Repetitive levosimendan for a LION's heart?

Abstract

This article refers to ‘Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial’ by J. Comín-Colet et al., published in this issue on pages 1128–1136. Advanced heart failure is characterized by progressive symptoms of heart failure despite optimal medical therapy. Functional capacity, along with quality of life, are low in affected patients. Repeat episodes of hospitalization for acute heart failure not only generate a high economic burden to the community, but are associated with high mortality. Availability of effective therapeutic interventions like heart transplantation or ventricular assist devices is limited due to a lack of donor organs, financial restrictions in various areas in the world, and not least the concomitance of substantial co-morbidities. Accordingly, there is an unmet need for innovative therapeutic strategies in patients suffering from advanced heart failure, which is defined as a condition that comprises severe cardiac dysfunction (left ventricular ejection fraction <35%), severe symptoms of heart failure (New York Heart Association functional class IIIb–IV), and/or repeated hospitalizations/emergency department visits equivalent to INTERMACS levels 4–6.1 Repeat and continuous administration of inotropes has traditionally been used as a palliative care concept as well as a bridging concept for patients being considered for heart transplantation. However, despite favourable haemodynamic and symptomatic improvements with classical inotropes such as dobutamine and milrinone in small clinical trials, serious safety concerns with these substances have been raised.2-4 In contrast, repetitive administration of the inodilator levosimendan showed promising results in various non-randomized and randomized clinical trials.5-9 The study by Comín-Colet and co-authors published in this issue of the Journal adds valuable information to the existing literature.10 LION-HEART was a prospective randomized, double-blind, placebo-controlled, parallel-group trial investigating safety and efficacy of pulsed administration of levosimendan to outpatients suffering from advanced chronic heart failure.10 Sixty-nine patients were randomized to levosimendan vs. placebo in a 2:1 fashion. Six cycles of levosimendan at a dosage of 0.2 μg/min/kg for 6 h were administered in bi-weekly intervals. The primary endpoint was met in the trial, indicating a significantly larger decrease in baseline adjusted area under the curve of N-terminal pro B-type natriuretic peptide (NT-proBNP) levels throughout the treatment period in patients treated with levosimendan compared to the placebo group. Also, secondary endpoints defined as hospitalization for heart failure or cardiovascular reasons were significantly reduced with levosimendan, whereas no significant between-group difference was found for all-cause death. Notably, levosimendan-treated patients were significantly less likely to experience a decline in patient-reported outcome as measured by EQ-5D visual analogue scale. The LION-HEART data are in line with previous studies investigating the effect of repetitive administration of levosimendan and recent meta-analyses, which demonstrated a reduction in hospitalization rate11 and mortality.12 Remarkably, LION-HEART is the first multicentre trial in this field with positive results in both primary and secondary endpoints. In the previously published LevoRep study, 120 outpatients were equally randomized to levosimendan or placebo.9 Dosage and bi-weekly intervals of drug administration were similar to LION-HEART with the exception of four treatment cycles in LevoRep. In this study, the primary endpoint, which was defined as a concomitant increase in functional capacity and quality of life after 8 and 24 weeks, was not met. The secondary endpoint, a composite of death, heart transplantation and acute heart failure, however, was reduced by 50% in the levosimendan arm after 24 weeks. Additionally, in a longitudinal analysis, the percentage of patients with a ≥30% drop in NT-proBNP levels after 8 weeks was significantly higher with levosimendan. Notably, safety and tolerability of levosimendan were favourable in both trials. Under the premise primum non nocere this is remarkable in two ways. First, administration of inotropic acting substances in a non-acute setting is followed with Argus eyes due to safety concerns. Classical inotropes are enhancing intracellular calcium concentration and myocardial oxygen demand. Long-term therapy with these substances has been associated with increased mortality.3 In contrast, the inodilator levosimendan acts as a calcium sensitizer and has no effect on intracellular calcium levels.13 Additionally, a long-acting active metabolite makes the drug specifically attractive for pulsed administration in heart failure.14 Second, levosimendan was associated with a non-significant increase of fatal cardiac events in the REVIVE study, a large endpoint trial in acute heart failure.15 In this trial, levosimendan was administered simultaneously with other vasoactive substances such as milrinone, nesiritide and dobutamine in a substantial proportion of patients. It can be speculated that this may have led to excessive cardio-circulatory responses, particularly in patients with low baseline blood pressure. In fact, an inverse correlation between death and low baseline blood pressure has been shown in the REVIVE study.15 In this study the detrimental interactions between drugs may have been escalated by a loading dose of levosimendan. In LevoRep and LION-HEART, concomitant administration of vasoactive substances and a loading dose of levosimendan were banned; also, diuretics were withheld on the day of study drug administration. Despite the positive results of LION-HEART and previous studies on pulsed administration of levosimendan in advanced heart failure, this appealing concept, which is already frequently applied in many centres, still needs to be confirmed in a prospective trial with firm clinical endpoints. In the ongoing Repetitive Levosimendan Infusion for Patients With Advanced Chronic Heart Failure (LeoDOR; ClinicalTrials.gov Identifier: NCT03437226), a global rank score that comprises time to death, high urgent heart transplantation, or ventricular assist device implantation and time to acute heart failure events along with time-averaged proportional change in NT-proBNP will be used as primary endpoint, allowing a more comprehensive interpretation of the effects of the study drug on the complex trajectory of the disease. The components of the primary endpoint will be analysed in a hierarchical manner with deaths as the most important events, followed by acute heart failure events and, finally, effect on NT-proBNP. Furthermore, the results of patient-reported outcomes using validated endpoints will be addressed again. The latter is of enormous importance in this patient population, as palliative care mainly focuses on improvement of health-related quality of life. In conclusion, LION-HEART supplements the already encouraging evidence for the repetitive administration of levosimendan in advanced heart failure and adds a piece to the puzzle of conservative treatment in these very sick patients. The study indicates a favourable neurohormonal response and suggests a reduction of clinically relevant endpoints. Most importantly, safety and tolerability of levosimendan in this indication were confirmed. This gives hope that the appealing concept of repetitive administration of levosimendan will finally be established in clinical practice. Undoubtedly, further studies focusing primarily on clinical endpoints are needed. Conflict of interest: A.J. and P.G. were the main investigators of the LevoRep study, which was supported by OrionPharma with an unrestricted grant and received lecture honoraria by OrionPharma.