NEJM：Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
抗炎药物治疗动脉粥样硬化性疾病
当前减慢动脉粥样硬化进展的药物几乎都集中在降低胆固醇水平。不过，临床和实验数据显示炎症在动脉粥样硬化性血栓形成过程中也起着关键作用。以前研究发现炎症的下游标记物比如超敏C反应蛋白和白介素-6与心血管事件增加有关，不依赖于胆固醇水平。同时还发现他汀能够降低胆固醇和炎性标记物水平，在一系列临床试验中发现他汀之所以能够获益是由于降低了胆固醇水平和炎性抑制作用。但是，截止到目前为止尚未发现任何一种降低血管炎症的药物在不降低血脂水平的情况下减少心血管病事件。就其本身而言，动脉粥样硬化炎症假说尚未被证实。
白介素-1β是一种重要的炎性反应细胞因子，具有驱动白介素-6信号传导通路的作用。卡那奴单抗，是一种针对白介素-1β的完整人类单克隆抗体，具有抗炎作用，已经被证明可以用于风湿病。在一项高血管风险糖尿病患者的2期试验中，研究者发现具有抑制白介素-1β作用的卡那奴单抗在不降低LDL胆固醇水平的情况下能够显著降低血浆白介素-6和超敏C反应蛋白水平。
2017年9月来自波士顿的P.M. Ridker等在NEJM上公布了CANTOS试验结果，他们假设卡那奴单抗可以验证动脉粥样硬化血栓形成的炎症假说。
CANTOS是研究者驱动，国际多中心，随机双盲对照试验。纳入的患者为虽然经过积极二级预防但是其超敏C反应蛋白水平仍然>=2mg/l的心肌梗死患者。该研究共纳入了10061例患者，随机给予三个不同剂量卡那奴单抗（50、150和300mg，皮下注射每三个月1次）和安慰剂。主要有效性终点为非致死性心肌梗死，非致死性卒中或心血管死亡。
在48个月时，与安慰剂相比三个不同剂量组（50、150、300mg）超敏C反应蛋白从基线水平降低的比率分别为26%、37%和41%。卡那奴单抗未能降低脂质水平。平均随访3.7，安慰剂组、50mg、150mg、300mg组主要终点发生率分别为4.5、4.11、3.86和3.9个事件/100患者-年。与安慰剂比较各个治疗组（50、150、300mg组）的HR分别为0.93（95% CI，0.80 to 1.07; P = 0.30），0.85 (95% CI, 0.74 to 0.98; P = 0.021)，0.86 (95% CI, 0.75 to 0.99; P = 0.031)。150mg剂量组符合预定义统计学标准，包括主要终点和二级终点（因为不稳定心绞痛住院并紧急血运重建）的显著性差异。与安慰剂相比，卡那奴单抗与致死性感染较高发生率有关。全因死亡没有显著性差异（卡那奴单抗所有剂量组vs安慰剂的HR，0.94；95% CI，0.83 - 1.06；P = 0.31）。
最终作者认为针对白介素-1β免疫途径的卡那奴单抗（150mg，每3个月1次皮下注射）能够降低复发性心血管事件（vs安慰剂），不依赖于脂质水平降低。
文献出处：
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
N Engl J Med. 2017 Sep 21;377(12):1119-1131.
Paul M Ridker, M.D., Brendan M. Everett, M.D., Tom Thuren, M.D., Jean G. MacFadyen, B.A., William H. Chang, Ph.D., Christie Ballantyne, M.D., Francisco Fonseca, M.D., Jose Nicolau, M.D., Wolfgang Koenig, M.D., Stefan D. Anker, M.D., John J.P. Kastelein, M.D., Jan H. Cornel, M.D., Prem Pais, M.D., Daniel Pella, M.D., Jacques Genest, M.D., Renata Cifkova, M.D., Alberto Lorenzatti, M.D., Tamas Forster, M.D., Zhanna Kobalava, M.D., Luminita Vida-Simiti, M.D., Marcus Flather, M.D., Hiroaki Shimokawa, M.D., Hisao Ogawa, M.D., Mikael Dellborg, M.D., Paulo R.F. Rossi, M.D., Roland P.T. Troquay, M.D., Peter Libby, M.D., and Robert J. Glynn, Sc.D., for the CANTOS Trial Group*
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.)
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