Colchicine in Patients With Acute Coronary Syndrome: Two-Year Follow-Up of the Australian COPS Randomized Clinical Trial

HomeCirculationVol. 144, No. 19Colchicine in Patients With Acute Coronary Syndrome: Two-Year Follow-Up of the Australian COPS Randomized Clinical Trial Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBColchicine in Patients With Acute Coronary Syndrome: Two-Year Follow-Up of the Australian COPS Randomized Clinical Trial David C. Tong, PhD, Jason E. Bloom, MBBS, Stephen Quinn, PhD, Arthur Nasis, PhD, Chin Hiew, MBBS, Philip Roberts-Thomson, PhD, Heath Adams, MBBS, Rumes Sriamareswaran, MBBS, Nay M. Htun, PhD, William Wilson, MBBS, Dion Stub, PhD, William van Gaal, MD, Laurie Howes, PhD, Allysha Yeap, MBBS, Brian Yip, MBBS, Sam Wu, MBBS, Padeepa Perera, MBBS, Nicholas Collins, MD, Andy Yong, PhD, Ravinay Bhindi, PhD, Robert Whitbourn, MBBS, Astin Lee, MBBS, Manuja Premaratne, MBBS, Kaleab Asrress, PhD, Melanie Freeman, MBBS, John Amerena, MBBS and Jamie Layland, PhD David C. TongDavid C. Tong https://orcid.org/0000-0002-7579-7072 St. Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia (D.C.T., R.W., J.L.). Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Jason E. BloomJason E. Bloom https://orcid.org/0000-0001-8838-0332 Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (J.E.B., D.S.). The Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.E.B.). Search for more papers by this author , Stephen QuinnStephen Quinn Swinburne University of Technology, Department of Health Science and Biostatistics, Hawthorn, Victoria, Australia (S.Q.). Search for more papers by this author , Arthur NasisArthur Nasis MonashHeart, Monash Health, Clayton, Victoria, Australia (A.N.). Search for more papers by this author , Chin HiewChin Hiew Barwon Health – University Hospital Geelong, Victoria, Australia (C.H., J.A.). Search for more papers by this author , Philip Roberts-ThomsonPhilip Roberts-Thomson https://orcid.org/0000-0002-5777-6331 Royal Hobart Hospital, Hobart, Tasmania, Australia (P.R.-T., H.A.). Search for more papers by this author , Heath AdamsHeath Adams Royal Hobart Hospital, Hobart, Tasmania, Australia (P.R.-T., H.A.). Search for more papers by this author , Rumes SriamareswaranRumes Sriamareswaran Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Nay M. HtunNay M. Htun Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , William WilsonWilliam Wilson Royal Melbourne Hospital, Parkville, Victoria, Australia (W.W.). Search for more papers by this author , Dion StubDion Stub https://orcid.org/0000-0001-8686-2709 Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia (J.E.B., D.S.). Western Health, St Albans, Victoria, Australia (D.S.). Search for more papers by this author , William van GaalWilliam van Gaal Northern Health, Epping, Victoria, Australia (W.v.G.). Search for more papers by this author , Laurie HowesLaurie Howes Gold Coast University Hospital, Southport, Queensland, Australia (L.H.). Search for more papers by this author , Allysha YeapAllysha Yeap Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Brian YipBrian Yip Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Sam WuSam Wu Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Padeepa PereraPadeepa Perera https://orcid.org/0000-0002-1348-5911 Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Nicholas CollinsNicholas Collins John Hunter Hospital, New Lambton Heights, New South Wales, Australia (N.C.). Search for more papers by this author , Andy YongAndy Yong https://orcid.org/0000-0002-6268-4300 Concord Repatriation General Hospital, New South Wales, Australia (A. Yong). Search for more papers by this author , Ravinay BhindiRavinay Bhindi Royal North Shore Hospital, St Leonards, New South Wales, Australia (R.B.). Search for more papers by this author , Robert WhitbournRobert Whitbourn St. Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia (D.C.T., R.W., J.L.). Search for more papers by this author , Astin LeeAstin Lee Wollongong Hospital, New South Wales, Australia (A.L.). Search for more papers by this author , Manuja PremaratneManuja Premaratne https://orcid.org/0000-0003-1561-7612 Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Search for more papers by this author , Kaleab AsrressKaleab Asrress Bankstown-Lidcombe Hospital, New South Wales, Australia (K.A.). Search for more papers by this author , Melanie FreemanMelanie Freeman Search for more papers by this author , John AmerenaJohn Amerena Barwon Health – University Hospital Geelong, Victoria, Australia (C.H., J.A.). Search for more papers by this author and Jamie LaylandJamie Layland Correspondence to: Jamie Layland, PhD, Cardiology, Department of Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Monash University, PO Box 52, Frankston 3199,s Victoria, Australia. