Now, in an analysis of data from a trial of the peptide hormone relaxin in the treatment of acute heart failure, Professor Metra and colleagues report that early and persistent relief of dyspnoea is stubbornly difficult to achieve, with around three-quarters of patients in the study unable to find "moderate to marked" symptom relief (when measured on a rating scale).1 In addition, around one in four patients developed recurrent breathing symptoms and worsening signs of heart failure during their first five days of hospitalisation.
The investigators further show that this lack of dyspnoea relief is associated with a poor outcome in the short and medium term. Thus, they conclude, in addition to being the main measure of acute heart failure symptoms, levels of dyspnoea "are also related to prognosis and hence are important and meaningful targets of therapy".
Behind the conclusions lie data from a preliminary trial of relaxin (RELAX-AHF) in which 232 subjects admitted to hospital with acute heart failure were randomised to placebo or four doses of relaxin and evaluated immediately and up to day 5 for dyspnoea relief and worsening signs of heart failure. Patients were followed for a further six months.
Early relief of dyspnoea was observed in only 25% of all patients, and improvement in symptoms at day 5 in 32% of those given placebo and 50% relaxin. Worsening heart failure to day 5 was observed in 21% on placebo and 14% on relaxin. This lack of ongoing dyspnoea improvement and worsening heart failure were associated with a longer length of hospital stay and deteriorating 60-day outcomes.
In the light of these findings, Professor Metra and colleagues propose that the relief of dyspnoea, beyond being an important treatment goal for symptom improvement, is also a predictor of better outcome to treatment and thus a major goal of therapy in AHF. "The early assessment of dyspnoea relief may add important prognostic information beyond the information available at the time of admission," said Professor Metra.
Relaxin is a peptide hormone usually associated with pregnancy in women and released cyclically from the ovary. Concentrations rise in the first trimester of pregnancy, promoting cardiovascular and renal adjustments to the maternal circulation. Studies in pregnancy have reported an increase in cardiac output, a decrease in systemic vascular resistance, and an increase in renal blood flow, raising the possibility that the effects of relaxin may be pharmacologically useful in modulating cardiovascular and renal function, particularly in heart failure.
Results from early studies of relaxin in heart failure have been encouraging, says Professor Metra, and administration of relaxin in this preliminary RELAX-AHF trial was associated with a trend towards improvement in persistent dyspnoea and prevention of worsening heart failure compared with placebo. The most effective dose, he adds, 30 mg/kg/day, is now being tested for efficacy in early and persistent dyspnoea relief and treatment outcome in the ongoing phase III RELAX-AHF study.
Presently, he notes, the treatment of acute heart failure remains "disappointing", even when therapy adheres closely to guideline recommendations, and new medications "have not shown convincing benefits". "The rapid and ongoing improvement of dyspnoea and congestion with no untoward effects on outcomes remains an important and unmet goal of heart failure therapy," he says.