Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials

Aernoud T L Fiolet^{1

2}, Michiel H F Poorthuis³, Tjerk S J Opstal⁴, Pierre Amarenco^{5

6}, Kevin Emery Boczar⁷, Ian Buysschaert⁸, Charley Budgeon⁹, Noel C Chan¹⁰, Jan H Cornel^{2

11

12}, Sanjit S Jolly¹³, Jamie Layland^{14

15}, Robin Lemmens^{16

17}, Nathan Mewton¹⁸, Stefan M Nidorf¹⁹, Domingo A Pascual-Figal^{20

21}, Christopher Price²², Binita Shah^{23

24}, Jean-Claude Tardif²⁵, Peter L Thompson^{9

19

26

27}, Jan G P Tijssen²⁸, Georgios Tsivgoulis²⁹, Cathal Walsh³⁰, Yongjun Wang³¹, Christian Weimar³², John W Eikelboom¹³, Arend Mosterd^{2

33}, Peter J Kelly^{34

35}; Colchicine Cardiovascular Trialists Collaboration

Affiliations

¹ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
² Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands.
³ Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Department of Cardiology, University Medical Center Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Neurology, Bichat University Hospital, Paris, France.
⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁷ Department of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
⁸ Department of Cardiology, Sint-Jan Hospital, Brugge, Belgium.
⁹ Cardiovascular Epidemiology Research Centre, School of Population and Global Health, University of Western Australia, Perth, Australia.
¹⁰ Department of Haematology and Thromboembolism, McMaster University, Hamilton, ON, Canada.
¹¹ Department of Cardiology, Northwest Clinics, Alkmaar, The Netherlands.
¹² Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹³ Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁴ Cardiology, Department of Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Monash University, VIC, Australia.
¹⁵ Peninsula Clinical School, Central Clinical School, Monash University, VIC, Australia.
¹⁶ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹⁷ Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
¹⁸ Department of Cardiology, Institut de Cardiologie des Hospices Civils de Lyon, Lyon, France.
¹⁹ Harry Perkins Institute of Medical Research, Perth, Australia.
²⁰ Department of Cardiology, Hospital Virgen de la Arrixaca, University of Murcia, Murcia, Spain.
²¹ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
²² Stroke Research Group, Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, UK.
²³ VA New York Harbor Healthcare System, New York, USA.
²⁴ Leon H Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY, USA.
²⁵ Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
²⁶ Sir Charles Gairdner Hospital, Perth, Australia.
²⁷ Heart and Vascular Research Institute of Western Australia, Australia.
²⁸ Department of Cardiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
²⁹ Second Department of Neurology, National & Kapodistrian University of Athens, "Attikon" University Hospital, Athens, Greece.
³⁰ TCD Biostatistics Unit, Discipline of Public Health and Primary Care, School of Medicine, Trinity College Dublin, Ireland.
³¹ Department of Neurology, Beijing Tiantan Hospital, Beijing, China.
³² Institute for Medical Informatics, Biometry and Epidemiology, University Hospital, University Duisburg-Essen, Germany.
³³ Department of Cardiology, Meander Medical Centre, Amersfoort, The Netherlands.
³⁴ Mater Misericordiae University Hospital and School of Medicine, University College Dublin, Ireland.
³⁵ Health Research Board Stroke Clinical Trials Network Dublin Ireland, Ireland.

PMID: 39431112
PMCID: PMC11490869
DOI: 10.1016/j.eclinm.2024.102835

Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials

Aernoud T L Fiolet et al. EClinicalMedicine. 2024.

. 2024 Oct 8:76:102835.

doi: 10.1016/j.eclinm.2024.102835. eCollection 2024 Oct.

Authors

Affiliations

¹ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
² Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands.
³ Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Department of Cardiology, University Medical Center Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Neurology, Bichat University Hospital, Paris, France.
⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁷ Department of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
⁸ Department of Cardiology, Sint-Jan Hospital, Brugge, Belgium.
⁹ Cardiovascular Epidemiology Research Centre, School of Population and Global Health, University of Western Australia, Perth, Australia.
¹⁰ Department of Haematology and Thromboembolism, McMaster University, Hamilton, ON, Canada.
¹¹ Department of Cardiology, Northwest Clinics, Alkmaar, The Netherlands.
¹² Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹³ Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁴ Cardiology, Department of Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Monash University, VIC, Australia.
¹⁵ Peninsula Clinical School, Central Clinical School, Monash University, VIC, Australia.
¹⁶ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
¹⁷ Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.
¹⁸ Department of Cardiology, Institut de Cardiologie des Hospices Civils de Lyon, Lyon, France.
¹⁹ Harry Perkins Institute of Medical Research, Perth, Australia.
²⁰ Department of Cardiology, Hospital Virgen de la Arrixaca, University of Murcia, Murcia, Spain.
²¹ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
²² Stroke Research Group, Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, UK.
²³ VA New York Harbor Healthcare System, New York, USA.
²⁴ Leon H Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY, USA.
²⁵ Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
²⁶ Sir Charles Gairdner Hospital, Perth, Australia.
²⁷ Heart and Vascular Research Institute of Western Australia, Australia.
²⁸ Department of Cardiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
²⁹ Second Department of Neurology, National & Kapodistrian University of Athens, "Attikon" University Hospital, Athens, Greece.
³⁰ TCD Biostatistics Unit, Discipline of Public Health and Primary Care, School of Medicine, Trinity College Dublin, Ireland.
³¹ Department of Neurology, Beijing Tiantan Hospital, Beijing, China.
³² Institute for Medical Informatics, Biometry and Epidemiology, University Hospital, University Duisburg-Essen, Germany.
³³ Department of Cardiology, Meander Medical Centre, Amersfoort, The Netherlands.
³⁴ Mater Misericordiae University Hospital and School of Medicine, University College Dublin, Ireland.
³⁵ Health Research Board Stroke Clinical Trials Network Dublin Ireland, Ireland.

