RELAX-AHF: Benefit of Serelaxin Extends Across Multiple Subgroups

September 10, 2013

AMSTERDAM, THE NETHERLANDS — An analysis of the Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF) study, an 1160-patient trial testing the safety and effectiveness of a investigational recombinant form of human relaxin 2, suggests serelaxin (Novartis Pharmaceuticals) works across multiple subgroups[1].

Overall, there was no difference in the effects of serelaxin vs placebo on dyspnea relief or the incidence of cardiovascular death/rehospitalizations for heart failure or renal failure at 60 days, report investigators. They did observe some treatment effects with regard to mortality in some subgroups.

"In terms of serelaxin vs placebo, while [the results were] homogenous across multiple subgroups with respect to the end points of the study, including 180-day mortality, potentially larger mortality benefits were seen in patients who were older, those with no previous hospitalizations for heart failure, those not treated with neurohormonal antagonists at the time of randomization, those with signs of inflammation, and those with more severe renal impairment," said Dr Marco Metra (University of Brescia, Italy) when presenting the results at the European Society of Cardiology (ESC) 2013 Congress .

However, Metra stressed the subgroup analysis is underpowered for mortality end points and should be considered hypothesis-generating only.

The study was also published online in the European Heart Journal to coincide with ESC presentation.

Lots of Subgroups Studied

During the clinical-trial-update session, Metra said that various clinical characteristics of HF patients have the potential to influence patient prognosis and response to treatment. For this reason, the group assessed the effects of serelaxin vs placebo on multiple subgroups of interest with respect to the primary and secondary end points.

With regard to the primary end point, Metra said the effects of serelaxin on dyspnea relief was homogenous across various subgroups, including patients stratified by gender, age, geographical area, race, previous hospitalizations for HF in the past year, and the time from presentation until randomization in the trial (less than six hours vs six hours or more). In addition, the effect was homogenous in patients with comorbidities, such as those with hypertension, diabetes, or atrial fibrillation, as well as among those receiving concomitant medications.

For the end point of cardiovascular death or heart-failure/renal-failure hospitalizations to day 60, the results were homogenous across the subgroups also. There appeared a trend that patients not treated with ACE inhibitors/angiotensin receptor blockers (ARBs) at baseline fared better than those treated with the drugs, but the interaction was not statistically significant.

With regard to cardiovascular mortality at day 180, there were a few significant interactions among subgroups, said Metra. For example, patients not with treated beta-blockers at baseline fared significantly better with serelaxin than those who were treated with beta-blockers. In addition, patients not hospitalized within the past year for HF had a lower risk of cardiovascular death than those who were hospitalized.

More than 20 different subgroups were studied overall.

 

The RELAX-AHF Study

Presented last November at the American Heart Association Scientific Sessions, the results of the RELAX-AHF trial, led by Dr John Teerlink (University of California, San Francisco), showed that treatment with 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 to day 60, the secondary end points, were not significantly improved with serelaxin. 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.

In addition, 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.

To heartwire , Dr Ileana Piña (Case Western Reserve University, Cleveland, OH), an HF specialist who was not involved in RELAX-AHF, said she was not surprised by the results, nor did she expect to see an interaction by subgroups. For clinicians not specializing in HF, the results are reassuring because regardless of the patient's background medication use or comorbidities, including diabetes, serelaxin is effective in providing relief, she said.

"If you're explaining RELAX-AHF to a private practitioner, you can say to them that regardless of the resting blood pressure, regardless of the [probrain natriuretic factor] proBNP levels, or regardless of the ejection fraction--the results were similar in patients with [heart failure with preserved ejection fraction] and those with [heart failure with reduced ejection fraction]--you can use this agent," said Piña.

She pointed out, however, that most patients in RELAX-AHF were not treated with intravenous nitrates at baseline. For her, she treats AHF patients with a diuretic and nitrate, a combination that costs $18/day.

In June, the US Food and Drug Administration awarded serelaxin "breakthrough-therapy" status, a designation that means the drug will likely face a speedier regulatory process.

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