PARIS (FRONTLINE MEDICAL NEWS) – Serelaxin’s failure to meet its primary endpoints in an acute heart failure trial with more than 6,500 patients, coupled with a similar failure by ularitide in the same patient population in pivotal trial results first reported in November 2016, led some experts to rethink their conception of potential interventions for patients hospitalized for acute heart failure decompensations.

“We learned in TRUE-AHF that giving a drug very early [in acute heart failure] does not prevent [long-term] death. It means that early is not early enough,” Alexandre Mebazaa, MD , said in a video interview at a meeting held by the Heart Failure Association of the European Society of Cardiology.

The TRUE-AHF results with ularitide, coupled with the new report on serelaxin from RELAX-AHF-2, suggest that “the only way to improve mortality [in acute heart failure patients] is by giving the oral heart failure drugs – beta blockers, ACE inhibitors, and [mineralocorticoid receptor antagonists] – as early as possible, when patients are stable,” said Dr. Mebazaa, a professor of anesthesiology and resuscitation at Lariboisière Hospital in Paris. “The best approach is probably prevention by giving patients optimal treatment” with these oral drugs at optimal dosages, he suggested.

In terms of finding new management strategies for patients who develop acute decompensations, “we need to better understand acute heart failure and the best subset of patients who might benefit” from existing or new drugs, he said.

The RELAX-AHF-2 trial enrolled and analyzed 6,545 patients hospitalized with an acute heart failure decompensation at more than 500 sites in 34 countries. The study compared the impact of a 48-hour IV infusion of serelaxin with placebo when begun within 16 hours of hospitalization for acute heart failure and added to standard treatment.

One of the study’s primary endpoints was cardiovascular mortality during the 6 months following intervention, and the rates in the two study arms were superimposable, 8.7% with serelaxin and 8.9% with placebo, Marco Metra, MD , reported at the meeting. The second primary endpoint was worsening heart failure through the first 5 days of treatment. While patients on serelaxin showed a nominal reduction, a 6.9% rate compared with a 7.7% rate in the placebo patients, the difference was not statistically significant despite the thousands of patients enrolled in the study, reported Dr. Metra, professor of cardiology at the University of Brescia, Italy.

These findings closely matched the performance of ularitide in a similar study design, TRUE-AHF (New Engl J Med. 2017 Apr 12. doi: 10.1056/NEJMoa1601895 ).

At the 2016 meeting of the Heart Failure Association of the ESC, the organization released revised guidelines for diagnosing and managing heart failure that stressed the importance of rapid response to acute heart failure, including possible treatment with vasodilator drugs. The guidelines acknowledged that while “Vasodilators are the second most often used agents in acute heart failure for symptomatic relief; however, there is no robust evidence confirming their beneficial effects” ( Eur Heart J. 2016 Jul 14;37[27]:2129-200 ).

Both ularitide and serelaxin are potent IV vasodilators, and their failure to meet their efficacy endpoints in these two trials put vasodilation and rapid decongestion into question as strategies to improve midterm prognosis in heart failure patients following acute decompensation episodes.

Serelaxin has been developed by Novartis, and ularitide has been developed by Cardiorentis. Dr. Mebazaa has received honoraria from Novartis and Cardiorentis, as well as from several other companies. Dr. Metra has been a consultant to Novartis. She has also served as consultant or spokesperson for Abbott Vascular, Amgen, AstraZeneca, Fresenius, Relypsa, and Servier.

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