Long-Term Efficacy of Colchicine in Patients With Chronic Coronary Disease: Insights From LoDoCo2
2022; Lippincott Williams & Wilkins; Volume: 145; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.121.058233
ISSN1524-4539
AutoresTjerk S.J. Opstal, Amber van Broekhoven, Aernoud T.L. Fiolet, Arend Mosterd, John W. Eikelboom, Stefan M. Nidorf, Peter L. Thompson, Charley A. Budgeon, Louis Bartels, Ron de Nooijer, Willem A. Bax, Jan G.P. Tijssen, Saloua El Messaoudi, Jan H. Cornel,
Tópico(s)interferon and immune responses
ResumoHomeCirculationVol. 145, No. 8Long-Term Efficacy of Colchicine in Patients With Chronic Coronary Disease: Insights From LoDoCo2 Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBLong-Term Efficacy of Colchicine in Patients With Chronic Coronary Disease: Insights From LoDoCo2 Tjerk S.J. Opstal, MD, Amber van Broekhoven, MD, Aernoud T.L. Fiolet, MD, Arend Mosterd, MD, John W. Eikelboom, MD, Stefan M. Nidorf, MD, Peter L. Thompson, MD, Charley A. Budgeon, PhD, Louis Bartels, MD, Ron de Nooijer, MD, Willem A. Bax, MD, Jan G.P. Tijssen, PhD, Saloua El Messaoudi, MD and Jan H. Cornel, MD Tjerk S.J. OpstalTjerk S.J. Opstal Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (T.S.J.O., A.v.B., S.E.M., J.H.C.). Department of Cardiology, Northwest Clinics, Alkmaar, The Netherlands (T.S.J.O., J.H.C.). , Amber van BroekhovenAmber van Broekhoven https://orcid.org/0000-0002-4204-7750 Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (T.S.J.O., A.v.B., S.E.M., J.H.C.). , Aernoud T.L. FioletAernoud T.L. Fiolet https://orcid.org/0000-0001-5328-2564 Department of Cardiology, University Medical Center Utrecht, The Netherlands (A.T.L.F.). Dutch Network for Cardiovascular Research (Werkgroep Cardiologische centra Nederland), Utrecht, The Netherlands (A.T.L.F., A.M., L.B., R.d.N., J.H.C.). Department of Cardiology, Meander Medical Center, Amersfoort, The Netherlands (A.T.L.F., A.M.). , Arend MosterdArend Mosterd https://orcid.org/0000-0002-6906-2643 Dutch Network for Cardiovascular Research (Werkgroep Cardiologische centra Nederland), Utrecht, The Netherlands (A.T.L.F., A.M., L.B., R.d.N., J.H.C.). Department of Cardiology, Meander Medical Center, Amersfoort, The Netherlands (A.T.L.F., A.M.). , John W. EikelboomJohn W. Eikelboom Department of Medicine, McMaster University, Hamilton, Canada (J.W.E.). , Stefan M. NidorfStefan M. Nidorf https://orcid.org/0000-0002-2226-538X Heart and Vascular Research Institute of Western Australia, Perth (S.M.N., P.L.T.). GenesisCare Western Australia, Perth (S.M.N.). , Peter L. ThompsonPeter L. Thompson Heart and Vascular Research Institute of Western Australia, Perth (S.M.N., P.L.T.). Sir Charles Gairdner Hospital, Perth, Australia (P.L.T.). University of Western Australia, Perth (P.L.T., C.A.B.). , Charley A. BudgeonCharley A. Budgeon https://orcid.org/0000-0002-1910-5561 University of Western Australia, Perth (P.L.T., C.A.B.). , Louis BartelsLouis Bartels Dutch Network for Cardiovascular Research (Werkgroep Cardiologische centra Nederland), Utrecht, The Netherlands (A.T.L.F., A.M., L.B., R.d.N., J.H.C.). Department of Cardiology, Martini Hospital, Groningen, The Netherlands (L.B.). , Ron de NooijerRon de Nooijer Dutch Network for Cardiovascular Research (Werkgroep Cardiologische centra Nederland), Utrecht, The Netherlands (A.T.L.F., A.M., L.B., R.d.N., J.H.C.). Department of Cardiology, Máxima Medical Center, Veldhoven, The Netherlands (R.d.N.). , Willem A. BaxWillem A. Bax https://orcid.org/0000-0002-2177-1475 Department of Internal Medicine, Northwest Clinics, Alkmaar, The Netherlands (W.A.B.). , Jan G.P. TijssenJan G.P. Tijssen Department of Cardiology, Amsterdam University Medical Center, The Netherlands (J.G.P.T.). Cardialysis BV, Rotterdam, The Netherlands (J.G.P.T.). , Saloua El MessaoudiSaloua El Messaoudi Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (T.S.J.O., A.v.B., S.E.M., J.H.C.). and Jan H. CornelJan H. Cornel Correspondence to: Jan H. Cornel, MD, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1006-2112 Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (T.S.J.O., A.v.B., S.E.M., J.H.C.). Department of Cardiology, Northwest Clinics, Alkmaar, The Netherlands (T.S.J.O., J.H.C.). Dutch Network for Cardiovascular Research (Werkgroep Cardiologische centra Nederland), Utrecht, The Netherlands (A.T.L.F., A.M., L.B., R.d.N., J.H.C.). Originally published21 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.058233Circulation. 