Review Article

Pharmacological Therapy of HFrEF in 2025: Navigating New Advances and Old Unmet Needs in An Eternal Balance Between Progress and Perplexities

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Abstract

Recent advances in medical therapy have significantly improved the prognosis of patients with heart failure and reduced ejection fraction (HFrEF). The established four pillars of HFrEF treatment – β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor– neprilysin inhibitors, mineralocorticoid receptor antagonists and sodium–glucose cotransporter 2 inhibitors – serve as the foundation for ongoing innovations in this domain. However, these represent only the starting point for the therapy and management of heart failure. New medications, new devices and improvements in the use of diuretic therapy are fundamental and recent advancements. This article aims to highlight the latest findings in HFrEF treatment. While emphasising the optimism these developments bring, the article also addresses the significant unresolved challenges that persist in the management of this syndrome, which remains a leading global cause of mortality, morbidity and poor quality of life with high use of resources and healthcare costs.

Keywords

Heart failure, diuretics, sodium–glucose cotransporter 2 inhibitors, vericiguat, angiotensin receptor–neprilysin inhibitors, finerenone, gene therapy,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2024.37

Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: MM and FMR are co-first authors.

Correspondence: Massimo Mapelli, Heart Failure Unit, Centro Cardiologico Monzino, IRCCS, University of Milan, Via Parea 4, 20138 Milan, Italy. E: massimo.mapelli@cardiologicomonzino.it

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a clinical syndrome consisting of cardinal symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema), due to a structural and/or functional abnormality of the heart that results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise.1 It remains a leading global cause of mortality, morbidity and poor quality of life, with high use of resources and healthcare costs.

During recent years, improvements in medical therapy have changed the prognosis of patients with HF with reduced ejection fraction (HFrEF).2 The four pillars for HFrEF treatment are now a fully established cornerstone and include: β-blockers; angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor–neprilysin inhibitors (ARNI; i.e. sacubitril/valsartan) or angiotensin receptor blockers (ARBs); mineralocorticoid receptor antagonists (MRAs); and sodium–glucose cotransporter 2 inhibitors (SGLT2Is).1

In a large meta-analysis among 95,444 patients with HFrEF, the estimated additional number of life-years gained for a 70-year-old patient receiving ARNI, β-blockers, MRAs and SGLT2Is was 5 years. Nevertheless, HF remains a leading cause of death and disability.3

In this framework, many other innovations have emerged in the landscape of this syndrome beyond left-ventricular (LV) ejection fraction (LVEF; Figure 1), bringing a breath of fresh air rarely seen in cardiology – and in medicine in general – given the remarkably favourable prognostic impact. This article aims to highlight the most recent findings for HFrEF treatment and, alongside a wave of optimism, should also provide an overview of the unresolved issues in this field.

Figure 1: Increasing Focus Beyond Ejection Fraction in Heart Failure Management

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The Eternal Work in Progress in Heart Failure Therapy

The Copernican Revolution in Heart Failure Treatment in the Era of ARNI

ACEis were the first drug class with solid evidence of reducing mortality and morbidity in HFrEF, followed by β-blockers and MRAs.4−9 In 2014, the PARADIGM-HF randomised trial demonstrated that a combination of sacubitril and valsartan was superior to enalapril in reducing the risks of death and of hospitalisation for HF, with a number needed to treat (NNT)of 14 for the primary outcome of cardiovascular (CV) mortality or HF hospitalisation.10 ARNIs were shown to reduce indications for arrhythmic primary prevention, induce cardiac remodelling and reduce N-terminal prohormone of brain natriuretic peptide (NT-proBNP), as well as being well tolerated by patients.11−15

Recently, the new non-steroidal MRA finerenone demonstrated a significantly lower rate of a composite of total worsening HF events and death from CV causes than placebo in patients with HF and mildly reduced or preserved ejection fraction (HFpEF).16 Although large trials in patients with HFrEF are lacking, finerenone was well tolerated among 1,066 patients with a mean LVEF of approximately 29%, leading to a ≥30% reduction in NT-proBNP levels in a similar proportion of patients to that achieved with eplerenone.17 Conversely, in a recent large meta-analysis of over 15,000 patients, despite being the safest MRA, finerenone showed limited evidence of efficacy in patients with HFrEF.18

Among novel MRAs, balcinrenone has been tested in small trials involving patients with HFrEF. A phase 3 trial of the balcinrenone–dapagliflozin combination is currently under way in patients with chronic HF and impaired kidney function who have experienced a recent HF event (NCT06307652).

