马昔腾坦用于射血分数保留或轻度降低且伴有肺血管疾病的心力衰竭：SERENADE随机临床试验及开放标签扩展研究结果
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.
作者信息
Shah Sanjiv J, Bonderman Diana, Borlaug Barry A, Cleland John G F, Lack Gabriela, Lu Wentao, Voors Adriaan A, Zannad Faiez, Gladwin Mark T
机构信息
Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
Division of Cardiology, Favoriten Clinic, Wiener Gesundheitsverbund, Vienna, Austria (D.B.).
出版信息
Circ Heart Fail. 2025 Mar;18(3):e011381. doi: 10.1161/CIRCHEARTFAILURE.123.011381. Epub 2025 Mar 11.
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]; =0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, -3.5 [90% CI, -8.2 to +1.2]; =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]; =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.
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，但在心力衰竭（HF）患者中并未改善预后，可能是因为它们会导致液体潴留。
方法
在这项随机、双盲、多中心试验（SERENADE [马西替坦治疗射血分数保留和肺血管疾病的心力衰竭]）中，我们评估了内皮素受体拮抗剂马西替坦对HF、左心室射血分数≥40%且患有肺血管疾病患者的影响。在为期4周的安慰剂导入期（以确保临床稳定性）后，接着是为期5周的单盲马西替坦导入期，未出现液体潴留的患者被随机分配至马西替坦组或安慰剂组。主要终点是NT - 脑钠肽前体（N末端B型利钠肽原；基线至24周）的变化；次要终点包括堪萨斯城心肌病问卷（KCCQ）临床总结评分（基线至24周）的变化以及至52周时HF恶化的时间。
结果
在入组的230例患者中，28例在安慰剂导入期被排除，60例在马西替坦导入期被排除，142例被随机分组。马西替坦对NT - 脑钠肽前体的变化无影响（几何平均比值[马西替坦/安慰剂]，1.02 [90% CI，0.88 - 1.19]；P = 0.79），对次要终点也无影响（KCCQ临床总结评分的安慰剂校正变化，-3.5 [90% CI，-8.2至 +1.2]；P = 0.22）。20例（28%）分配至马西替坦组的患者和13例（18%）分配至安慰剂组的患者发生HF恶化（风险比，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例[23%]对10例[14%]）和心脏不良事件（33例[46%]对22例[31%]）。
结论
尽管采用了针对肺血管疾病的新型富集试验设计，并排除了HF且左心室射血分数保留/轻度降低患者中与治疗相关的液体潴留，但马西替坦既未降低NT - 脑钠肽前体，也未改善HF预后。
注册信息
网址：https://www.clinicaltrials.gov；唯一标识符：NCT03153111和NCT03714815。
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