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2002-5785 St. Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia (D.C.T., R.W., J.L.). Cardiology, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia (D.C.T., J.E.B., R.S., N.M.H., A. Yeap, B.Y., S.W., P.P., M.P., J.L.). Peninsula Clinical School, Central Clinical School, Monash University, Victoria, Australia (J.L.). Search for more papers by this author Originally published8 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.054610Circulation. 2021;144:1584–1586Colchicine has recently emerged as a novel therapeutic candidate for cardiovascular disease because of its potent anti-inflammatory properties that have been shown to be implicated in atherosclerotic plaque formation and acute coronary syndrome events. Recent clinical trial data have investigated the use of colchicine among patients with cardiovascular disease. The COLCOT (Colchicine Cardiovascular Outcomes Trial) and the LoDoCo 2 (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease) trials have demonstrated a significant reduction in adverse cardiovascular events in patients with acute coronary syndrome (ACS) and stable coronary artery disease who received colchicine 0.5 mg daily in addition to standard secondary prevention therapies compared with standard medical therapy alone.1,2 Although these data have demonstrated reduced adverse cardiovascular events in those treated with colchicine, there has been a concerning signal suggesting a potential increase in noncardiovascular death in those receiving colchicine in clinical studies.We recently presented the 1-year outcomes of the Australian COPS trial (Colchicine in Patients with Acute Coronary Syndromes), a multicenter, randomized, double-blind, placebo-controlled trial in patients presenting with ACS who were randomly assigned to colchicine (0.5 mg oral colchicine twice daily for the first month, followed by 0.5 mg daily for 11 months) or placebo commenced during their index admission after coronary angiography.3 There was no difference in the primary outcome: a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke.3 However, at 1 year, there was a higher rate of total death and, in particular, noncardiovascular deaths in those receiving colchicine. This noncardiovascular death signal was also demonstrated in the larger LoDoCo 2 trial. We present a prespecified 2-year analysis of the COPS cohort to assess the enduring legacy effect of colchicine, after cessation at 12 months, following an index ACS event. It is important to note, in LoDoCo2 and COLCOT, colchicine was continued for the duration of the trials (typically >12 months).A total of 795 patients were randomly assigned between December 2015 and September 2018. There were 396 patients assigned to colchicine and 399 in the placebo group.3 Over a period of 24 months from randomization, complete follow-up data were available for 765 (96%) study participants. In accordance with the trial protocol, blinding of investigators was maintained for the 24-month follow-up with all events adjudicated by a clinical events committee who were unaware of treatment allocation. All patients provided informed consent, and the trial was approved by St Vincent’s Hospital Ethics Committee. We found that there was a significant reduction in the primary end point in the colchicine group compared with placebo (32 [8.1%] versus 54 [13.5%]; P=0.02, log-rank test; Figure) over a 24-month period. There was a total of 13 deaths over the 2-year window (9 versus 4; hazard ratio [HR], 2.28 [95% CI, 0.7–7.4]; P=0.17), with noncardiovascular death numerically higher among those receiving colchicine (5 versus 2; HR, 2.54 [95% CI, 0.49–13]; P=0.27). The 2 additional noncardiovascular deaths occurring between year 1 and year 2 were attributable to acute myeloid leukemia and gastrointestinal malignancy. With respect to the other components of the primary end point, there were nonsignificant numeric differences in favor of colchicine (ACS 17 versus 27; HR, 0.64 [95% CI 0.34–1.21]; stroke 3 versus 7; HR, 0.43 [95%, 0.11–1.67]; and a significant reduction in urgent revascularization (3 versus 16; HR, 0.19 [95% CI, 0.05–0.66]; P=0.009). A landmark analysis was performed at 12-months (Figure), and this demonstrated that the effect of colchicine over this time frame was not significant (P=0.109). Moreover, the curves appeared to converge at the 730-day mark, and thus the 5-year follow-up data exploring this relationship will be of interest.Download figureDownload PowerPointFigure. Kaplan-Meier survival for primary end point in the intention-to-treat population at 730 days. A second landmark analysis is displayed from 1 year to 730 days. Shown are the Kaplan-Meier event curves for the primary composite end point of death from all causes, acute