Treatment of advanced heart failure

Introduction

Heart failure (HF) is a clinical syndrome caused by various structural and/or functional abnormalities of the heart that lead to reduced cardiac output and/or increased ventricular filling pressure at rest or exercise. It is characterized by symptoms such as shortness of breath and general fatigue, and signs such as increased jugular venous pressure, lung crepitations and peripheral edema (1).

It is estimated that 64.3 million people in the world suffer from HF. The prevalence is about 1–2% in the adult population and increases with age. In people over the age of 70, the total prevalence is above 10%. HF significantly affects the patients’ quality of life and is characterized by high mortality and morbidity (1–5). Jones et al. conducted a meta-analysis that included more than 1.5 million patients with HF and estimated one-year survival at 86.5%, two-year at 72.6%, five-year at 56.7% and ten-year at 34.9% (6).

HF represents an increasing financial problem due to the high total cost of treatment, and it is estimated that in developed countries about 2–3% of the total health system cost relate to the treatment of HF. Furthermore, it is predicted that the number of patients with HF will increase by 46% and that HF-related costs will increase by 127% in the period from 2012 to 2030 (7, 8).

Chronic HF ultimately progresses to the end stage of the disease, which is characterized by poor prognosis, i.e. one-year mortality ranging between 25% and 75%. Patients with acute HF can also present with an advanced clinical picture. It is estimated that 1–10% of patients with HF are in the end stage, and the prevalence is continuously increasing due to the ageing of the population and the increasing number of patients with risk factor for cardiovascular diseases (1, 9).

Advanced or end-stage heart failure

According to the Heart Failure Association of the European Society of Cardiology (HFA-ESC) all the following criteria must be met to define end-stage HF despite the optimal guideline-directed medical therapy (GDMT):

1. severe and persistent symptoms of HF (NYHA class III or IV),
2. severe cardiac dysfunction characterized by at least one of the following criteria: reduced left ventricular ejection fraction (LVEF) ≤ 30% isolated right ventricular failure inoperable severe valvular disease inoperable severe congenital defects persistently high (or increasing) levels of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) and presence of severe diastolic dysfunction or structural abnormalities of the left ventricle,
3. episodes of pulmonary or systemic congestion requiring high-dose intravenous diuretics (or combinations of diuretics); or episodes of reduced cardiac output that require inotropic support or the use of vasoactive drugs; or malignant arrhythmias causing > 1 unplanned visit to the doctor or hospitalization in the last 12 months,
4. significant exercise intolerance with the inability to perform physical activity or the six-minute walk test (6MWT) < 300 m or the peak oxygen consumption (peakVO2) on the exercise test < 12–14 mL/kg/min, which are assumed to be of cardiac aetiology.

It is important to point out that the definition of end-stage HF refers to heart failure with reduced but also with preserved ejection fraction (9).

A universal definition of end-stage HF was also proposed by the Heart Failure Society of America (HFSA), HFA-ESC and the Japanese Heart Failure Society (JHFS). According to the consensus, end-stage HF is defined as stage D, which is characterized by severe symptoms and/or signs of HF at rest, frequent rehospitalizations despite GDMT, patients are refractory or do not tolerate GDMT, which is why it is necessary to consider heart transplantation, implantation of a mechanical circulatory support (MCS) or palliative care (PC) (Figure 1) (10).

FIGURE 1. Stages of heart failure (adjusted from (10)). CMP – cardiomyopathy; CVD – cardiovascular disease; DM – diabetes mellitus; GDMT – guideline-directed medical therapy; HF – heart failure; HTN – hypertension; HTX – heart transplantation; MCS – mechanical circulatory support; PC – palliative care

Dunlay et al conducted a study that included 6,836 patients with HF, of which 936 (13.7%) met the end-stage criteria. The average age of patients with end-stage HF was 77 years, and 55.5% were men. Only 42.3% of patients with end-stage HF had a reduced ejection fraction, 14.3% had a moderately/mildly reduced ejection fraction and 43.4% had a preserved ejection fraction. The prevalence of end-stage HF increased with age and was higher in men, and the median survival from the moment of end stage diagnosis to death was 12.2 months. End-stage HF was shown to be associated with poor prognosis irrespective of LVEF (11). According to Kalogeropoulos et al, every year 4.5% of patients progress from stage C to stage D (12).

Symptoms and signs of HF can be more or less typical and specific (13). They are multiple and more pronounced in the advanced stage of HF. HF is characterized by the retention of fluid and sodium, which leads to pulmonary congestion in the left-sided, and peripheral congestion in the right-sided HF (14). The most common symptoms of left ventricular failure are dyspnea during exercise, orthopnea and paroxysmal nocturnal dyspnea. As HF progresses, dyspnea begins to appear even at rest. Patients are often tachycardic and tachypnoic, and those with severe HF may also be cyanotic. The most common symptoms of right ventricular failure are fatigue, heaviness in legs and weakness, and the signs are peripheral pitting edema, ascites, hepatomegaly and increased jugular venous pressure (15). Patients with end-stage HF present with a specific hemodynamic profile characterized by high left ventricular filling pressure, and an additional feature is the reduced cardiac output resulting in systemic hypoperfusion. Bendopnea, i.e. the dyspnea that happens when the patient bends over, is considered a specific symptom of end-stage HF. On the other hand, rales, which can be a sign of HF, are absent in more than 80% of patients in the end stage (16). The most common clinical manifestations of patients with end-stage HF include exercise intolerance, unintentional weight loss, recurrent ventricular arrhythmias, refractory volume overload, hypotension and signs of inadequate perfusion that occur despite optimal therapy (17).

Treatment of advanced heart failure

PHARMACOTHERAPY

According to the guidelines, drug therapy that affects the prognosis of the disease must be titrated up to the maximum prescribed dose or the maximum tolerable dose (Table 1), but one of the challenges in treatment is the fact that end stage HF patients often do not tolerate GDMT due to hypotension or renal dysfunction, which is also a predictor of a worse outcome. Reduction of optimal drug therapy in end-stage HF can temporarily improve symptoms, especially if introduction of inotropic support and the use of advanced treatment methods is anticipated or planned. If possible, it is necessary to treat specifically the aetiology of heart failure (1).

DRUGS THAT MODIFY THE COURSE OF THE DISEASE

Drugs that modify the course of the disease should be given to all patients with heart failure with reduced ejection fraction (HFrEF) if there are no contraindications. Those include angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), sacubitril/valsartan - angiotensin receptor-neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i). The optimal therapy for the treatment of HFrEF consists of a combination of ARNI, beta blockers, MRA and SGLT2i. The classical approach of gradual introduction of each drug group up to the target dose is increasingly being abandoned because it takes too long, even several months, to reach GDMT, especially after the STRONG-HF study publication at the end of 2022, which showed that intensive titration of all groups of HF drugs early after stabilization is safe and more effective in reducing HF hospitalizations and mortality (18). This intensive approach is supported by the fact that most of these drugs reduce morbidity and mortality within 30 days of therapy introduction (19). Gradual and intensive approach to treatment is shown in Figure 220.

FIGURE 2. Heart failure optimal therapy optimisation – A) conventional; B) intensified (adjusted from (20)). ACE-I – angiotensin-converting enzyme inhibitor; ARB – angiotensin receptor blocker; ARNI – angiotensin receptor-neprilysin inhibitor; BB – beta blocker; GDMT – guideline-directed medical therapy; MRA – mineralocorticoid receptor antagonist; SGLT2 – sodium-glucose co-transporter 2

BETA BLOCKERS

Beta blockers are one of the basic therapies for HF, but only a few studies have focused on their use in the end stage HF. The COPERNICUS study included 2,289 patients with significantly reduced left ventricular ejection fraction (LVEF <25%) and significant symptoms (NYHA class III and IV) despite the use of optimal therapy. The patients were randomized into two groups: one received carvediol and the other placebo. A significant reduction in mortality was recorded in patients who received carvediol (21). Given the lack of evidence on the impact of beta blockers on the quality of life in patients with end-stage HF, their use is recommended in combination with other drugs that modify the course of the disease. Furthermore, beta blocker therapy is recommended for all patients in the end stage HF starting with a low dose and subsequent titration, i.e. with a 50% dose increase every 2–4 weeks. Beta blockers with the least hypotensive effect, such as bisoprolol and metoprolol with prolonged release, are preferred (16).

MODULATORS OF THE RENIN-ANGIOTENSIN SYSTEM

The PARADIGM-HF study included 8,842 patients with optimal therapy and reduced ejection fraction; they were classified as NYHA class II–IV and <1% of patients were classified as NYHA class IV. The patients were randomized into groups, one of which received sacubitril/valsartan, and the other enalapril with other HF therapy. The group that received sacubitril/valsartan showed a reduction in the number of hospitalizations by 21% and a reduction in mortality by 20% (22).

The LIFE study compared the effect of sacubitril/valsartan versus valsartan in patients classified as NYHA class IV, with LVEF ≤35% and elevated NT-proBNP level. The results of this study showed that there was no statistical difference in the use of sacubitril/valsartan and valsartan in terms of NT-proBNP reduction (23).

It is considered that sacubitril/valsartan should be used in the treatment of end-stage HF, but its application should be carefully implemented as patients in the end stage HF tolerate higher doses less. The recommended starting dose is 24/26 mg twice a day and it should be gradually titrated so that every 2 weeks the daily dose is doubled to a total of 97/103 mg twice a day (16, 24). According to the guidelines, sacubitril/valsartan is currently in the second line of treatment, i.e. it is used in patients with HFrEF if ACEi or ARB cannot control the symptoms and disease. When introducing sacubitril/valsartan, it is very important that patients who were on ACEi have a wash out period of 36 hours between stopping ACEi and starting ARNI (1).

MINERALOCORTICOID RECEPTOR ANTAGONISTS

The most effective strategy for complete RAAS inhibition is the combination of ARNI and MRA (16).

In the RALES study, the use of spironolactone resulted in reduced mortality and hospitalization in patients with end-stage HF. The effectiveness of the use of spironolactone has also been recorded in patients with impaired renal function or moderate hyperkalemia (16, 25).

However, there is insufficient evidence of a definitive effect on quality of life, but spironolactone is nonetheless recommended for all patients with end-stage HF and a serum potassium level 6 mEq/L after MRA introduction, it is recommended to discontinue all drugs that interact with RAAS (16). Eplerenone, as a more selective MRA than spironolactone, is a better choice due to a lower side effect rate.

SGLT2 INHIBITORS

SGLT2i are new drugs in the treatment of chronic HF. Initially developed as hypoglycemics, their positive effect on major cardiovascular (CV) outcomes in HF, regardless of the presence of diabetes, was proven by two studies at the end of the last decade: EMPEROR-Reduced for empagliflozin and DAPA-HF for dapagliflozin (26, 27). SGLT2i are the only group of drugs that affects HF prognosis across the ejection fraction spectrum with a good safety profile, multiple beneficial effects and simple dosing. There is clear evidence of benefit in HF with slightly reduced and preserved ejection fraction for empagliflozin (EMPEROR-Preserved) and dapagliflozin (DELIVER) (28, 29). The mechanisms by which SGLT2i act to improve the disease are multiple and still insufficiently investigated. In addition to glycemic control, some of them include natriuresis, reduction of endothelial dysfunction, reduction of pro-inflammatory cytokine production, reduction of oxidative stress, regulation of hyperuricemia and hyperfiltration in kidneys, reduction of intraglomerular pressure and albuminuria.

