Patients with acute heart failure who received the recombinant form of human relaxin-2, serelaxin, did not have a lower incidence of cardiovascular death at 180 days, or a lower incidence of worsening heart failure at 5 days, according to a new phase 3 trial.
Marco Metra, MD, with the Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy; John R. Teerlink, MD, with the Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco; and colleagues reported their findings in the August 22, 2019 issue of The New England Journal of Medicine.
The Centers for Disease Control and Prevention (CDC) reports that approximately 5.7 million adults in the United States have heart failure. Hospital admission for acute decompensated heart failure is associated with increased short and long-term cardiovascular mortality. About one-half of heart failure patients are rehospitalized within six months, and up to 15% of patients die within three months of their initial hospitalization. The CDC notes that one-half of those who develop heart failure die within five years of diagnosis.
The search for new and better therapies for acute heart failure has led to research into a hormone called relaxin. Discovered in 1926, relaxin is produced primarily by cells of the corpus luteum and is associated with several cardiovascular changes of pregnancy. It acts as a vasodilator, via the nitric oxide pathway, an antifibrotic, and an anti-inflammatory agent. Discovery of these properties led to the study of relaxin in heart failure, using a recombinant form of the hormone, called serelaxin. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin was associated with a lower incidence of worsening heart failure during hospitalization and lower cardiovascular mortality at 180 days when compared to placebo. The RELAX-AHF trial was not powered to show an effect on mortality; thus, whether serelaxin reduced cardiovascular mortality in acute heart failure remained unclear.
This study, RELAX-AHF-2, is a phase 3b, multi-center, randomized, placebo-controlled, event-driven trial. The trial enrolled 6600 adults hospitalized for acute heart failure, with dyspnea and vascular congestion on chest radiography, elevated natriuretic peptide levels, mild-moderate renal impairment, and systolic blood pressure of 125 mm Hg or greater. After excluding 55 patients randomized in error, 3274 patients were randomly assigned to receive serelaxin 30 µg per kilogram per day plus usual therapy, and 3271 patients to receive placebo plus usual therapy. The rates of cardiovascular death at 180 days and worsening heart failure at 5 days were compared between groups.
Measured at day 180, cardiovascular death occurred in 8.7% in the serelaxin group, and in 8.9% in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). Measured at day 5, worsening heart failure occurred in 6.9% in the serelaxin group, and in 7.7% in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). The length of hospital stay and the incidence of rehospitalization due to heart failure or renal failure were also unchanged between groups.
There was no significant difference in the rate of adverse events reported between the groups (53.1% in the serelaxin group and 52.1% in the placebo group reporting at least one adverse event).
The study was funded by Novartis Pharma.
Metra, M., et al. Effects of Serelaxin in Patients with Acute Heart Failure. N Engl J Med 2019; 381:716-26.
Comments
- RELAX-AHF-2 shows the importance of a properly powered trial: the authors conclude that the lack of cardiovascular mortality benefit observed in this trial shows that the benefit seen in the RELAX-AHF trial was consistent with a chance outcome
- Heart failure is a complex disease – further subgroup analyses of this and other heart failure trials may identify a particular patient population that benefits from relaxin therapy
- Heart failure is a chronic disease – attention to pre-hospital care may see greater results in reducing cardiovascular mortality