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Praliciguat治疗射血分数保留的心力衰竭患者不能改善峰值耗氧量
作者:小柯机器人 发布时间:2020/10/24 22:27:20

美国塔夫茨医疗中心Marvin A. Konstam团队研究了Praliciguat治疗射血分数保留的心力衰竭患者对峰值耗氧量的影响。2020年10月20日,该研究发表在《美国医学会杂志》上。

射血分数保留的心力衰竭(HFpEF)通常以一氧化氮缺乏为特征。

为了评估口服可溶性鸟苷酸环化酶刺激剂Praliciguat治疗HFpEF患者的疗效和不良反应,研究组进行了一项随机、双盲、安慰剂对照的2期临床试验。2017年11月15日至2019年4月30日,研究组在59个地点招募了196名心力衰竭患者,其射血分数至少为40%,峰值耗氧率(峰值VO2)受损,至少有2种与一氧化氮缺乏有关的疾病(糖尿病、高血压、肥胖或高龄)。

将这些患者随机分组,其中91例接受每日40 mg的praliciguat治疗,90例接受安慰剂治疗,为期12周。主要疗效终点为完成至少8周指定剂量治疗的患者的V?O2峰值相对于基线的变化。次要终点包括6分钟步行测试距离和通气效率相对于基线的变化。

181名患者的平均年龄为70岁,41%为女性,共有155名(86%)完成了试验。在安慰剂组(78例)和praliciguat组(65例)中,VO2的峰值变化分别为0.04和-0.26 mL/kg/min,安慰剂校正后的组间平均变化的最小二乘方差为-0.30 mL/kg/min。

3个预先指定的次要终点均无统计学意义。在安慰剂组和praliciguat组中,6分钟步行测试距离与基线相比的变化分别为58.1 m和41.4 m;安慰剂校正后的组间平均变化的最小二乘方差为–16.7 m。

在安慰剂组和praliciguat组中,安慰剂校正后的通气效率平均变化的最小二乘方差为-0.3。与安慰剂组相比,praliciguat组紧急不良事件(TEAE)的发生率较高,其中头晕发生率分别为9.9%和1.1%,低血压分别为8.8%和0%,头痛分别为11%和6.7%。两组之间发生严重TEAE的概率相差不大,其中praliciguat组为10%,安慰剂组为11%。

总之,可溶性鸟苷酸环化酶刺激剂praliciguat治疗HFpEF患者,与安慰剂相比,并没有显著改善从基线到第12周的VO2峰值。

附:英文原文

Title: Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial

Author: James E. Udelson, Gregory D. Lewis, Sanjiv J. Shah, Michael R. Zile, Margaret M. Redfield, John Burnett, John Parker, Jelena P. Seferovic, Phebe Wilson, Robert S. Mittleman, Albert T. Profy, Marvin A. Konstam

Issue&Volume: 2020/10/20

Abstract:

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 Vo2), 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 Vo2 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 Vo2 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 Vo2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF.

DOI: 10.1001/jama.2020.16641

Source: https://jamanetwork.com/journals/jama/article-abstract/2771902

期刊信息

JAMA-Journal of The American Medical Association:《美国医学会杂志》,创刊于1883年。隶属于美国医学协会,最新IF:51.273
官方网址:https://jamanetwork.com/
投稿链接:http://manuscripts.jama.com/cgi-bin/main.plex