Importance Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. Objective To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. Design, Setting, and Participants CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Interventions Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). Main Outcomes and Measures The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Results Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). Conclusions and Relevance Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. Trial Registration ClinicalTrials.gov Identifier: NCT03254485.

中文翻译：

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普瑞西格对射血分数保留心力衰竭患者耗氧峰值率的影响

重要性射血分数保留的心力衰竭 (HFpEF) 通常以一氧化氮缺乏为特征。目的 评估普乐利昔（一种口服可溶性鸟苷酸环化酶刺激剂）对 HFpEF 患者的疗效和不良反应。设计、设置和参与者 CAPACITY HFpEF 是一项随机、双盲、安慰剂对照的 2 期试验。59 个地点招募了 196 名心力衰竭患者，射血分数至少为 40%，氧消耗峰值速率受损（峰值 V̇o2），以及至少 2 种与一氧化氮缺乏相关的疾病（糖尿病、高血压、肥胖或晚期年龄）。该试验将患者随机分配到 3 个普瑞利呱剂量组中的 1 个或安慰剂组，但早期重新聚焦于 40 毫克普瑞利呱剂量与安慰剂的比较。参与者是从 11 月 15 日开始注册的，2017 年至 2019 年 4 月 30 日，最终随访时间为 2019 年 8 月 19 日。 干预 患者随机接受 12 周的治疗，每天服用 40 毫克普立利呱（n = 91）或安慰剂（n = 90）。主要结果和测量主要疗效终点是完成至少 8 周指定给药的患者的峰值 V̇o2 相对于基线的变化。次要终点包括 6 分钟步行测试距离和通气效率（通气/二氧化碳产生斜率）相对于基线的变化。主要不良事件终点是治疗中出现的不良事件 (TEAE) 的发生率。结果 在 181 名患者（平均 [SD] 年龄，70 [9] 岁；75 [41%] 名女性）中，155 名 (86%) 完成了试验。在安慰剂 (n = 78) 和普立利呱 (n = 65) 组中，峰值 V̇o2 的变化为 0.04 mL/kg/min（95% CI，-0.49 至 0）。56) 和 -0.26 mL/kg/min（95% CI，-0.83 至 0.31）；安慰剂调整的最小二乘组间平均变化与基线的差异为 -0.30 mL/kg/min（[95% CI，-0.95 至 0.35]；P = .37）。3 个预设的次要终点均无统计学意义。在安慰剂组和帕利西格组中，6 分钟步行测试距离的变化分别为 58.1 m（95% CI，26.1-90.1）和 41.4 m（95% CI，8.2-74.5）；与基线相比，安慰剂调整的最小二乘组间平均变化差异为 -16.7 m（95% CI，-47.4 至 13.9）。在安慰剂组和普瑞利西格组中，经安慰剂调整的最小二乘组间通气/二氧化碳产生斜率平均变化差异为 -0.3（95% CI，-1.6 至 1.0）。头晕（9.9% vs 1.1%）、低血压（8.8% vs 0%）和头痛（11% vs 6. 7%) 与安慰剂相比，含普立利呱的 TEAE。两组之间严重 TEAE 的频率相似（普瑞利呱组为 10%，安慰剂组为 11%）。结论和相关性 在 HFpEF 患者中，与安慰剂相比，可溶性鸟苷酸环化酶刺激剂 praliciguat 没有显着改善从基线到第 12 周的峰值 V̇o2。这些发现不支持在 HFpEF 患者中使用 praliciguat。试验注册 ClinicalTrials.gov 标识符：NCT03254485。没有显着改善从基线到第 12 周的峰值 V̇o2。这些发现不支持在 HFpEF 患者中使用普立利呱。试验注册 ClinicalTrials.gov 标识符：NCT03254485。没有显着改善从基线到第 12 周的峰值 V̇o2。这些发现不支持在 HFpEF 患者中使用普立利呱。试验注册 ClinicalTrials.gov 标识符：NCT03254485。