020;Aug 31:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Prevention, Stable Ischemic Heart Disease, ACS and Cardiac Biomarkers, Nonstatins, Novel Agents, Statins, Chronic Angina

Keywords: Angina, Stable, Hydroxymethylglutaryl-CoA Reductase Inhibitors, C-Reactive Protein, Plaque, Atherosclerotic, Colchicine, Interleukin-1beta, Acute Coronary Syndrome, Clarithromycin, Antifungal Agents, Tubulin, Creatinine, Fibrinolytic Agents, Platelet Aggregation Inhibitors, Secondary Prevention

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