Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure

Relaxin, a pleiotropic vasodilator for the treatment of heart failure

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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

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 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/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 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/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 mm x h [SD 8712] vs 4622 mm x h [9003]; 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% CI 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

Design of the RELAXin in Acute Heart Failure Study

BACKGROUND: Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF. METHODS: The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 μg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled. CONCLUSIONS: Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effect