A phase II study (PRE-RELAX-AHF), as reported in an article published Online First and in an upcoming edition of The Lancet, coinciding with the announcement of the findings at the American College of Cardiology (ACC) meeting in Florida USA, reveals an improvement of cardiovascular mortality and shortness of breath as well as other clinical end points for heart failure patients with high blood pressure when prescribed the naturally occurring hormone Relaxin.
Nearly all patients admitted for severe heart failure (between 60 to 80 percent) have normal to raised blood pressure. Expectant mothers adjusting to the physiological demands of pregnancy produce Relaxin- a naturally occurring hormone made up of chains of amino acids affecting vascular controlled pathways.
Professor John R Teerlink (San Francisco Veterans Affair Medical Center, University of California, San Francisco) and colleagues, conducted a randomized controlled trial assessing the dose response of Relaxin´s effect on symptom relief, safety and other clinical outcomes on 234 volunteer patients, from 54 sites in 8 countries, diagnosed with symptoms of heart failure and systolic blood pressure greater than 125 mm Hg. Within sixteen hours of presentation, patients were enrolled and received at random standard care (typically includes interventions such as oxygen, diuretics, and occasionally morphine) in addition to a 48-h intravenous infusion of placebo (62 patients), Relaxin 10 µg/kg (40 patients), 30 µg/kg (43 patients), 100 µg/kg (39 patients), or 250 µg/kg (50 patients) per day.
Evidence showed an improvement in shortness of breath in 40 percent of patients with relaxin 30 µg/kg compared with 23 percent of placebo patients. At day 60, the number of patients facing the combined endpoint of cardiovascular death or readmission due to heart or kidney failure was reduced with Relaxin 30 µg/kg (2.6 percent) versus placebo (17.2 percent). At 180 days, there was no cardiovascular death in the Relaxin 30 µg/kg group. In the placebo group 14.3 percent died due to cardiovascular causes. Ultimately, although the evidence was not statistically significant, Relaxin 30 µg/kg reduced hospital stay (10.2 days versus 12.0 days) and increased the days alive out of hospital (47.9 days versus 44.2 days). Higher doses of Relaxin blunted the effect of the drug, in particular the most elevated dose studied. This is frequent with this kind of agent. In the 30 µg/kg dose, no safety concerns were reported.
The authors indicate that the PRE-RELAX-AHF strong points are that, unlike the majority of prior studies in this area, it exclusively included patients with normal to raised blood pressure and that every one of them was enrolled within an average of 6.6 hours within presentation (much faster than in prior randomized controlled trials in acute heart failure). The writers point out that while shortness of breath caused by heart failure, and high blood pressure caused by this disease, they are cured 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 write in conclusion: “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 post-discharge 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 ?g/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 additional observation, Dr Adrian F Hernandez and Dr Christopher B Granger, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA, remark: “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.”