When starting therapy with RAAS inhibitors, ARNI or SGLT2i, a temporary deterioration of renal function can be expected so there is no need to rush to discontinue these drugs, especially if the increase in creatinine is 25 mL/min/1.73 m2 (1).

DIURETICS AND TREATMENT OF CONGESTION

Improvement of the symptoms of congestion in patients with end-stage HF can be achieved by using diuretics in high dose or continuous infusion, and decongestion is considered as a significant prognostic factor of survival. A mild and transient increase in creatinine in the treatment of acute HF is not associated with a worse outcome if the patient shows no signs of congestion. However, the clinical course of end-stage HF is characterized by the development of cardiorenal syndrome and resistance to diuretics, which further complicates treatment. In order to achieve the desired effect, it is necessary to progressively increase the dose due to resistance, and one of the main mechanisms of resistance is remodelling of the nephron due to prolonged treatment with diuretics. In the case of resistance, the first therapeutic option is to increase the oral dose of loop diuretics, and patients with an inadequate response should receive intravenous diuretics with an initial dose higher than the oral one. If adequate diuresis is not achieved with the applied therapy, further treatment includes a combination of loop diuretics and other diuretics. It is important to point out that this combination can result in hypokalemia and hyponatremia. If the applied therapy did not achieve the desired outcome and adequate diuresis, it is necessary to consider ultrafiltration as the next therapeutic option. It is necessary to determine the speed of ultrafiltration. Due to reduced capillary refill, ultrafiltration speed >250 mL/h is not recommended (9, 16, 30, 31). Resistance to diuretics and deterioration of renal function are indicators of end-stage HF and the need for advanced treatment (32, 33).

OTHER DRUGS IN CHRONIC HEART FAILURE

For certain groups of patients, the use of some other drugs is also considered. Ivabradine – an If channel blocker in the sinoatrial node can be given to HF patients who are in sinus rhythm with heart rate >70/min and who cannot tolerate beta blockers. Digoxin, an antiarrhythmic and inotrope, is a therapeutic option in patients with HFrEF who have persistent tachyarrythmic form of atrial fibrillation (1). Administration of iron-hydroxymaltose intravenously in iron-deficient patients is safe and improves symptoms regardless of presence of anaemia (34). Therefore, a routine check for iron deficiency in HF patients is recommended.

Vericiguat is a new drug as an option in the treatment of HF. It is a soluble guanylate cyclase (sGC) stimulator which increases nitric oxide production. It achieves its effect by directly stimulating sGC independently of nitric oxide and sensitises sGC to endogenous nitric oxide. This stabilises the binding of nitric oxide to the binding site. The VICTORIA study included patients with worsening symptoms and HFrEF who had recently been hospitalized or who had received intravenous diuretic therapy. The study included 5,050 patients with chronic heart failure, NYHA class II–IV, LVEF < 45% and elevated natriuretic peptide level within 30 days before randomization. The patients were divided into two groups, one of which received vericiguat and the other placebo in addition to GDMT. The primary composite endpoint was CV death or first HF hospitalization. The results of the study showed the occurrence of the primary endpoint in 35.5% of patients who received vericiguat compared to 38.5% of patients who received placebo. HF hospitalization was recorded in 27.4% of patients who received vericiguat, compared to 29.6% of patients on placebo (HR 0.90; 95% CI, 0.81–1.00). Furthermore, a lower incidence of CV death was recorded in the group that received vericiguat. Symptomatic hypotension occurred in 9.1% of patients on vericiguat versus 7.9% on placebo, and syncope occurred in 4% of patients receiving vericiguat versus 3.5% on placebo. Thus, vericiguat has been shown to reduce the incidence of CV death and HF hospitalization (35). It has been shown that the use of vericiguat will reduce the primary composite endpoint and its components in patients with NT-proBNP level <8000 pg/mL and that vericiguat has the most significant therapeutic effect at NT-proBNP level <4000 pg/mL (36). According to the guidelines, vericiguat can be considered as an adjunct to standard HFrEF therapy, but with a recommendation level of IIb (1).

INOTROPIC SUPPORT

Inotropic drugs increase heart contractility and consequently cardiac output as well. They also have a vasodilating or vasoconstricting effect depending on the specific drug and dose. They are used in severe HF manifestations, sometimes with the parallel need to give vasoconstrictors. Inotropes can improve hemodynamic parameters and end organ function in patients with end-stage HF, and are used to relieve symptoms or as bridge therapy until transplantation or MCS device implantation. However, routine use is not recommended because inotropic support is not associated with improving the prognosis, and in some cases can even worsen it. Furthermore, long-term use is also not recommended in patients waiting for a heart transplant, but it can be used in the long term as a palliative measure in patients without other therapeutic options (9, 31).

Used inotropic intravenous drugs include beta-adrenergic agonists, phosphodiesterase 3 inhibitors and calcium sensitizers. The most commonly used inotropes are dobutamine, milrinone and levosimedan, which will be described in more detail below. Administration principle is to give the smallest effective dose in the shortest time necessary to achieve a clinical effect (33, 37). According to a meta-analysis, long-term use of inotrope infusion resulted in an improvement of the NYHA class in patients with end-stage HF and reduced ejection fraction; however, no significant statistical difference in mortality compared to controls was recorded. There is limited evidence of the risks and benefits of inotrope infusion in non-hospitalized patients with end-stage HF (38).

