November 6th, 2012
RELAX-AHF Stirs Interest in Novel Drug for Acute Heart Failure
A new drug modeled 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 REALX-AHF trial, 1161 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 meeting 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% improvement compared with placebo, resulting in a mean difference of 448 mm per hour (p=0.007). The trial therefore reached the prespecfied criterion for efficacy. However, there was no significant difference 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 6 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 6-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.”
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