Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study
Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study
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DOI：
10.1016/s0140-6736(09)60622-x
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发表时间：
2009-04-01
期刊：
影响因子：
168.9
通讯作者：
Cotter, Gad
中科院分区：
文献类型：
--
作者：
Teerlink, John R.;Metra, Marco;Cotter, Gad
背景大多数因急性心力衰竭入院的患者血压正常或升高。松弛素是一种天然的人类多肽，可以影响多条血管控制通路，这表明对这类患者有潜在的益处机制。我们评估了松弛素在缓解症状、其他临床结果和安全性方面的剂量效应。方法在一项安慰剂对照、平行分组、剂量范围研究中，234名急性心力衰竭、呼吸困难、胸片充血、脑利钠肽(BNP)或BNP N末端前激素升高、轻度至中度肾功能不全、收缩压>125 mm Hg的患者从8个国家的54个地点招募，并在发病16h内入选。患者通过基于电话的交互式语音应答系统以双盲方式被随机分配到标准护理加48h静脉滴注安慰剂(n=62)或松弛素(n=40)、30mg/kg(n=43)、100mg/kg(n=39)或250mg/kg(n=50)。我们探索了几个临床终点，以评估是否应该在更大的急性心力衰竭研究中使用静脉松弛素，以确定最佳剂量，并帮助评估终点选择和能量计算。采用改良意向处理进行分析。这项研究在ClinicalTrials.gov上注册，编号NCT00520806。在改进的意向治疗人群中，61名患者被评估为安慰剂组，40名患者为松弛素组，40名患者为每日10微克/公斤体重组，42名患者为松弛素30微克/公斤每日组，37名患者为松弛素100微克/公斤每日组，49名患者为松弛素250微克/公斤每日组。与安慰剂相比，服用松弛素30 mg/kg的患者呼吸困难得到改善，根据Likert评分(6小时、12小时和24小时中有17名患者(40%)和61名患者中有14名(23%)有中度或显著改善；p=0.044)和第14天的视觉模拟评分(8214 mm×h[SD 87121 vs 4622 mm xh[90031；p=0.053])。接受松弛素治疗的患者住院时间为10.2天(SD 6.1)，而服用安慰剂的患者为12.0天(7.3天)，出院存活天数分别为47.9天(10.1天)和44.2天(14.2天)。60天时因心脏或肾功能衰竭导致的心血管死亡或再入院用松弛素组减少(2.6%[95%Cl0.4-16.8]vs 17.2%[9.6-29.6]；p=0.053)。两组之间严重不良事件的数量相似。当对急性心力衰竭和血压正常至升高的患者使用松弛素时，松弛素与良好的呼吸困难缓解和其他临床结果相关，安全性可接受。
Background Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety.Methods In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and 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 were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion Of placebo (n=62) or relaxin 10 mu g/kg (n=40), 30 mu g/kg (n=43), 100 mu g/kg (n=39), or 250 mu g/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806.Findings In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 mu g/kg per day group, 42 in the relaxin 30 mu g/kg per day group, 37 in the relaxin 100 mu g/kg per day group, and 49 in the relaxin 250 mu g/kg per day group. Dyspnoea improved with relaxin 30 mu g/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mmxh [SD 87121 vs 4622 mmxh [90031; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% Cl 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups.Interpretation When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety.