Interleukin-1 blockade in acute myocardial infarction

描述(由申请人提供)：尽管目前有早期再通的策略，但急性心肌梗死(AMI)仍然是发病率和死亡率的主要原因。许多患者在病程中过早死亡，而那些幸存下来的患者死于不利的心脏重构和心力衰竭(HF)的风险增加。事实上，尽管急性心肌梗死的治疗有所改善，早期死亡率也有所下降，但心力衰竭的发病率和患病率继续上升到前所未有的水平。因此，对预防急性心肌梗死后心力衰竭的额外治疗的迫切需要尚未得到满足。IL-1阻断可能代表了一种全新的预防心力衰竭的方法，可能导致改善生活质量，减少住院，降低成本，并最终改善长期生存。心肌最初的缺血性损伤会引发强烈的炎症反应，导致进一步的损伤，并促进心功能不全和心衰。白介素1(IL-1)是参与组织损伤反应的典型炎性细胞因子。在急性心肌梗死中，IL-1活性增加，并放大炎症反应，导致心肌细胞死亡。Anakinra是一种重组形式的人IL-1受体拮抗剂(rhIL-1ra)，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。我们最近完成了两项试验性安全性和可行性研究，VCU-ART(n=10)和VCU-ART2(n=30)，用于急性ST段抬高性心肌梗死(STEMI)患者，随机1：1每日服用阿那金拉100 mg或服用安慰剂14天。阿纳金拉耐受性良好，不良反应极少。在两项试验的联合分析中，Anakinra与炎症标记物的显著降低(-50%，P=0.035)和3个月后症状性心力衰竭的发生率下降(5%对30%，P=0.035)相关。我们提出了一项随机、双盲、多中心的初步研究，采用两种不同的Anakinra方案(每天两次与每天两次)，以确定Anakinra对STEMI期间急性炎症反应的最大影响，并评估Anakinra对STEMI后12个月心力衰竭发生率的影响。尽管目前的初步研究可能不足以检测死亡率或再住院率之间在统计学上的显著差异，但这项研究将提供对 潜在的效果，然后可以在更大的III期临床试验中进行探索(作为R1应用的一部分)。

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).