Los Angeles, CA—Reductions in dyspnea and cardiovascular (CV) death, and improvement in the signs and symptoms of congestion and worsening heart failure (HF), in the RELAX-AHF study were attributed to serelaxin, a novel investigational agent for the treatment of acute HF, which was compared with placebo plus conventional therapy.
“All of the benefits were achieved with less use of intravenous diuretics and less use of other vasoactive therapies,” by approximately 25%, said coprimary investigator John R. Teerlink, MD, FACC, FAHA, Professor of Clinical Medicine, University of California, San Francisco, and San Francisco VA Medical Center, at the 2012 meeting of the American Heart Association. In addition, “serelaxin was well tolerated and safe,” Dr Teerlink said.
Serelaxin is the recombinant form of human relaxin, which is present in men and women and is elevated throughout pregnancy, where it mediates “marked improvements in cardiac, arterial, and renal function—the changes desired in acute heart failure,” said Dr Teerlink. Relaxin also has anti-ischemic, anti-inflammatory effects.
A total of 1161 patients (mean age, 72 years) were hospitalized for HF and were randomized within an average of 8 hours of presenting for a 48-hour infusion of intravenous serelaxin (30 mcg/kg daily) or to placebo plus usual therapy for HF. All patients had dyspnea, objective signs of congestion, normal-to-elevated systolic blood pressure, and mild-to-moderate renal dysfunction.
Dyspnea relief, the first coprimary end point, was significantly improved with serelaxin, with a 19.4% increase in the area under the curve (AUC) from baseline through day 5 compared with placebo (P = .075). The mean difference between the 2 arms was 448 mm per hour from baseline as assessed with the visual analog scale.
The second coprimary end point of dyspnea relief as measured by the Likert scale showed improvement at hours 6, 12, and 24, but did not reach significance, because it did not show moderate or marked improvement at each of the 3 time periods as prespecified.
CV death or rehospitalization resulting from HF or renal failure through day 60, the first secondary end point, was not different between groups; the improvement in CV death was offset by a slight increase in rehospitalization rates. The number of days alive and out of hospital showed an overall increase of 0.6 days with serelaxin, but did not reach significance (P = .37).
“We were able to show a 37% reduction in cardiovascular death up through day 180,” said Dr Teerlink, “with a number needed to treat of 29 patients to prevent 1 cardiovascular death,” with serelaxin (P = .028). All-cause mortality through day 180 was reduced by 37%, with a number needed to treat of 25 patients (P = .020).
Marked reductions in congestions were seen through day 2, and “early and persistent reductions in worsening of heart failure,” said Dr Teerlink; by day 14, there was a significant 30% reduction in the risk of worsening HF in the patients treated with serelaxin. There were reductions in the length of care in the intensive care unit by approximately 0.33 days, and in the length of the initial hospitalization by approximately 0.9 days (P = .039).
“While we did not see a reduction in rehospitalization in this trial, the significant reductions in worsening of heart failure and death are encouraging signals that we can change the course of this devastating disease,” said coprincipal investigator Marco Metra, MD, Associate Professor of Cardiology, Section on Cardiovascular Diseases, University of Brescia, Italy.
“There is little doubt that this agent was beneficial, and the totality of the evidence (the breathlessness measurement, signs and symptoms, the use of other therapies) quite clearly indicates that this drug is doing something good in terms of relief of symptoms and congestion,” commented John J. McMurray, MD, Professor of Cardiology, University of Glasgow, Scotland, the designated discussant of the trial.
Dr McMurray said that there will be discussions about the meaning of the change in the AUC and whether a single trial is sufficient for regulators to approve a therapy. “This trial is paradigm-shifting at least in making us think about what is going on in acute heart failure, and what we are trying to do for this condition,” he noted.
The lack of benefit for rehospitalization for HF or for renal failure is a concern, Dr McMurray added, because it is unusual to see a treatment for HF that improves survival but not hospitalization. Another concern is the robustness of the mortality improvement, noting that with such small numbers, the benefit may not be reliable, and that if only 2 deaths moved from the serelaxin arm to the placebo arm, the finding would no longer be significant.
If the findings in this study are replicated, “it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or life-saving therapies,” Dr McMurray concluded.