Heart failure (HF) is a progressive condition that affects around 26 million people worldwide and 1–2% of the European population.1,2 It is associated with high symptomatic burden and mortality, as well as a significant impact on health care systems, accounting for around 2% of health expenditure in Western countries,3,4 with 40–60% of this cost being attributable to hospital admissions.5

It is estimated that the prevalence of HF in Portugal will double, affecting 500000 individuals by 2035, with an expected increase in the rate of HF hospitalizations and HF-associated mortality, leading to a significant economic burden.6,7

In recent decades, evidence-based pharmacological and device therapies have led to significant reductions in event rates in this population. However, it is estimated that 1–10% of the overall HF population will progress to an advanced stage of the disease.8,9 Advanced HF is characterized by persistent symptoms despite maximal therapy, extremely poor quality of life (QoL) and a high event rate, specifically recurrent episodes of systemic and/or pulmonary congestion or arrhythmic events that result in recurrent hospitalizations and poor prognosis, with one-year mortality ranging between 25% and 75%.10,11

In advanced HF, heart transplantation (HT) or mechanical circulatory support (MCS) are the treatments of choice, not only improving QoL but also conferring a survival benefit compared to conventional management. However, only a small proportion of advanced HF patients are eligible for HT or MCS.10,11

To fulfill this unmet need in the management of advanced HF patient, infusion of inotropes has been proposed as a bridge to HT or MCS, leading to improvement in symptoms. However, a meta-analysis of randomized trials suggested increased mortality with long-term inotropic support, and this strategy is not currently supported by HF guidelines.11

The inodilator levosimendan has emerged as an interesting therapeutic option due to its unique pharmacological, hemodynamic and cardioprotective properties: its inotropic effect may last for approximately two weeks, despite being less pro-arrhythmic than traditional inotropes.12–14

Three randomized, placebo-controlled, double-blind clinical trials (Levo-Rep, LION-HEART, and LAICA) examined the application of repeated cycles of levosimendan therapy in outpatients with advanced HF, and demonstrated that it reduces N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and admissions for acute decompensated HF, with a trend towards reduced mortality.15–17 Furthermore, this approach has been shown to be cost-effective, generating savings for health care systems compared to the no-treatment option, mainly driven by a significant reduction in HF hospitalizations.18

Our aim was to assess the safety and efficacy of intermittent outpatient administration of levosimendan in a cohort of advanced HF patients at our center.

Advanced HF is associated with marked reductions in QoL, volume overload and/or hypoperfusion, end-organ dysfunction, diuretic resistance and inability to tolerate standard HF therapies, and survival without heart transplantation or LVAD therapy remains extremely poor.10,11 Furthermore, there are few data on the effectiveness of medical therapy for patients with advanced HF and a lack of trials addressing this population. For this reason, management in these patients is less evidence-based than in the earlier stages of the disease. It is thus of paramount importance to integrate palliative care into evidence-based heart failure management in order to improve QoL in this setting.19

A recent trial (LIFE) showed that sacubitril/valsartan on top of optimal medical therapy did not reduce NT-proBNP or improve clinical outcomes among patients with advanced HF and reduced ejection fraction (HFrEF) and comorbidities during a mean follow-up of 24 weeks.20 However, GALACTIC-HF revealed that in patients with HFrEF, those who received omecamtiv mecarbil had a lower risk of a composite of HF events (hospitalization or urgent visit for HF) and cardiovascular death than those who received placebo; this benefit was consistent across most prespecified subgroups, including LVEF, systolic blood pressure and renal function, patients with LVEF ≤28% having a greater benefit.21 This was the first trial showing that an oral inotrope could improve the prognosis of patients with advanced HF. Likewise, in the VICTORIA trial, high-risk HF patients with a recent HF hospitalization or intravenous diuretic use (mean LVEF 29%, 40% in NYHA class III and median NT-proBNP of 2816 pg/ml) receiving vericiguat had a lower rate of cardiovascular death or hospitalization for HF.22

Despite the survival improvement associated with advanced HF therapies, patients on the waiting list for HT or LVAD have a poor QoL and are still at a high risk for HF events, which can lead to functional deterioration and end-organ damage that may render them ineligible for these therapies.10,11 Historically, there has been an interest in drugs that can increase cardiac contractility and cardiac output, however, traditional beta-agonist inotropes are associated with adverse outcomes related to an increase in cyclic adenosine monophosphate (cAMP), which predisposes to life-threatening arrhythmias, cell death and development of tolerance.23 In this context, levosimendan, a calcium sensitizer, has emerged as an interesting therapeutic option, as it does not lead to an increase in intracellular calcium, and is thus less pro-arrhythmic, consumes less energy and does not induce tolerance. Furthermore, the long half-life of its active metabolite confers a long-lasting clinical effect.