Serendipity and the Tale of SGLT2Is

The use of SGLT2Is has increased markedly in recent years, leading to a class 1a recommendation in both European and American guidelines.1,19,20 Beyond their well-established efficacy in treating diabetes, SGLT2Is have demonstrated CV benefits through mechanisms that remain not fully understood and independent of their glycosuric effect. The primary mechanisms underlying these effects include enhanced endothelial function, protection of the endothelium from intracellular reactive oxygen species production, increased nitric oxide (NO) bioavailability, reduction of microvascular dysfunction and a reduction of insulin resistance and both visceral and subcutaneous adipose tissue.19

After the introduction of sacubitril/valsartan, dapagliflozin was the first medication evaluated in a large-scale trial to assess its efficacy in the treatment of HFrEF (Figure 2).10 In the DAPA-HF trial, among 4,700 patients with a significantly reduced mean LVEF (31% ± 6.7), most classified as New York Heart Association (NYHA) class II, dapagliflozin provided a 26% RR reduction in the primary composite outcome (CV death, HF hospitalisation and urgent visits for worsening HF), regardless of the presence or absence of type 2 diabetes (T2D), with a NNT of 21.21 Additionally, 8 months after starting therapy, the increase in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ; indicating fewer symptoms) was significantly greater in the dapagliflozin group compared with the placebo group. The EMPEROR-Reduced trial demonstrated the efficacy of empagliflozin versus placebo in 3,730 patients with HFrEF (mean LVEF 27%), hospitalised for HF within the previous 12 months and with higher levels of natriuretic peptides compared with DAPA-HF.22 The primary outcome – a composite of CV death and HF hospitalisation – was reduced by 25% in the empagliflozin treatment group, regardless of LVEF and the presence of T2D. However, in contrast to dapagliflozin, empagliflozin did not achieve a statistically significant reduction in CV death among HFrEF patients.

Figure 2: The Continuous Work as the Foundation of Heart Failure Therapy

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A recent meta-analysis of patients with HFrEF enrolled in the DAPA-HF and EMPEROR-Reduced trials demonstrated a 14% reduction in CV death and a 31% reduction in first hospitalisation for HF, whereas the composite outcome of CV death and HF hospitalisation was reduced by 25%, regardless of the presence or absence of T2D.23 These beneficial effects were consistent across various baseline characteristics, including age (except for those under 55 years), sex, race, estimated glomerular filtration rate, NYHA class (with major benefits in NYHA class II), history of HF hospitalisation and use of ARNIs.

The impressive results led to evaluation of other gliflozins. In SOLOIST-WHF, sotagliflozin improved clinical outcomes in patients with T2D after an episode of decompensated HF, independently of the presence or absence of HFrEF or HFpEF.24 In a post hoc analysis by Pitt et al., among those enrolled with HFrEF, sotagliflozin led to a 22% risk reduction of CV death or HF-related event (HF hospitalisation or urgent care visit) occurring within 90 and 30 days after discharge for worsening HF hospitalisation, emphasising the importance of starting SGLT2I treatment before discharge.25 As data on their protective effects irrespective of LVEF are accumulating, international societies have recently expanded their recommended use to the entire spectrum of HF.19,26 The entire body of these data, along with recent trials involving new-generation (non-steroidal) MRAs, suggests a new way of classifying and conceptualising HF that goes far beyond the rigid cage of LVEF.

Vericiguat: The Fifth Pillar of Heart Failure Management?

