Another Acute Heart Failure Drug Fails In Large Clinical Trial

–In RELAX-AHF-2 serelaxin didn’t improve clinical outcomes.

Yet another promising drug for acute heart failure has failed to improve long-term outcomes.

In the RELAX-AHF-2 trial 6,600 patients hospitalized for acute heart failure were randomized to a 48-hour infusion of serelaxin or placebo. There was no significant difference between the two groups in either of the two primary endpoints, cardiovascular mortality at 180 days (8.7% for serelaxin versus 8.9% for placebo) or a reduction in worsening heart failure in the first 5 days (6.9% versus 7.7%).

There were no differences in the important secondary endpoints of all cause mortality at 180 days, length of initial hospital stay, or the combined endpoint of CV death or hospitalization.

Serelaxin, a novel recombinant vasodilator under development by Novartis, has had a tortured history. In 2012 the first RELAX-AHF trial provoked both controversy and promise. The much smaller trial (1,161 patients) had mixed results, meeting one of its two short term primary endpoints but unexpectedly showing a mortality benefit at 6 months. The 6 month mortality benefit electrified the heart failure field, since it suggested that early aggressive treatment might improve the long term outcome of patients with acute heart failure. However, the finding was also viewed with skepticism, since there was no mortality difference earlier in the trial and the 6 month endpoint was not prespecified. In the end the trial was not strong enough to gain approval for serelaxin from the FDA or in Europe; RELAX-AHF-2 was designed to demonstrate the drug’s clinical benefits.

The main results of RELAX-AHF-2 were presented at the Heart Failure 2017 meeting in Paris by John Teerlink (UCSF).

“This was a huge disappointment as we had such encouraging data from previous studies,” said Teerlink, in a press release issued by the European Society of Cardiology.

The results of RELAX-AHF-2 are concordant with the results of TRUE-AHF, initially presented last year at the American Heart Association and published subsequently in the New England Journal of Medicine. At the time the trial’s principal investigator, Milton Packer (Baylor University) said that he thought that TRUE-AHF effectively ended the idea that short term IV therapy for heart failure would have long lasting benefits. “We have created a set of expectations for IV drugs which were entirely unrealistic,” he said.

Asked to comment on RELAX-AHF-2, Packer offered the following statement:

“I was always skeptical about the mortality reduction shown in RELAX-AHF1, so I was not surprised by the lack of a mortality benefit in RELAX-AHF-2. But I was surprised by the trial’s results in one respect. I had expected some benefit of serelaxin on the coprimary endpoint of worsening heart failure, but there was none to be found. The effect reported in RELAX-AHF2 was not significant… RELAX-AHF1 had originally shown a 50% reduction in the risk of in-hospital worsening heart failure, and the investigators hoped to find a 20% reduction in risk in RELAX-AHF1. In the end, they actually found very little effect, and the control-group event rate was much lower than projected. This is the real disappointment. It makes us wonder whether future trials can actually target a reduction in-hospital heart failure events as a therapeutic goal. If this is true, it is impossible to know how one would possibly design an efficacy trial for a new drug for acute heart failure. This, of course, assumes that innovators will still want to pursue new treatments for this condition. Acute heart failure is actually an event — not a disease.”