Background

Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of serelaxin.

Methods

In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (n = 1132). Renal impairment was defined as an eGFR <60 ml/min/1.73 m(2) estimated by creatinine.

Results

817 (72.2 %) patients had a baseline eGFR <60 ml/min/1.73 m(2). In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33-7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34-5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 -2.64; p for interaction = 0.106, and HR 1.15 95 % CI 0.56-2.34 respectively; p for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34-0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51-3.29).

Conclusion

Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial.

Background

Atrial fibrillation (AFib) is a common comorbidity in HF and affects patients' outcome. We sought to assess the effects of serelaxin in patients with and without AFib.

Methods

In a post hoc analysis of the RELAX-AHF trial, we compared the effects of serelaxin on efficacy end points, safety end points and biomarkers in 1161 patients with and without AFib on admission electrocardiogram.

Results

AFib was present in 41.3% of patients. Serelaxin had a similar effect in patients with and without AFib, including dyspnea relief by visual analog scale through day 5 [mean change in area under the curve, 541.11 (33.79, 1048.44), p = 0.0366 in AFib versus 361.80 (-63.30, 786.90), p = 0.0953 in non-AFib, interaction p = 0.5954] and all-cause death through day 180 [HR = 0.42 (0.23, 0.77), p = 0.0051 in AFib versus 0.90 (0.53, 1.52), p = 0.6888 in non-AFib, interaction p = 0.0643]. Serelaxin was similarly safe in the two groups and induced similar reductions in biomarkers of cardiac, renal and hepatic damage. Stroke occurred more frequently in AFib patients (2.8 vs. 0.8%, p = 0.0116) and there was a trend for lower stroke incidence in the serelaxin arm in AFib patients (odds ratios, 0.31, p = 0.0759 versus 3.88, p = 0.2255 in non-AFib, interaction p = 0.0518).

Conclusions

Serelaxin was similarly safe and efficacious in improving short- and long-term outcomes and inducing organ protection in acute HF patients with and without AFib.

Aims

Women with heart failure are typically older, and more often have hypertension and a preserved left ventricular ejection fraction as compared with men. We sought to analyze if these sex differences influence the course and outcome of acute heart failure.

Methods and results

We analyzed sex differences in acute heart failure in 1161 patients enrolled in the RELAX-AHF study. The pre-specified study endpoints were used. At baseline, women (436/1161 patients) were older, had a higher left ventricular ejection fraction, a higher rate of hypertension, and were treated differently from men. Early dyspnea improvement (moderate or marked dyspnea improvement measured by Likert scale during the first 24 h) was greater in women. However, dyspnea improvement over the first 5 days (change from baseline in the visual analog scale area under the curve (VAS AUC) to day 5) was similar between men and women. Women reported greater improvements in general wellbeing by Likert, but no such benefits were evident with the VAS score. Multi-variable predictors of moderate or marked dyspnea improvement were female sex (p = 0.0011), lower age (p = 0.0026) and lower diuretic dose (p = 0.0067). The additional efficacy endpoints of RELAX-AHF were similar between men and women and serelaxin was equally effective in men and women.

Conclusions

Women exhibit better earlier dyspnea relief and improvement in general wellbeing compared with men, even adjusted for age and left ventricular ejection fraction. However, in-hospital and post-discharge clinical outcomes were similar between men and women. This trial is registered at ClinicalTrials.gov, NCT00520806.

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.