Sex differences in early dyspnea relief between men and women hospitalized for acute heart failure: insights from the RELAX-AHF study

Clin Res Cardiol DOI 10.1007/s00392-016-1051-4 ORIGINAL PAPER Sex differences in early dyspnea relief between men and women hospitalized for acute heart failure: insights from the RELAX-AHF study Sven Meyer1,2 • John R. Teerlink3 • Marco Metra4 • Piotr Ponikowski5 • Gad Cotter6 • Beth A. Davison6 • G. Michael Felker7 • Gerasimos Filippatos8 • Barry H. Greenberg9 • Tsushung A. Hua10 • Thomas Severin11 • Min Qian12 • Adriaan A. Voors1 Received: 5 September 2016 / Accepted: 3 November 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract 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 & Adriaan A. Voors 1 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 2 Department of Cardiology, Heart Center Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany 3 University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA 4 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy 5 Medical University, Clinical Military Hospital, Wroclaw, Poland 6 Momentum Research Inc., Durham, NC, USA 7 Duke University School of Medicine, Duke Heart Center, Durham, NC, USA 8 Athens University Hospital, Attikon, Athens, Greece 9 University of California at San Diego, La Jolla, CA, USA 10 Novartis Pharmaceuticals Corp., East Hanover, NJ, USA 11 Novartis Pharma AG, Basel, Switzerland 12 Columbia University Medical Center, New York, NY, USA 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. Multivariable 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. Keywords Serelaxin
Acute heart failure
Sex
Gender
Dyspnea Introduction Women and men show marked differences both in the onset of heart failure and in established chronic heart failure [1, 2]. We recently showed that clinical characteristics of men and women admitted for acute heart failure 123 Clin Res Cardiol are also different [3]. Relative to men, women typically more often show features such as hypertension, atrial fibrillation and preserved left ventricular ejection fraction, whereas men usually present with ischemic heart disease, history of myocardial infarction, reduced left ventricular ejection fraction, and specific medical and device treatment [3]. In previous studies, women admitted for acute heart failure received lower oral and intravenous diuretic doses, had fewer dose increases, lost less body weight during hospitalization, and had a longer length of hospitalization compared with men [3, 4]. However, no studies have specifically focused on differences in dyspnea relief and changes in general wellbeing between men and women admitted for acute heart failure. Here, we investigate sex differences in early and persistent dyspnea relief as well as additional efficacy endpoints, and analyzed patient features and heart failure characteristics in men and women hospitalized for acute heart failure enrolled in the RELAX-AHF study [5]. The RELAX-AHF study tested the effects of serelaxin, a recombinant form of the natural hormone human relaxin 2, vs. placebo on dyspnea relief on top of standard of care [5], and provided insights into specific effects of serelaxin in acute heart failure [6, 7]. Patients and methods Study design, population and treatment The RELAX-AHF study was a multi-center, double-blind, randomized, controlled trial, comparing the intravenous administration of serelaxin for up to 48 h vs. placebo on top of standard of care. Patients were randomized within the initial 16 h of hospital admission for AHF with congestion and dyspnea, additionally having elevated natriuretic peptide levels, mild to moderate renal dysfunction, and systolic blood pressure [125 mmHg. Notably, patientreported dyspnea improvement was evaluated by the two primary efficacy endpoints of the RELAX-AHF study: first, change from baseline to day 5 in the visual analog scale area under the curve (VAS AUC) and, second, the proportion of patients with moderate or marked dyspnea improvement as indicated by Likert scale ratings at 6, 12 and 24 h (all three), both analyzed by intention to treat [5]. The VAS was a 0–100-mm long scale on which each patient marked the level of dyspnea and the distance from the 0-level of the scale was measured. VAS appropriately allows quantification of within-subject changes of repeated measurements as it has the sensitivity required to measure changes. The 7-item Likert scale is a psychometric instrument for the grading of dyspnea. Patients were asked 123 to rate the degree of improvement in response to therapy within the spectrum of categories ranging from markedly better to markedly worse. Notably, for the patients with available dyspnea Likert assessments, those following death, worsening heart failure or heart failure/renal failure rehospitalization event were imputed as the worst score of the Likert scale as ‘markedly worse’ (worse Likert score = -3); for the ‘‘Time to Moderately or Markedly Better Dyspnea Through Day 5’’ analyses, for patients who died, had worsening heart failure or re-hospitalization due to heart failure, the day was set to 6 days. Ethics The RELAX-AHF study was approved by all local Ethics Committees and complied with the Declaration of Helsinki guidelines. Written informed consent was obtained from all p (...truncated)