Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.
Mediterranea Cardiocentro, Naples, Italy.
Curr Atheroscler Rep. 2020 Jan 13;22(1):4. doi: 10.1007/s11883-020-0819-1.
Despite major advances in terms of prevention, diagnosis, risk-stratification, management and rehabilitation, atherosclerosis and atherothrombosis continue to have major morbidity and mortality implications worldwide. Since the unraveling of the pivotal role of inflammation in atherothrombosis pathophysiology, several focused treatments have been proposed with the ultimate goal of preventing or treating myocardial infarction, stroke, and peripheral artery disease. In particular, given the centrality of interleukin-1 (IL-1), targeted anti-IL-1 agents have attracted substantial attention and efforts. Yet, uncertainty persists on the real risk-benefit and cost-benefit balance of anti-IL-1 agents in patients with or at risk of atherothrombosis.
Several trials have been recently completed on atherothrombosis prevention and treatment with anti-IL-1 agents, ranging, for instance, from the large Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial to the series of translational studies conducted within the Virginia Commonwealth University-Anakinra Remodeling Trial (VCU-ART) platform. In light of the present scoping umbrella review, it appears evident that anti-IL-1 agents can reduce systemic inflammation and improve surrogate markers of cardiac and vascular function, with potential benefits on the risk of new/worsening heart failure. One trial suggested an increased risk of major adverse events with anti-interleukin-1 agents, possibly due to a rebound phenomenon, but this was based on a post-hoc analysis of a small number of events, and it was not supported by all other pertinent trials. The CANTOS study showed a potential hazard due to an increased risk of fatal infections, but the effect size was rather small. In addition, cost issues limit the foreseeable scope of these treatment strategies in unselected patients, calling instead for more refined prescribing. The evidence base on the risk-benefit and cost-benefit profile of anti-IL-1 agents for atherothrombosis prevention and treatment has expanded substantially in the last decade. While largely dominated by the landmark CANTOS trial, effect estimates also including the VCU-ART trials suggest complex short- and long-term effects which may prove favorable in carefully selected patients with acute or chronically sustained inflammation. Conversely, more liberal use appears less promising, and further studies with currently available agents or novel ones are eagerly needed to better define their role in the era of precision molecular medicine.
尽管在预防、诊断、风险分层、治疗和康复方面取得了重大进展，但动脉粥样硬化和动脉血栓形成仍然在全球范围内导致严重的发病率和死亡率。自从炎症在动脉血栓形成病理生理学中的关键作用被揭示以来，已经提出了几种有针对性的治疗方法，最终目标是预防或治疗心肌梗死、中风和外周动脉疾病。特别是，鉴于白细胞介素-1 (IL-1) 的核心作用，靶向抗 IL-1 药物引起了广泛关注和努力。然而，在动脉粥样硬化患者或有风险的患者中，抗 IL-1 药物的实际风险-效益和成本-效益平衡仍然存在不确定性。
最近已经完成了几项关于动脉粥样硬化预防和治疗的抗 IL-1 药物试验，例如，从大型的卡那单抗抗炎血栓结局研究（CANTOS）到弗吉尼亚联邦大学-阿那白滞素重塑试验（VCU-ART）平台内进行的一系列转化研究。鉴于目前的范围伞式综述，很明显，抗 IL-1 药物可以降低全身炎症并改善心脏和血管功能的替代标志物，从而有可能降低新发/恶化心力衰竭的风险。一项试验表明，抗白细胞介素-1 药物的主要不良事件风险增加，可能是由于反弹现象，但这是基于少数事件的事后分析，并非所有其他相关试验都支持这一点。CANTOS 研究显示由于致命感染风险增加而存在潜在危害，但效应大小相当小。此外，成本问题限制了这些治疗策略在未选择患者中的可预见范围，因此需要更精细的处方。在过去十年中，抗 IL-1 药物在动脉粥样硬化预防和治疗中的风险-效益和成本-效益概况的证据基础已经大大扩展。尽管主要由具有里程碑意义的 CANTOS 试验主导，但包括 VCU-ART 试验在内的效应估计也表明，在急性或慢性持续炎症的精心选择患者中，可能会产生复杂的短期和长期影响，这可能是有利的。相反，更自由的使用似乎不太有希望，并且迫切需要使用当前可用的药物或新型药物进行进一步研究，以更好地定义它们在精准分子医学时代的作用。
