RELAX-AHF: Serelaxin Reduces Dyspnea, But Questions Surround Mortality Benefit

November 06, 2012

LOS ANGELES — A novel recombinant form of human relaxin 2 used in the treatment of acute heart failure (AHF) reduced shortness of breath as assessed using one of two dyspnea end points, according to the results of a new study. Investigators were also excited by the reduction in all-cause and cardiovascular mortality with serelaxin (Novartis Pharmaceuticals), as well as reductions in the signs and symptoms of congestion and worsening heart failure.

"All of these benefits were done in the context of less use of intravenous diuretics and less use of other IV vasoactive therapies, both of which were reduced approximately 25% in the serelaxin group," said lead investigator Dr John Teerlink (University of California, San Francisco) during a press briefing announcing the results here today at the American Heart Association 2012 Scientific Sessions."In addition, there was about one-third day reduction in the duration of ICU care and almost a full-day reduction in the initial hospital length of stay."

Dr John Teerlink

The results of the Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF)study were simultaneously published in the Lancet to coincide with the AHA late-breaking clinical-trials presentation.

RELAX-AHF Study

As previously reported by heartwire , relaxin modulates the cardiovascular responses during pregnancy by increasing vasodilation and renal function. Speaking with the media, Teerlink explained that relaxin can modulate various important hemodynamic and neurohormonal effects, such as increases in cardiac output and decreases in systemic vascular resistance, pulmonary capillary wedge pressure, and n-terminal probrain natriuretic peptide (NT-proBNP).

The RELAX-AHF study included 1160 patients with AHF and systolic blood pressure >125 mm Hg randomized to treatment with serelaxin via a 48-hour intravenous infusion within 16 hours of presentation or placebo. The dose of serelaxin, 30 µg/kg per day, was selected based on a phase 2 dose-ranging study.

In terms of the primary end point, serelaxin resulted in a 19% improvement in the area-under-the-curve (AUC) from baseline to day 5 on a dyspnea visual analog scale (VAS). There was a moderate improvement in dyspnea, as measured using a Likert scale, but the improvement was not statistically significant. Days alive out of the hospital at day 60 and cardiovascular death or heart failure/renal failure hospitalizations up to day 60, the secondary end points, were not significantly improved with serelaxin.

There were significant improvements in the signs and symptoms of heart failure, a significant reduction in the percentage of patients who had worsening heart failure, and a significant reduction in hospital length of stay with serelaxin. There were also improvements in a number of biomarkers, including NT-proBNP, creatinine, and troponin T.

Overall, there was a significant 37% reduction in risk of all-cause mortality at six months, as well as a significant 37% reduction in risk of cardiovascular mortality with serelaxin. For cardiovascular death, 9.5% of placebo-treated patients died from cardiovascular causes at six months compared with 6.0% of patients treated with serelaxin (p=0.028). This translated into a number needed to treat to prevent one cardiovascular death of 29.

Is the Reduction in Mortality Real?

Speaking with the media, Dr John McMurray (University of Glasgow, Scotland), who was not affiliated with the trial, pointed out that RELAX-AHF reached statistical significance with only one of its two co–primary dyspnea end points and did not meet statistical significance on its two secondary end points, that being days alive at day 60 and a composite of cardiovascular death and heart-/renal-failure hospitalizations up to day 60.

"In terms of its primary end point, breathlessness, I think there is little doubt that this agent was beneficial," said McMurray. "The totality of the evidence, the breathlessness measurement, the signs, the symptoms, and the use of other therapies, to me at least, quite clearly indicate that this drug is doing something good in terms of relief of symptoms and congestion."

Despite the in-hospital and clinical improvements, the reduction in all-cause and cardiovascular mortality generated the most interest among heart-failure experts, with many urging caution in the interpretation of the data. For McMurray, RELAX-AHF has the potential to be paradigm shifting, "at least in terms of making us think about what's going on in acute heart failure and what we're trying to do for this condition."

It might even be paradigm shifting in terms of what physicians can achieve with such a treatment, but he is less certain of that right now. He cautioned that the mortality data are not robust, given the small trial and small number of clinical events, and need to be confirmed in other trials. For example, he is concerned about the disconnect between a reduction in mortality and lack of a reduction in heart-failure and renal hospitalizations.

"It is very unusual to see a treatment in heart failure that can improve survival and not reduce rehospitalization," said McMurray. "The other concern is that this is based on small numbers of a nonprespecified outcome. In heart failure, we've been famously misled by small numbers."

To heartwire , Dr Gregg Fonarow (University of California, Los Angeles) said the results would have been clearer if both primary end points in RELAX-AHF had been met, instead of just one co–primary end point, and this does give him some pause. However, he said that the symptom improvement, as well as the favorable improvement in biomarkers--particularly the reduction in troponin T with serelaxin--is an encouraging sign. Like McMurray, though, he questions why there was no reduction in heart-failure hospitalizations. "Most of us are thinking it would be a phenomenal, tremendous advance if the mortality reduction was real, but there are enough caveats here," said Fonarow. "It wasn't a prespecified end point or even a secondary clinical outcome, so it requires replication."

Figuring Out What the Results Mean

Speaking with the media, Dr Milton Packer (University of Texas Southwestern, Dallas) said that one of the most amazing aspects of the RELAX-AHF study is that treatment with serelaxin was started within seven hours, on average, upon admission to the hospital.

"No trial has ever pulled this off before," said Packer. "If that early vulnerable period when the heart is being actively distended, if decompression at that point in time reduces troponin, reduces myocardial injury, and therefore reduces risk long term and is responsible for the mortality effect, that transforms clinical practice, because it means, just like in myocardial infarction where time is of the essence, it could be that in acute heart failure time is also of the essence. That would be transformative in the way we do things."

Packer added that if the mortality reduction with serelaxin is real, not only would heart-failure doctors want to use it, but it would be mandated for use in every patient who arrived at the hospital with acutely decompensated heart failure. "We don't have any drugs for acutely decompensated heart failure that change the natural history of the disease," said Packer.

Also speaking with media, Dr John Harold (Cedars-Sinai Medical Center, Los Angeles, CA), president-elect of the American College of Cardiology, said he thinks serelaxin would be a good addition to the physician's toolbox, although he would like to see longer-term follow-up. Like McMurray, Harold noted that one drug, vesnarinone, was shown to reduce the risk of mortality in small heart-failure studies, but larger definitive trials showed the drug actually increased the risk of death. He thinks that serelaxin might become an agent that is effective in selected patients, such as those with symptoms and refractory to other heart-failure agents.

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