It has been shown that the use of inotropes in the form of intravenous infusion at home represents a significant burden for the patient’s family and at the same time can increase the risk of death due to arrhythmias. This raises an ethical dilemma related to improving the quality of life and shortening the duration of life. It is necessary to make a joint decision on them introduction of continuous inotropic support in patients who are not eligible for transplantation and left ventricular assist device (LVAD) implantation (39). When deciding on the continuous use of inotrope infusion, it is necessary to consider the need for symptom relief as well as the patient’s wishes. However, most patients will be rehospitalized after the introduction of continuous inotrope therapy (40). The goal of applying inotropic support in patients with end-stage HF in palliative treatment should be to improve the quality of life and functional capacity (30).

DOBUTAMINE

Dobutamine is a beta-adrenergic agonist that increases cardiac output and decreases pulmonary capillary pressure. Its use is recommended in the treatment of patients with reduced cardiac output and reduced organ perfusion. Despite the potential effectiveness of dobutamine in the treatment of end-stage HF, there is a small number of studies that addressed the effect of dobutamine in patients with end-stage HF (30, 33).

In the FIRST study, it was reported that continuous intravenous dobutamine was associated with a higher 6-month mortality rate in patients with end-stage HF (41).

MILRINONE

Milrinone is a phosphodiesterase 3 inhibitor that increases intracellular calcium concentration and has an inotropic and vasodilating effect. The vasodilating effect may result in hypotension and additional hypoperfusion in patients who are already hypotensive. Nevertheless, milrinone is the therapy of choice for patients with systemic and pulmonary hypertension and reduced cardiac output, and for those who need inotropic support due to the aggravation of disease and beta receptors have been blocked by the earlier use of beta blockers (33, 37).

The OPTIME-CHF study included 951 patients randomized to receive 48 hours of intravenous milrinone therapy or placebo, and the aim was to determine whether short-term milrinone therapy could improve clinical outcomes in patients hospitalized for exacerbation of chronic HF. The results showed that there was no significant difference in mortality and rehospitalization, but the use of milrinone was significantly associated with a higher incidence of hypotension and the occurrence of arrhythmias (42).

LEVOSIMENDAN

Levosimendan enhances the sensitivity of myocytes to calcium, but has no effect on intracellular calcium concentration. It activates ATP-sensitive potassium channels of smooth muscles and mitochondria and consequently causes systemic and pulmonary vasodilation. It is also cardioprotective. Conventional inotropes such as beta-adrenergic agonists and phosphodiesterase 3 inhibitors increase the concentration of serum calcium and consequently their use entails a higher risk of ventricular arrhythmias. Given the prolonged effect, even up to 14 days, it can be used as a periodic maintenance infusion for patients with end-stage HF (16).

In the PERSIST study, 307 patients classified as NYHA IIIb–IV were randomized in two groups, one of which received levosimendan and the other placebo. The results showed an improvement in quality of life and a decrease in NT-proBNP level in patients who received levosimendan (43).

On the other hand, the LevoRep study included 120 patients with end-stage HF randomized to receive levosimendan or placebo. The results showed that there was no significant improvement in functional capacity or quality of life in patients in the end stage who received levosimendan (44).

In the LION-HEART study, 69 patients with end-stage HF were randomized into two groups to receive placebo or levosimendan at a dose of 0.2 µg/kg/min (over 6 hours, every 2 weeks for 12 weeks). In the group that received levosimendan, there was a reduction in the plasma concentration of NT-proBNP and a lower frequency of hospitalization compared to patients who received placebo (45). It is considered that levosimendan infusions are well tolerated by patients and that it has a good therapeutic effect in selected patients with end-stage HF as maintenance therapy in patients who are not eligible for heart transplantation and LVAD implantation (46).

Referring patients to specialised centres

Advanced treatment of end-stage HF includes heart transplantation and MCS implantation, and timely referral to specialised advanced heart failure centres (AHFC) is one of the prerequisites for a successful outcome (9, 47).

It is important to emphasize that too late referral can result in numerous unwanted consequences that significantly affect the outcome of treatment. Namely, by being referred to specialised centres too late, patients may be exposed to a greater risk of the deterioration of the condition and cardiogenic shock occurrence. Irreversible organ dysfunction such as progressive renal and hepatic failure may occur, as a result of which the patient may not be eligible for heart transplantation or LVAD implantation (47).

The first step towards making a decision to refer a patient to a specialised centre is identifying patients with a clinical picture of end-stage HF, which is why it is recommended to assess the progression of the disease at each follow-up examination. Clinical indicators suggestive of progression include the use of inotropic support, NYHA class III or IV, persistently elevated natriuretic peptides, end organ dysfunction, LVEF <20%, frequent defibrillation shocks, more than one hospitalization in the last 12 months, persistent edema, persistently low arterial pressure and GDMT intolerance (9, 47, 48).

There are certain criteria according to which candidates for transplantation and MCS implantation are triaged and identified. However, there are no exact guidelines and criteria according to which patients would be timely referred to an AHFC (29, 31). Identification of patients who need advanced treatment is further complicated by the unpredictable clinical picture of HF, given that in some cases there is a sudden progression of the disease and significant sudden cardiac death occurrence (49, 50).

HFA-ESC proposed criteria on which patients would be referred to an AHFC and they include clinical, laboratory, imaging parameters and risk assessment models shown in Table 29.

