Repetitive levosimendan treatment in the management of advanced heart failure

Abstract

Inotropes may be an appropriate treatment for patients with advanced heart failure (AdHF) who remain highly symptomatic despite optimized standard therapies. Objectives for inotrope use in these situations include relief of symptoms and improvement of quality of life, and reduction in unplanned hospitalizations and the costs associated with such episodes. All of these goals must be attained without compromising survival. Encouraging findings with intermittent cycles of intravenous levosimendan have emerged from a range of exploratory studies and from three larger controlled trials (LevoRep, LION-HEART, and LAICA) which offered some evidence of clinical advantage. In these settings, however, obtaining statistically robust data may prove elusive due to the difficulties of endpoint assessment in a complex medical condition with varying presentation and trajectory. Adoption of a composite clinical endpoint evaluated in a hierarchical manner may offer a workable solution to this problem. Such an instrument can explore the proposition that repetitive administration of levosimendan early in the period after discharge from an acute episode of worsening heart failure may be associated with greater subsequent clinical stability vis-à-vis standard therapy. The use of this methodology to develop a 'stability score' for each patient means that all participants in such a trial contribute to the overall outcome analysis through one or more of the hierarchical endpoints; this has helpful practical implications for the number of patients needed and the length of follow-up required to generate endpoint data. The LeoDOR study (NCT03437226), outlined in this review, has been designed to explore this new approach to outcome assessment in AdHF.

Keywords: Intermittent treatment; Outcome; Quality of life; Rehospitalization; Repetitive inotrope.

Figure 1

Illustration of the complementary designs of the LevoRep and LION-HEART studies.

Figure 2

Principal endpoint results from LevoRep (composite of percentage of patients with improvement in the 6-min walk test of ≥20% and Kansas City Cardiomyopathy Questionnaire clinical summary score ≥15%) at 2 and 18 weeks after completion of four cycles of levosimendan treatment during a 6-week interval. The percentages of patients who reached the primary endpoint did not differ between the two groups (Fisher’s exact test). From Altenberger et al.

Figure 3

LION-HEART: comparison of mean NT-proBNP by visit (analysis of covariance for repeated measures). NT-proBNP, N-terminal pro-brain natriuretic peptide; SEM, standard error of the mean.

Figure 4

Changes in days in hospital (DIH) and number and duration of hospital admissions for heart failure (HF) in the 6 months after start of levosimendan treatment compared to the preceding 6 months in the RELEVANT-HF registry. Data are mean ± standard deviation and non-parametric P-values are shown. From Oliva et al.

Figure 5

The variable course of decompensation in advanced heart failure means that it should be possible in many instances to identify intervals during which the timely recognition of the signs and symptoms of decompensation permit interventions that can avert unplanned hospitalizations due to haemodynamic deterioration. T: Interval during which the timely recognition of signs and symptoms of decompensation and its timely treatment can avoid unplanned hospitalization due to haemodynamic crisis, which usually accompanies loss of myocardial tissue. See text for further discussion.