Late Sodium Current Blockade in High-Risk ICD Patients - CCC - Lead Application

描述（由申请人提供）： 对于室性心律失常事件高风险患者，治疗选择有限。单独的β-受体阻滞剂不能提供足够的保护，索他洛尔的有效性有限，胺碘酮虽然在某些患者组中有效，但由于其副作用和长期使用的局限性而很少使用。缺血和心肌病与心肌细胞的钠超载有关。晚钠电流在这一过程中起着关键作用。钠超负荷导致心肌细胞钙超负荷，从而增加心肌对室性快速性心律失常的脆弱性以及增加心肌舒张期舒张的损害，从而增加缺血和心肌损伤的风险。 雷诺嗪是一种具有抗缺血和抗心肌缺血特性的新型药物，其独特地阻断晚期钠电流，降低细胞内钙超载，并改善心室的舒张。雷诺嗪的抗缺血和抗心律失常特性可能降低心律失常事件的可能性，并改善有室性心律失常风险的患者的临床病程。 我们提出了一项随机双盲安慰剂对照临床试验，纳入1,200例高危ICD患者，这些患者除了接受最佳药物治疗外，还将接受雷诺嗪或安慰剂治疗。本研究的主要目的是确定在植入ICD的高风险患者中给予雷诺嗪是否有助于减少达到复合心律失常终点的患者数量，复合心律失常终点包括需要适当ICD电击的室性心动过速或颤动或死亡（以先发生者为准）。本研究的次要目的是：1）确定雷诺嗪给药是否会降低由心脏原因住院或死亡组成的复合主要终点的可能性，2）确定雷诺嗪给药是否会降低由CHF住院或死亡组成的复合次要终点的可能性，3）确定雷诺嗪治疗是否会减少因心脏原因而重复住院的次数，4）评估雷诺嗪给药是否会减少重复ICD治疗的可能性，5）评价雷诺嗪给药是否会降低适当ICD电击的可能性，6）确定雷诺嗪治疗是否与通过6分钟步行试验（6 MWT）测量的运动能力和通过明尼苏达心力衰竭问卷（MLHFQ）测量的生活质量的改善相关，和7）利用记录所有类型室性快速性心律失常（包括尖端扭转型室性心动过速）的ICD询问数据评价雷诺嗪治疗的安全性。 本提案由两个集群应用程序组成，涵盖试验的各个组成部分：临床核心-领先应用程序和数据协调中心。 (End摘要）

DESCRIPTION (provided by applicant): There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta- blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage. Ranolazine is a novel drug with anti-ischemic and anti-arrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The anti-ischemic and anti-arrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients at the risk for ventricular arrhythmias. We propose a randomized double-blind placebo-controlled clinical trial enrolling 1,200 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy. Primary aim of the study is to determine whether ranolazine administration in high-risk patients with ICDs contributes to a decrease in the number of patients reaching a composite arrhythmia endpoint consisting of ventricular tachycardia or fibrillation requiring appropriate ICD shocks, or death (whichever occurs first). Secondary aims of the study are: 1) to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints consisting of hospitalization for cardiac causes or death, 2) to determine whether ranolazine administration will decrease the likelihood of a composite secondary endpoint consisting of CHF hospitalization or death, 3) to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac causes, 4) to assess whether ranolazine administration will decrease the likelihood of repeated ICD therapies, 5) to evaluate whether ranolazine administration will decrease the likelihood of appropriate ICD shocks, 6) to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured by the 6-minute walk test (6MWT) and in the quality of life measured by the Minnesota Leaving with Heart Failure Questionnaire (MLHFQ), and 7) to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of ventricular tachyarrhythmias (including torsade de pointes). This proposal consists of two clustered applications covering respective components of the trial: Clinical Core - Leading Application, and Data Coordination Center. (End of Abstract)