It is important to point out that more than two hospitalizations in the last 12 months indicate a very high risk of a bad outcome. Those patients have a one-year mortality rate of more than 40%. The ideal time for referring a patient to competent centres is the period in which irreversible end organ damage has not yet occurred and the clinical picture is consistent with the end stage HF or the end stage can be anticipated in the near future (47).

According to the research conducted by Herr et al, at the time of referral to a tertiary centre, 51.5% of patients had LVEF <20% and 74.5% of them were dependent on inotropic support or had a temporary MCS device. The largest number of patients were referred due to worsening failure defined by progressive symptoms, therapy intolerance and hypotension. Other causes of referral included hospitalizations, use of inotropic support and cardiogenic shock. 78.3% of patients were evaluated for heart transplantation and 76.5% for MCS implantation. However, the majority of patients were not eligible for transplantation, and the most common reasons were the patient’s severe condition due to end-organ dysfunction or associated comorbidities. Psychosocial reasons were also recognized. Not a single method of advanced treatment was offered in 37.4% of patients (51).

Lund et al conducted a study on the screening of candidates for advanced treatment in patients with existing cardiac resynchronization therapy (CRT) and/or an implantable cardioverter defibrillator (ICD) with LVEF ≤40% and NYHA class III–IV and with an indication for advanced treatment. The results showed that 26% of patients were not eligible for heart transplantation or LVAD implantation (52).

According to the above, patients are often referred to an AHFC too late, at a time when advanced treatment is no longer possible or is associated with a high probability of an unfavourable outcome. Therefore, the need for timely recognition of disease progression as well as timely referral to competent centres is emphasized. In order to achieve timely referral and improve the treatment of end-stage HF, the concept of active screening of patients who need advanced treatment was proposed (9).

The most commonly used risk assessment models for non-hospitalized patients with end-stage HF are the Heart Failure Survival Score (HFSS) and the Seattle Heart Failure Model (SHFM) which are used to evaluate patients for heart transplantation. SHFM has been shown to reduce 1-year mortality and the need for urgent transplantation and LVAD implantation, so it is used in combination with cardiopulmonary exercise test while deciding on listing for transplantation (53). Several risk stratification models have been proposed for selecting patients for MCS implantation; however, most models are focused on specific devices and do not take into account other important conditions such as patient frailty and psychosocial support (54).

If patients do not tolerate GDMT and are still significantly symptomatic, it is necessary to consider heart transplantation and MCS implantation as the next therapeutic option (9, 55). The treatment for end-stage HFrEF is shown in Figure 3 (30).

FIGURE 3. Algorithm for advanced heart failure management (adjusted from (30)). ACEI – angiotensin-converting enzyme inhibitors; ARNI – angiotensin receptor neprilysin inhibitor; BB – beta blockers; CRT – cardiac resynchronization therapy; FCM – ferric carboxymaltose; GDMT – guideline-directed medical therapy; HFREF – heart failure with reduced ejection fraction; HTX – heart transplantation; ICD – implantable cardioverter defibrillator; LVAD – left ventricular assist device; MRA – mineralocorticoid receptor antagonists; SGLT2 – sodium-glucose co-transporter 2

In case of a sudden deterioration or compromised function of end organs, and if it is not a palliative patient, short-term therapy is applied, which includes inotropic support, the use of intravenous vasodilators and vasopressors and the implantation of a short-term MCS device such as extracorporeal membrane oxygenation (ECMO) (9).

Heart transplantation

Heart transplantation is the gold standard for the treatment of end-stage HF which significantly improves the patient’s quality of life. Post-transplantation one-year survival is about 90% with a median survival of 12.5 years (1, 56). The number of patients with end-stage HF is increasing, but the number of donor organs is limited, and this disparity is the main limiting factor in number of heart transplantation. Furthermore, there is an increasing number of complex candidates, i.e. over 65 years of age, sensitized to human leukocyte antigens (HLA) and with an implanted MCS device (57). More complex candidates have a higher risk of developing primary graft dysfunction (PGD) and antibody-mediated rejection (AMR), which are the main challenges in the post-transplantation period along with cardiac allograft vasculopathy (CAV) and late graft dysfunction (1, 57).

One of the prerequisites for a successful transplantation outcome is a good selection of candidates. Before being enlisted for transplantation, patients must undergo a detailed examination in order to confirm the indication for the procedure and rule out possible contraindications. Some of the contraindications are relative and must be considered in the context of the overall clinical picture (58, 59).

The leading causes of HF in transplant candidates are non-ischemic dilated cardiomyopathy (51%) and ischemic cardiomyopathy (32%) (56). One of the most important criteria when setting an indication for an elective transplant list is the patient’s functional capacity and the objectification is achieved with a cardiopulmonary exercise test or 6MWT. Heart transplantation is indicated in patients with peak oxygen consumption (VO2) on the cardiopulmonary exercise test ≤12 mL/kg/min, or ≤14 mL/kg/min if the patient does not tolerate beta blockers. Furthermore, inclusion on the transplant list is indicated in women and patients younger than 50 years if they achieve a peak VO2 ≤50% of the predicted value in the stress test. If patients are not able to perform the maximum load test, then the ventilation equivalent for carbon dioxide (VE/VCO2) can be used as an additional marker, and inclusion on the list is indicated if VE/VCO2 is >35 (53). In addition to the cardiopulmonary stress test, risk assessment models are also used; transplantation should be considered if the estimated one-year survival according to the SHFM is <80% or if the patient is in the high or medium risk range according to HFSS (53).

