The main goal in the treatment of advanced heart failure is to maintain the patient's functional capacity and quality of life (QoL). Advanced heart failure can be challenging to treat; unfortunately there is limited guidance from national or international authorities because of a lack of data and experience (Fruhwald et al., 2016).
The ultimate therapy for advanced heart failure is heart transplantation, but because the availability of donor hearts does not meet the need, the implantation of LVADs has become more common. However, heart transplantation and LVADs are under-utilised in patients with advanced HF. The ScrEEning for advanced Heart Failure treatment (SEE-HF) study assessed patients receiving cardiac resynchronisation therapy and/or an implantable cardioverter-defibrillator to see if they may be eligible for guideline-based heart transplantation or LVAD indication. Interestingly, 7% of the 1,722 patients screened were found to have NYHA class III-IV heart failure with an ejection fraction ≤40%. Of these patients, 26% were eligible for either heart transplantation or LVAD treatment (Lund et al., 2018).
Before patients can be selected for heart transplantation and LVAD therapy, they must first be referred by their general physicians¬¬ – patients are often referred too late or not at all. Timely referral is crucial to the success of these treatments and, in contrast to the complex criteria for specialist treatment, the indication for referral to a HF specialist should simply be clinical deterioration despite optimal HF care (Thorvaldsen & Lund, 2019).
Inotropes can improve haemodynamics and help reverse end-stage organ function in advanced heart failure. However, they are not currently recommended for routine use, but may be offered in refractory heart failure as a bridge to other therapies. They may also be used as short-term therapy in patients with low cardiac output and evidence of end-organ dysfunction, such as during decongestion (Crespo-Leiro et al., 2018). The conventional inotropes,such as dobutamine and milrinone, appear to be a suboptimal pharmacological choice because their prolonged use may have a negative impact on survival (Fruhwald et al., 2016).
Levosimendan, a calcium-sensitiser with inotropic, cardioprotective and vasodilatory properties, may be an option for patients who continue to progress and develop more severe symptoms despite optimal pharmacological therapy. A meta-analysis showed that repetitive use of levosimendan reduced mortality in patients with advanced heart failure with an odds ratio of about 0.5 while another recent meta-analysis suggested intermittent levosimendan resulted in reduced hospitalisation at 3 months (Silvetti & Nieminen, 2016; Silvetti et al., 2017). Meanwhile, a recent study explored the use of bi-weekly administration of levosimendan for advanced heart failure in an outpatient setting. Over the 12-week treatment period, patients who received levosimendan had reduced NT-proBNP levels (p=0.003) and were less likely to be hospitalised (HR 0.25; 95% CI, 0.11–0.56; p=0.001) or have a clinically significant decline in HRQoL (p=0.022) compared with placebo (Comín-Colet et al., 2018). The NT-proBNP level was also significantly reduced and the 6-minute walking test (6MWT) was significantly increased in a group of 80 patients with acute heart failure, who were randomised to two groups: a control group receiving conventional treatment and the observational group receiving conventional treatment plus levosimendan (Li et al., 2019). The 6MWT in the observation group was 452.63±86.51 m versus 366.85±70.46 (p<0.05) (Figure 6). The positive effects of levosimendan in heart failure have also been demonstrated using echocardiography (Camelli et al., 2019), which provides a non-invasive, fast and accurate method for evaluating the positive haemodynamic effects of levosimendan on both systolic and diastolic left ventricular function.
Similar results were seen in patients with ambulatory advanced heart failure (AAHF); the RELEVANT-HF registry study included 185 patients who had NYHA class III-IV symptoms, depressed LVEF and ≥2 heart failure hospitalisations or emergency visits in the previous 6 months. The addition of levosimendan on top of optimal medical management appeared to be beneficial for survival and improved patient outcomes. The percentage of days spent in hospital decreased significantly from the 6 months prior to study enrolment to the 6 months after levosimendan treatment (9.4% vs. 2.8%, p<0.0001). The number and length of heart failure admissions were also lower following levosimendan treatment compared to the previous 6 months (1.3 vs. 1.8, 17.4 vs. 21.6, respectively; both p=0.0001). Importantly, the survival rate was high with 86% of patients alive at 1-year post treatment, and 76% had event-free survival at 1-year (Oliva et al., 2018).
