RELAX-AHF-2: Lack of Benefit With Serelaxin in Acute HF Still a Puzzle for Investigators

Two years after it was first announced that the RELAX-AHF-2 study failed to show that a recombinant form of the hormone relaxin-2 could make a difference in cardiovascular mortality and worsening of heart failure, the full results have been published and investigators are still pondering why the promising therapy came up short.

The initial results showing that the trial did not meet its endpoints were presented at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure and were met with disappointment: the earlier, phase III RELAX-AHF trial had shown that a serelaxin infusion reduced the rate of death over the subsequent 6 months by 37%. The RELAX-AHF-2 results were published today in the New England Journal of Medicine.

“RELAX-AHF-2 was a logical follow on to RELAX-AHF,” co-principal investigator John R. Teerlink, MD (University of California, San Francisco), said in an interview with TCTMD. “It did not confirm the prior beneficial effects in terms of survival, but there still remains some intriguing potential for the clinical utility of serelaxin or the relaxin agonists.”

The multicenter, event-driven RELAX-AHF-2 trial enrolled 6,545 patients hospitalized with acute heart failure and randomized them equally to the study agent or placebo.

Compared with patients who received placebo, those who received a 48-hour serelaxin infusion (30 μg/kg of body weight per day) within 16 hours after presentation had a similar rate of death from cardiovascular causes at 180 days (8.7% vs 8.9; P = 0.77). Worsening heart failure rates also were similar, at 6.9% in the serelaxin group and 7.7% in the placebo group (P = 0.19). Other endpoints, including death from any cause at 180 days, death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, length of index hospital stay, and rate of adverse events, also were similar between the two groups.

In an accompanying editorial, Milton Packer, MD (Baylor University Medical Center, Dallas, TX), notes that RELAX-AHF-2 is now the second “large-scale, definitive” trial to suggest that the dramatic mortality reductions seen using vasodilator therapy—such as those seen in RELAX-AHF—were “spurious.” The other trial known as TRUE-AHF and headed by Packer, “a 48-hour intravenous infusion of the natriuretic peptide ularitide did not result in lower all-cause mortality in the long term than placebo, even though the drug caused an immediate reduction in cardiac-wall stress, as evidenced by a reduction in levels of N-terminal pro-brain natriuretic peptide,” he notes.

To TCTMD, Teerlink questioned the appropriateness of “lumping all of these vasodilator and acute heart failure therapies together.” Unlike serelaxin, ularitide never showed any benefit in terms of renal function, troponins, and other organ protective mechanisms, he observed, adding, “With serelaxin, even in our phase II trials, we showed multiple potential benefits in terms of clinical things beyond just survival.”

Serelaxin: What Happens Now?

In their paper, Teerlink and colleagues do not discount the idea that the mortality reductions in RELAX-AHF may have been due to chance. They also suggest that different patient characteristics between RELAX-AHF and RELAX-AHF-2 may account for the disparate results. Additionally, death from noncardiovascular causes was higher in RELAX-AHF-2 than in RELAX-AHF, suggesting risk profile differences.

Shortly after the announcement regarding the failure of RELAX-AHF-2 to meet its endpoint, the study’s sponsor, Novartis, issued a press release thanking patients and investigators but left the fate of serelaxin unclear. To TCTMD, Teerlink said he believes this type of therapy is needed and hopes dialogue about it will continue among the clinical and research communities (eg, addressing why helping patients with heart failure feel better is not valued), referencing other potential benefits that have been observed with serelaxin beyond survival.

“We need to start questioning why payers are willing to pay for symptom relief in other fields yet there is a clear indicator that they are not [willing to do so] in the cardiovascular realm,” he said.

While Packer concludes in his editorial that more “focus on intensive outpatient care (rather than an obsession with inpatient therapy) is needed to reduce the burden of heart failure,” Teerlink said keeping patients out of the hospital and preventing disease progression can be balanced with continuing to search for additional ways to help patients with heart failure feel better, as well as working toward identifying those who might benefit from adding therapies like serelaxin to standard care.