A phase II study has shown that the naturally occurring hormone relaxin reduces cardiovascular mortality and shortness of breath, and improves other clinical endpoints for heart failure patients with high blood pressure. The findings of this study (PRE-RELAX-AHF) are discussed in an Article published Online First and in an upcoming edition of The Lancet. Publication of the Article coincides with the announcement of the findings at the American College of Cardiology (ACC) meeting in Florida, USA.
Most patients admitted for acute heart failure (around 60-80%) have normal to raised blood pressure. Relaxin — a naturally occurring hormone made up of chains of amino acids — affects multiple vascular control pathways and is thought to be responsible for helping expectant mothers adjust to the physiological demands of pregnancy. In this multicentre, randomised controlled trial, Professor John R Teerlink (San Francisco Veterans Affairs Medical Center, University of California, San Francisco, USA) and colleagues assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety.
The study recruited 234 patients, from 54 sites in eight countries, with a range of symptoms indicating heart failure and systolic blood pressure greater than 125 mm Hg. The patients were enrolled within 16 hours of presentation, and randomly assigned to standard care* plus 48-h intravenous infusion of placebo (62 patients), relaxin 10 µg/kg (40), 30 µg/kg (43), 100 µg/kg (39), or 250 µg/kg (50) per day.
The researchers found that shortness of breath improved with relaxin 30 µg/kg— with 40% of patients showing improvement compared with 23% of placebo patients. Patients experiencing the combined endpoint of cardiovascular death or readmission due to heart or kidney failure at day 60 was reduced with relaxin 30 µg/kg (2.6%) versus placebo (17.2%). At 180 days, no cardiovascular deaths had occurred in the relaxin 30 µg/kg group, compared with 14.3% of placebo patients having died due to cardiovascular causes. Finally, relaxin 30 µg/kg reduced both hospital stay (10.2 days vs 12.0 days) and increased days alive out of hospital (47.9 days vs 44.2 days) versus placebo, although these last two findings were not statistically significant. Higher doses of relaxin, especially the highest dose studied, blunted the effect of the drug, as is common with agents of this type. No safety concerns were noted with the 30 µg/kg dose.
The authors believe that the strengths of PRE-RELAX-AHF are that, unlike most previous studies in this area, it specifically enrolled patients with normal to raised blood pressure, and that all patients were enrolled within a few hours (median 6.6 hours) of presentation – much faster than in previous randomised controlled trials in acute heart failure. The authors say that while shortness of breath due to heart failure, and increased blood pressure due to this disease, resolve over time with standard therapy, "evidence from PRE-RELAX AHF suggests that early administration of this drug in addition to standard therapy might be associated with more rapid, sustained, and complete resolution of acute heart failure, as well as with more favourable long-term outcomes."
The authors conclude: "When given to selected patients with acute heart failure, relaxin was associated with favourable trends in the relief of shortness of breath, resolution of heart failure signs, in-hospital measures of heart failure, and postdischarge clinical outcomes. Relaxin had an acceptable safety profile and no apparent adverse renal effects. On the basis of these results, a relaxin dose of 30 μg/kg per day has been selected for further assessment in a phase III study (RELAX-AHF-1) of intravenous relaxin in acute heart failure. If established in larger studies, the benefits of relaxin might represent an important advance in the treatment of patients with acute heart failure."
In an accompanying Comment , Dr Adrian F Hernandez and Dr Christopher B Granger, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA, say: "The signals that relaxin was reasonably safe with trends of clinical improvement warrant further investigation in proper outcomes studies. Beyond showing the potential therapeutic value of relaxin, the study highlights the challenge of clinical development in acute heart failure. Acute heart failure is a heterogeneous syndrome with distinct presentations... Success of future trials will depend on improving the network and infrastructure to enrol patients efficiently and as early as possible in their presentation, to reflect the timing of initiation of acute therapies for patients in practice."
Professor John R Teerlink, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, USA T) +1-415-221-4810 ext 4160 / +1-415-902-6240 E) john.teerlink@ucsf.edu
Dr Adrian F Hernandez and Dr Christopher B Granger Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA T) +1 919-812-3463 / +1 919 724 5343 E) adrian.hernandez@duke.edu
For full Article and Comment see: http://press.thelancet.com/relaxinfinal.pdf
Notes to editors: *Standard care varies from site-to-site, but usually consists of interventions such as oxygen, diuretics, and sometimes morphine
Journal
The Lancet