From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and the Department of Medicine, Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W.); the Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (F.J.R.), and the Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town (D.J.B.) - both in South Africa; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.R.); the Sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine, and the Center for Cardiovascular Disease Prevention, Houston Methodist DeBakey Heart and Vascular Center, Houston (C.M.B.); Amgen, Thousand Oaks, CA (R. Somaratne, J.L., S.M.W., R. Scott); Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); and the Metabolic and Atherosclerosis Research Center, Cincinnati (E.A.S.).
N Engl J Med. 2015 Apr 16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15.
BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).
背景：依洛尤单抗是一种单克隆抗体，可抑制前蛋白转化酶枯草溶菌素 9（PCSK9），在短期研究中显著降低了低密度脂蛋白（LDL）胆固醇水平。我们进行了两项扩展研究以获得更长期的数据。
方法：在两项开放标签、随机试验中，我们纳入了完成依洛尤单抗的 12 项 2 期或 3 期研究（“母试验”）之一的 4465 例患者。无论母试验中的分组如何，符合条件的患者以 2:1 的比例随机分配接受依洛尤单抗（每 2 周 140mg 或每月 420mg）加标准治疗或仅接受标准治疗。中位随访 11.1 个月，评估血脂水平、安全性和（作为预设的探索性分析）包括死亡、心肌梗死、不稳定型心绞痛、冠状动脉血运重建、卒中和短暂性脑缺血发作以及心力衰竭在内的心血管不良事件。两项试验的数据合并。
结果：与单独标准治疗相比，依洛尤单抗使 LDL 胆固醇水平降低 61%，从每分升 120mg 降至每分升 48mg（P<0.001）。两组的大多数不良事件发生频率相似，尽管依洛尤单抗组报告的神经认知事件更为频繁。不良事件的风险，包括神经认知事件，与 LDL 胆固醇的降低程度没有显著相关性。依洛尤单抗组的心血管事件发生率从标准治疗组的 1 年 2.18%降至 0.95%（依洛尤单抗组的风险比为 0.47；95%置信区间为 0.28 至 0.78；P=0.003）。
结论：在大约 1 年的治疗期间，与单独标准治疗相比，依洛尤单抗加标准治疗显著降低了 LDL 胆固醇水平，并降低了预先设定的探索性分析中的心血管事件发生率。（由 Amgen 资助；OSLER-1 和 OSLER-2 临床试验.gov 编号，NCT01439880 和 NCT01854918）。
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