Interleukin-1 blockade in acute myocardial infarction

描述（由申请人提供）：尽管目前采取了早期再灌注策略，但急性心肌梗死（AMI）仍然是发病率和死亡率的主要原因。许多患者在过程中早期死亡，并且那些存活的患者因不良心脏重塑和心力衰竭（HF）而死亡的风险增加。事实上，尽管AMI治疗的改善和早期死亡率的降低，HF的发病率和患病率继续上升到前所未有的速度。因此，迫切需要额外的治疗来预防AMI后的HF。IL-1阻断可能代表一种预防HF的全新方法，可能导致生活质量改善，住院率降低，成本降低，并最终改善长期生存率。心肌的初始缺血性损伤引发强烈的炎症反应，导致进一步损伤并促进心功能障碍和HF。白细胞介素-1（IL-1）是参与组织对损伤的反应的原型炎性细胞因子。在AMI中，IL-1活性增加并放大炎症反应并诱导心脏细胞死亡。阿那白滞素是一种重组形式的人IL-1受体拮抗剂（rhIL-1 Ra），FDA批准用于治疗类风湿性关节炎，在治疗几种炎症性疾病方面非常有效。我们最近完成了2项安全性和可行性初步研究，VCU-ART（n=10）和VCU-ART 2（n=30），在急性ST段抬高型心肌梗死（STEMI）患者中，以1：1的比例随机接受阿那白滞素100 mg/d或安慰剂治疗14天。阿那白滞素耐受性良好，与很少的不良事件相关。在两项试验的综合分析中，阿那白滞素与炎性标志物的显著降低（-50%，P=0.01）和3个月时症状性HF发生率降低的趋势（5% vs 30%，P=0.035）相关。我们提出了一项随机、双盲、多中心、试点研究，采用两种不同的阿那白滞素方案（每日两次vs每日一次），以确定阿那白滞素对STEMI期间急性炎症反应的最大影响，并估计阿那白滞素对STEMI后12个月内HF发生率的影响。尽管目前的初步研究可能不足以检测死亡率或再住院率的统计学显著差异，但本研究将提供死亡率或再住院率的估计值。 潜在的影响，然后可以在更大的III期临床试验中探索（作为R1申请的一部分）。

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality despite current strategies for early reperfusion. Many patients die early during the course, and those who survive are at increased risk of death from adverse cardiac remodeling and heart failure (HF). Indeed, despite the improvement in AMI treatment and the reduction in early mortality, the incidence and prevalence of HF continue to rise to unprecedented rates. There is hence an urgent unmet need for additional treatments to prevent HF after AMI. IL-1 blockade may represent a completely novel approach for the prevention of HF potentially leading to improved quality of life, reduced hospitalizations, reduced costs, and ultimately improved long-term survival. The initial ischemic damage to the myocardium initiates an intense inflammatory response resulting in further damage and promoting cardiac dysfunction and HF. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine involved in the tissue response to injury. In AMI, IL-1 activity is increased and amplifies the inflammatory response and induces cardiac cell death. Anakinra is a recombinant form of human IL-1 receptor antagonist (rhIL-1Ra) that is FDA approved for the treatment of rheumatoid arthritis and is highly effective in the treatment of several inflammatory diseases. We recently completed 2 pilot safety and feasibility studies, VCU-ART (n=10) and VCU-ART2 (n=30), in patients with acute ST-segment elevation myocardial infarction (STEMI), randomized 1:1 to anakinra 100 mg daily or placebo for 14 days. Anakinra was well tolerated and associated with very few adverse events. In the combined analysis of both trials, anakinra was associated with a significant reduction in inflammatory markers (-50%, P=0.01) and a trend toward reduced incidence of symptomatic HF at 3 months (5% vs 30%, P=0.035). We propose a randomized, double-blinded, multi-center, pilot study with two different anakinra regimens (twice daily vs daily) to determine the maximum effect of anakinra on the acute inflammatory response during STEMI and to estimate the effect of anakinra on the incidence of HF up to 12 months after STEMI. Although the current pilot study is likely not sufficiently powered to detect statistically signifiant differences in the mortality or rehospitalization rates, this study will provide an estimate of the potential effect, which could be then explored in a larger phase III clinical trial (as part of a R1 application).