Several clinical studies have addressed the use of intermittent outpatient levosimendan infusions in advanced HF patients. Levo-Rep, a prospective, randomized, double-blind, placebo-controlled, multicenter trial that was the largest study on this strategy, revealed that the administration of four cycles of levosimendan therapy did not significantly improve functional capacity or QoL as compared with placebo, despite a numerical trend in favor of levosimendan.15 The LION-HEART trial revealed that biweekly infusions of levosimendan for 12 weeks reduced NT-proBNP, improved QoL and reduced hospitalizations without adverse effects in patients with advanced HF, increasing the probability of survival in Kaplan-Meier curve analysis at 180 days.16 LAICA, which investigated monthly 24-hour infusions of levosimendan for a year in addition to optimal medical therapy, did not demonstrate statistical significance for the primary endpoint, but the results favored levosimendan in terms of both fewer admissions for acute decompensated HF and lower mortality.17 Despite a trend in favor of the repeated use of levosimendan in the majority of studies,14 more robust data on associated hospitalization and mortality rates are needed, like the ongoing LeoDOR trial.24

Our analysis aimed to determine the real-life safety and beneficial effect of six-hour outpatient levosimendan infusions in patients with advanced HF, aiming to fulfill an unmet clinical need in contemporary cardiology and HF therapy. In this regard, our study's protocol was very similar to that of the above-mentioned trials, as we included only highly symptomatic patients with evidence of poor functional status and a recent HF hospitalization, despite optimal medical therapy, in a total of more than 200 outpatient sessions. There were no major safety events and the infusions were well tolerated.

In line with the available literature, our population experienced a significant symptomatic improvement with intermittent outpatient pulses of levosimendan, as there was a 41.7% reduction in patients in NYHA functional class IV at six-month follow-up.15–17 Furthermore, CPET parameters also improved, as assessed by mean improvements in CPET duration, peak oxygen uptake and VE/VCO2 slope. Mushtaq et al. showed that a 24-h cycle of levosimendan significantly improved peak oxygen uptake and reduced VE/VCO2 slope as assessed by CPET performed 24 hours after treatment.25 However, data are scarce regarding the effect of repeated levosimendan cycles on CPET variables and exercise performance, and our work may lay the foundations for further studies in this area.

In the LION-HEART study, outpatient levosimendan treatment led to a significant reduction in NT-proBNP levels, a finding which was replicated in our analysis, with a mean reduction of 3807.4 pg/ml at six months (p=0.038).16 Natriuretic peptide concentrations after treatment have prognostic significance as treatments leading to a greater relative reduction are associated with a better prognosis, and it is well established that discharge natriuretic peptide concentrations are an excellent predictor of one-year death or rehospitalization among patients with acute HF.26 Thus, the reduction of NT-proBNP levels and the improvement in CPET parameters after six months are reflected in a reduction in HF events, as assessed by a significant reduction in HF hospitalizations during follow-up.

Several small studies have assessed the effect of different regimens of levosimendan infusion on various echocardiographic parameters, including LVEF and end-diastolic and end-systolic volumes and dimensions, showing that it is associated with improvements in LV systolic function and some degree of reverse remodeling.27 Similarly, in our analysis treatment was associated with significant improvements in LV systolic function in terms of both LVEF and GLS, with mean improvements of almost 6% and 5%, respectively. Although there was a trend toward reverse remodeling after six months, with reductions in end-diastolic and end-systolic diameters, these differences did not attain statistical significance.

At baseline, all patients were receiving optimal HF medical and device therapy, however, there was a significant increase in MRA dosage at six-month follow-up, as well as numerically higher dosages of the other HF drugs, including beta-blockers and ARNI. This may be either due to frequent patient follow-up that enables uptitration of HF medication or a consequence of levosimendan therapy, as its beneficial effect on cardiac contractility could make uptitration more easily tolerated, without causing symptomatic hypotension. The optimization of HF medical therapy enabled by the levosimendan outpatient program may thus result from the beneficial effects of calcium sensitization.

Our work establishes outpatient levosimendan infusion as a promising approach not only for patients referred for advanced HF therapies (as a bridge to HT or LVAD), reducing morbidity events and preventing end-organ damage that could render these patients ineligible for such therapies, but also to reduce the symptomatic burden of end-stage patients (as palliative therapy). Furthermore, it can also be assumed that it could be useful as a bridge to recovery during the vulnerable post-discharge period after a prolonged hospitalization for acute coronary syndrome or HF, enabling stabilization of LV function and uptitration of neurohormonal blockade medication in patients with a hypotensive profile. This is an important point to address in future trials.

In this single-center experience, outpatient levosimendan administration proved to be a safe strategy and led to significant reductions in natriuretic peptides and HF events at six months, as well as improvement in exercise performance and LV systolic function of patients suffering from advanced HF. It is important to raise awareness of this therapeutic weapon, as it can both help stabilize HF patients eligible for HT or LVAD, preventing further end-organ damage that could render them unsuitable for advanced therapies, and improve QoL and reduce the symptomatic burden of patients referred for palliative care.

The authors have no conflicts of interest to declare.