ANTHEM-HFrEF 试验：迷走神经刺激治疗射血分数降低的心力衰竭
ANTHEM-HFrEF 试验纳入 NYHA II–III 级、LVEF≤35%、NT-proBNP≥800 pg/mL 的射血分数降低的心力衰竭患者，按 2:1 随机分配至迷走神经刺激或对照组。入组 532 例后申办方非因无效或有效而提前终止。主要疗效终点未达到，但安全性、可行性和长期自主神经调节作用得到证实。
要点
- 迷走神经刺激主要疗效终点未达统计学显著，HR 0.84（95%CI 0.62–1.12，P=0.115）。
- 主要安全性终点达 96.7% 无操作或器械相关严重不良事件。
- 心衰住院、KCCQ、NYHA 分级和 6 分钟步行距离呈有利趋势，但仅具假设生成意义。
核心结论
- 主要疗效终点为中性，但数据证实迷走神经刺激的可行性、安全性和长期自主神经调节作用。
- 结局、症状和功能方面的有利趋势不具结论性，仅具有假设生成意义。
研究设计与样本
- 随机对照试验，按 2:1 分配至迷走神经刺激组或对照组，计划适应性样本量不超过 1000 例。
- 入组标准为 NYHA 心功能 II 或 III 级、LVEF≤35%、NT-proBNP≥800 pg/mL。
- 随机化 532 例后申办方终止入组，终止原因与无效或有效无关。
主要发现
- 主要疗效终点为心血管死亡或心衰住院时间，未达到统计学显著：HR 0.84，95%CI 0.62–1.12，P=0.115。
- 主要安全性终点为免于操作或器械相关严重不良事件，达到 96.7%。
- 心衰住院、KCCQ、NYHA 心功能分级和 6 分钟步行距离均呈有利趋势，但不具结论性。
- LVEF 无变化。
- 预设的单一探索性结局-症状胜率比结果有利，但仅具假设生成意义。
关键数值与推荐
- 入组标准：NYHA 心功能 II 或 III 级、LVEF≤35%、NT-proBNP≥800 pg/mL。
- 主要疗效终点 HR 0.84，95%CI 0.62–1.12，P=0.115。
- 主要安全性终点免于操作或器械相关严重不良事件率为 96.7%。
- 随机分组比例为 2:1（迷走神经刺激组:对照组），实际随机化 532 例。
临床怎么用
- 数据支持迷走神经刺激在射血分数降低心衰患者中的可行性和安全性，但疗效尚不明确。
- 探索性胜率比结果有利，但由于主要终点中性、多重性、主观偏倚和边际统计学意义，不能用于临床决策。
- 作者为面临试验提前终止的研究者提供了保持科学和伦理完整性、优化数据报告的指导。
局限性
- 申办方在数据监查委员会流程之外提前终止入组，导致主要终点检验效能不足。
- 探索性胜率比受多重性、主观偏倚和边际统计学意义限制，仅具假设生成意义。
- 主要疗效终点未达到统计学显著。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
BACKGROUND: Vagal nerve stimulation (VNS) may reverse autonomic dysfunction in heart failure (HF). This paper describes results from a pivotal trial, while addressing challenges investigators face following premature trial termination. OBJECTIVES: We report VNS actions in patients with HF with reduced ejection fraction and investigators response to early discontinuation. METHODS: Randomization was 2:1 to VNS or control. 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. Primary efficacy endpoint was time to cardiovascular death or HF hospitalization. Secondary endpoints included LVEF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Adaptive sample sizing targeted ≤1,000 patients. P values are 1-sided. RESULTS: After randomizing 532 patients, the sponsor terminated enrollment, unrelated to futility or efficacy. The primary efficacy endpoint was not met (HR: 0.84; 95% CI: 0.62-1.12; P = 0.115). The primary safety endpoint achieved 96.7% freedom from procedure- or device-related serious adverse events. Autonomic engagement persisted long-term. Findings were favorable, although inconclusive, for the primary endpoint, HF hospitalization, Kansas City Cardiomyopathy Questionnaire, NYHA functional class, and 6-minute walk distance. LVEF was unchanged. The still-blinded investigators, seeking to extend data reporting while maintaining scientific integrity, had prespecified a single exploratory outcomes-symptoms win ratio. Results were favorable although merely hypothesis-generating, given primary endpoint neutrality, multiplicity, subjective bias, and marginal statistical significance. CONCLUSIONS: Early termination outside Data Monitoring Committee processes challenged investigators to maintain scientific and ethical integrity and transparency, while optimizing data reporting. The underpowered primary endpoint was neutral. Data documented feasibility, safety, and autonomic engagement. Trends favoring outcomes, symptoms, and function were inconclusive although hypothesis-generating. Importantly, we provide guidance for investigators facing trial discontinuation. (ANTHEM-HFrEF Pivotal Study [Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction]; NCT03425422).
引用
- Konstam, Udelson, Mann, et al. Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction: The ANTHEM-HFrEF Trial. J Am Coll Cardiol. 2026. PMID: 42159539. doi:10.1016/j.jacc.2026.03.040
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。