RELAX-AHF-2 Results on Serelaxin in Acute Heart Failure Published

Debra L. Beck

August 21, 2019

The negative findings of the RELAX-AHF-2 trial, which tested serelaxin, a recombinant form of human relaxin-2, for the treatment of patients with acute heart failure (AHF), are now published.

The results were first reported in 2017 at the European Society of Cardiology Heart Failure (ESC-HF) meeting, and are published online August 21 in the New England Journal of Medicine.

The trial led to Novartis opting out of further development of the drug, which might seem to mark the end of any discussion around the drug's usefulness, but, according to John Teerlink, MD, from the University of California, San Francisco, coprincipal investigator with Marco Metra, MD, from Brescia, Italy, there is more to discuss and consider.

"We did not confirm the mortality benefit seen in RELAX-AHF in RELAX-AHF-2, but we hope that now, with the publication of the primary manuscript, we will be able to also perform secondary analyses that further elucidate some of the distinctions between serelaxin and other drugs that have failed in acute heart failure, namely ularitide, which have been lumped together with serelaxin as failed agents."

RELAX-AHF-2 was a phase 3b multicenter, randomized, double-blind, placebo-controlled, event-driven trial that studied the addition of serelaxin to standard care in patients with AHF.

The trial enrolled 6545 patients hospitalized for AHF with dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of 125 mm Hg or higher.

Participants were assigned to a 48-hour infusion of either serelaxin or placebo, in addition to standard care.

As reported previously, serelaxin failed to reduce either of the trial's two primary endpoints: death from cardiovascular causes at 180 days or worsening heart failure at 5 days.

At the 180-day mark, the cardiovascular death rates were 8.7% in the serelaxin arm compared with 8.9% for the placebo arm (hazard ratio [HR], 0.98; P = .77). At day 5, worsening heart failure, defined as a worsening of signs or symptoms of heart failure leading to an intensification of treatment, was seen in 6.9% and 7.7%, respectively (HR, 0.89; P = .19).

The study was completed in February 2017. Limited findings were reported a month later by Novartis, who also said they planned to halt further development of the drug, and the full findings were presented in May 2017 at the ESC-HF meeting in Paris.

Serelaxin is a recombinant form of human relaxin-2, a hormone that, among other things, mediates vasodilation. It is produced during pregnancy and contributes to the marked cardiovascular and renal adaptations seen during pregnancy. 

The drug was originally tested in the phase 3 RELAX-AHF trial, where a 48-hour infusion decreased the release of troponin, significantly reduced one of two primary dyspnea endpoints, and resulted in a 37% reduction in the risk for death, compared with placebo, during the 6 months after the acute decompensation event.

Challenging the common assumption that more data are better data, Teerlink feels that the findings of RELAX-AHF remain valuable and relevant even in the context of the second trial.

"RELAX-AHF-2 was designed solely as a mortality trial, worsening heart failure was elevated to a primary endpoint later…and a 48-hour infusion like we gave is unlikely to have an impact on survival unless it has significant effects on organ protection, which means you have to have patients who are sick enough to actually derive that benefit."

While the second trial tried to include patients at higher risk for cardiovascular death — those with worse renal function and a higher threshold for natriuretic peptides — the cardiovascular mortality rates in the placebo group of RELAX-AHF-2 was less than in RELAX-AHF, while the noncardiovascular mortality was actually higher in RELAX-AHF-2.

"There's something about going from a 1,161-patient trial to a 6,500 plus-patient trial where you don't have that same patient selection," Teerlink said.

Does AHF (or Serelaxin) Need a Rethink?

The way in which acute heart failure is viewed is leading down a path of continual disappointment, according to Milton Packer, MD, from Baylor University Medical Center, Dallas, Texas, who provided an editorial accompanying the RELAX-AHF-2 findings. He sees AHF not so much as a distinct disease, but as an event.

"Although it is important to achieve clinical stabilization, it is more critical to ensure that patients are treated vigorously between hospitalizations to decrease the risk of readmission and death," he writes.

"RELAX-AHF was a phase three regulatory trial that hit its primary endpoint of a reduction in dyspnea," Teerlink notes, "and there were more than 100 deaths in that trial," and a reduction in the prespecified secondary endpoint of death from any cause at 180 days.

"But the [US Food and Drug Administration] panel said no because it was only one study, so RELAX-AHF-2 was an informed and proper approach to try to figure out whether there was a mortality benefit, which we didn't see in this trial."

More to the point, however, Teerlink notes that some drugs help patients with AHF feel better — as RELAX-AHF clearly showed with serelaxin — but may not prolong survival, but still should not be dismissed.

"I agree with Dr Packer that chronic therapies that can potentially prevent the progression of heart failure, prevent deterioration, are very important…but I also think cardiology has been a victim of its own success in that while we've successfully found therapies that can help people live longer, I think we may have lost sight of helping people live better and feel better. Clearly there is an important unmet clinical need for improving symptoms, as well as the clinical course of patients with acute heart failure," he added.

"I believe there are reasons to continue investigating the potential utility of serelaxin in treating heart failure," Teerlink concludes.

RELAX-AHF-2 was sponsored by Novartis, from which Teerlink discloses receiving research grants, consulting fees, and nonfinancial compensation. Packer reported receiving consulting fees from a number of pharmaceutical companies, but not from Novartis.  

New Engl J Med. 2019;381:716-726. Article; Editorial

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