1. Contraindications for heart transplantation: irreversibly increased pulmonary vascular resistance (PVR) or transpulmonary gradient (TPG) systemic disease or other disease with expected survival 35 kg/m2 alcohol or drug addiction lack of social support that would ensure adequate care outside the hospital system (9, 58).

In most cases, end-stage HF leads to deterioration of kidney and liver function and is characterized by the development of cardiorenal syndrome which can rapidly progress to an irreversible stage. Creatinine clearance and estimated glomerular filtration rate are used to assess renal function, however no predictive factor is available to assess the recovery of renal function after transplantation. Renal dysfunction significantly affects the post-transplant outcome, and sometimes a combined heart and kidney transplantation is required. Abnormal liver function is associated with a worse outcome after transplantation, and an additional challenge is the assessment of irreversible damage, given that imaging methods often provide inconsistent results (32, 53, 58).

Right heart catheterization is a mandatory test performed in all candidates for heart transplantation and must be repeated periodically while the patient is waiting on the transplant list (53). If PVR or TPG are elevated, it is necessary to check its reversibility using vasodilators or inotropic support. Pulmonary hypertension is reversible if the pulmonary systolic pressure falls under 50 mmHg, transpulmonary gradient <15 mmHg and pulmonary vascular resistance (PVR) <4 Wood’s units using the vasodilation test. It is important to point out that a decrease in PVR <3 Wood’s units with a systolic pressure <85 mmHg on the vasodilation test is associated with a higher risk of the development of primary graft dysfunction after transplantation (31, 59). For the purpose of reversibility of pulmonary hypertension, which according to the test is absent, an LVAD is implanted, and in this case it is necessary to reevaluate the hemodynamic parameters. The patient can be included on the transplant list if an improvement in the parameters of PVR and TPG has been confirmed by heart catheterization (53, 60, 61).

Frailty is a clinical syndrome of increased vulnerability and reduced physiological reserve and function, which is associated with existing comorbidities and old age, and is especially pronounced in patients with end-stage HF. Patients are considered frail if three of the following five criteria are met: low grip strength, slow walking speed, unintentional weight loss, low physical activity and low energy. It is important to point out that frailty can be completely or partially reversible after transplantation or LVAD implantation, which is especially important when selecting patients for advanced treatment. Therefore, it is necessary to distinguish frailty related to age as compared to frailty related to HF. Frailty proved to be an independent predictor of increased mortality after heart transplantation and should be assessed in every candidate. However, due to the lack of standardization, its evaluation and use as a definitive criterion for inclusion on the transplant list is difficult (53, 62–65).

LIMITED NUMBER OF DONOR ORGANS

According to Eurotransplant data, at the end of 2021 there were 1,150 candidates on the active heart transplant waiting list and 571 patients were transplanted in that year. In June 2022, there were 1,064 patients on the active waiting list and, in the period from January to June, 307 patients were transplanted (65). According to the OPTN/SRTR report, in the period from 2009 to 2020 there was an increase in the number of candidates included on the transplant list by 32.5% and an increase in the number of candidates over the age of 65. Furthermore, there was also an increase in the number of candidates with an implanted device for left ventricular support, whereby 36.4% of candidates had an implanted device at the time of inclusion on the transplant list (66).

The increase in the number of candidates included on the transplant list additionally affects the imbalance in the number of organ recipients and donors, and as a result, patients wait for a transplant for an increasingly longer period of time (32). According to the Eurotransplant report, only 42% of candidates on the list will receive a transplant within one year, and 58% after three years of waiting. During the first year of waiting in the period from 2014 to 2018, 11% of patients died, and 2% of candidates were removed from the list (67).

In an effort to increase the number of available donor organs, the criteria for transplant selection have been expanded and there has been an increase in the age of organ donors and recipients, which is particularly noticeable in Europe. The average age of transplant recipients is 55 and donors 35 (56). On the other hand, a transplant from an elderly donor can improve the survival and quality of life of elderly recipients if they are carefully selected, thus increasing the number of available donors (58). According to some studies, there is no significant difference in survival between patients who receive a transplant from a donor older than 50 years compared to those who receive a transplant from a younger donor (68–70).

Priority patients for transplantation are those with implanted devices for short-term MCS, those who depend on inotropic support and patients with frequent intractable malignant arrhythmias.

Due to all of the above, a longer wait on the list is expected mainly for stable patients, especially those on LVAD, and there is an increasing share of sensitized patients whose choice of donors is narrow. According to the ISHLT registry, 17.9% of patients have elevated panel reactive antibodies (PRA > 20%), and it is believed that the number of sensitized patients is increasing due to the increasingly frequent MCS implantation as bridge therapy (55, 71, 72). The allocation system needs to be improved in order to optimize resources in a fair and ethical manner, which is especially challenging because a further increase in the organ demand/supply ratio is expected (73).

Mechanical circulatory support

The limited number of donor organs and the increase in the number of patients who are not eligible for heart transplantation have resulted in the advancement in MCS technology and its use in the treatment of patients with end-stage HF. MCS can be implanted percutaneously or surgically, and there are devices for short-term and long-term use. Short-term devices are used over several days or weeks in order to achieve cardiogenic shock stabilization, most often as a bridge to decision (BTD) or a bridge to recovery (BTR). Care for patients with implanted short-term devices is very complex and requires a decision to remove the device if there is no recovery of function and no exit strategy. Long-term devices are used in carefully selected patients as a bridge therapy until heart transplantation (bridge to transplantation, BTT) or a bridge to candidacy (BTC), and the number of implanted devices as destination therapy (DT) in patients who are not candidates for transplantation is increasing (table 3) (1, 54).

