Importance The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population.

Objective To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms.

Design, Setting, and Participants A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk.

Intervention Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy.

Main Outcomes and Measures The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy.

Results Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns.

Conclusions and Relevance The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels.

Trial Registration ClinicalTrials.gov Identifier: NCT02816736

重要性 由于在该人群中的临床经验有限，实践指南不认可使用沙库巴曲/缬沙坦用于射血分数降低的纽约心脏协会 IV 级心力衰竭患者。

目的 比较沙库巴曲/缬沙坦治疗晚期心力衰竭、射血分数降低和近期纽约心脏协会 IV 级症状的患者。

设计、设置和参与者 进行了一项双盲随机临床试验；共纳入 335 名晚期心力衰竭患者。该试验于 2017 年 3 月 2 日开始，由于存在 COVID-19 风险，于 2020 年 3 月 23 日早些时候停止。

干预 除了推荐的治疗外，患者被随机分配接受沙库巴曲/缬沙坦（目标剂量，200 mg，每天两次）或缬沙坦（目标剂量，160 mg，每天两次）。

主要结果和测量 N-末端脑钠肽前体 (NT-proBNP) 与通过 24 周治疗测量的基线相比的曲线下面积 (AUC)。

结果 纳入分析的 335 名患者中，男性 245 人（73%）；平均 (SD) 年龄为 59.4 (13.5) 岁。72 名符合条件的患者 (18%) 在短期磨合期内不能耐受 100 mg/d 的沙库巴曲/缬沙坦，49 名患者 (29%) 在 24 周试验期间停用沙库巴曲/缬沙坦。缬沙坦治疗组 (n = 168) 的中位 NT-proBNP AUC 为 1.19 (IQR, 0.91-1.64)，而沙库巴曲/缬沙坦治疗组 (n = 167) 的 AUC 为 1.08 (IQR, 0.75-1.60) . NT-proBNP AUC 的估计变化比率为 0.95（95% CI 0.84-1.08；P = .45)。与缬沙坦相比，沙库巴曲/缬沙坦治疗并未改善生存天数、出院天数和无心力衰竭事件的临床复合数据。除了在沙库巴曲/缬沙坦组中非危及生命的高钾血症有统计学意义的增加（28 [17%] vs 15 [9%]；P  = .04），没有观察到安全问题。

结论和相关性 该试验的结果表明，在射血分数降低的慢性晚期心力衰竭患者中，沙库巴曲/缬沙坦和缬沙坦在降低 NT-proBNP 水平方面没有统计学上的显着差异。

试验注册 ClinicalTrials.gov 标识符：NCT02816736