Effect of evolocumab on saphenous vein graft patency after coronary artery bypass surgery (NEWTON-CABG CardioLink-5): an international, randomised, double-blind, placebo-controlled trial

Subodh Verma¹, Lawrence A Leiter², Hwee Teoh³, G B John Mancini⁴, Adrian Quan⁵, Randi Elituv⁶, Meena Verma⁷, Elizabeth Misner⁵, Michael Szarek⁸, Kevin E Thorpe⁹, Tarit Saha¹⁰, Richard P Whitlock¹¹, Bobby Yanagawa¹², Béla Merkely¹³, Peter Jüni¹⁴, Michael J Koren¹⁵, Stephen J Nicholls¹⁶, Deepak L Bhatt¹⁷, C David Mazer¹⁸

Affiliations

¹ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; North York Diagnostic and Cardiac Centre, Toronto, ON, Canada. Electronic address: subodh.verma@unityhealth.to.
² Division of Endocrinology and Metabolism, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
³ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Division of Endocrinology and Metabolism, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada.
⁴ Division of Cardiology, Centre for Cardiovascular Innovation, Dilawri Cardiovascular Institute, University of British Columbia, Vancouver, BC, Canada.
⁵ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada.
⁶ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; North York Diagnostic and Cardiac Centre, Toronto, ON, Canada.
⁷ Royal College of Surgeons in Ireland, Dublin, Ireland.
⁸ Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA; CPC Clinical Research, University of Colorado School of Medicine, Aurora, CO, USA; Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Anesthesiology and Perioperative Medicine, Kingston Health Sciences Centre, Kingston, ON, Canada; Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada.
¹¹ Department of Surgery, McMaster University, Hamilton, ON, Canada; Department of Health Research Methodology, Evidence and Impact, McMaster University, Hamilton, ON, Canada; Perioperative and Surgery Research Program, Population Health Research Institute, Hamilton, ON, Canada.
¹² Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
¹³ Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
¹⁴ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁵ Jacksonville Center for Clinical Research, Flourish Research Group, Jacksonville, FL, USA.
¹⁶ Victorian Heart Institute, Monash University, Melbourne, VIC, Australia.
¹⁷ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Anesthesia, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada. Electronic address: david.mazer@unityhealth.to.

PMID: 40907505
DOI: 10.1016/S0140-6736(25)01633-2

Randomized Controlled Trial

Effect of evolocumab on saphenous vein graft patency after coronary artery bypass surgery (NEWTON-CABG CardioLink-5): an international, randomised, double-blind, placebo-controlled trial

Subodh Verma et al. Lancet. 2025.

. 2025 Sep 20;406(10509):1223-1234.

doi: 10.1016/S0140-6736(25)01633-2. Epub 2025 Sep 1.

Authors

Affiliations

¹ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; North York Diagnostic and Cardiac Centre, Toronto, ON, Canada. Electronic address: subodh.verma@unityhealth.to.
² Division of Endocrinology and Metabolism, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
³ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Division of Endocrinology and Metabolism, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada.
⁴ Division of Cardiology, Centre for Cardiovascular Innovation, Dilawri Cardiovascular Institute, University of British Columbia, Vancouver, BC, Canada.
⁵ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada.
⁶ Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; North York Diagnostic and Cardiac Centre, Toronto, ON, Canada.
⁷ Royal College of Surgeons in Ireland, Dublin, Ireland.
⁸ Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA; CPC Clinical Research, University of Colorado School of Medicine, Aurora, CO, USA; Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Anesthesiology and Perioperative Medicine, Kingston Health Sciences Centre, Kingston, ON, Canada; Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada.
¹¹ Department of Surgery, McMaster University, Hamilton, ON, Canada; Department of Health Research Methodology, Evidence and Impact, McMaster University, Hamilton, ON, Canada; Perioperative and Surgery Research Program, Population Health Research Institute, Hamilton, ON, Canada.
¹² Division of Cardiac Surgery, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
¹³ Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
¹⁴ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁵ Jacksonville Center for Clinical Research, Flourish Research Group, Jacksonville, FL, USA.
¹⁶ Victorian Heart Institute, Monash University, Melbourne, VIC, Australia.
¹⁷ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Anesthesia, St Michael's Hospital-Unity Health Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada. Electronic address: david.mazer@unityhealth.to.