Evaluation and selection of candidates along with timely MCS consideration are the foundation for a successful treatment outcome. Candidates for this type of treatment of advanced HF are patients with persistent severe symptoms despite optimal therapy, without severe right ventricular dysfunction and/or severe tricuspid regurgitation, with a stable psychosocial status and without contraindications, and who also meet at least one of the following criteria:

• LVEF 2 2
• ≥3 hospitalizations in the previous 12 months without a clear precipitating cause
• dependence on intravenous inotropic support or a short-term MCS
• progressive end-organ dysfunction (deterioration of renal and/or liver function, type 2 pulmonary hypertension, cardiac cachexia) due to reduced perfusion and not to inadequately low ventricular filling pressure (PCWP ≥20 mmHg, systolic blood pressure ≤90 mmHg, cardiac index ≤2 L/min/m2) (1).

The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) classification is used for selecting patients for MCS implantation. Patients are divided into 7 groups based on the clinical picture of end-stage HF:

• INTERMACS 1 – cardiogenic shock – intervention required within a few hours
• INTERMACS 2 – progressive decline with escalation of inotropic support – intervention required within days
• INTERMACS 3 – patient stable but inotrope dependent – elective intervention within a few weeks or months
• INTERMACS 4 – frequent decompensation and discomfort at minimum exertion (‘frequent flyer’) – elective intervention within a few weeks or months
• INTERMACS 5 – no complaints at rest and basic minimal activity – variable urgency of intervention
• INTERMACS 6 – ‘walking wounded’ – patient can leave the house, but has fatigue after the first few minutes of any meaningful activity – variable urgency of intervention
• INTERMACS 7 – NYHA class III – without recent decompensation – consider treatment without intervention (1).

Patients referred for implantation are mostly classified as INTERMACS 1–4. However, it is important to point out that profile 1 is associated with high mortality after LVAD implantation (54). In patients classified as INTERMACS 1 and 2, a short-term MCS is implanted as a bridge to decision or to implantation of long-term devices or to urgent transplantation (1). Implantation of a long-term LVAD should be considered in patients of INTERMACS 2–4, but also in INTERMACS 5 and 6 if they have some of the following high-risk factors: repeated hospitalizations, progressive end organ failure, refractory congestion, inability to perform cardiopulmonary exercise test or achieved peak oxygen consumption <12 mL/min/kg or <50% of expected value (1).

However, the selection of patients based only on the INTERMACS profile is not sufficient and it is necessary to take into account other factors such as end organ function, age, gender, frailty and psychosocial status (50).

Absolute contraindications for implanting a device are irreversible neurological injuries, systemic diseases that affect survival, disseminated malignant disease with a low chance of survival, severe coagulopathies, existing contraindications for the use of anticoagulant therapy, significant aortic or peripheral arterial disease, significant cognitive and/or psychosocial problems (54). Patients considered for MCS implantation must be able to tolerate the anticoagulant therapy necessary to prevent pump thrombosis. Currently, initially heparin and then warfarin is administered with a target INR in the range of 2.0-3.0 (54).

A minority of patients with biventricular cardiomyopathy will be eligible for a biventricular assist device (BiVAD) or a total artificial heart.

Outcomes of patients treated with permanent LVAD devices have improved significantly in recent years, especially with the current generation of HeartMate3 pumps (Abbott, USA). According to the latest INTERMACS report from 2023, one-year survival after latest LVAD implantation is 86%, and five-year survival is 64%, almost comparable to that after heart transplantation. The vast majority of patients (82.3%) received LVAD as destination therapy, which is a much higher share compared to the earlier period (only 44% in 2013). Less than 3% of patients who received an LVAD had an INTERMACS profile > 4. In the BTT indication, 54% of patients received a heart transplant within five years, and 26% of them were still alive (74). The MOMENTUM 3 study has been the largest LVAD study to date, showing a two-year survival of almost 80%, and a five-year survival on the HeartMate3 LVAD of almost 60% (75). Similar 5-year survival was also described in other publications that analysed large registries of patients with LVAD (74, 76).

The age limit for LVAD implantation is not fixed, and patients should always be evaluated in a broader aspect. A large number of elderly patients have significant comorbidities that can affect treatment outcome, such as frailty and multiorgan dysfunction (77). According to the INTERMACS analysis, older age is associated with a worse outcome after LVAD implantation; one-year survival in patients ≥ 75 years was 69.6% and two-year survival was 46.2%. Furthermore, it was shown that age is a significant predictor of mortality after LVAD implantation and that older patients have a higher incidence of gastrointestinal bleeding (78). However, another study reported similar survival in patients above 70 years of age with an implanted LVAD compared to younger patients, and the frequency of complications was also similar between the groups (79).

Frailty is associated with higher mortality in patients with end-stage HF and LVAD implantation, and also prolongs the duration of hospitalization. Frailty increases the chance of adverse events in patients with an implanted LVAD, and therefore it is necessary to take into account the potential benefits and risks of implantation in frail patients (80). However, regression of frailty may occur after device implantation. Maurer et al conducted a study involving frail patients above 60 years of age who were eligible for LVAD implantation as DT. Frailty was assessed before and after implantation, and a decrease in frailty was noted in an average of 50% of patients. Also, frailty regression had an effect on improving the quality of life and reducing the number of hospitalizations (81). It is assumed that the difference in outcome after device implantation and heart transplantation in frail patients depends on cardiac and non-cardiac causes of frailty. Furthermore, frailty can be fully or partially reversible after LVAD implantation as a BTT in younger patients with end-stage HF, which should be taken into account during patient evaluation. Further research is needed to uncover factors to differentiate between reversible and irreversible frailty (62).