coronary syndrome, stroke, and urgent revascularization in the colchicine group and placebo group in a time-to-event analysis.This study demonstrated that, in patients presenting with an ACS event, the addition of low-dose oral colchicine to standard medical therapy during their acute hospitalization and continued for 12 months resulted in a significant reduction in the primary composite outcome at 2 years compared with standard medical therapy alone. We postulate that this ongoing effect may be attributable to the anti-inflammatory and plaque-modulating properties that have been observed with colchicine, reducing high-risk plaque volume and the potential development of ischemic complications.4 Because the drug was only administered for 12 months, the enduring 2-year results suggest the possibility of a legacy effect of colchicine.A recent meta-analysis of colchicine trials has still highlighted the issue of noncardiovascular death, and, unfortunately, because colchicine was discontinued in our study, an inference regarding deaths after 12 months cannot be made.5 Therefore, further large studies assessing colchicine in ACS and other cardiovascular populations are required to definitively prove the utility of this agent and ameliorate concerns regarding its safety. We eagerly await the results from large randomized clinical trials currently recruiting, such as the CLEAR SYNERGY (Colchicine and Spironolactone in Patients with MI/SYNERGY Stent Registry; NCT03048825) and CONVINCE (Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke; NCT02898610) trials, to help determine the place of colchicine among a myriad of cardiovascular therapies.Article InformationAcknowledgmentsWe thank all the patients who participated in this study. Drs Tong and Layland conducted literature search and study design and completed the first draft. Dr Quinn performed the statistical analyses. Dr Sriamareswaran assisted in data entry and management. All authors contributed to data collection and subsequent revisions of the manuscript.Sources of FundingThe study was supported by Cardiology Department of Peninsula Health and St Vincent’s Hospital Melbourne and received philanthropic support from the CASS Foundation Australia. Additional funding support was obtained from Peninsula Health and Faculty of Medicine, Nursing and Health Sciences, Monash University. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Dr Bloom is supported by the National Health and Medical Research Council Post Graduate Scholarship (#2003944) and The National Heart Foundation Post Graduate Scholarship (#104621). Dr Stub is supported by National Heart Foundation Future Leader Fellowship (#101908). A. Yong received honoraria from Abbott Vascular and Philips.Disclosures None.Footnoteshttps://www.ahajournals.org/journal/circThe data underlying this article will be shared on reasonable request to the corresponding author. REGISTRATION: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615000861550.For Sources of Funding and Disclosures, see page 1586.Correspondence to: Jamie Layland, PhD, Cardiology, Department of Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Monash University, PO Box 52, Frankston 3199,s Victoria, Australia. Email [email protected]vic.gov.auReferences1. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, et al.; LoDoCo2 Trial Investigators. Colchicine in patients with chronic coronary disease.N Engl J Med. 2020; 383:1838–1847. doi: 10.1056/NEJMoa2021372CrossrefMedlineGoogle Scholar2. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, et al.. Efficacy and safety of low-dose colchicine after myocardial infarction.N Engl J Med. 2019; 381:2497–2505. doi: 10.1056/NEJMoa1912388CrossrefMedlineGoogle Scholar3. Tong DC, Quinn S, Nasis A, Hiew C, Roberts-Thomson P, Adams H, Sriamareswaran R, Htun NM, Wilson W, Stub D, et al.. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial.Circulation. 2020; 142:1890–1900. doi: 10.1161/CIRCULATIONAHA.120.050771LinkGoogle Scholar4. Vaidya K, Martínez G, Patel S. The role of colchicine in acute coronary syndromes.Clin Ther. 2019; 41:11–20. doi: 10.1016/j.clinthera.2018.07.023CrossrefMedlineGoogle Scholar5. Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, Jolly SS, Keech AC, Kelly P, Tong DC, Layland J, Nidorf SM, et al.. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.Eur Heart J. 2021; 42:2765–2775. doi: 10.1093/eurheartj/ehab115CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails November 9, 2021Vol 144, Issue 19Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.054610PMID: 34748393 Originally publishedNovember 8, 2021 Keywordscolchicineanti-inflammatory agentscardiovascular diseasesacute coronary syndromesecondary preventionPDF download Advertisement SubjectsClinical StudiesInflammationSecondary Prevention