Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Am Heart J. 2011 Oct;162(4):597-605. doi: 10.1016/j.ahj.2011.06.012. Epub 2011 Sep 14.
Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates.
The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation.
If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.
炎症参与动脉粥样硬化血栓形成过程的所有阶段，高敏 C 反应蛋白（hsCRP）等炎症生物标志物升高的患者血管风险增加。然而，直接抑制炎症是否会降低心血管事件发生率仍不清楚。
CANTOS 将评估白细胞介素-1β（IL-1β）抑制与安慰剂相比是否可以降低稳定型冠心病患者（尽管采用了当代二级预防策略，但由于 hsCRP 持续升高（>2mg/L），患者仍处于高血管风险）复发性心肌梗死、中风和心血管死亡的发生率。Canakinumab 是一种人源单克隆抗体，可选择性中和 IL-1β，IL-1β 是一种促炎细胞因子，在动脉粥样硬化血栓形成过程中发挥多种作用，并被核苷酸结合富含亮氨酸重复的吡喃受体 3 炎性体激活，该过程由胆固醇晶体促进。Canakinumab 可显著降低全身 C 反应蛋白和其他炎症生物标志物水平，通常具有良好的耐受性，目前被批准用于治疗遗传性 IL-1β 驱动的炎症性疾病，如 Muckle-Wells 综合征。在一项使用事件驱动意向治疗方案的多国合作努力中，CANTOS 将随机分配 17200 例稳定型心肌梗死后 hsCRP 持续升高的患者接受安慰剂或 canakinumab 治疗，剂量为每 3 个月 50、150 或 300mg，皮下给药。所有参与者将在估计的 4 年时间内接受随访，以评估试验的主要终点（非致命性心肌梗死、非致命性中风、心血管死亡）以及其他血管事件、总死亡率、不良事件和与炎症相关的特定临床终点，包括新发糖尿病、静脉血栓形成和心房颤动。
如果结果为阳性，CANTOS 将证实动脉粥样硬化血栓形成的炎症假说，并为心血管疾病的二级预防和新发糖尿病提供一种新的基于细胞因子的治疗方法。