PMID: 40907505
DOI: 10.1016/S0140-6736(25)01633-2

Abstract

Background: Saphenous vein graft (SVG) failure remains a substantial challenge after coronary artery bypass graft (CABG). LDL cholesterol (LDL-C) is a causal risk factor for atherosclerosis, but its role in SVG failure is not well established. We evaluated whether early initiation of intensive LDL-C lowering with evolocumab could reduce SVG failure.

Methods: NEWTON-CABG CardioLink-5 was a multicentre, double-blind, randomised, placebo-controlled trial conducted at 23 sites in Canada, the USA, Australia, and Hungary. Eligible participants were adults (age ≥18 years) who underwent CABG with at least two SVGs and were being treated with statin therapy of moderate or high intensity. Participants were randomly allocated (1:1; variable block size) within 21 days of CABG to subcutaneous evolocumab 140 mg or placebo every 2 weeks. The primary endpoint was the 24-month vein graft disease rate (VGDR; the proportion of SVGs with ≥50% occlusion on coronary CT angiography or clinically indicated invasive angiography) in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03900026, and is completed.

Findings: Between June 17, 2019, and Nov 10, 2022, 782 individuals were randomly assigned (389 to evolocumab and 393 to placebo). At baseline, among the 554 participants with primary outcome data available, the median age was 66 years (IQR 60-72), 471 (85%) of 554 participants were male and 83 (15%) were female, and the median LDL-C was 1·85 mmol/L (IQR 1·25-2·84) in the evolocumab group and 1·86 mmol/L (1·20-2·76) in the placebo group. Evolocumab resulted in a mean 48·4% placebo-adjusted reduction in LDL-C at 24 months (-52·4% vs -4·0%). The 24-month VGDR was 21·7% (149 of 686 grafts) in the evolocumab group and 19·7% (127 of 644 grafts) in the placebo group (difference 2·0% [95% CI -3·1 to 7·1]; p=0·44). Treatment was well tolerated, with similar adverse event profiles between the groups.

Interpretation: Among patients who underwent CABG, evolocumab did not reduce SVG disease at 24 months following the index surgery despite substantial LDL-C lowering. Further LDL-C lowering does not appear to meaningfully affect the pathophysiological mechanisms responsible for early SVG failure.

Funding: Amgen Canada.

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Conflict of interest statement

