Background:The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function.Methods:The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point—reduction in the composite of cardiovascular death or first HF hospitalization—and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score).Conclusions:Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.

中文翻译：

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自主调节疗法对心力衰竭患者的影响：ANTHEM-HFrEF关键研究设计。

背景：ANTHEM-HFrEF（通过减少射血分数来增强心肌功能和减少心力衰竭进展的自主调节疗法）关键性研究是一项自适应，开放标签，随机对照研究，旨在评估自主调节疗法是否会使晚期HFrEF患者受益。尽管早期研究支持迷走神经刺激可能为HFrEF提供自主调节疗法，但较大的临床试验结果却不一致。ANTHEM-HFrEF研究采用新颖的设计，具有自适应的样本量选择，评估对发病率和死亡率以及症状和功能的影响。方法：ANTHEM-HFrEF研究将使患者（2：1）随机接受自主调节疗法加指南导向的药物治疗，或仅针对指南的药物治疗。发病率和死亡率试验采用传统的频度方法分析主要结局终点-减少心血管死亡或首次HF住院的综合因素-以及针对样本量选择的贝叶斯自适应方法。纳入ANTHEM-HFrEF研究的第二项试验是评估症状和功能的改善。症状/功能的成功将需要满足2个与风险相关的条件（减少心血管死亡/ HF住院的趋势以及充分摆脱与器械相关的严重不良事件的趋势）和3个疗效终点要素（左心室EF的改变，步行6分钟的路程） ，以及堪萨斯城心肌病问卷调查的整体评分。）结论：迷走神经刺激仍然是一种有希望但尚未得到证实的HFrEF治疗方法。成功的ANTHEM-HFrEF关键性研究将为HFrEF治疗提供重要的进展，并为加快对新疗法的评估提供模型。临床试验注册：URL：http://www.clinicaltrials.gov。唯一标识符：NCT03425422。