An expert panel recommended the flexible dosing of intravenous levosimendan, 0.05–0.2 μg/kg/min for 6–24 hours, every 2–4 weeks. During the treatment period, the monitoring of blood pressure, heart rate, body weight, serum sodium and potassium levels and serum creatinine levels is recommended for safety reasons (Nieminen et al., 2014). The long-acting active metabolite of levosimendan facilitates the use of repetitive infusions at low doses. Levosimendan could be a bridging measure for patients waiting for heart transplantation or a LVAD.
A meta-analysis of published literature up to January 2018 was carried out to determine the efficacy of intermittent levosimendan infusion in patients with advanced heart failure. Eleven studies were found comprising 586 patients at doses of intermittent levosimendan ranging from 0.1 to 0.4 μg/kg/min, for between 6 and 24 hours, repeated every 2 to 4 weeks, for a follow up period between 3 and 12 months, The analysis demonstrated a significant 55% reduction in mortality (OR 0.45; 95% CI 0.26-0.78), a reduction in natriuretic peptide levels and an improvement in left ventricular ejection fraction. The results were limited by the relatively small numbers of studies and the heterogeneous infusions used for comparison. However, taking into account these limitations, the results are consistent with previous meta-analysis supporting a reduction in mortality with the use of levosimendan in patients with advanced heart failure (Garcia Pena et al., 2018).
Levosimendan has three main mechanisms of action:
An expert panel review in 2017 concluded that, although levosimendan has been identified as a treatment that reduces re-hospitalisation and improves quality of life, there was a lack of studies powered to show statistical significance for key outcome measures, such as mortality. As evaluation of symptoms was difficult and unreliable, they suggested a composite endpoint combining deaths and admissions. The panel concluded that repetitive levosimendan may help patients with advanced heart failure, as suggested by improved haemodynamics, improved symptoms, reduced readmission rates and changes in biomarkers. However, it also noted that their conclusions were limited by the consistency of the evidence of the studies reviewed (Pölzl et al., 2017).
The publication of real-world data may help to provide greater clarity on the benefits of pharmacological agents in the management of advanced heart failure. In a recent small real-world study comparing 25 levosimendan-treated patients with a control group, levosimendan improved LVEF and reduced hospitalisations over 12 months of follow-up (Ortis et al., 2017). In addition, the use of levosimendan for heart failure in different settings was described in a series of four case studies (Barbici et al., 2015). Another anecdotal example is the use of a 24-hour infusion, 0.05 μg/kg/min in reversing single ventricle heart failure in a 44 year old male with adult congenital heart disease and a modified Blalock-Taussig shunt (Tavares et al., 2019). Intravenous furosemide and levosimendan has been used to treat effectively a patient with acute decompensated anthracycline-induced cardiomyopathy (Li et al., 2019). Anthracycline chemotherapy induces cardiomyopathy in a dose-related fashion with no specific treatment except standard medical therapy and a poor prognosis.
Published data have shown potential advantages of levosimendan in the management of acute decompensated heart failure and advanced heart failure when standard medical therapies threaten haemodynamics and organ perfusion, and are unable to alleviate clinical symptoms. The LION-HEART and LAICA trials of intermittent infusions of levosimendan demonstrated several clinical benefits, such as improved cardiac biomarkers, symptoms, quality of life, rehospitalization rates, and reduction of heart failure-related mortality. Levosimendan distinguishes itself from other catecholaminergic inotropes by its three mechanisms of action: positive inotropy, vasodilation, and cardioprotection. In addition, its pharmacokinetics allow for a longer duration of action from metabolite OR1896, allowing for further therapeutic cardiovascular effects for several days, even after discontinuation of the parent drug. Data supporting the use of levosimendan show that the medication is generally well tolerated and has encouraging future perspectives in the management of acute and advanced heart failure (Pashkovetsky et al., 2019).
