Colchicine as a Novel Therapy for Suppressing Chemokine Production in Patients With an Acute Coronary Syndrome: A Pilot Study

Tucker, Bradley; Kurup, Rahul; Barraclough, J.; Henriquez, Rodney; Cartland, Siân P.; Arnott, Clare; Misra, Ashish; Martínez, Gonzalo; Kavurma, Mary M.; Patel, Sanjay

doi:10.1016/j.clinthera.2019.07.015

Cited by 38 publications

(30 citation statements)

References 28 publications

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“…In support of this, we previously reported a substantially higher release of neutrophil-derived microparticles and MPO into the coronary circulation after PCI of unstable lesions (versus stable lesions) 19 . Results of the present study corroborate these findings; PCI results in a marked release of NETs and neutrophils from ACS Colchicine is an inexpensive and widely available anti-inflammatory medication with an increasing evidence base demonstrating its efficacy in the secondary prevention of cardiovascular disease 15,16,[30][31][32] . A small placebo controlled randomised trial showed lower cardiac enzyme release and reduced infarct size in colchicine treated STEMI patients versus controls 33 .…”

Section: Discussionsupporting

confidence: 87%

Colchicine inhibits neutrophil extracellular trap formation in acute coronary syndrome patients after percutaneous coronary intervention

Vaidya

Tucker

Kurup

et al. 2020

Preprint

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Objective: Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with peri-procedural myocardial infarction, as a result of microvascular obstruction via pro-inflammatory and pro-thrombotic pathways. Colchicine is a potent, well-established anti-inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS has not been explored. Approach and Results: 60 patients (40 ACS; 20 stable angina pectoris [SAP]) were prospectively recruited and allocated to colchicine or no treatment. Within 24 h of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 ACS patients post-PCI and 4 healthy controls were treated in vitro with colchicine (25 nM) and stimulated with either ionomycin (5 µM) or phorbol 12-myristate 13-acetate (PMA, 50 nM). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst and anti-alpha tubulin. Baseline characteristics were similar across both treatment and control arms. ACS patients had higher NET release versus SAP patients (p<0.001), which was reduced with colchicine treatment (AUC: 0.58 vs. 4.29; p<0.001). In vitro, colchicine suppressed spontaneous (p=0.004), PMA-induced (p=0.03) and ionomycin-induced (p=0.02) NET formation in neutrophils isolated from ACS patients post-PCI, but not healthy controls. Tubulin organisation was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions: Colchicine suppresses NET formation in ACS patients post-PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomised trials powered for clinical endpoints.

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Section: Discussionsupporting

confidence: 87%

Colchicine inhibits neutrophil extracellular trap formation in acute coronary syndrome patients after percutaneous coronary intervention

Vaidya

Tucker

Kurup

et al. 2020

Preprint

Self Cite

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“…Tucker et al 41 conducted an open-label study to examine whether colchicine reduces transcoronary gradients of chemokine ligand 2 (CCL2), CCL5, and C-X3-C motif chemokine ligand 1 (CX3CL1), which are known to induce inflammatory cell migration. An additional objective was to determine whether colchicine affects migration of monocytes from healthy patients.…”

Section: Resultsmentioning

confidence: 99%

Colchicine in Acute Coronary Syndrome: A Systematic Review

2020

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Objective: The purpose of this review is to evaluate the efficacy and safety of colchicine after acute coronary syndrome (ACS). Data Sources: English-language searches were made of MEDLINE and EMBASE from database inception through mid-June 2020. Study Selection and Data Extraction: Randomized trials characterizing the effects of colchicine in ACS were considered. Of 627 title and abstracts identified, nine trials were included. Two reviewers extracted data and rated study quality. Data Synthesis: Four studies showed colchicine did not attenuate C-reactive protein production. Colchicine did modulate the NOD-like receptor family pyrin domain containing 3 inflammasome in 3 studies and reduced production of chemokine ligand 2 (CCL2), CCL5, and C-X3-C motif chemokine ligand 1 in 1 study. Major adverse cardiovascular events (MACE) were not significantly different at 30 days in 3 studies, administered as 1.8 mg preprocedurally or scheduled 1 mg daily. One study found a significant reduction in MACE with colchicine 0.5 mg daily over median 22.6 months (hazard ratio = 0.77; 95% CI = 0.61-0.96). Colchicine is associated with increased gastrointestinal adverse events but was generally well tolerated. Relevance to Patient Care and Clinical Practice: Colchicine is likely to reduce MACE in an ACS population if administered for greater than 30 days but does not improve MACE when administered only preprocedurally. Conclusions: Adjunctive colchicine 0.5 mg daily for greater than 30 days is reasonable for an ACS population on guideline-directed medical therapy treated with PCI. Additional studies are needed to validate and determine the durability of these benefits.

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“…In a double-blind placebo-controlled trial of patients with CAD short-term colchicine therapy significantly reduced systemic inflammation and improved endothelial function [ 43 ]. In another study, patients with acute coronary syndromes (ACS) planned for PCI were randomized to treatment with add-on colchicine ( n = 12) or just standard treatment ( n = 13); those on colchicine had lower levels of chemokines, suggesting a reduction in local inflammatory activity at the site of pathology [ 44 ]. In the low dose colchicine for myocardial infarction (LoDoCo-MI) study, 237 patients with acute myocardial infarction were randomized to receive colchicine or placebo in addition to standard care, and C-reactive protein (CRP) levels were compared at 1 month.…”

Section: Colchicinementioning

confidence: 99%

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates

2020

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Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.

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Colchicine as a Novel Therapy for Suppressing Chemokine Production in Patients With an Acute Coronary Syndrome: A Pilot Study

Cited by 38 publications

References 28 publications

Colchicine inhibits neutrophil extracellular trap formation in acute coronary syndrome patients after percutaneous coronary intervention

Colchicine inhibits neutrophil extracellular trap formation in acute coronary syndrome patients after percutaneous coronary intervention

Colchicine in Acute Coronary Syndrome: A Systematic Review

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates

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