Marked or moderate early dyspnea improvement using the 7-item Likert scale was seen more often in women admitted for acute heart failure within the first 24 h, and persisted over the first 5 days. These improvements were not paralleled by the VAS-scale assessments. Similarly, general wellbeing, using the Likert scale over the first 5 days, improved significantly better in women, but this was not seen when the VAS wellbeing score was used. Other clinical outcome parameters were similar between men and women, and serelaxin was equally effective in men and women.
Dyspnea improvement by sex
Dyspnea is a complex symptom in patients with acute heart failure. Patient-reported dyspnea relief is a clinically meaningful treatment goal because persistent dyspnea is associated with adverse outcome [9, 10]. It is advocated as a patient-relevant endpoint for heart failure trials by regulatory authorities .
Therefore, our findings that women have a greater early dyspnea relief may be of clinical relevance. Although this difference could likely be explained by factors related to female sex, such as hypertension and heart failure with preserved ejection fraction (HFpEF), our multivariable analysis showed that female sex was an independent predictor of early dyspnea relief. No sex differences in dyspnea relief between men and women were found in a post hoc analysis of the PROTECT pilot study. However, patient numbers were small and no adjustments for preserved left ventricular ejection fraction were made . Comparable studies of early dyspnea relief in acute heart failure patients have not considered sex as covariate .
The underlying cause of our findings is likely multifactorial. Remarkably, more intense dyspnea relief in women occurred despite using lower total IV and oral loop diuretic doses and less weight loss through day 5 in women compared to men, and comparable drops of NT-proBNP values were seen in both sexes. These findings can be explained pathophysiologically by a typical mechanism of cardiac decompensation in women, which is frequently caused by fluid redistribution and related to the higher proportion of HFpEF and hypertension among women . In this context, the slightly higher proportion of women being treated with intravenous nitrates during the first days of treatment could have favored the faster improvement of dyspnea in women. However, the absolute numbers of patients who were treated with intravenous inotrope/vasoactive medication were relatively low and it appears unlikely that this fully explains the differential dyspnea response by sex.
Theoretically, the higher rates of concomitant pulmonary disease, such as asthma, bronchitis, or COPD, in men, might have negatively affected dyspnea response in men. However, patients with relevant severity of these diseases were not included in the trial based on the exclusion criteria. Also, less diuretic treatment and less weight loss could be required in women to reach comparable outcome and better symptomatic relief. It is evidenced by trial results and registry data in acute heart failure that the overall outcome does not differ between men and women despite significantly lower diuretic doses and less absolute weight loss [3, 14]. It should be noted that all measured surrogates of congestion at baseline, such as edema, orthopnea, jugular venous pressure, dyspnea on exertion, and rales, were well balanced between men and women. Thus, it might be speculated that different symptom perception per se is responsible for the higher rates of moderate to marked dyspnea relief in women over men. Alternatively, underlying pathophysiological differences in fluid distribution may have translated to differences in symptoms. An acute cardiovascular, hypertensive type of failure has been proposed as subtype of acute heart failure . It is common in the elderly, patients with history of hypertension, and women, and is characterized by preserved left ventricular ejection fraction . In this type of heart failure, ventricular and vascular stiffness play important pathophysiological roles, with a vulnerability to any disorder of fluid balance, resulting in a rapid increase of vascular resistance, blood pressure and increased pulmonary pressure . Notably, the increase in pulmonary arterial pressure and the pulmonary capillary wedge pressure was previously identified as major determinants of dyspnea in an analysis of the hemodynamics of acute heart failure patients . Because data from community dwelling subjects have proven that women have greater aortic stiffening and lower total arterial compliance than men , it might be speculated that rapid changes of intracardiac and intrapulmonary pressures as surrogates for dyspnea depend, to a greater extent, on changes of vascular volume load in women than in men. This could explain why early vasoactive and decongestive therapy might have more intense effects in women than in men, and that this could translate into differences in perceived dyspnea relief. These effects are more likely to be pronounced early during standard treatment, when the most intense reduction of vascular resistance and ventricular afterload is usually seen in acute heart failure patients .
The question why marked or moderate early dyspnea improvement was seen more often in women using the 7-item Likert scale and not by the VAS-scale assessments could be due to the different aspects that are covered by the two different measurement scales. Notably, the Likert scale was used to assess early (6–24 h) dyspnea relief, whereas the VAS-scale was used to quantify persistent dyspnea relief by the change in VAS area under the curve (VAS AUC) through day 5, as specified in the study protocol . The MEASURE-HF study indicated that the Likert scale categories reflect initial improvement relative to the baseline status without capturing relevant improvement at later timepoints; contrarily, VAS scores of dyspnea improved steadily . Likert scale assessment emphasizes the change of perceived dyspnea compared to the most severe symptom sensation at baseline. The effect is more clearly measurable as an improvement on its categorical scale with higher initial symptom severity, but it is increasingly difficult to be captured as more time passes by. VAS scores capture the particular instantaneous state of dyspnea on a continuous scale individually at different timepoints. However, it is noteworthy that a trend towards higher change from baseline VAS score (mm) in women compared to men was detectable at the time points 6 and 12 h and after 1 day (p = 0.0933, p = 0.0518 and p = 0.0701, respectively) which also translated to a trend toward higher change from dyspnea VAS AUC (mm × h) from day 1 to day 5 (p = 0.0938) in women.
Serelaxin effects in men and women
Although relaxin is commonly known to exert various biologic effects in women during pregnancy [19, 20], data on sex-specific cardio-vascular effects are scarce. Debrah et al. demonstrated in a rat model that recombinant relaxin increases cardiac output and reduces arterial load in both male and female rats . In a recent subgroup analysis, it was shown that serelaxin was equally effective in men and women . The results of our interaction analyses confirm that sex does not modify the effects of serelaxin on dyspnea relief and/or any death- or rehospitalization-related outcomes in men and women.
All limitations of retrospective subgroup analyses apply to our study. No hypotheses regarding sex differences have been pre-specified, the ratio of men to women is unbalanced and, thus, our results could be biased. All results only have a hypothesis-generating character. The great majority of the women were white (i.e., 95%), so that results are not generalizable to black women, an increasing proportion of the heart failure population with high likelihood for poor outcomes. Also, validation of the VAS and the Likert scale in acute heart failure is largely based on data from men and lacking sex-specific validation.