Several clinical studies have suggested intermittent cycles of intravenous levosimendan may reduce hospitalisation and mortality rates in patients with advanced heart failure, but were not sufficiently powered to be conclusive. LeoDOR (levosimendan infusions for patients with advanced chronic heart failure) is a randomised, double‐blind, placebo‐controlled, international, multicentre trial that will assess the efficacy and safety of intermittent levosimendan therapy started during the vulnerable phase following a hospitalisation for acute HF. The study hypothesis is that, compared with placebo, repetitive administration of levosimendan during the post‐acute phase will be associated with greater clinical stability over a follow‐up period of 14 weeks (Pölzl G et al., 2019).
The primary endpoint will rank all patients across three hierarchical groups, ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalisation and, lastly, time‐averaged proportional change in N‐terminal pro‐brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.
Vasopressors, such as dopamine, noradrenaline and adrenaline, have been associated with worse patient outcomes. Low-dose dopamine was comparable to placebo at improving congestion and cardiovascular outcomes in patients with acute decompensated heart failure. Thus, it is recommended that these agents are reserved for patients with low systolic blood pressure considered reversible and organ hypoperfusion (Crespo-Leiro et al., 2018).
Short-term mechanical circulatory support (MCS) may be provided to patients with cardiogenic shock to allow recovery of the heart and other organs over a few days to several weeks. It can also be used as a bridge-to-decision for patients being considered for long-term MCS or heart transplantation. Various devices are available and include intra-aortic balloon pump, extracorporeal membrane oxygenation (ECMO) that provides full systemic circulatory support and several ventricular assist devices/systems that can be percutaneous or require surgical implantation (Crespo-Leiro et al., 2018).
Ventricular assist devices are gaining increased traction, both as a bridge to transplantation, and a destination therapy. Transplantation is reserved for patients of younger age with otherwise good prognosis and compliance. Assist devices are a potential therapy, but again may be unwanted in the very elderly and frail patients. As devices improve, becoming smaller and overcoming various technical limitations, they are becoming a more attractive option for the management of advanced heart failure in cases suitable for care according to the national care pathway. Data have shown 80% survival at 1 year, 70% at 2-years, with a 5-year survival of 59% in a follow-up to the ReVOLVE trial. They do have significant potential for complications – stroke, bleeding and pump thrombosis are the most severe – and therapeutic anticoagulation is required (Schmitto et al., 2016; Aleksova & Chih, 2017; Krabatsch et al., 2017; Rogers et al., 2017). These complications can place a substantial burden on emergency department admissions, one small study identified a rate of ~7.3 emergency department visits per year alive with LVAD among their patients (Tainter et al., 2017). However, improvements in LVADs mean costs may be reduced in future. In the MOMENTUM 3 Long-Term Outcome study of 366 patients with advanced heart failure, patients who received an updated LVAD had fewer hospitalisations per patient year (p=0.015) and an average of 8.3 fewer hospital days per patient year (p=0.003) compared with those who received an older system. These differences were driven by fewer hospitalisations for suspected pump thrombosis and stroke and resulted in a reduction in post-discharge costs of 51% (Mehra et al., 2018).
Furthermore, it is not just a mortality benefit LVADs offer; symptomatic improvement has also been noted, with 6-minute walk distances increasing alongside quality of life measures including anxiety and depression scores (Gustafsson & Rogers, 2017; Yost et al., 2017). However, the benefits of LVADs are not universal; approximately one third of high-acuity patients experienced poor outcomes in the year following LVAD treatment (Fendler et al., 2017). In the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management) Study, LVAD therapy improved patient health status in patients with a low self-reported HRQoL but not in patients who already had an acceptable HRQoL at the time of LVAD implantation. This suggests that patient-reported HRQoL may be considered when deciding on the use and timing of LVAD therapy in patients who remain ambulatory (Stehlik et al., 2017).
