Importance Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients’ condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies.

Objective To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial.

Design, Setting, and Participants The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months.

Interventions Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo.

Main Outcomes and Measures The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability.

Results Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo.

Conclusions and Relevance In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited.

Trial Registration ClinicalTrials.gov Identifier: NCT02929329

重要性 射血分数降低的心力衰竭是一种进行性临床综合征，尽管经过治疗，许多患者的病情会随着时间的推移而恶化。患有更严重疾病的患者通常不能耐受可用的药物治疗。

目的 评估 omecamtiv mecarbil 治疗严重心力衰竭 (HF) 患者的疗效和安全性，该患者参加了通过改善心力衰竭收缩力降低心脏不良结局的全球方法 (GALACTIC-HF) 随机临床试验。

设计、设置和参与者 GALACTIC-HF 研究是一项全球双盲、安慰剂对照的 3 期随机临床试验，于 2017 年 1 月至 2020 年 8 月期间在多个中心进行。共有 8232 名症状性 HF 患者（定义为纽约心脏协会症状类别II-IV) 和 35% 或更低的左心室射血分数被随机分配接受 omecamtiv mecarbil 或安慰剂，中位随访时间为 21.8 个月（范围，15.4-28.6 个月）。目前的事后分析评估了 omecamtiv mecarbil 治疗在被归类为严重 HF 的患者与没有严重 HF 的患者中的疗效和安全性。重度心衰定义为存在以下所有标准：纽约心脏协会症状等级 III 至 IV，左心室射血分数 30% 或更低，

干预 参与者以 1:1 的比例随机接受 omecamtiv mecarbil 或安慰剂。

主要结果和测量 主要终点是到第一次 HF 事件或心血管 (CV) 死亡的时间。次要终点包括 CV 死亡时间以及安全性和耐受性。

结果 在参加 GALACTIC-HF 临床试验的 8232 名患者中，2258 名患者（27.4%；平均 [SD] 年龄，64.5 [11.6] 岁；1781 名男性 [78.9%]）符合严重 HF 的指定标准。其中，1106 名患者被随机分配到 omecamtiv mecarbil 组，1152 名患者被随机分配到安慰剂组。接受 omecamtiv mecarbil 的重度心衰患者在主要终点方面经历了显着的治疗获益（风险比 [HR]，0.80；95% CI，0.71-0.90），而没有重度心衰的患者没有显着的治疗获益（HR，0.99 ; 95% CI, 0.91-1.08; P  = .005 (交互作用)。对于 CV 死亡，结果相似（患有严重 HF 与不患有严重 HF 的患者的 HR：0.88 [95% CI，0.75-1.03] vs 1.10 [95% CI，0.97-1.25]；P = .03 用于交互）。Omecamtiv mecarbil 治疗在重度 HF 患者中耐受性良好，与安慰剂相比，血压、肾功能或钾水平没有显着变化。

结论和相关性 在这项对 GALACTIC-HF 临床试验数据的事后分析中，omecamtiv mecarbil 治疗可能使重度 HF 患者首次发生 HF 事件或 CV 死亡的复合终点时间减少，具有临床意义。这些数据支持 omecamtiv mecarbil 治疗在当前治疗选择有限的患者中的潜在作用。

试验注册 ClinicalTrials.gov 标识符：NCT02929329