RELAX-AHF Stirs Interest In Novel Drug For Acute Heart Failure

A new drug modelled on a hormone active in pregnancy may prove beneficial to patients with acute decompensated heart failure. Serelaxin is a recombinant form of human relaxin-2, which is known to mediate the hemodynamic changes that occur during pregnancy. The drug is under development by Novartis for use in acute heart failure.

In the RELAX-AHF trial, 1,161 patients were randomized to serelaxin or placebo in the first hours of acute decompensated heart failure. Results of the trial, presented by John Teerlink at the American Heart Association in in Los Angeles and published simultaneously in the Lancet, have sparked considerable interest in the heart failure community, since few options have proven successful in this setting.

RELAX-AHF had co-primary endpoints. For the first primary endpoint, dyspnea relief  through day 5 (as measured by the visual analog scale area under the curve), serelaxin was associated with a statistically significant 19.4% improvement, resulting in a mean difference of 448 mm per hour (p=0.0075). The trial therefore reached the prespecfied criterion for efficacy. However, there were no significant differences in the other primary endpoint, dyspnea relief at 24 hours. There were also no significant differences in the secondary endpoints of cardiovascular death or hospital readmission for heart failure or renal failure through day 60.

At six months, however, cardiovascular deaths were significantly reduced in the serelaxin group:

  • 9.5% (55) in the placebo group versus 6% (35) in the serelaxin group (HR 0.63, CI 0.41-0.96, p=0.028, NNT = 29)

The investigators also reported that serelaxin was associated with significant reductions in the signs and symptoms of congestion at day 2, fewer patients with worsening heart failure, and the use of lower doses of IV diuretics.

The results, concluded the authors, “provide supportive evidence for a beneficial effect of serelaxin improving symptoms and other clinical outcomes in selected patients with acute heart failure.” The trial discussant, John McMurray, said that he believed serelaxin “does improve dyspnea and other symptoms and signs of congestion” but wondered about the clinical significance of the magnitude of the improvement and, also, whether the single trial would be sufficient to gain marketing approval.

A Surprising Reduction In Mortality

McMurray, along with trial investigators and other heart failure experts present at the AHA, expended considerable energy thinking about the reduction in mortality. The Lancet authors acknowledged that the findings of a six month survival benefit “for a drug given for 48 h with a moderate number of death events (107 total) raises the question of whether this benefit is due to chance and whether another, confirmatory trial should be done.” McMurray noted that if only two deaths had moved from one group to the other then the mortality finding would not have been significant.

But at an AHA news conference Milton Packer emphasized that “if the mortality effect is true then this trial changes the way we do things.” If confirmed, he said, it would mean that cardiologists would need to treat acute heart failure patients like ACS patients and deliver immediate treatment. Other heart failure cardioloigsts, including Mariel Jessup and Greg Fonarow, agreed that the mortality finding, if confirmed, would mean that serelaxin treatment would represent a genuine breakthrough in the treatment of acute heart failure. But, said Packer, “the real question is whether the mortality difference seen in this trial is true and replicable.”

Here is the press release from the AHA:

New drug may hold promise for hospitalized heart failure patients

Study Highlights:
  • Hospitalized heart failure patients showed some benefit from taking an investigational drug called serelaxin that helps relax the blood vessels.
  • Patients given serelaxin experienced improved symptoms, spent less time in intensive care and had shorter hospital stays than patients given placebo, but did not have fewer hospital readmissions.
  • The drug reduced cardiovascular and all-cause deaths.
LOS ANGELES, Nov. 6, 2012 — Hospitalized heart failure External link patients given an investigational drug had improved symptoms and other clinical benefits including fewer deaths, than those given standard of care plus a placebo, according to late-breaking clinical trial research presented at the American Heart Association’s Scientific Sessions 2012.
The full manuscript for RELAXin in Acute Heart Failure (RELAX-AHF) Trial, is published inLancet.
Compared to those given a placebo, patients given serelaxin experienced a significant reduction in heart failure symptoms including a 20 percent reduction in a measure of shortness of breath. Additionally, patients receiving serelaxin:
  • experienced over 45 percent fewer episodes of worsening heart failure symptoms during hospitalization;
  • Spent almost half a day less time in the intensive care units;
  • Had almost a full day shorter hospital stay.
There were 37 percent fewer deaths from any cause at six months among the serelaxin group, including significantly fewer cardiovascular-related deaths (7.3 percent in serelaxin patients versus 11.3 percent with placebo).
Serelaxin did not reduce rehospitalizations among heart failure patients.
Serelaxin is a peptide hormone or a chain of molecules that relax blood vessels and improve blood flow to organs, potentially protecting them from acute injury.
“Current therapy for acute heart failure has remained unchanged for decades,” said John R. Teerlink, M.D., co-principal investigator of the trial and professor of medicine at the University of California in San Francisco. “Acute heart failure is a major public health problem and an expensive one due to repeat hospitalizations since patients’ worsening symptoms keep coming back.”
“Our findings suggest serelaxin holds promise as the first evidence-based therapy for acute heart failure to substantially improve patients’ symptoms and clinical outcomes, including death,” said Teerlink, who is director of the heart failure program at the San Francisco Veterans Affairs Medical Center.
The multicenter phase III, conducted October 2009-February 2012, included 1,161 patients at 96 sites in 11 countries.
Researchers randomly assigned patients to receive 30 mcg/kg per day of serelaxin or a placebo through a 48-hour intravenous infusion. Patients received the medication within 16 hours of hospitalization for heart failure-related symptoms of shortness of breath with evidence of decline in kidney function. They also received standard therapy with diuretics to help flush fluid or congestion from the body and reduce swelling.
Nearly two-thirds of the patients were men, most were Caucasian and average age was 72 years. Most patients had multiple diseases: 87 percent had high blood pressure; 53 percent high cholesterol; 52 percent ischemic heart disease; 52 percent atrial fibrillation; 48 percent diabetes; and 14 percent had suffered a stroke.
“We are pleased with the results,” said Marco Metra, M.D., co-principal investigator of the trial, professor of cardiology at the University of Brescia and head of the Cardiology Institute of the Civil Hospital of Brescia, Italy. “While we did not see a reduction in rehospitalizations 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.”
Co-authors are Gad Cotter, M.D.; Beth A. Davison, Ph.D.; G. Michael Felker, M.D.; Gerasimos Filippatos, M.D.; Barry H. Greenberg, M.D.; Piotr Ponikowski, M.D.; Elaine Unemori, Ph.D.; Adriaan A. Voors, M.D.; Angelo Trapani, Ph.D.; Christopher A. Bush, Ph.D.; Christoph Schumacher, Ph.D.; and Thomas M. Severin, M.D.
Corthera, Inc., a Novartis affiliate company, funded the study.
Follow news from the American Heart Association’s Scientific Sessions 2012 via Twitter: @HeartNews External link

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