Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction: The ANTHEM-HFrEF Trial.

This paper describes results from a pivotal trial, while addressing challenges investigators face following premature trial termination.

本文描述了一项关键试验的结果，同时讨论了研究者在试验提前终止后面临的挑战。

We report VNS actions in patients with HF with reduced ejection fraction and investigators response to early discontinuation.

我们报告了在射血分数降低的心力衰竭患者中进行迷走神经刺激（VNS）的行动以及研究者对早期停药的反应。

Methods

Randomization was 2:1 to VNS or control.

随机分配比例为2:1，分为VNS组或对照组。

Entry required NYHA functional class II or III, left ventricular ejection fraction (LVEF) ≤35%, and N-terminal pro-B-type natriuretic peptide ≥800 pg/mL.

入组要求纽约心脏病协会(NYHA)功能II级或III级，左心室射血分数(LVEF)≤35%，以及N末端前体B型利钠肽≥800 pg/mL。

Primary efficacy endpoint was time to cardiovascular death or HF hospitalization.

主要疗效终点是心血管死亡或心力衰竭住院的时间。

Secondary endpoints included LVEF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire.

次要终点包括左心室射血分数（LVEF）、6分钟步行距离和堪萨斯城心肌病问卷。

Adaptive sample sizing targeted ≤1,000 patients.

自适应样本量设计目标为≤1000名患者。

P values are 1-sided.

P值是单侧的。

Results

After randomizing 532 patients, the sponsor terminated enrollment, unrelated to futility or efficacy.

在随机化了532名患者后，赞助商因与无效或疗效无关的原因终止了招募。

The primary efficacy endpoint was not met (HR: 0.84; 95% CI: 0.62-1.12; P = 0.115).

主要疗效终点未达到（风险比：0.84；95%置信区间：0.62-1.12；P = 0.115）。

The primary safety endpoint achieved 96.7% freedom from procedure- or device-related serious adverse events.

主要安全性终点实现了96.7%的无与程序或设备相关的严重不良事件的自由。

Autonomic engagement persisted long-term.

自主神经参与持续长期存在。

Findings were favorable, although inconclusive, for the primary endpoint, HF hospitalization, Kansas City Cardiomyopathy Questionnaire, NYHA functional class, and 6-minute walk distance.

尽管结果不确定，但对主要终点、心力衰竭住院、堪萨斯城心肌病问卷、NYHA功能等级和6分钟步行距离的发现是有利的。

LVEF was unchanged.

左心室射血分数（LVEF）保持不变。

The still-blinded investigators, seeking to extend data reporting while maintaining scientific integrity, had prespecified a single exploratory outcomes-symptoms win ratio.

在保持科学诚信的同时，希望延长数据报告的尚未揭盲的研究者们，已经预先设定了一项单一的探索性结果-症状胜率。

Results were favorable although merely hypothesis-generating, given primary endpoint neutrality, multiplicity, subjective bias, and marginal statistical significance.

尽管主要终点结果中性、多重性、主观偏倚以及边缘统计显著性，结果是有利的，但仅仅是假设生成性的。

Conclusions

Early termination outside Data Monitoring Committee processes challenged investigators to maintain scientific and ethical integrity and transparency, while optimizing data reporting.

在数据监测委员会流程之外的早期终止，挑战了研究者保持科学和伦理的完整性以及透明度，同时优化数据报告。

The underpowered primary endpoint was neutral. Data documented feasibility, safety, and autonomic engagement.

主要终点的统计功效不足，结果为中性。记录的数据表明了可行性和安全性，以及自主神经的参与。

Trends favoring outcomes, symptoms, and function were inconclusive although hypothesis-generating.

尽管具有假设生成性，但支持结果、症状和功能趋势的证据尚不明确。

Importantly, we provide guidance for investigators facing trial discontinuation.

重要的是，我们为面临试验终止的研究人员提供了指导。

(ANTHEM-HFrEF Pivotal Study [Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction]; NCT03425422).

（ANTHEM-HFrEF 关键研究[自主神经系统调节疗法以增强心肌功能并减少射血分数降低的心力衰竭进展]；NCT03425422）。