Old Drug Found to Have New Benefits: Colchicine in Chronic Coronary Artery Disease
Author: Christine Zink, MD
People with chronic coronary artery disease live with an ongoing inflammatory battle inside their major blood vessels. This creates arterial plaque which can eventually rupture, leading to thrombosis. Scientists have been searching for a way to combat this inflammatory process, and colchicine is an old drug with potential new use in this patient population. This article will discuss the evolution and insights behind the research conducted on colchicine use in patients with coronary artery disease. Here are the highlights:
- We now know that proliferative inflammatory mechanisms are involved in the continued maintenance of plaque formation in arteries, and these complex processes can lead to plaque rupture and thrombosis.
- Colchicine is an anti-inflammatory that inhibits 𝛃-tubulin and activation of interleukin-1𝛃, a proinflammatory cytokine.
- The LoDoCo trial showed that adding colchicine 0.5 mg/day to standard therapy with antiplatelet and lipid-lowering agents in people with chronic coronary artery disease significantly reduced cardiovascular events.
- The CANTOS trial evaluated canakinumab, a monoclonal antibody that targets interleukin-1𝛃, in people with coronary artery disease, and researchers found a modest benefit at the 150-mg dose. However, patients were subject to life-threatening infections, neutropenia, and thrombocytopenia.
- The LoDoCo2 trial reconfirmed the benefits of colchicine in chronic coronary artery disease, and results showed a 31% lower relative risk of cardiovascular events.
- The COLCOT study also showed benefits to using colchicine but studied the addition of the medication to standard therapy in people who recently had a myocardial infarction rather than in people with chronic coronary artery disease.
- In contrast, the COPS trial did show a benefit to the use of colchicine in the acute setting.
- In 2021, five systematic reviews and meta-analyses that included over 11,000 patients reiterate the potential benefits of adding colchicine to standard therapy in people with coronary artery disease. They also note that the drug is safe—diarrhea and stomach pains are the most common adverse effects.
The mechanisms behind the development of chronic atherosclerosis have evolved, and now we have a better understanding of the role of inflammation in the disease process. Previously, research focused on the effects of cholesterol and lipoproteins on the development of fatty lesions in arteries. Now we know that these factors alone do not account for the burden of atherosclerosis. Instead, there are complex proliferative processes that involve the immune system and lead to chronic inflammation.1 Evidence suggests that self-assembly of free cholesterol into a crystalline form promotes an inflammatory process within atherosclerotic plaque.2 Eventually, many factors that compete in positive and negative ways to regulate arterial plaque lead to disruption and an avenue for thrombosis.
Colchicine is an anti-inflammatory agent that has been used to treat gout and familial Mediterranean fever.3 In gout, it prevents the activation, degranulation, and migration of neutrophils through inhibition of 𝛃-tubulin. In familial Mediterranean fever, it interferes with the assembly of the inflammasome complex in neutrophils and monocytes, thus calming the activation of interleukin-1𝛃, a proinflammatory cytokine.4 Patients with familial Mediterranean fever tolerate lifelong colchicine therapy, so the question arose whether long-term treatment with colchicine would help treat other chronic inflammatory problems like chronic coronary artery disease.5
In 2013, the LoDoCo (Low-Dose Colchicine) trial was a prospective, randomized, observer-blinded trial that evaluated the addition of colchicine 0.5 mg/day to standard therapy with antiplatelet agents, including aspirin or clopidogrel and statins. Approximately 500 patients with stable coronary artery disease were enrolled and followed for a median of 3 years. Researchers found that the addition of colchicine to standard therapy significantly reduced the risk of cardiovascular events, including acute coronary syndrome, out-of-hospital cardiac arrest, and noncardioembolic ischemic stroke.5 During a similar time frame, other research studies showed that people with gout who were regular users of colchicine had a reduced risk of cardiovascular events and all-cause mortality.6,7
These findings helped spur ideas on tackling the inflammatory problem of coronary artery disease from a different angle. Thus researchers devised the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) trial. Canakinumab is a monoclonal antibody that targets interleukin-1𝛃, and it is approved for clinical use in rheumatological disorders.8 This trial compared three doses of canakinumab versus placebo in approximately 10,000 patients with previous myocardial infarction and an elevated C-reactive protein level. After 4 years of follow-up, the results were not as impressive as those found with colchicine. The researchers did find a modest reduction of cardiovascular events with canakinumab 150 mg, but patients were subject to life-threatening infections, neutropenia, and thrombocytopenia. Additionally, the drug was costly, and it did not change all-cause mortality.8
Two recent randomized, controlled, double-blind trials studied much larger study populations to further elucidate the potential benefits of colchicine in coronary artery disease. In LoDoCo2 (Low Dose Colchicine 2), 5,522 patients with stable coronary artery disease were included and followed for a median of 28.6 months. Patients were treated with colchicine 0.5 mg versus placebo, and almost all patients had been taking an antiplatelet and a lipid-lowering agent. Once-daily colchicine resulted in a 31% lower relative risk of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization.9
The COLCOT (Colchicine Cardiovascular Outcomes Trial) study was different in that researchers evaluated the use of colchicine in the acute setting and recruited patients within 30 days of having a myocardial infarction. A total of 4,745 patients were enrolled and treated with colchicine 0.5 mg daily versus placebo. Similar to other studies, almost all patients had been taking an antiplatelet agent and a statin. After a median follow-up of 22.6 months, colchicine significantly reduced the risk of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring revascularization.10
In contrast, the COPS (Colchicine in Patients with Acute Coronary Syndromes) trial evaluated the use of colchicine in the acute setting in patients who presented to the hospital with acute coronary syndrome with evidence of coronary artery disease that was managed with percutaneous coronary intervention or medical therapy. Colchicine was added to standard medical therapy and continued for 12 months. The researchers did not find a benefit in mortality, acute coronary syndrome, ischemia-driven urgent revascularization, or stroke.11 However, the researchers noted that treatment with colchicine in the COPS study began immediately during the initial hospitalization, whereas in the COLCOT trial, therapy began within 2 weeks of the initial visit. Additionally, during the first month of the COPS trial, patients were treated with colchicine 0.5 mg twice daily instead of once daily. The researchers also mention that they had recruitment problems, and their study lacked power to demonstrate colchicine benefits.11
The interest in colchicine has continued unabated. In 2021, at least five systematic reviews and meta-analyses on colchicine use in patients with coronary artery disease have confirmed reductions in the risk of major cardiovascular events and stroke.12-14 These studies utilize large population samples and incorporate over 11,000 patients into the analyses. All studies show similar rates and types of adverse events, and the most common are gastrointestinal side effects that mainly include diarrhea and abdominal discomfort.5,10,11,13,14 Generally, colchicine is well tolerated. Gastrointestinal bleeding is not a common side effect, especially at low-dose.
Utilizing all of the available information at this time, experts have growing confidence that colchicine 0.5 mg daily used in patients with chronic coronary artery disease in addition to antiplatelet and lipid-lowering agents can reduce the risk of cardiovascular events and stroke. The evidence is more conflicting in acute coronary syndrome. Colchicine is safe for use, and the medication is cheap and readily available. Experts recommend avoiding its use in people with advanced renal disease or hematologic conditions associated with neutropenia.2
Further work evaluating the utility of colchicine in people with coronary artery disease and other chronic inflammatory problems is ongoing. Consider whether any of your patients might benefit from colchicine. Learn more about other preventive cardiology options and explore more Cardiology CME/CE at Pri-Med.
References
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