Declaration of interests SV reports grants, research support, speaking honoraria from, or acting as an advisor to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Heart Research Centre, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management, Sanofi, and Sun Pharma; holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and is President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. LAL reports research support from, speaking honoraria from, or acting as an advisor to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, HLS Therapeutics, Lexicon, Merck, Novartis, Novo Nordisk, Regeneron, and Roche; and membership of a data safety monitoring board for CRISPR Therapeutics and vTv Therapeutics. HT reports personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group and LMC Healthcare. GBJM reports research support from, speaking honoraria from, or acting as an advisor to Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, GSK, HLS Therapeutics, Merck, Novartis, Novo Nordisk, Sanofi, and Ultragenyx. MS reports salary support from CPC, a non-profit academic research organisation affiliated with the University of Colorado, which has received research grant and consulting funding between July, 2021, and July, 2025, from 35Pharma, Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma Godo Kaisha, the American Heart Association, American Journal Managed Care, Amgen, Amgen USA, Anthos Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals, AstraZeneca UK, Autonomy Bio, Bayer, Bayer Aktiengesellschaft, the Beth Israel Deaconess Medical Center, Better Therapeutics, the Boston Clinical Research Institute, Bristol Myers Squibb, Cleerly, Clergy United for the Transformation of Sandtown, the Colorado Department of Public Health and Environment, Congress, Cook Regentec, Eidos Therapeutics, EluraBio, Esperion Therapeutics, Faraday Pharmaceuticals, Gasherbrum Bio, Insmed, IsomAb, JanOne Biotech Holdings, Janssen Global Services, Janssen Pharmaceuticals, Janssen Scientific Affairs, Las Animas and Huerfano Counties, the District Health Department, Lexicon Pharmaceuticals, Lilly USA, Medison Pharma, Medpace, Merck Sharp & Dohme, Nectero Medical, NewAmsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Piper Sandler & Co, PPD Development, Prothena Biosciences, Regeneron, Regents of the University of Colorado, Sanifit Therapeutics, Sanofi, Silence Therapeutics, Stanford University, Stealth BioTherapeutics, The Brigham and Women's Hospital, the Thrombosis Research Institute, Tourmaline Bio, the University of Colorado, the University of Pittsburgh, VarmX, Verve Therapeutics, and WraSer; and consultancy for or research support from Amarin, Lexicon, NewAmsterdam, Novartis, Regeneron, Sanofi, Silence, and Tourmaline. RPW reports institutional research grants from Abbott, AtriCure, Bayer, Boehringer Ingelheim, BMS-Pfizer, Boston Scientific, Cytosorbent, and Roche; and consulting payments or honoraria from AtriCure and Boehringer Ingelheim. BY reports speaker fees from Edwards Life Sciences. BM reports speaker fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daichii Sankyo, the Duke Clinical Research Institute, Medtronic, and Novartis; and being the Honorary President of the Hungarian Society of Cardiology. MJK reports employment by Flourish Research, a clinical research company supported by grants from multiple manufacturers of lipid and other therapeutics. SJN reports grants or research support from Amgen, Anthera, AstraZeneca, Cerenis, Cyclarity, Eli Lilly, Esperion, InfraReDx, NewAmsterdam Pharma, Novartis, Resverlogix, Roche, Sanofi-Regeneron, The Medicines Company, and LipoScience; consultancy for Abcentra, Akcea, Amarin, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, CSL Seqirus, Daiichi Sankyo, Eli Lilly, Esperion, Merck, Omthera, Resverlogix, Sanofi-Regeneron, Scribe Therapeutics, Silence Therapeutics, Takeda, and Vaxxinity; stock options in NewAmsterdam Pharma; being a named inventor on a patent of PCSK9 inhibitors on plaque; and board membership of the Cardiac Society of Australia and New Zealand. DLB reports advisory board membership for Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, and Tourmaline Bio; board of directors membership for the American Heart Association, Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; stock options with Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; consultancy for Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GSK, Hims, SERB, SFJ, Summa Therapeutics, and Worldwide Clinical Trials; data monitoring committee membership for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, the Baim Institute for Clinical Research, Boston Scientific, Cleveland Clinic, Contego Medical, the Duke Clinical Research Institute, the Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY-DM trial, funded by Concept Medical, and for ALLAY-HF, funded by Alleviant Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the US National Institutes of Health-funded MINT Trial); honoraria from the American College of Cardiology, Arnold and Porter, the Baim Institute for Clinical Research, Belvoir Publications, the Canadian Medical and Surgical Knowledge Translation Research Group, CSL Behring, the Duke Clinical Research Institute, Engage Health Media, HMP Global, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Philips, the Population Health Research Institute, WebMD, and Wiley; being Deputy Editor for Clinical Cardiology and Progress in Cardiovascular Diseases; a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon, for which neither DLB nor Brigham and Women's Hospital receives any income; research funding from Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, the Reid Hoffman Foundation, Roche, Sanofi, Stasys, and 89Bio; royalties from Elsevier; and being a site co-investigator for Cleerly. CDM reports honoraria from the University of Toronto Department of Anesthesiology and Pain Medicine and St Michael's Hospital–Unity Health Toronto; advisory board honoraria or consulting fees from Amgen, Alexion, AstraZeneca, BioAge, Biotest, Boehringer Ingelheim, Cardior, Cytosorbents, Delex, ONA, PhaseBio, Sandoz, Trimedic Therapeutics, VarmX, and Werfen; and data safety monitoring board stipends from the Beth Israel Deaconess Medical Center, Cerus, and Takeda. All other authors declare no competing interests.

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Effect of evolocumab on saphenous vein graft patency after coronary artery bypass surgery (NEWTON-CABG CardioLink-5): an international, randomised, double-blind, placebo-controlled trial

Affiliations

Effect of evolocumab on saphenous vein graft patency after coronary artery bypass surgery (NEWTON-CABG CardioLink-5): an international, randomised, double-blind, placebo-controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

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