Seeing Colchicine in a New Light: Repurposing Low-dose Colchicine for Secondary Prevention of Cardiovascular Disease.

This review presents a modern perspective on the cardiovascular re-purposing of colchicine, the oldest drug in the pharmacopeia other than aspirin that is still in regular use. This article presents a brief overview of colchicine's long history as a medicine, as well as a critical review of safety and efficacy from the results of recent cardiovascular clinical trials. Long-term continuous colchicine use at doses between 0.6 and 2.4 mg has been used to prevent inflammatory flares in patients with gout and familial Mediterranean fever and less commonly employed in a range of other inflammatory conditions. In these settings, lifelong therapy has been found to be safe and well tolerated. Understanding the central role of inflammation in atherosclerosis has led to the search for effective anti-inflammatory agents that can be used continuously in combination with a range of other medications, including lipid-lowering therapies, antiplatelet therapy, and anticoagulants. The results of recent robust randomized clinical trials of low-dose colchicine (0.5 mg daily) in patients with coronary disease recently led the US Food and Drug Administration to approve its use as a new cornerstone therapy for secondary prevention in patients with coronary disease. Several misconceptions regarding the safety and tolerability of low dose colchicine are addressed. Colchicine has emerged from its traditional role in medicine as the prevention of gout flare as the first anti-inflammatory agent to be approved by the US Food and Drug Administration for the secondary prevention of atherosclerosis.

Nidorf SM 《-》

The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics.

Because patients with stable coronary artery disease are at continued risk of major atherosclerotic events despite effective secondary prevention strategies, there is a need to continue to develop additional safe, effective and well-tolerated therapies for secondary prevention of cardiovascular disease. RATIONALE AND DESIGN: The LoDoCo (Low Dose Colchicine) pilot trial showed that the anti-inflammatory drug colchicine 0.5 mg once daily appears safe and effective for secondary prevention of cardiovascular disease. Colchicine's low cost and long-term safety suggest that if its efficacy can be confirmed in a rigorous trial, repurposing it for secondary prevention of cardiovascular disease would have the potential to impact the global burden of cardiovascular disease. LoDoCo2 is an investigator-initiated, international, multicentre, double-blind, event driven trial in which 5522 patients with stable coronary artery disease tolerant to colchicine during a 30-day run-in phase have been randomized to colchicine 0.5 mg daily or matching placebo on a background of optimal medical therapy. The study will have 90% power to detect a 30% reduction in the composite primary endpoint: cardiovascular death, myocardial infarction, ischemic stroke and ischemia-driven coronary revascularization. Adverse events potentially related to the use of colchicine will also be collected, including late gastrointestinal intolerance, neuropathy, myopathy, myositis, and neutropenia. CONCLUSION: The LoDoCo2 Trial will provide information on the efficacy and safety of low-dose colchicine for secondary prevention in patients with stable coronary artery disease.

Nidorf SM ，Fiolet ATL ，Eikelboom JW ，Schut A ，Opstal TSJ ，Bax WA ，Budgeon CA ，Tijssen JGP ，Mosterd A ，Cornel JH ，Thompson PL ，LoDoCo2 Investigators ... -  《-》

Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overview.

Colchicine is a widely available, inexpensive drug with a range of antiinflammatory properties that may make it suitable for the secondary prevention of atherosclerosis. This review examines how past and contemporary approaches to antiinflammatory therapy for atherosclerosis have led to a better understanding of the nature of the disease and sets out the reasons why colchicine has the potential to become a cornerstone therapy in its management. We performed a literature search using PubMed, the Cochrane library, and clinical trial registries to identify completed and ongoing clinical studies on colchicine in coronary artery disease, and a PubMed search to identify publications on the mechanism of action of colchicine relevant to atherosclerosis. A large body of data confirms that inflammation plays a pivotal role in atherosclerosis. The translation of this extensive knowledge into improved clinical outcomes has until recently been elusive. Findings from statin trials support the possibility that targeting inflammation may be beneficial, but this evidence has been inconclusive. Direct inhibition of atherosclerotic inflammation is being explored in current clinical trials. Targeted inhibition of interleukin 1β with canakinumab provided the proof of principle that limiting inflammation can improve outcomes in atherosclerotic vascular disease, but long-term treatment with a monoclonal antibody is unlikely to have widespread uptake. Other approaches using agents with a wider set of targets are being explored. Findings from observational studies suggest that methotrexate may reduce cardiovascular risk in patients with rheumatoid arthritis, but CIRT (Cardiovascular Inflammation Reduction Trial) demonstrated that methotrexate provided no cardiovascular benefit in patients with atherosclerotic vascular disease. Recent demonstration that cholesterol crystals trigger the NLRP3 (nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3) inflammasome and the release of inflammatory cytokines that also drive uric acid crystal-induced inflammation indicates that the multiple actions of colchicine that make it effective in gout may be relevant to preventing inflammation and limiting inflammatory injury in atherosclerosis. The ongoing LoDoCo2 (Low Dose Colchicine2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) trials and several other planned large-scale rigorous trials will determine the long-term tolerability and efficacy of low-dose colchicine for secondary prevention in patients with coronary disease. Colchicine holds promise as an important, accessible drug that could be successfully repurposed for the secondary prevention of atherosclerotic cardiovascular disease should its tolerability and cardiovascular benefits be confirmed in ongoing clinical trials.

Nidorf SM ，Thompson PL 《-》

Colchicine's Role in Cardiovascular Disease Management.

Buckley LF ，Libby P 《-》

Colchicine in Stable Coronary Artery Disease.

Disease management of stable coronary artery disease consists of controlling hemostasis and lipid regulation. No treatment strategies preventing plaque erosion or rupture are yet available. Cholesterol crystal-induced inflammation leading to plaque destabilization is believed to be an important factor contributing to plaque instability and might well be amenable to treatment with anti-inflammatory drugs. Colchicine has anti-inflammatory properties with the potential to address both the direct and indirect inflammatory mechanisms in the plaque. A literature search was performed in MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials, as well as in the clinical trial registries, to identify finished and ongoing clinical studies on colchicine in stable coronary artery disease. Preclinical findings of colchicine in stable coronary artery disease have shown protective effects on surrogate outcomes, such as myocardial infarction size and postangioplasty restenosis. Retrospective cohort studies in patients with gout report a lower incidence of combined cardiovascular outcomes in those treated with colchicine. Thus far, one prospective, randomized clinical trial has provided evidence on a possible protective effect of colchicine in stable coronary artery disease. Meta-analysis of trials of colchicine in multiple cardiovascular diseases revealed a decrease in myocardial infarction with varying levels of evidence. Currently, 5 major clinical trials involving >10,000 patients are recruiting patients, all focusing on major cardiovascular outcomes. The body and quality of evidence regarding the efficacy of colchicine for secondary prevention of stable and acute phases of coronary artery disease will be greatly expanded in the upcoming years, providing less biased and more accurate effect estimates. If colchicine's anti-inflammatory characteristics translate to improved event-free cardiovascular survival, this relatively safe, low-cost, and well-known drug may become the third pillar (next to lipid regulation and platelet inhibition) in the medical management of stable coronary artery disease.

Fiolet ATL ，Nidorf SM ，Mosterd A ，Cornel JH ... -  《-》