Pilot Randomized Trial with Flecainide in ARVC Patients

致心律失常性右室心肌病(ARVC)是一种遗传性心律失常 有很高的室性心动过速或纤颤风险，以及植入型心律转复除颤器 仍然是姑息治疗的首选。使用不同的药物进行抗心律失常治疗，包括 β-受体阻滞剂、索他洛尔和胺碘酮在降低心律失常风险方面通常无效 事件。使用心脏特异性三苯氧胺的一种新的小鼠模型的最新实验数据 诱导的PKP2缺乏表明触发活性增强和肌浆网增加 通过RyR2通道的网状(SR)钙释放参与肾上腺素能诱导 ARVC环境中的心律失常。这项研究还报告了氟卡胺有效地防止了 在实验动物身上观察到的心律失常。分开临床前和轶事 临床报告还表明，氟卡胺可能通过阻断RyR2受体，可能是 ARVC中有希望的抗心律失常方法。此外，在一项小型随机试验中 氟卡胺可有效降低儿茶酚胺能患者的室性心律失常 多形性室性心动过速，一种与RyR2突变导致SR增加有关的疾病 释放并引发心律失常。这些结果为以下结论提供了有力的理论基础 实施确定性随机临床试验以确定氟卡胺是否会 减少高危ARVC患者危及生命的VT/VF事件；但在进行 如此大规模的研究是一个试验性项目，重点是氟卡胺治疗的抗心律失常作用和 ARVC患者的安全性是必要的。因此，我们建议进行一项先导研究，目的是 随机、双盲、安慰剂对照交叉试验，100 mg，2次/d 氟卡胺或与之匹配的安慰剂，为期4周，每种药物都有一个洗脱期。研究人口意愿 包括38名符合2010年ARVC工作组标准的ARVC患者，他们至少 21岁，植入了ICD，在24小时的Holter记录中至少显示了500个VPB。 这项试验性试验的主要具体目的是确定氟卡胺给药是否 与ARVC中室性早搏(VEB)的数量显著减少相关 患有ICD的患者。 次要的具体目标是：1)评估氟卡胺的安全性，特别是 2)评价氟卡胺对室性心动过速负荷的影响 7天心电记录；3)评价氟卡胺对房性早搏负荷的影响 7天录音；4)论证罕见遗传性心律失常ARVC入选的可行性 根据计划中的未来VT/VF/死亡大型临床试验进行的随机研究的患者 作为终结点。

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with high risk of ventricular tachycardia or fibrillation, and implantable cardioverter defibrillator remains as palliative therapy of choice. Antiarrhythmic therapy with different agents including beta-blockers, sotalol and amiodarone are usually not effective in reducing risk of arrhythmic events. Recent experimental data using a novel murine model with cardiac-specific tamoxifen induced PKP2 deficiency indicated that enhanced triggered activity and increased sarcoplasmic reticulum (SR) calcium release via RyR2 channels could contribute to adrenergic-induced arrhythmias in the setting of ARVC. This study also reported that flecainide effectively prevented the arrhythmias observed in the experimental animals. Separate preclinical and anecdotal clinical reports also suggest that flecainide, likely through a block of the RyR2 receptor, may be a promising antiarrhythmic approach in ARVC. Furthermore, in a small randomized trial flecainide was effective in reducing ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia, a condition linked to RyR2 mutations causing increased SR release and triggered arrhythmias. These results provide a strong rationale for the implementation of a definitive randomized clinical trial to determine whether flecainide will reduce life-threatening VT/VF episodes in high-risk ARVC patients; however before conducting such a large study a pilot project focused on antiarrhythmic effects of flecainide therapy and its safety in ARVC patients is needed. Therefore, we propose to conduct a pilot study designed as randomized double-blinded placebo-controlled crossover trial with administration of 100 mg bid of Flecainide or matching placebo for 4 weeks each with a washout period. Study population will include 38 ARVC patients diagnosed with the 2010 ARVC Task Force Criteria who are at least 21 years old, have implanted ICD, and show at least 500 VPBs in a 24-hour Holter recording. Primary specific aim of this pilot trial is to determine whether Flecainide administration is associated with a significant reduction of number of ventricular ectopic beats (VEBs) in ARVC patients with ICDs. Secondary specific aims are: 1) to assess safety of flecainide administration with particular emphasis on proarrhythmic response; 2) to assess effects of flecainide on burden of VT runs in 7-day ECG recordings; 3) to assess effects of flecainide on burden of atrial premature beats in 7-day recordings; 4) to demonstrate feasibility of enrollment of rare inherited arrhythmia ARVC patients in a randomized study in the light of planned future large clinical trial with VT/VF/death as endpoint.