Late Sodium Current Blockade in High-Risk ICD Patients - DCC

高危 ICD 患者的晚期钠电流阻断 - DCC

基本信息

批准号：
8392239
负责人：
ARTHUR J. MOSS
金额：
$ 72.18万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8392239
关键词：
Address Adrenergic beta-Antagonists Adverse effects Amiodarone Anti-Arrhythmia Agents Archives Arrhythmia Atrial Fibrillation Back Calcium Cardiac Cardiomyopathies Cells Cessation of life Clinical Clinical Trials Communication Confidentiality Controlled Clinical Trials Data Data Analyses Data Collection Data Coordinating Center Data Reporting Data Set Development Double-Blind Method Effectiveness Enrollment Event Exercise Heart failure Hospitalization Human Resources Impairment Implantable Defibrillators Internet Investigation Ischemia Left Maintenance Manuals Measures Medical Minnesota Monitor Mosses Myocardial Myocardial Infarction Myocardial Ischemia Myocardium National Heart, Lung, and Blood Institute Online Systems Patients Pharmaceutical Preparations Placebo Control Placebos Play Printing Process Property Quality Control Quality of life Questionnaires Randomized Records Recurrence Relaxation Reporting Research Risk Role Safety Secure Shock Sodium Sodium Channel Sotalol Stress System Tachyarrhythmias Testing Torsades de Pointes Training Universities Update Ventricular Ventricular Arrhythmia Ventricular Fibrillation Ventricular Tachycardia Walking abstracting arm base computerized data acquisition data management design effective therapy follow-up high risk implantable device improved interest mortality novel operation public health relevance randomized trial ranolazine

项目摘要

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)

描述（由申请人提供）：对于室性心律失常事件高危患者来说，治疗选择有限。单独使用β受体阻滞剂并不能提供足够的保护，索他洛尔的有效性有限，胺碘酮虽然对某些患者组有效，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钠超载有关。晚钠电流在此过程中起着关键作用。钠超载导致心肌细胞钙超载，从而增加心肌对室性快速心律失常的脆弱性以及心肌舒张舒张的损害增加，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律失常特性的新型药物，能够独特地阻断晚期钠电流，减少细胞内钙超载，并改善心室舒张期。雷诺嗪的抗缺血和抗心律失常特性可能会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。我们提出一项随机双盲安慰剂对照临床试验，招募 1,200 名高危 ICD 患者，除了最佳药物治疗外，他们还将接受雷诺嗪或安慰剂治疗。该研究的主要目的是确定使用 ICD 的高危患者服用雷诺嗪是否有助于减少达到复合心律失常终点（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）的患者数量。该研究的次要目的是：1) 确定雷诺嗪给药是否会降低复合主要终点（包括因心脏原因住院或死亡）的可能性，2) 确定雷诺嗪给药是否会降低复合次要终点（包括 CHF）的可能性住院或死亡，3) 确定雷诺嗪治疗是否会减少因心脏原因重复住院的次数，4) 评估雷诺嗪给药是否会减少重复 ICD 治疗的可能性，5) 评估是否雷诺嗪给药将降低适当 ICD 电击的可能性，6) 确定雷诺嗪治疗是否与通过 6 分钟步行测试 (6MWT) 测量的运动能力的改善以及通过明尼苏达州离开心脏协会测量的生活质量的改善相关失败问卷 (MLHFQ) 和 7) 利用记录所有类型室性快速心律失常（包括扭转型室性心动过速）的 ICD 询问数据来评估雷诺嗪治疗的安全性足尖）。该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。（摘要完）