Duke University School of Medicine and the Duke Clinical Research Institute, Durham, North Carolina, USA.
British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
JACC Heart Fail. 2021 Feb;9(2):146-157. doi: 10.1016/j.jchf.2020.10.012. Epub 2020 Nov 25.
The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events.
Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF).
This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic).
In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation.
Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325).
本研究的主要目的是确定急性心力衰竭（AHF）患者中 cimlanod 的耐受剂量。次要目的是确定包括生物标志物、症状和临床事件在内的疗效信号。
亚硝酰（HNO）供体具有血管扩张、正性肌力和变力性作用。百时美施贵宝-986231（cimlanod）是一种正在开发用于急性心力衰竭（AHF）的 HNO 供体。
这是一项为期 48 小时的双盲、随机、安慰剂对照的 IIb 期临床试验，比较 cimlanod 与安慰剂在因 AHF 住院的射血分数≤40%的左心室患者中的疗效。在第一部分中，患者以 1:1 的比例随机接受递增剂量的 cimlanod 或匹配的安慰剂治疗。在第二部分中，患者以 1:1:1 的比例随机接受第一部分中两种最高耐受剂量的 cimlanod 或安慰剂之一。主要终点是临床相关低血压（收缩压<90mmHg 或患者出现症状）的发生率。
在第一部分（n=100）中，cimlanod 比安慰剂更常见临床相关低血压（20%比 8%；相对风险 [RR]：2.45；95%置信区间 [CI]：0.83 至 14.53）。在第二部分（n=222）中，安慰剂的临床相关低血压发生率为 18%，cimlanod 6μg/kg/min 的发生率为 21%（RR：1.15；95%CI：0.58 至 2.43），cimlanod 12μg/kg/min 的发生率为 35%（RR：1.9；95%CI：1.04 至 3.59）。与安慰剂相比，cimlanod 输注期间 N 末端脑钠肽前体和胆红素降低，但在治疗停止后这些差异并未持续。
与安慰剂相比，cimlanod 剂量为 6μg/kg/min 时耐受性良好。cimlanod 降低了充血标志物，但这种作用在治疗期结束后并未持续。（评估 48 小时输注 HNO（亚硝酰）供体在心力衰竭住院患者中的安全性和疗效[STANDUP AHF]；NCT03016325）。
