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, and unfortunately there is limited guidance from national or international authorities because data and experience are lacking (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 ventricular assist devices (LVADs) has become more common. However, heart transplantation and LVADs may remain under-utilised in patients with advanced heart failure. 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 identified 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).
Short-term pharmacological treatment
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 one option for the 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 three 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). An expert panel recommends the flexible dosing of i.v. levosimendan of 0.05 μg/kg/min to 0.2 μg/kg/min, for 6 to 24 h, 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 well be a bridging measure for the patients waiting for heart transplantation or implantation of a ventricular assist device.
Levosimendan has three main mechanisms of action:
Calcium sensitisation – Levosimendan binds to cardiac troponin C and stabilises the troponin C–calcium complex in a calcium-dependent way. Thereby levosimendan enhances the sensitivity of the myofilament to calcium and this facilitates the actin-myosin cross-bridge formation. This results in increased contractile force of the myofibrils and the myocardium without any appreciable increase in intracellular calcium concentration. Due to the calcium-dependent binding, levosimendan increases contractile force only during systole (when intracellular calcium is increased), but does not impair relaxation during diastole (when intracellular calcium is decreased) (Szilagyi et al., 2004).
Opening of ATP-sensitive potassium (KATP) channels in the vascular smooth muscle cells – Levosimendan opens the ATP-sensitive potassium channels in the sarcolemma of smooth muscle cells in the vasculature. This mechanism induces vasodilatation in both arterial and venous vascular beds, which results in reduced pre- and afterload (Yokoshiki et al., 1997).
Opening of KATP channels in the mitochondria of the cardiomyocytes – by opening mitochondrial ATP-sensitive potassium channels in the cardiac myocytes, levosimendan exerts cardioprotective effects. Levosimendan thus protects the heart against ischaemia-induced reperfusion injury, and limits or prevents apoptosis in the cardiac myocytes (Kopustinskiene et al., 2004).
A review from a panel of experts into the role of levosimendan, published in 2017, suggested that although it has been identified as a treatment that reduces re-hospitalisation and improves quality of life, studies have not been powered to show statistical significance with regards to key outcome measures, such as mortality. They recommended that evaluation of symptoms was difficult and unreliable – suggesting a composite endpoint combining deaths and admissions. Their conclusion was that repetitive levosimendan may help patients with advanced heart failure – with several benefits being evident in terms of improved haemodynamics, symptoms, reduced readmission rates and biomarkers. However, it must also be noted that the studies reported thus far had differences that limit the consistency of the evidence (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 has been described in a series of four case studies (Barbici et al., 2015).
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 and so it is recommended that these agents are reserved for patients with low systolic blood pressure that is considered reversible and organ hypoperfusion (Crespo-Leiro et al., 2018).
Short-term mechanical circulatory support
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).
Long-term mechanical circulatory support
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 (Aleksova & Chih, 2017; Krabatsch et al., 2017; Rogers et al., 2017; Schmitto et al., 2016). 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 left ventricular assist system 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 l., 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 is recommended for very end-stage heart failure where transplantation and ventricular assist devices are not indicated or available. 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 J 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).