From the Division of Cardiology, University of Colorado School of Medicine, Aurora (G.G.S.); Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris Diderot University, Sorbonne Paris Cité, FACT (French Alliance for Cardiovascular Trials), and INSERM Unité 1148 (P.G.S.), and Sanofi (C.H., G.L.) - all in Paris; the National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London (P.G.S.); the State University of New York Downstate School of Public Health, Brooklyn (M.S.), and Regeneron Pharmaceuticals, Tarrytown (R.P., W.J.S.) - both in New York; Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston (D.L.B.); the Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham (V.A.B.); Estudios Cardiológicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.); Sanofi, Bridgewater, NJ (J.M.E., A.M., J.-F.T.); the Canadian VIGOUR Centre, University of Alberta, Edmonton, and St. Michael's Hospital, University of Toronto, Toronto - both in Canada (S.G.G.); Stanford Center for Clinical Research, Department of Medicine, Stanford University, Stanford, CA (R.A.H., K.W.M.); the Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands (J.W.J.); Duke Clinical Research Institute, Duke University Medical Center (K.Q., M.T.R., P.T.), and the Division of Cardiology, Department of Medicine, Duke University School of Medicine (M.T.R.), Durham, NC; Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand (H.D.W.); and the Department of Medicine III, Goethe University, Frankfurt am Main, Germany (A.M.Z.).
N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7.
BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).
背景：发生急性冠状动脉综合征的患者存在发生复发性缺血性心血管事件的高风险。我们旨在确定在接受高强度他汀类药物治疗的急性冠状动脉综合征患者中，抗前蛋白转化酶枯草溶菌素 9（PCSK9）的人源单克隆抗体阿利西尤单抗是否会改善心血管结局。
方法：我们进行了一项多中心、随机、双盲、安慰剂对照试验，纳入了 18924 例在 1 至 12 个月前发生急性冠状动脉综合征、低密度脂蛋白（LDL）胆固醇水平至少 70mg/dL（1.8mmol/L）、非高密度脂蛋白胆固醇水平至少 100mg/dL（2.6mmol/L）或载脂蛋白 B 水平至少 80mg/dL、并正在接受高强度剂量或最大耐受剂量他汀类药物治疗的患者。患者被随机分配至接受皮下注射 75mg 阿利西尤单抗（9462 例患者）或匹配安慰剂（9462 例患者），每 2 周 1 次。阿利西尤单抗的剂量在盲法条件下进行调整，以将 LDL 胆固醇水平目标设定为 25 至 50mg/dL（0.6 至 1.3mmol/L）。主要终点是由冠心病死亡、非致死性心肌梗死、致死性或非致死性缺血性卒中和需要住院治疗的不稳定型心绞痛组成的复合终点。
结果：中位随访时间为 2.8 年。阿利西尤单抗组发生 903 例（9.5%）复合主要终点事件，安慰剂组发生 1052 例（11.1%）（风险比，0.85；95%置信区间[CI]，0.78 至 0.93；P<0.001）。阿利西尤单抗组共有 334 例（3.5%）患者死亡，安慰剂组有 392 例（4.1%）（风险比，0.85；95%CI，0.73 至 0.98）。与基线 LDL 胆固醇水平较低的患者相比，基线 LDL 胆固醇水平为 100mg/dL 或更高的患者使用阿利西尤单抗的复合主要终点获益更大。两组的不良事件发生率相似，但局部注射部位反应除外（阿利西尤单抗组为 3.8%，安慰剂组为 2.1%）。
结论：在先前发生急性冠状动脉综合征且正在接受高强度他汀类药物治疗的患者中，与安慰剂相比，接受阿利西尤单抗治疗的患者发生复发性缺血性心血管事件的风险更低。（由赛诺菲和再生元制药公司资助；ODYSSEY OUTCOMES ClinicalTrials.gov 编号，NCT01663402）。
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