Verma Subodh, Leiter Lawrence A, Teoh Hwee, Mancini G B John, Quan Adrian, Elituv Randi, Verma Meena, Misner Elizabeth, Szarek Michael, Thorpe Kevin E, Saha Tarit, Whitlock Richard P, Yanagawa Bobby, Merkely Béla, Jüni Peter, Koren Michael J, Nicholls Stephen J, Bhatt Deepak L, Mazer C David
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.
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.
Lancet. 2025 Sep 20;406(10509):1223-1234. doi: 10.1016/S0140-6736(25)01633-2. Epub 2025 Sep 1.
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.
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.
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.
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.
Amgen Canada.
在冠状动脉旁路移植术（CABG）后，大隐静脉移植血管（SVG）失败仍然是一个重大挑战。低密度脂蛋白胆固醇（LDL-C）是动脉粥样硬化的一个因果危险因素，但其在SVG失败中的作用尚未明确确立。我们评估了早期开始使用依洛尤单抗强化降低LDL-C是否能减少SVG失败。
NEWTON-CABG CardioLink-5是一项在加拿大、美国、澳大利亚和匈牙利的23个地点进行的多中心、双盲、随机、安慰剂对照试验。符合条件的参与者为成年患者（年龄≥18岁），他们接受了至少两根SVG的CABG手术，并正在接受中等强度或高强度的他汀类药物治疗。参与者在CABG术后21天内被随机分配（1:1；可变区组大小），每2周皮下注射140mg依洛尤单抗或安慰剂。主要终点是改良意向性治疗人群中24个月时的静脉移植血管疾病发生率（VGDR；冠状动脉CT血管造影或临床指征的有创血管造影显示闭塞≥50%的SVG比例）。该试验已在ClinicalTrials.gov注册，注册号为NCT03900026，且已完成。
在2019年6月17日至2022年11月10日期间，782名个体被随机分配（389名接受依洛尤单抗，393名接受安慰剂）。在基线时，在554名有主要结局数据的参与者中，中位年龄为66岁（四分位间距60-72岁），554名参与者中471名（85%）为男性，83名（15%）为女性，依洛尤单抗组的中位LDL-C为1.85mmol/L（四分位间距1.25-2.84），安慰剂组为1.86mmol/L（1.20-2.76）。依洛尤单抗在24个月时使LDL-C平均降低了48.4%（经安慰剂校正后，-52.4%对-4.0%）。依洛尤单抗组24个月时的VGDR为21.7%（686根移植血管中的149根），安慰剂组为19.7%（644根移植血管中的127根）（差异2.0%[95%置信区间-3.1至7.1]；p=0.44）。治疗耐受性良好，两组之间的不良事件谱相似。
在接受CABG的患者中，尽管LDL-C大幅降低，但依洛尤单抗在首次手术后24个月时并未降低SVG疾病发生率。进一步降低LDL-C似乎并未对导致早期SVG失败的病理生理机制产生有意义的影响。
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