Significant aortic regurgitation in LVAD candidates results in a closed circuit in the circulation between the left ventricle and the device. Therefore, in that scenario the valve should be repaired or replaced when implanting an LVAD. In most cases, a bioprosthetic valve is implanted, considering that mechanical valves are associated with a higher risk of thrombosis. It is recommended to replace the already implanted mechanical valves with bioprosthetic valves before device implantation (40, 82).

Renal dysfunction in patients with end-stage HF should be classified as primary or secondary, given that secondary dysfunction may become reversible after LVAD implantation. Significant dysfunction is a risk factor for early right ventricular failure, infection and increased mortality in patients with an implanted LVAD. It is necessary to rule out primary irreversible kidney disease with significant dysfunction, as it is considered a contraindication for long-term MCS implantation due to the poor prognosis (77, 83).

Right ventricular failure is a significant complication that occurs in 25–30% of patients after LVAD implantation (75). During evaluation and selection, it is necessary to identify patients with a high risk of developing right ventricular failure, given that it is associated with high postoperative mortality and morbidity. Predictors of right ventricular failure include right ventricular function index 2, central venous pressure to pulmonary capillary wedge pressure (CVP/PCWP) ratio >0.63, pulmonary artery pulsatility index (PAPi) <2, 0 and echocardiographically proven right ventricular dysfunction (54, 84). Nevertheless, there are no known exact levels of right ventricular function that would constitute an absolute contraindication for LVAD implantation.

Candidates for LVAD implantation must be highly motivated and cooperative throughout the entire treatment process. Alcohol and drug use are contraindications for LVAD implantation. The support of family and friends is extremely important in adapting the patient to a new lifestyle, and the lack of support is considered a contraindication for implantation. Psychosocial evaluation should determine the stability and availability of family support, which is needed for psychological support, help with dressing the driveline on the abdomen surface, changing batteries and supervising the medication. Such support is necessary for patients who are unable to take care of themselves (77, 85, 86).

Permanently implanted devices are associated with certain risks and complications such as infections, bleeding, thrombosis and right ventricular failure (40). According to the INTERMACS report, the most common causes of rehospitalization after device implantation include bleeding, infections, neurological disorders and right ventricular failure (74).

Infections of the driveline on the abdomen surface are one of the most common complications. Most infections are superficial, however, they can spread through the channel on the abdominal wall to the entire system. In order to reduce the risk of thrombosis, the use of anticoagulation therapy is mandatory. Bleeding is the main complication after device implantation. Gastrointestinal bleeding is considered a very challenging clinical dilemma affecting the management of LVAD patients. It most often occurs in the upper part of the digestive system, however, in 30–50% of cases the active site of bleeding cannot be detected. It is also known that LVAD can stimulate the development of angiodysplasia (9, 77, 83, 87). Pump thrombosis can occur in any part of the LVAD through which blood passes. It can consequently result in the development of cerebrovascular insult, pump dysfunction and, in some cases, pump failure, the development of cardiogenic shock and death. The gold standard in treatment is pump replacement; however, it is associated with significant morbidity and mortality. Stroke as a complication of LVAD implantation is the leading cause of disability and death in patients after implantation, and risk factors for its occurrence include infections, pump thrombosis and inadequate use of antithrombotic therapy (88).

Palliative care

Palliative care is an interdisciplinary approach aimed at improving the quality of life of patients and their caregivers in a way that provides physical, emotional, psychosocial and spiritual support to patients who are not eligible for active treatment. Although it is most often associated with patients suffering from malignant diseases, it is also very important in HF patients (89). This type of treatment should not necessarily be associated and given by a tertiary centre.

The ideal time for introducing PC in cases of HF is not fully defined. The conversation about the introduction of PC should certainly be initiated in patients who are not eligible for advanced treatment methods, and who have frequent rehospitalizations related to the worsening of their condition, with recurrent ICD shocks and with severe anxiety and depression that significantly affect the quality of life (90). The aim of PC is to control symptoms, reduce distress, not hasten or delay death, provide support and help for patients to live as actively and as good as possible until death. Adequate implementation of PC includes interdisciplinary cooperation and coordination of different systems (medical, social, religious and others) and specialities (family doctor, nurse, psychologist and others).

The benefits of introducing PC were demonstrated in the PAL-HF study, which included 150 patients with end-stage HF. The patients were randomized into two groups, one of which received the usual care, and the other received PC in addition to the usual care. The research showed that interdisciplinary PC in patients with end-stage HF resulted in a better quality of life, reduction of anxiety and depression (91).

In a study conducted by Sahlolbey et al, it was shown that the introduction of PC in patients with end-stage HF is associated with a reduction in the number of hospitalizations, symptoms severity and quality of life improvement, but even so, its introduction had no effect on mortality compared to the usual care (92).

Despite the progress in this area, additional efforts should be made for the timely introduction of PC considering that only 34% of patients are referred to PC in the last month of their life, and the average time from referral to death is less than 2 weeks (50).

Conclusion

Advanced HF is characterized by a poor prognosis despite advances in treatment and represents a significant clinical challenge. Timely referral of HF patients to specialized centres for advanced treatment methods (heart transplantation and MCS) is extremely important in order to improve the prognosis for these patients. Further efforts to improve the prevention, early detection and treatment of HF and good allocation of limited resources in the treatment of advanced HF are necessary to reduce mortality and improve the lives of many patients suffering from this clinical syndrome with a ‘malignant’ course.