Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis

Hemkens, Lars G; Ewald, Hannah; Gloy, Viktoria; Arpagaus, Armon; Olu, Kelechi K; Nidorf, Mark; Glinz, Dominik; Nordmann, Alain; Briel, Matthias

doi:10.1136/heartjnl-2015-308542

Cited by 50 publications

(26 citation statements)

References 27 publications

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“…No statistically significant differences in adverse events between colchicine and placebo patients were detected, however, there was a trend toward an increase in noncardiovascular mortality (pooled HR: 1.38; 95% CI: 0.99-1.93) [17]. This trend is inconsistent with the results of colchicine safety studies in patients with gout, familial Mediterranean fever and pericarditis [18,19] and was likely skewed by a chance finding in a few studies. Given the trend toward a decrease in cardiovascular mortality with colchicine (pooled HR: 0.82; 95% CI: 0.46-1.18), the incidence of all-cause mortality, however, did not differ between treatment groups in pooled analyses [17].…”

mentioning

confidence: 81%

Lessons Learned From Large Cardiovascular Outcome Trials Targeting Inflammation in Cardiovascular Disease (CANTOS, CIRT, Colcot and LoDoCo2)

Samuel

Tardif

2021

Future Cardiol.

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Lipid-lowering therapies, blood pressure control, glucose control and antithrombotic therapies constitute the mainstay therapeutic strategy for patients with cardiovascular disease (CVD). Although these therapies have been effective in reducing the incidence and burden of CVD, it still remains the leading cause of morbidity and mortality worldwide [1][2][3]. Over the past two decades, inflammation has been identified as an additional pathway for the initiation, progression and complication of CVD. Inflammation has been shown to have a pathologic role in atherosclerosis progression, plaque destabilization and rupture, and as a response to cardiomyocyte death after myocardial infarction (MI) [1,2]. Optical coherence tomography and inflammatory biomarker studies suggest that more than 50% of cardiovascular events may be due, in part, to inflammation [1,2,[4][5][6][7]. Further, elevated levels of the inflammatory biomarker high sensitivity C-reactive protein (hsCRP) has been shown to be associated with an increased relative risk of coronary heart disease (37%), ischemic stroke (27%) and vascular mortality (55%) [8]. Thus, identifying an efficacious pharmacological agent to inhibit or reduce inflammation in CVD has become the focus of several recent large Cardiovascular Outcome Trials (CVOTs).CANTOS was the first large CVOT to test the hypothesis that inhibition of inflammation may translate into a reduction in cardiovascular events [9]. In this randomized, double-blind placebo-controlled trial, 10,061 patients with a previous MI and hsCRP ≥2 mg/l were randomized to canakinumab (injectable doses of 50, 150 or 300 mg every 3 months) or placebo [9]. Canakinumab is a monoclonal antibody which inhibits IL-1β and subsequently reduces IL-6 and hsCRP [9]. Over a median follow-up of 3.7 years, patients randomized to canakinumab 150 and 300 mg had statistically significant reductions in the incidence of the primary composite end point of MI, stroke and cardiovascular death compared with placebo ([150 mg HR: 0.85; 95% CI: 0.74-0.98]; 300 mg HR: 0.86 [95% CI: 0.75-0.99]) [9]. Patients randomized to the 50 mg dose of canakinumab demonstrated a trend toward a reduction in the primary end point (50 mg HR: 0.93 [95% CI: 0.90-1.07]) [9]. Further, patients in the canakinumab arms had 26-41% relative reductions in hsCRP levels compared with patients in the placebo arm [9]. Thus, patients with the lowest tertile of hsCRP at the end of the trial had the greatest reduction in the incidence of the primary end point (HR: 0.73 [95% CI: 0.62-0.85]) [9]. The association between IL-6 and the primary end point followed a similar trend [9]. Although canakinumab was ultimately not approved for secondary cardiovascular prevention, CANTOS demonstrated that interference in the inflammatory pathway involving the NLRP3 inflammasome and IL-1β reduces cardiovascular events [2,10].In contrast, CIRT investigated the anti-inflammatory effects of low-dose methotrexate on cardiovascular outcomes among 4786 patients with a previous MI or multivessel disease wi...

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confidence: 81%

Lessons Learned From Large Cardiovascular Outcome Trials Targeting Inflammation in Cardiovascular Disease (CANTOS, CIRT, Colcot and LoDoCo2)

Samuel

Tardif

2021

Future Cardiol.