Prolonged immobility in patients with heart failure can have a substantial impact on their physical function and promote muscle wasting that could accelerate the course of their heart failure (Amiya & Taya, 2018). Exercise training has been suggested as a potential intervention to improve outcomes in advanced heart failure. A recent study started with low-intensity monitored sessions, gradually increasing them to 30–60 minutes over the course of 3 months. It was noted that in a certain patient group (those on optimal medical therapy and with high B-type natriuretic peptide level), significantly increased peak VO2 was found following exercise training, alongside more favourable clinical outcomes (Nakanishi et al., 2017). The use of high-intensity aerobic exercise has also been assessed in in-patients with advanced heart failure. A protocol of 3 or 4 sessions of 1-minute high-intensity exercise (80% peak VO2 or 80% heart rate reserve) followed by a 4-minute recovery period, showed that high-intensity interval training can positively impact skeletal muscle strength among this patient group (Taya et al., 2018). The benefits of exercise training have been extended to those patients with severe advanced heart failure who require continuous inotropic infusion therapy. However, many of these patients are unable to perform the exercise test at the initiation of training creating uncertainty over the choice of exercise protocol. Even the lowest intensity aerobic training has been demonstrated to produce a positive effect in cardiac patients with reduced exercise capacity and so this should be prescribed first and increased gradually as exercise tolerance increases (Amiya & Taya, 2018).
Palliative care focusing on symptomatic control has been recommended for very end-stage heart failure where transplantation and ventricular assist devices are not indicated or available. Among patients with advanced heart failure, the need for palliative care remains high. One study assessing the World Health Organization Palliative Needs tool (NECPAL) found that 55% (n/N = 45/82) of patients with advanced heart failure were eligible for palliative cate, and physicians reported that death within the next 12 months would not be surprising in 56.1% of patients (n = 46). However, only 36% of patients or their families requested palliative care initiation (n = 30) (Orzechowski et. al., 2019).
In general, the application and quality of palliative care has not kept pace with that provided for cancer. In part, this has been due to the lack of accurate survival prediction; recent recommendations from North American and European heart failure societies have suggested a shift in emphasis away from prognosis, towards symptom-centred referral. The tools available to distinguish symptom severity, quality of life and emotional distress require further discussion and validation to ensure they lead to optimal assessment (MacIver et al., 2017). A recent review has sought to provide more clarity and has collated the latest evidence and recommendations for the palliative management of symptoms commonly experienced by patients with advanced heart failure (Lowey, 2017).
Another potential hurdle faced is the lack of a standardised clinical protocol to treat heart failure in the palliative setting. A small-scale study of 32 patients worked to develop a protocol using guideline-directed medical therapy with digoxin, opioids and oral bumetanide progressing to levodopa rather than intravenous diuretics. They found this resulted in few admissions, allowing patients to die at home (Taylor et al., 2017).
A study aiming to break some of the barriers to palliative care for patients with heart failure identified patients with NYHA class 3 or 4 symptoms who had one or more emergency department visits, or two or more admissions for symptom control, as likely to have an unmet clinical need for palliative care. They found that integrating a model of palliative care for patients with advanced heart failure led to positive feedback from patients and families, allowing advance decisions that can lead to beneficial patient, family and system outcomes (Lewin et al., 2017).
However, too few patients have access to adequate palliative care for their clinical situation. A review by Cross et al. (2019) discusses contributory factors to the underuse of hospices among patients with heart failure, identifying seven major themes that drive hospice underuse in HF (Figure 7). Despite differing social issues and healthcare systems, barriers to hospice use for patients with HF are remarkably similar in high-income countries. Overcoming the barriers to care is particularly important when nearly 39% of adults needing palliative care have cardiovascular disease (WHO, 2014). Inadequate follow-up care is a major factor in hospital readmissions, while hospice use has been associated with a lower risk of 30-day hospital readmission among patients with HF. Improving communication and developing trust must be priorities in improving end of life care for all. Innovative programmes and models of care may extend the reach of palliative and hospice care in institutions and in more remote geographical areas.
Due to the increasing prevalence of HF and the shortage in the palliative care workforce, cardiologists will need to develop comfort and proficiency in advanced care directives and primary palliative care. Following the recent publication of several trials on the usefulness of starting palliative treatment alongside cardiac treatment for advanced HF, a review by Solis Garcia Del Pozo et al., (2019) concluded that physicians need to be able to incorporate this type of intervention while still ensuring they are pursuing active treatment of the patient's heart failure.
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