Lancet：重组人松弛素-2Serelaxin治疗急性心力衰竭

　　背景  重组人松弛素-2 serelaxin是一种血管活性肽激素，可产生多种生物学和血流动力学效应。初步研究显示，serelaxin治疗急性心力衰竭患者是安全的且耐受性良好，同时可见积极的临床转归征象。RELAX-AHF试验对如下假说进行了检验：接受serelaxin治疗的患者呼吸困难缓解程度大于接受标准治疗和安慰剂治疗的患者。

　　方法  RELAX-AHF是一项国际性、双盲、安慰剂对照试验，纳入症状出现后16 h内入院治疗的急性心力衰竭患者，利用对研究中心设盲的中心随机分组方案进行随机分配（1：1），接受标准治疗加48小时安慰剂或serelaxin（30 μg/kg/d）静脉输注治疗。所有患者都有呼吸困难、胸部X线片提示充血、脑钠肽（BNP）或N末端B型钠尿肽前体水平增加、轻至中度肾功能不全、收缩压＞125 mmHg。患者、给研究药物的人员以及进行研究相关评估的工作人员都不知晓治疗分配。评价呼吸困难改善的主要终点包括5天时视觉模拟评分曲线下面积（VAS AUC）较基线的变化以及治疗后24 小时利克特量表测定的中等或显著呼吸困难改善的患者比例，均采用意向性治疗分析。

　　结果  1161例患者被随机分配接受serelaxin（n=581）或安慰剂（n=580）治疗。与安慰剂相比，serelaxin可显著改善呼吸困难这一主要终点（VAS AUC）（448 mm × h，95%CI 120~775；P=0·007），但对其他主要终点无显著影响[利克特量表；安慰剂组，150例患者（26%）；serelaxin组，156例（27%）；P=0.70]。在包括心血管死亡和因心力衰竭或肾衰竭再次住院的次要终点方面，无显著影响[安慰剂组，75例事件（60天Kaplan-Meier估计值），13.0%；serelaxin组，76例事件（13.2%）；风险比（HR），1.02（0.74~1.41），P=0.89]或出院后生存时间达60天[安慰剂组，47.7（SD 12.1）天；serelaxin组，48.3（11.6）；P=0.37）]。Serelaxin治疗可显著减少其他预先规定的终点，包括180天死亡更少（安慰剂组，65例死亡；serelaxin组，42例；HR 0.63，95%CI 0.42~0.93；P=0.019）。

　　结论  在急性心力衰竭的治疗中，serelaxin可缓解呼吸困难，改善其他临床转归，但对再次住院无影响。Serelaxin治疗耐受性良好且安全，180天死亡率降低为此提供了支持。

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

Background

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

Methods

RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.

Findings

1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120—775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74—1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42—0·93; p=0·019).

Interpretation

Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality.

Funding

Corthera, a Novartis affiliate company.