From the Center for Cardiovascular Disease Prevention (P.M.R., B.M.E., J.G.M., R.J.G.) and the Cardiovascular Division (P.M.R., B.M.E., P.L.), Brigham and Women's Hospital, Harvard Medical School, Boston; Novartis, East Hanover, NJ, and Basel, Switzerland (T.T., W.H.C.); Baylor College of Medicine, Houston (C.B.); Federal University of São Paulo (F.F.) and the Heart Institute (InCor), University of São Paulo Medical School (J.N.), São Paulo, and Faculdade Evangelica de Medicina do Parana, Curitiba (P.R.F.R.) - all in Brazil; Deutsches Herzzentrum München, Technische Universität München, German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich (W.K.), and the Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies, Charité Campus Virchow Klinikum, Universitätsmedizin Berlin, Berlin (S.D.A.) - both in Germany; Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.), Alkmaar Medical Center, Alkmaar (J.H.C.), and VieCuri Medical Center for Northern Limburg, Venlo (R.P.T.T.) - all in the Netherlands; Manipal Hospital, St. John's Research Institute, Bangalore, India (P.P.); Pavol Jozef Safarik University, Kosice, Slovakia (D.P.); McGill University, Montreal (J.G.); First Faculty of Medicine and Thomayer Hospital, Prague, Czech Republic (R.C.); Cordoba Hospital, Cordoba, Argentina (A.L.); University of Szeged, Szeged, Hungary (T.F.); City Hospital No. 64, Medical Institute RUDN University, Moscow (Z.K.); Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (L.V.-S.); University of East Anglia, Norwich Medical School, Norwich, United Kingdom (M.F.); Tohoku University Hospital, Sendai (H.S.), and National Cerebral and Cardiovascular Center, Osaka (H.O.) - both in Japan; and Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden (M.D.).
N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.
BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).
背景：实验和临床数据表明，在不影响血脂水平的情况下降低炎症水平可能会降低心血管疾病的风险。然而，动脉粥样硬化血栓形成的炎症假说尚未得到证实。
方法：我们进行了一项随机、双盲试验，涉及 10061 名既往心肌梗死和高敏 C 反应蛋白水平为每升 2 毫克或以上的患者，研究了一种靶向白细胞介素-1β的治疗性单克隆抗体卡那单抗。该试验比较了卡那单抗（50mg、150mg 和 300mg，每 3 个月皮下注射一次）与安慰剂的疗效。主要疗效终点是非致死性心肌梗死、非致死性卒中和心血管死亡。
结果：在 48 个月时，接受 50mg 卡那单抗剂量组的高敏 C 反应蛋白水平从基线降低了 26 个百分点，150mg 组降低了 37 个百分点，300mg 组降低了 41 个百分点，而安慰剂组降低了 26 个百分点。卡那单抗没有从基线降低血脂水平。在中位随访 3.7 年期间，安慰剂组的主要终点发生率为每 100 人年 4.50 例，50mg 组为每 100 人年 4.11 例，150mg 组为每 100 人年 3.86 例，300mg 组为每 100 人年 3.90 例。与安慰剂相比，其危险比如下：50mg 组为 0.93（95%置信区间[CI]，0.80 至 1.07；P=0.30）；150mg 组为 0.85（95%CI，0.74 至 0.98；P=0.021）；300mg 组为 0.86（95%CI，0.75 至 0.99；P=0.031）。150mg 剂量达到了主要终点和次要终点的预先规定的多重调整统计学显著性阈值，次要终点额外包括导致紧急血运重建的不稳定型心绞痛住院（与安慰剂相比，危险比为 0.83；95%CI，0.73 至 0.95；P=0.005），但其他剂量未达到。卡那单抗与安慰剂相比，致命感染的发生率更高。全因死亡率无显著差异（所有卡那单抗剂量与安慰剂相比，危险比为 0.94；95%CI，0.83 至 1.06；P=0.31）。
结论：以每 3 个月 150mg 的剂量使用卡那单抗靶向白细胞介素-1β先天免疫途径的抗炎治疗，与安慰剂相比，可显著降低复发性心血管事件的发生率，而不降低血脂水平。（由诺华公司资助；CANTOS 临床试验。net 注册号，NCT01327846）。
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