PMID: 39431112
PMCID: PMC11490869
DOI: 10.1016/j.eclinm.2024.102835

Abstract

Background: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes.

Methods: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320.

Findings: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58-0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65-0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76-1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82-1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91-1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89-1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65-1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98-1.64]).

Interpretation: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death.

Funding: There was no funding source for this study.

Keywords: Colchicine; MACE; Meta-analysis; Safety; Stroke.

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Conflict of interest statement

Funding: Michiel Poorthuis reports support for travel to Dublin from Dr. Jan Meerwaldt stichting. Pierre Amarenco reports grants from the French Government for Reducing Inflammation in Ischemic Stroke with Colchicine (RIISC); Ticagrelor in High-risk patients-Extended Treatment in Ischemic Stroke (THETIS); Treat Stroke to Target 40; Treat Stroke to Target Cholesterol and Colchicine in Cerebral Small Vessel Disease (TST 3C SVD), from Pfizer for Treat Stroke to Target Trial, consulties fees from Neuraltide for TIDE-IN Trial, honoraria from Novartis, Sanofi, and Viatris, support from Novartis, Participation on a Data Safety Monitoring Board or Advisory Board for Cell Prothera, and from AstraZeneca for Ticagrelor supply (Ticagrelor in High-risk patients-Extended Treatment in Ischemic Stroke (THETIS)). Kevin Boczar reports grants from Novartis paid to his institution. Noel Chan is supported by a Heart and Stroke of Canada New Investigator Award, and received a project grant from the Canadian Institutes of Health Research for a randomized trial investigating the risk-benefit of colchicine in peripheral artery disease. Sanjit Jolly reports honoraria from Pharmascience. Binita Shah reports grants from NIH NHLBI and VA Office of Research and Development paid to her institution, support for attending meetings and/or travel from NovoNordisk as US national leader and co-chair of the global expert panel for the ARTEMIS trial, leadership or fiduciary role for the Society of Cardiovascular Angiography and Interventions (Board of Trustees) and the American Heart Association (Associate Editor for Circulation Cardiovascular Intervention), and from Philips Volcano (advisory board). Jean-Claude Tardif reports grants from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Merck, Novartis, Pfizer paid tot his institution, consulting fees from DalCor Pharmaceuticals paid to him, honoraria for lectures from HLS Pharmaceuticals, Pendopharm, Pfizer paid to him, patent for Pharmacogenomics-guided CETP inhibition (waived his right in this patent), patent for Use of colchicine after myocardial infarction (his institution submitted a patent on this topic and he was an author, but waived his rights in this patent and did not stand to gain financially), and a minor equity interest in DalCor Pharmaceuticals. John Eikelboom reports grants from Anthos, Bayer, BI, BMS, Daiichi-Sankyo, Ionis, Janssen, Merck, Pfizer, USV; consulting fees from Anthos, Bayer, BI, BMS, Daiichi-Sankyo, Ionis, Janssen, Merck, Pfizer, USV.

Figures

**Fig. 1**
**Flowchart of included studies**.

**Fig. 2**
**a: Po**oled estimate of colchicine treatment for prevention of ischaemic stroke. b: Pooled estimate of colchicine therapy for prevention of ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death (MACE). c: Pooled estimate of colchicine therapy for prevention of ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death (MACE) in patients with prior stroke or TIA.

**Fig. 3**
**a: Efficacy of colchicine for prevention of ischaemic stroke in key clinical subgroups. b: Efficacy of colchicine for prevention of MACE in key clinical subgroups**.

**Fig. 4**
Mortality (all-cause death, cardiovascular death, and non-cardiovascular death). a: Pooled estimate of colchicine treatment for prevention of all-cause death. b: Pooled estimate of colchicine treatment for prevention of cardiovascular death. c: Pooled estimate of colchicine treatment for prevention of non-cardiovascular death. CONVINCE included 51 cardiovascular deaths, among which are 18 late deaths (10 in the colchicine arm and 8 in the control arm) beyond 30 days of the qualifying event. Deftereos et al., 2013 reported no non-cardiovascular deaths in both treatment and control arm and was therefore omitted in this meta-analysis.

See this image and copyright information in PMC

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Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials

Affiliations

Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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