Macitentan for Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Pulmonary Vascular Disease: Results of the SERENADE Randomized Clinical Trial and Open-Label Extension Study.

IF 7.8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Heart Failure Pub Date : 2025-03-01 Epub Date: 2025-03-11 DOI:10.1161/CIRCHEARTFAILURE.123.011381

Sanjiv J Shah, Diana Bonderman, Barry A Borlaug, John G F Cleland, Gabriela Lack, Wentao Lu, Adriaan A Voors, Faiez Zannad, Mark T Gladwin

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引用次数: 0

Abstract

Background: Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention.

Methods: In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks.

Results: Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88-1.19]; P=0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, -3.5 [90% CI, -8.2 to +1.2]; P=0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83-2.67]; P=0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo.

Conclusions: Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes.

Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03153111 and NCT03714815.

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马西坦治疗心力衰竭伴射血分数保留或轻度降低和肺血管疾病：SERENADE随机临床试验和开放标签扩展研究的结果

背景：尽管内皮素受体拮抗剂具有良好的血流动力学和神经激素效应，但它们并没有改善心衰患者的预后，这可能是因为它们会导致体液潴留：在这项随机、双盲、多中心试验（SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]）中，我们评估了内皮素受体拮抗剂马西替坦对心力衰竭、左室射血分数≥40%和肺血管疾病患者的作用。经过为期4周的安慰剂试验（以确保临床稳定性）和为期5周的单盲马西替坦试验后，未出现液体潴留的患者被随机分配到马西替坦或安慰剂中。主要终点是NT-proBNP（N-末端前B型钠尿肽；基线至24周）的变化；次要终点包括KCCQ（堪萨斯城心肌病问卷）临床总分（基线至24周）的变化和52周内HF恶化的时间：在230名入选患者中，28人在安慰剂试验期间被排除，60人在马西替坦试验期间被排除，142人被随机分组。马西替坦对NT-proBNP的变化（几何平均比值[马西替坦/安慰剂]，1.02 [90% CI，0.88-1.19]；P=0.79）或次要终点（安慰剂校正后的KCCQ临床总分变化，-3.5 [90% CI，-8.2至+1.2]；P=0.22）没有影响。20例（28%）接受马西替坦治疗的患者和13例（18%）接受安慰剂治疗的患者出现了HF恶化（危险比为1.48 [90% CI, 0.83-2.67]；P=0.24）。与安慰剂相比，更多接受马西替坦治疗的患者出现液体潴留（16[23%]对10[14%]）和心脏不良事件（33[46%]对22[31%]）：结论：尽管采用了新颖的增强试验设计，以肺血管疾病为目标，并排除了左室射血分数保留/轻度降低的 HF 患者与治疗相关的体液潴留，但玛吉替坦既不能降低 NT-proBNP 也不能改善 HF 预后：URL：https://www.clinicaltrials.gov；唯一标识符：NCT03153111和NCT03714815。

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来源期刊

Circulation: Heart Failure 医学-心血管系统

CiteScore

12.90

自引率

3.10%

发文量

271

审稿时长

6-12 weeks

期刊介绍： Circulation: Heart Failure focuses on content related to heart failure, mechanical circulatory support, and heart transplant science and medicine. It considers studies conducted in humans or analyses of human data, as well as preclinical studies with direct clinical correlation or relevance. While primarily a clinical journal, it may publish novel basic and preclinical studies that significantly advance the field of heart failure.