2022;145:626–628Patients with chronic coronary disease remain at risk for recurrent cardiovascular events, despite optimal contemporary medical management. This "residual risk" is believed to be partly explained by ongoing vascular inflammation.1 The COLCOT Trial (Colchicine Cardiovascular Outcomes Trial) and the LoDoCo2 Trial (Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2) demonstrated that the anti-inflammatory drug colchicine reduces the risk of cardiovascular events in patients after recent myocardial infarction and with chronic coronary disease, respectively.2,3 However, it remains unclear whether the benefits of colchicine in these patients are limited to a shorter initial period of treatment or continue to accrue during long-term treatment.The LoDoCo2 trial (URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12614000093684) randomized 5522 patients to placebo (n=2760) or colchicine 0.5 mg once daily (n=2762) and followed them for a median of 28.6 months (interquartile range, 20.5–44.4). Participants were eligible if they were ages 35 to 82 years, had established chronic coronary disease irrespective of previous acute coronary event, were clinically stable for at least 6 months before randomization, and were able to tolerate colchicine during a 30-day run-in period. The trial protocol was approved by a centralized institutional review board in each participating country. All participants provided written informed consent. Additional details of the design, baseline characteristics of the patients, and primary results of LoDoCo2 have been published.3,4 The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven revascularization. All reported events were adjudicated by a clinical events committee, which was blinded to treatment allocation. The data that support the findings of this study are available from the corresponding author on reasonable request.The current exploratory study performed landmark analyses for the primary efficacy end point and its individual components at yearly intervals from randomization in patients who were alive and on trial medication at the start of each landmark period, using Cox proportional hazard models and the Kaplan-Meier method. The occurrence of a nonfatal event did not exclude patients from inclusion in the next landmark periods.Landmark analyses of patients on treatment in the LoDoCo2 trial showed that the effects of colchicine on the risk of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization were consistent in all yearly landmarks compared to placebo: year 1, incidence, 2.4 versus 3.6 events per 100 person-years; hazard ratio (HR), 0.68 (95% CI, 0.50–0.93); year 2, incidence, 2.1 versus 3.1 events per 100 person-years; HR, 0.68 (95% CI, 0.47–0.99; year 3, incidence, 3.0 versus 5.0 events per 100 person-years; HR, 0.61 (95% CI, 0.41–0.92); and year 4 until end of follow-up, incidence, 2.2 versus 4.1 events per 100 person-years; HR, 0.53 (95% CI, 0.33–0.87) (Figure). A similar pattern was evident in the individual end points of ischemia-driven coronary revascularization (year 1, incidence, 1.7 versus 2.3 events per 100 person-years; HR, 0.76 [95% CI, 0.52–1.10]; year 2, incidence, 1.4 versus 1.8 events per 100 person-years; HR, 0.77 [95% CI, 0.48–1.23]; year 3, incidence, 2.1 versus 3.8 events per 100 person-years; HR, 0.56 [95% CI, 0.35–0.91]; year 4 until end of follow-up, incidence, 1.5 versus 2.2 events per 100 person-years; HR, 0.67 [95% CI, 0.36–1.25]) and myocardial infarction (year 1, incidence, 1.0 versus 1.7 events per 100 person-years; HR, 0.60 [95% CI, 0.37–0.96]; year 2, incidence, 0.9 versus 0.9 events per 100 person-years; HR, 0.95 [95% CI, 0.51–1.77]; year 3, incidence, 1.2 versus 1.9 events per 100 person-years; HR, 0.65 [95% CI, 0.34–1.24]; year 4 until end of follow-up, incidence, 1.1 versus 2.2 events per 100 person-years; HR, 0.51 [95% CI, 0.26–1.00]) with comparable hazard ratios between the first and last years of treatment with study medication.Download figureDownload PowerPointFigure. Long-term effect of colchicine for the composite of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization in patients with chronic coronary disease. The effect of colchicine 0.5 mg once daily versus placebo on the cumulative incidence of the composite end point of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization in patients with chronic coronary disease. Kaplan-Meier curves are shown of "on treatment" landmark analyses at yearly intervals from randomization in patients who were alive and on trial medication at the start of each landmark period. CIs and hazard ratios (HRs) were calculated with Cox proportional hazard models of the "on treatment" cohort as well as the original "intention to treat" (ITT) cohort, which included all randomized patients of the LoDoCo2 trial (Low-Dose Colchicine 2).This exploratory analysis of the