血管紧张素 II 型 1 受体偏倚配体在急性心力衰竭患者中的应用：一项随机、双盲、安慰剂对照、IIB 期、剂量范围试验（BLAST-AHF）。
Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF).
机构信息
Department of Emergency Medicine, Indiana University School of Medicine & Indianapolis EMS, Indianapolis, IN, USA.
SUNY Stonybrook School of Medicine, New York, NY, USA.
出版信息
Eur Heart J. 2017 Aug 7;38(30):2364-2373. doi: 10.1093/eurheartj/ehx196.
AIMS
Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.
METHODS AND RESULTS
BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.
CONCLUSION
In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.
目的
目前，尚无急性心力衰竭（AHF）治疗方法能明确改善预后。降低急性心力衰竭（AHF）的发病率和死亡率仍是一项未满足的需求。TRV027 是一种新型血管紧张素 II 型 1 型受体（AT1R）“偏向性”配体，可选择性拮抗血管紧张素 II 的负面作用，同时保留 AT1R 刺激的潜在促收缩作用。BLAST-AHF 旨在确定 TRV027 的安全性、疗效和最佳剂量，以推进未来的研究。
方法和结果
BLAST-AHF 是一项多中心、国际性、随机、双盲、安慰剂对照、平行组、IIb 期剂量范围研究，将 AHF 患者纳入 4 组：安慰剂、1、5 或 25mg/h 的 TRV027。治疗采用静脉输注 48-96 小时。主要复合终点包括以下内容：（i）从基线到第 30 天的死亡时间，（ii）从基线到第 30 天心力衰竭再入院的时间，（iii）心力衰竭恶化后第 5 天的第一个评估时间点，（iv）呼吸困难视觉模拟量表（VAS）评分的变化，计算为从基线到第 5 天的时间曲线下面积（AUC），代表从基线的变化，以及（v）从基线到第 5 天的初始住院时间（天）。分析采用意向治疗的改良方法。共有 621 例患者入组。在 254 例患者后，进行了一项预设的中期分析，导致了几项方案变更，包括降低血压纳入标准以及采用 2:1:2:1 的新分配方案，使安慰剂和 5mg/h 剂量权重增加。与安慰剂相比，无论剂量如何，TRV027 都没有在主要复合终点或任何单一指标上带来任何益处。TRV027 没有出现任何重大安全性问题。
结论
在这项 IIb 期剂量范围的 AHF 研究中，与安慰剂相比，TRV027 并不能改善患者的临床状况，随访至 30 天。
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