Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
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DOI：
10.1056/nejmoa1707914
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发表时间：
2017-09-21
影响因子：
158.5
通讯作者：
Glynn, R. J.
中科院分区：
文献类型：
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作者：
Ridker, P. M.;Everett, B. M.;Glynn, R. J.
背景实验和临床数据表明，在不影响脂质水平的情况下减少炎症可以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。 方法我们对 Canakinumab（一种针对白细胞介素 1 β 的治疗性单克隆抗体）进行了一项随机、双盲试验，涉及 10,061 名既往患有心肌梗塞且高敏 C 反应蛋白水平为每升 2 毫克或以上的患者。该试验将三种剂量的卡那奴单抗（50 mg、150 mg 和 300 mg，每 3 个月皮下注射一次）与安慰剂进行了比较。主要疗效终点是非致死性心肌梗死、非致死性中风或心血管死亡。 结果在 48 个月时，接受 50 mg 剂量卡那奴单抗组的高敏 C 反应蛋白水平较基线的中位降低幅度比安慰剂组高 26 个百分点，150 mg 组高 37 个百分点，300 mg 组高 41 个百分点。卡那奴单抗并未降低基线血脂水平。中位随访时间为 3.7 年，主要终点的发生率为安慰剂组每 100 人年 4.50 起事件，50 mg 组每 100 人年 4.11 起事件，150 mg 组每 100 人年 3.86 起事件，300 mg 组每 100 人年 3.90 起事件。组。与安慰剂相比，风险比如下：50 mg 组为 0.93（95% 置信区间 [CI]，0.80 至 1.07；P = 0.30）； 150 mg 组为 0.85（95% CI，0.74 至 0.98；P = 0.021）； 300 mg 组为 0.86（95% CI，0.75 至 0.99；P = 0.031）。 150 mg 剂量（而非其他剂量）满足主要终点和次要终点统计显着性的预设多重调整阈值，次要终点还包括因不稳定心绞痛住院并导致紧急血运重建（风险比与安慰剂相比，0.83；95% CI，0.73 至 0.95；P = 0.005）。与安慰剂相比，卡那奴单抗与更高的致命感染发生率相关。全因死亡率没有显着差异（所有卡那奴单抗剂量与安慰剂的风险比为 0.94；95% CI，0.83 至 1.06；P = 0.31）。 结论 以每 3 个月 150 mg 剂量的卡那奴单抗针对白细胞介素 1 β 先天免疫途径的抗炎治疗，与安慰剂相比，心血管事件复发率显着降低，与安慰剂无关。血脂水平降低。
BACKGROUNDExperimental 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.METHODSWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1 beta, 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.RESULTSAt 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).CONCLUSIONSAntiinflammatory therapy targeting the interleukin-1 beta 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.