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

基本信息

批准号：
8884625
负责人：
Wojciech Zareba
金额：
$ 104.65万
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：
2010-08-25 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884625
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 Health 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 myocardial damage novel pre-clinical 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）：对于患有心室心律不齐事件的高风险的患者的治疗选择有限。仅靠β受体阻滞剂不能提供足够的保护，索洛尔醇的有效性有限，尽管由于长期使用的副作用和局限性，因此很少使用某些患者的胺碘酮。缺血和心肌病与心肌细胞的钠超载有关。晚期钠电流在此过程中起关键作用。钠过载导致心肌细胞的钙过载，从而增加心肌对心室心律失常的脆弱性，并增加心肌舒张性舒张性障碍，从而增加缺血和心肌损伤的风险。雷诺嗪是一种新型药物，具有抗缺血性和抗心律失常特性，可独特地阻断晚期钠电流，减少细胞内钙的过载，并改善心室的舒张性舒张性。雷诺嗪的抗缺血性和抗心律失常特性可能会降低心律不齐事件的可能性，并改善患有心律失常风险的患者的临床病程。我们提出了一项随机的双盲安慰剂对照临床试验，其中包括1,200名高风险ICD患者，除最佳医疗疗法外，还将接受雷诺嗪或安慰剂治疗。该研究的主要目的是确定ICDS高危患者的雷诺嗪在达到复合心律失常终点的患者数量减少，该终点是由心室心动过速组成的或需要适当的ICD冲击或死亡（首先发生的）的颤动或纤维化。 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雷诺嗪的给药是否会降低重复ICD疗法的可能性，5）评估雷诺嗪的给药是否会降低适当的ICD冲击的可能性，6）确定雷诺津治疗是否会与6分钟步行测试（6mmwt）和质量的质量质量的锻炼能力相关的运动能力是否与锻炼能力相关联（ 7）使用ICD询问数据来评估雷诺嗪治疗的安全性，记录了所有类型的心室心律失常（包括尖角）。该提案由两个涵盖试验组成部分的聚类应用程序组成：临床核心 - 领先应用和数据协调中心。（抽象的结尾）

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Arrhythmic and Mortality Outcomes Among Ischemic Versus Nonischemic Cardiomyopathy Patients Receiving Primary ICD Therapy.

DOI：
10.1016/j.jacep.2021.06.020
发表时间：
2022-01
期刊：
JACC. Clinical electrophysiology
影响因子：
0
作者：
Narins CR;Aktas MK;Chen AY;McNitt S;Ling FS;Younis A;Zareba W;Daubert JP;Huang DT;Rosero S;Kutyifa V;Goldenberg I
通讯作者：
Goldenberg I

Survival After Implantable Cardioverter-Defibrillator Shocks.

DOI：
10.1016/j.jacc.2021.03.329
发表时间：
2021-05-25
期刊：
Journal of the American College of Cardiology
影响因子：
24
作者：
Aktaş MK;Younis A;Zareba W;Kutyifa V;Klein H;Daubert JP;Estes M;McNitt S;Polonsky B;Goldenberg I
通讯作者：
Goldenberg I