Serelaxin Trial Latest to Challenge Today's Approach to Treating Acute Heart Failure

May 02, 2017

PARIS, FRANCE — Once again, early administration of a proprietary intravenous vasodilating drug in patients admitted with acute heart failure, one that looked promising in smaller studies, failed to make a difference to clinical outcomes compared with standard care in a large, multicenter randomized trial.

This time the drug is serelaxin (RLX030, Novartis) and the big trial is RELAX-AHF-2[1,2], and some see it as just a bump in a potentially fruitful avenue of research, while others, judging from impassioned discussion here at European Society of Cardiology (ESC) Heart Failure 2017, see it as fuel for revisionist thinking about the nature of acute HF and the most appropriate way to treat it.

Some pair RELAX-AHF-2 with the recently disappointing TRUE-AHF trial of ularitide (Cardiorentis) as the latest in an oft-cited, notoriously long list of studies that similarly tested vasodilating IV agents like nesiritide (Natrecor, Scios/Johnson & Johnson), tolvaptan (Samsca, Otsuka American Pharmaceutical), and many others.

TRUE-AHF was a "neutral" trial, but ularitide "does accelerate improvement of symptoms during the period of administration, so you get a short-term intervention and short-term gain. But that doesn't seem to impact subsequent mortality," observed Dr John GF Cleland (Harefield Hospital, Imperial College London, UK) at a high-profile forum on these issues.

"Similar results might be obtained with nitrates," he said. "TRUE-AHF is telling us that in terms of short-term gain, the patient's needs have been met by existing therapy."

Dr John

But according to RELAX-AHF-2 co–principal investigator Dr John Teerlink (San Francisco VA Medical Center and University of California, San Francisco), "It's a major mistake to use the term 'vasodilators' for all these agents. I think it's also a major mistake to say that the currently available vasodilators will achieve the same outcomes."

The total serelaxin clinical-trial experience, Teerlink told heartwire from Medscape, says that the drug has other, possibly useful biological actions than vasodilation. "Nitrates don't seem to have that," nor did such ancillary effects emerge in the nesiritide trials, he said.

Superimposable Curves

Prof Marco Metra

Cursory results of RELAX-AHF-2 were reported last month. But as presented in detail by Teerlink and co-PI Prof Marco Metra (University of Brescia, Italy) at the ESC HF sessions, RELAX-AHF-2 randomized about 6600 patients with acute HF in 34 countries to receive a 48-h IV infusion of either placebo or 30 µg/kg/day of serelaxin, a bioengineered version of the human hormone relaxin 2 that is structurally related to insulin. The infusions were on top of standard therapies. Patients were randomized within 16 hours of presentation.

There were no significant differences in either of the two co–primary end points, CV mortality at 180 days (8.7% and 8.9% for serelaxin and placebo respectively) or worsening heart failure in the first 5 days (6.9% and 7.7%, respectively, P=0.97).

Moreover, 180-day curves for secondary clinical end points were almost "superimposable," observed Metra; they included all-cause mortality and the composite of CV death or rehospitalizations due to heart or renal failure.

There are indeed biological and clinical signs that these drugs are working, it's just that the disease is poorly understood and the trials "are not good enough to let us detect an improvement," Prof Alexandre Mebazaa (Hôpital Lariboisière, Paris, France) said at the sessions.

"I still can't believe that furosemide is the best treatment for acute heart failure," he said. But with these agents tested in big trials, "it's surely difficult to show a difference. But we have to persist."

"The Disease Is Poorly Understood"

One fairly recent idea now with some high-profile doubters: perhaps it's important to intervene early with IV therapy with a minimal "door-to-infusion time" to minimize cardiac damage that would worsen late outcomes. The idea is often characterized as analogous to the ACS treatment paradigm based on managing plaque rupture.

However, "We were misled by our analogy with acute coronary syndromes," said Dr Frank Ruschitzka (University Heart Center, Zurich, Switzerland) at the sessions.

"It was to start with, I think, always a daunting proposition to believe that a short-term infusion, no matter what, 24 or 48 hours, would have an effect after 6 months," he said. "It's probably that we don't have a plaque-rupture equivalent."

TRUE-AHF co-PI Dr Milton Packer (Baylor University Medical Center, Dallas TX) said the field's misunderstanding of acute HF goes even deeper, in a way that explains why so few IV-drug trials in acute HF have been successful, at least for clinical outcomes.

Overwhelmingly, he told heartwire , acute HF "is not a disease. It's an event." Usually, "what we're looking at is variability in a chronic disorder. And we're labeling that a separate disease." It's not, he said, "but we keep doing trials as if it's a separate disease. The trials don't work, and we wonder why did we give a drug for only 48 hours and it didn't work after 6 months? And the reason is, it never made sense to do that."

Speaking with heartwire, Dr Gadi Cotter (Momentum Research, Durham, NC) took a related approach, but one that recognizes a disease called acute HF.

Severe chronic heart failure can take an acute turn for the worse and send the patient to the hospital, but less often there seem to be patients with a perhaps milder chronic disease characterized by severe, rapid-onset flare-ups with need for hospital admission. Acute HF appears to be the less common, latter disorder, he said.

"They come to the hospital in a terrible situation that 2 weeks ago did not exist. And in these acute patients, an acute intervention might help." But that help might be "entirely different" from what the other form of heart failure calls for. "The treatment that is given for one might actually harm the other," said Cotter, who is a RELAX-AHF-2 investigator.

"I think if we find a way to define which patients really have acute heart failure, the short-term benefits will actually translate into a long-term effect."

At the very least, the acute-HF trials have demonstrated that "a more targeted approach" is likely to work better, said Ruschitzka, stating a sensibility oft repeated at the ESC HF sessions. The problem is that "we don't understand the enemy." The phenotype is apparent, but "we haven't gotten the 'genotype' right. We have to get more selective."

Targeted Therapy

Teerlink observed that acute-HF trial-entry criteria are already getting more selective and are perhaps closer to identifying the kind of patients who could reap long-term benefit from a day or two of treatment in the acute phase.

"An emergency-room visit for heart failure puts you on a different trajectory," he said. "So if you want to call it an event, that's fine, but then these events, this disease state, however we want to put it, has a dramatic impact on the clinical course of the patient."

He said there seems to indeed be a "plaque equivalent" associated with acute HF that might represent the best treatment target if only the appropriate studies could be performed to identify it. "There's something that's triggering that event, and my sense is that there is in fact a heightened and perhaps different pathophysiologic response to it compared with the chronic compensated heart-failure patient."

He bristled at the idea that next to nothing is known about acute heart failure. On the contrary, "we've learned tremendous amounts about the demographics, the time course, and the patient properties during these acute heart-failure exacerbations. The challenge is, are we smart enough to be able to select those patient groups and apply the right types of therapies?"

RELAX-AHF-2 was sponsored by Novartis, from which Teerlink discloses receiving research grants, consulting fees, and nonfinancial compensation. Metra received consulting honoraria from Amgen, AstraZeneca, Novartis, Servier, Relypsa, and Trevena. Packer discloses that he has been a consultant to Admittance, Amgen, AstraZeneca, Bayer, BioControl, Boehringer Ingelheim, Boston Scientific, Celyad, Cardiorentis, Daiichi Sankyo, GlaxoSmithKline, Novartis, Novo Nordisk, Relypsa, Takeda, and ZS Pharma. Cleland has disclosed receiving research support from Novartis, Amgen, and Phillips; speaking fees and/or  honoraria from Novartis, Amgen, Servier, and Sorin; and consulting for Novartis, Amgen, Medtronic, Phillips, Merck, Siemens, Servier, and Sorin.

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