Exploration of the regional effects of colchicine in the LoDoCo2 trial

Charley A Budgeon; Stefan Nidorf; Arend Mosterd; Aernoud Fiolet; John Eikelboom; Sean O'Halloran; David Joyce; Astrid Schut; Jan Tijssen; Jan H Cornel; Kevin Murray; Peter Thompson

doi:10.1016/j.ahj.2024.09.006

Exploration of the regional effects of colchicine in the LoDoCo2 trial

Am Heart J. 2024 Sep 21:278:186-194. doi: 10.1016/j.ahj.2024.09.006. Online ahead of print.

Authors

Charley A Budgeon¹, Stefan Nidorf², Arend Mosterd³, Aernoud Fiolet⁴, John Eikelboom⁵, Sean O'Halloran⁶, David Joyce⁶, Astrid Schut⁷, Jan Tijssen⁸, Jan H Cornel⁹, Kevin Murray¹⁰, Peter Thompson¹¹

Affiliations

¹ Cardiovascular Epidemiology Research Centre, University of Western Australia, Perth, Australia; School of Population and Global Health, University of Western Australia, Perth, Australia. Electronic address: [email protected].
² Heart and Vascular Research Institute, Harry Perkins Institute of Medical Research, Perth, Australia.
³ Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands; Department of Cardiology, Meander Medical Centre, Amersfoort, The Netherlands.
⁴ Department of Cardiology, Meander Medical Centre, Amersfoort, The Netherlands; Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁵ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶ Clinical Pharmacology and Toxicology, PathWest Laboratory Medicine and Sir Charles Gairdner Hospital, Perth, Australia; School of Biomedical Sciences, University of Western Australia, Perth, Australia.
⁷ Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands.
⁸ Department of Cardiology, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
⁹ Dutch Network for Cardiovascular Research (WCN), Utrecht, The Netherlands; Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Cardiology, Northwest Clinics, Alkmaar, The Netherlands.
¹⁰ Cardiovascular Epidemiology Research Centre, University of Western Australia, Perth, Australia; School of Population and Global Health, University of Western Australia, Perth, Australia.
¹¹ Heart and Vascular Research Institute, Harry Perkins Institute of Medical Research, Perth, Australia; Medical School, University of Western Australia, Perth, Australia.

PMID: 39313104
DOI: 10.1016/j.ahj.2024.09.006

Abstract

Background: The Low Dose Colchicine 2 (LoDoCo2) trial randomized 5,522 patients with chronic coronary disease to colchicine 0.5mg daily or placebo in a 1:1 ratio and demonstrated the cardiovascular benefits of colchicine. In the trial, which was conducted in Australia and The Netherlands, a prespecified subgroup analysis suggested a difference in magnitude of treatment effect of colchicine by region (Australia: HR 0.51; 95% CI 0.39-0.67 vs The Netherlands: HR 0.92; 95% CI 0.71-1.20). The aim of this study was to explore possible explanations for the apparent difference in magnitude of treatment effect of colchicine by region in the LoDoCo2 trial.

Methods: The analysis explored potential determinants of variations in the magnitude of effectiveness of colchicine treatment across the regions. This included investigating differences in investigational product, clinical characteristics, concurrent medical therapies and the duration of follow-up using a range of statistical techniques, including sub-group, landmark and effect modification analyses.

Results: No differences were found in the colchicine product used in each region. Despite minor differences observed in baseline clinical characteristics and concomitant therapies, the effect modifier analyses demonstrated that these factors did not explain the difference in magnitude of treatment effect of colchicine by region. Randomization in Australia began more than 2 years before The Netherlands, with shorter duration of follow-up in The Netherlands compared to Australia. In a landmark analysis, over the period when more than 90% of patients in each region had been followed, the effects of colchicine were similar (Australia hazard ratio [HR] 0.58; 95% CI 0.34-0.97 vs The Netherlands HR 0.67; 95% CI 0.47-0.96).

Conclusions: After examining several plausible explanations for the observed differences in the magnitude of treatment effect of colchicine between regions in the LoDoCo2 trial could be due to the differences in duration of follow-up but a substantial portion of the differences remain unexplained.

Clinical trial registration: https://www.anzctr.org.au/ACTRN12614000093684.