LoDoCo2 trial shows that, in patients with chronic coronary disease, continued long-term anti-inflammatory therapy with low-dose colchicine produced a consistent reduction in major cardiovascular events year by year during 5 years of follow-up. The main drivers of the primary composite end point, ischemia-driven coronary revascularization and myocardial infarction, were both consistently reduced by long-term colchicine treatment. These findings are in line with the hypothesis that subclinical vascular inflammation is an ongoing process and the notion that modulation of the innate immune system cannot be achieved by short-term treatment.5This study has limitations. The landmark analyses begin observation at a time after randomization and were restricted to patients who did not permanently discontinue medication. Including patients with previous nonfatal events in subsequent landmark periods affects the risk profile of the population being analyzed and could thereby affect the results. However, any effect is likely to be minimal because baseline characteristics remained well balanced between treatment groups for each landmark. After 3 years, the number of patients available for analysis was reduced, leading to a reduction of power and a higher risk of play of chance.In conclusion, in patients with chronic coronary disease, the benefit of colchicine continues to accumulate during long-term follow-up.Article InformationAcknowledgmentsThe authors thank all the patients for their participation in the trial; the trial investigators and coordinators at all the centers; and the trial monitors and staff from GenesisCare, including Penny Buczec, Denny Craig, Karen Doherty, Louise Ferguson, Louise Nidorf, and Karen Youl, from the Heart and Vascular Research Institute of Sir Charles Gairdner Hospital, including Louise Ferguson, and from the Dutch Network for Cardiovascular Research, including Marjelle van Leeuwen (project manager), Ingrid Groenenberg and Glentino Rodriguez for data management, Erik Stroes, Max Silvis, and Tim de Vries for medical review, and Petra Bunschoten and Wendy Tousain for site monitoring.Sources of FundingThis trial was supported by the National Health Medical Research Council of Australia, a grant from the Sir Charles Gairdner Research Advisory Committee, the Withering Foundation, The Netherlands, The Netherlands Heart Foundation, The Netherlands Organization for Health Research and Development, and a consortium of Teva, Disphar, and Tiofarma in The Netherlands. The funders did not have any role in the design or conduct of the study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the article.DisclosuresA.M. reports grants from Novartis and personal fees from Amarin, Amgen, BMS, Boehringer Ingelheim, MSD, and Pfizer. J.W.E. reports consulting/honoraria support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi-Aventis, and Servier, and grants or in-kind support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi-Aventis. P.L.T. reports grants, travel support, and honoraria from Amarin, Amgen, AstraZeneca, Bristol Myers Squibb, Merck, and Pfizer. J.H.C. reports membership on advisory boards for Amgen and AstraZeneca. The other authors report no conflicts.Nonstandard Abbreviations and AcronymsHRhazard ratioFootnotesCirculation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 628.Correspondence to: Jan H. Cornel, MD, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands. Email janhein.[email protected]nlReferences1. Everett BM. Residual inflammatory risk: a common and important risk factor for recurrent cardiovascular events.J Am Coll Cardiol. 2019; 73:2410–2412. doi: 10.1016/j.jacc.2019.02.056CrossrefMedlineGoogle 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. 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 Scholar4. Nidorf SM, Fiolet ATL, Eikelboom JW, Schut A, Opstal TSJ, Bax WA, Budgeon CA, Tijssen JGP, Mosterd A, Cornel JH, et al.; LoDoCo2 Investigators. The effect of low-dose colchicine in patients with stable coronary artery disease: the LoDoCo2 trial rationale, design, and baseline characteristics.Am Heart J. 2019; 218:46–56. doi: 10.1016/j.ahj.2019.09.011CrossrefMedlineGoogle Scholar5. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis - from experimental insights to the clinic.Nat Rev Drug Discov. 2021; 20:589–610. doi: 10.1038/s41573-021-00198-1CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 22, 2022Vol 145, Issue 8Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.058233PMID: 35188792 Originally publishedFebruary 21, 2022 Keywordscardiovascular diseasescolchicinecoronary artery diseaseinflammationPDF download Advertisement
Referência(s)