Low-dose colchicine for atherosclerosis: long-term safety.

Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical practice. In this State-of-the-Art Review, data were collated from contemporary systemic reviews of case reports, drug registries, and placebo-controlled trials that assessed specific issues of safety related to the continuous use of colchicine in a range of clinical settings to inform physicians, pharmacists, and patients of the absolute risks of continuous use of low-dose colchicine, including among individuals taking statin therapy. Based upon these collective data, it is concluded that aside mild diarrhoea on initiation of colchicine that typically subsides in the vast majority of patients within a week of therapy, continuous use of low-dose colchicine is well tolerated and very safe. It does not affect renal, liver, or cognitive function, has no adverse effects on bleeding, wound healing, fertility, or pregnancy, and does not increase risks of cancer, serious infection, or cause-specific mortality. When appropriately prescribed to patients without significant renal or hepatic impairment, reports of myelosuppression, myotoxicity, and serious drug-drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy. Physicians, pharmacists, and patients can be reassured that in the absence of significant renal or hepatic impairment continuous use of low-dose colchicine can be used safely in patients with atherosclerosis for the purpose of reducing cardiovascular risk.

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

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Viewing atherosclerosis through a crystal lens: How the evolving structure of cholesterol crystals in atherosclerotic plaque alters its stability.

Reducing the residual risk of cardiovascular (CV) events in patients with atherosclerosis continues to be a challenge. Thus, understanding how cholesterol spontaneously self assembles into metastable structures that evolve into flat plate cholesterol crystals (CCs) in atherosclerotic plaque, and why they fundamentally change the nature of the disease provides a paradigm for the development of additional therapies. Specifically, flat plate CCs that form within lysosomes of macrophages may become large enough to disrupt lysosomal membranes leading to the release of cathepsin B and CCs fragments directly into the cytosol. In the cytosol, the surface of flat plate CCs can be recognized by complosome that together with cathepsin B may trigger pyrin domain-containing inflammasome. In addition, flat plate CCs in the cytosol may trigger caspase 8 initiating apoptosis. In the interstitial space, the surface of flat plate CCs can be recognized by complement and receptors on proinflammatory cells, and larger fragments can induce "frustrated phagocytosis" that together perpetuate inflammatory injury. In addition, rapid transition of metastable CCs into large flat plate CCs within lipid rich plaques can lead to traumatic injury by expansion of the plaque's necrotic core causing plaque disruption or rupture that may precipitate further inflammation. Other crystalloids in plaque including monosodium urate and calcium phosphate crystals can augment these processes. Thus, therapies that further limit the deposition of cholesterol in the vascular bed, slow the formation of flat plate CCs and inhibit crystal-induced inflammation may lead to further reduce CV risk in patients with established CV disease.

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

PURPOSE: 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. METHODS: 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. FINDINGS: 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 1ß 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. IMPLICATION: 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.