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

高危 ICD 患者的晚期钠电流阻断 - CCC - 先导应用

• 批准号: 7885028
• 负责人: Wojciech Zareba
• 金额: $ 144.94万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-25 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885028
• 关键词: Action Potentials; Address; Adrenergic beta-Antagonists; Adverse effects; Amiodarone; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Calcium; Cardiac; Cardiomyopathies; Cells; Cessation of life; Clinical; Clinical Trials; Controlled Clinical Trials; Data; Data Coordinating Center; Development; Double-Blind Method; Effectiveness; Enrollment; Event; Exercise; Heart failure; Hospitalization; Impairment; Implantable Defibrillators; Ischemia; Lead; Left; Lidocaine; Measures; Medical; Minnesota; Minor; Molecular Structure; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; National Heart, Lung, and Blood Institute; Patients; Pharmaceutical Preparations; Piperazines; Placebo Control; Placebos; Play; Process; Property; Quality of life; Questionnaires; Randomized; Records; Recurrence; Relaxation; Risk; Role; Safety; Shock; Sodium; Sodium Channel; Sotalol; Stress; Tachyarrhythmias; Testing; Torsades de Pointes; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; Walking; abstracting; diabetic patient; effective therapy; follow-up; glycemic control; high risk; implantable device; improved; interest; mortality; novel; pre-clinical; public health relevance; ranolazine

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) PUBLIC HEALTH RELEVANCE: The trial with late sodium channel blockade ranolazine in high-risk ICD patients is very much needed since there is no safe and effective treatment for a large number of patients with high risk of ventricular tachyarrhythmias. It is of interest to clinicians, NHLBI, and patients to improve the very low survival of patients at increased risk of ventricular tachyarrhythmias. It is worth stressing that late sodium current blockade represents a new scientifically attractive concept of anti-arrhythmic therapy after two decades of no significant developments in pharmacologic treatment of ventricular arrhythmias. Conducting such a trial might open the door to the development of an entire line of compounds targeting the late sodium current as their main mode of anti-arrhythmic action.

描述(由申请人提供)： 对于室性心律失常事件的高危患者，治疗选择有限。单独使用β-受体阻滞剂不能提供足够的保护，索他洛尔的效果有限，胺碘酮虽然对某些患者有效，但由于其副作用和长期使用的限制，使用频率很低。心肌缺血和心肌病与心肌细胞钠超载有关。晚期钠电流在这一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性心律失常的易感性，增加心肌舒张性损伤，从而增加缺血和心肌损伤的风险。 雷诺嗪是一种新药，具有抗缺血和抗心律失常的特性，独特地阻断晚期钠电流，减少细胞内钙超载，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。 我们提出了一项随机、双盲、安慰剂对照的临床试验，招募了1200名高危ICD患者，他们将在最佳药物治疗的基础上接受雷诺嗪或安慰剂治疗。这项研究的主要目的是确定在ICD高危患者中使用雷诺拉秦是否有助于减少达到复合性心律失常终点的患者数量，所述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纤颤，或者死亡(以先发生者为准)。这项研究的次要目的是：1)确定雷诺嗪的应用是否会降低由心脏原因住院或死亡组成的复合初级终点的可能性，2)确定雷诺嗪的应用是否会降低由心力衰竭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再次住院的次数，4)评估雷诺嗪的应用是否会降低重复ICD治疗的可能性，5)评估雷诺嗪的应用是否会降低适当的ICD休克的可能性，6)通过6分钟步行试验(6MWT)测量的运动能力和明尼苏达心力衰竭问卷(MLHFQ)测量的生活质量的改善，确定雷诺拉秦治疗是否与改善运动能力有关；7)利用记录所有类型的室性快速性心律失常(包括尖端扭转室性心动过速)的ICD问询数据，评估雷诺拉秦治疗的安全性。 该提案由两个集群应用程序组成，分别涵盖试验的各个组件：临床核心领先应用程序和数据协调中心。 (摘要结束) 公共卫生相关性： 在高危ICD患者中进行晚期钠通道阻滞剂雷诺拉秦的试验是非常必要的，因为目前还没有安全有效的治疗方法来治疗大量高危室性心律失常患者。临床医生、NHLBI和患者感兴趣的是改善室性快速性心律失常风险增加的患者的低存活率。值得强调的是，在室性心律失常的药物治疗20年来没有重大进展后，晚期钠电流阻断代表了一种新的具有科学吸引力的抗心律失常治疗概念。进行这样的试验可能会为开发一系列以晚期钠电流为主要抗心律失常作用模式的化合物打开大门。