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“…In patients with coronary artery disease, low dose colchicine effectively reduces hs-CRP independent of atorvastatin and aspirin use [93]. A Cochrane review analyzing 4992 patients in 39 trials showed that cardiovascular death and myocardial infarction may be reduced at the expense of increased gastrointestinal intolerance [94].…”

Section: Colchicinementioning

confidence: 99%

Immunotherapy for the prevention of atherosclerotic cardiovascular disease: Promise and possibilities

et al. 2018

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Cardiovascular disease remains the leading cause of death worldwide with coronary atherosclerotic heart disease being the largest contributor. The mechanisms behind the presence and progression of atherosclerosis remain an area of intense scientific focus. Immune dysregulation and inflammation are key contributors to the development of an atherosclerotic plaque and its progression to acute coronary syndromes. Increased circulating levels of biomarkers of systemic inflammation including hsCRP are correlated with a higher cardiovascular risk. Targeting specific inflammatory pathways implicated in atherosclerotic plaque formation is an exciting area of ongoing research. Target specific therapies directed at pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, and CCL2 have demonstrated slowing in the progression of atherosclerosis in animal models and improved cardiovascular outcomes in human subjects. Most notably, treatment with the monoclonal antibody canakinumab, which directly targets and neutralizes IL-1β, was recently shown to be associated with reduced risk of adverse cardiovascular events compared to placebo in a randomized, placebo-controlled trial. Several other therapies including colchicine, methotrexate and leukotriene inhibitors demonstrate the potential for lowering cardiovascular risk through immunomodulation, though further studies are needed. Understanding the role of inflammation in atherosclerosis and the development of targeted immunotherapies continues to be an evolving area of research that is rapidly becoming clinically relevant for the 21st century cardiac patient.

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“…From this time onward, colchicine-despite its narrow therapeutic-toxicity window and the most common complaint of gastrointestinal upset-was increasingly administered orally for therapy of cardiovascular diseases (Deftereos et al, 2013;Nidorf et al, 2013;Vogel and Forrester, 2013;Campbell et al, 2015;Hemkens et al, 2016;Lee et al, 2016;Alsarah et al, 2017;Antonopoulos et al, 2017;Lennerz et al, 2017;Salih et al, 2017;Vaidya et al, 2017). It has also been demonstrated that excess MT density is important for myocardial contractile dysfunction, suggesting that this may be one mechanism contributing to the development of heart failure due to cardiac hypertrophy (Cheng et al, 2010(Cheng et al, , 2012.…”

Section: Cells (Figuresmentioning

confidence: 99%

Colchicine, a microtubule‐disassembling drug, in the therapy of cardiovascular diseases

Chaldakov

2018

Cell Biology International

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Colchicum autumnale, from which colchicine has been isolated more than 100 years ago, has been used as a treatment for pain and swelling for thousands of years. It is one of the few drugs known from that time period whose use has survived to modernity. Over the past decades, advances in the knowledge of (i) cytoskeletal microtubules (МТ), and (ii) anti-inflammatory and anti-fibrotic effects of colchicine, a classical MT-disassembling (tubulin-targeting) agent, have led to potential new uses for this very old drug extended beyond acute gouty arthritis and familial Mediterranean fever. Here, in brief, I present the Bulgarian contribution to possible potential of colchicine in the therapy of cardiovascular diseases that has emerged in the early 1970s in the Laboratory of Electron Microscopy, Medical Institute, Varna, Bulgaria, studying the secretory function of vascular smooth muscle cells. From this time onward, low-dose colchicine (0.5-1.0 mg/daily) was increasingly administered orally for therapy of cardiovascular diseases such as acute coronary syndromes, postoperative atrial fibrillation (in cardiac surgery), pericarditis, cardiac hypertrophy-associated heart failure, restenosis after angioplasty, and systemic necrotizing vasculitis. Thus, colchicine might be a new tool in the present therapeutic armamentarium for cardiovascular diseases. It is simply an example of MT-disassembling drugs. Further studies will definitely be required before gaining real confidence in this kind of antitubulin pharmacology and therapy. This may lead to developing new and more specific antitubulins for cardiovascular diseases.

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Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis

Cited by 50 publications

References 27 publications

Lessons Learned From Large Cardiovascular Outcome Trials Targeting Inflammation in Cardiovascular Disease (CANTOS, CIRT, Colcot and LoDoCo2)

Lessons Learned From Large Cardiovascular Outcome Trials Targeting Inflammation in Cardiovascular Disease (CANTOS, CIRT, Colcot and LoDoCo2)

Immunotherapy for the prevention of atherosclerotic cardiovascular disease: Promise and possibilities

Colchicine, a microtubule‐disassembling drug, in the therapy of cardiovascular diseases

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