Vericiguat is a stimulator of soluble guanylate cyclase (sGC), an important enzyme in the NO signalling pathway. Binding of NO to sGC triggers the production of cyclic guanosine monophosphate (cGMP), activating effectors such as protein kinases (PKGs) and phosphodiesterases, predominating in the CV system.27–29 In the vascular endothelium, cGMP-PKG signalling promotes cell proliferation and increases permeability, while in smooth muscle, it reduces proliferation and induces vasorelaxation. In the myocardium, it prevents hypertrophy and modulates contractility. HFrEF is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. The increase in cGMP levels after administration of vericiguat can lead to smooth muscle relaxation and vasodilation and thus to improvement of the signs and symptoms of HF.30 Vericiguat shows promise because of its pharmacokinetics, including a 30-hour half-life that supports once-daily administration, high bioavailability, low variability when taken with food and minimal potential for drug–drug interactions.28,31

In the VICTORIA trial, 5,050 patients with chronic HF, systolic blood pressure >100 mmHg and a LVEF <45% were randomised to receive vericiguat (2.5 mg titrated to a target dose of 10 mg once daily) or placebo.27 Enrolled patients had to have had a recent (<6 months) worsening HF event, with three prespecified subgroups (HF hospitalisation <3 months, 3–6 months, or worsening HF receiving outpatient intravenous diuretics at <3 months). The incidence of CV death or hospitalisation for HF was lower in the vericiguat group compared with the placebo group, with a NNT of 34. The benefit of vericiguat did not differ significantly across subgroups, suggesting it can be initiated at various times after the worsening of HF.32 One of the main limitations of the vericiguat pivotal studies was the smaller number of patients and shorter follow-up times compared with other clinical trials in HF.32 Regarding the echocardiographic changes in patients receiving vericiguat, the results from the VICTORIA echocardiographic substudy are still limited. Compared with placebo, it did not prove a significant benefit in LV end-systolic volume index and LVEF fraction from baseline to 8 months.33

Future clinical trials focusing on larger patient numbers and longer follow-up periods could both evaluate the drug’s efficacy in the real-life population and study its long-term clinical effects.32 More importantly, an on-going trial (EudraCT 005941–18) aims to demonstrate whether vericiguat reduces the composite endpoint of CV death and hospitalisation for HF versus placebo in patients not recently hospitalised. A positive outcome from this study would establish this drug as the true fifth pillar of HF management. The challenge of the next studies will be to identify the high-risk patients who can most benefit from the vericiguat treatment before they have an episode of worsening HF or hospitalisation.32

Omecamtiv Mecarbil: A False Start Dampening Enthusiasm for Myosin Activators?

Omecamtiv mecarbil (OM) augments cardiac contractility by selectively binding to cardiac myosin, thus increasing the number of myosin heads that can bind to the actin filament and initiate a power stroke at the start of systole.34 In early clinical studies, short-term intravenous administration of OM improved cardiac performance.35,36

In the GALACTIC-HF trial, 8,256 patients with HFrEF, who had either made an urgent visit to the emergency department or been hospitalised for HF within 1 year before screening, were randomised to receive oral OM at a dose of 25, 37.5 or 50 mg twice daily or placebo.37 Patients in the OM group had an 8% lower RR. The modest but significant lowering was achieved with many limitations. Firstly, the trial excluded patients aged >85 years and those with a clinically unstable condition. Secondly, among those enrolled, <20% were taking ARNIs and <3% taking SGLT2Is. Furthermore, GALACTIC-HF failed to improve secondary outcomes (CV death, change in KCCQ, the first HF hospitalisation and death from any cause).37 The METEORIC-HF trial failed to demonstrate an improvement in exercise tolerance in patients with HFrEF, with no significant difference in peak oxygen uptake, maximal exercise workload and ventilatory efficiency in patients taking OM versus placebo.38 These findings led to the Food and Drug Administration’s decision that the drug would not be reimbursable in 2023. Taken together, these data do not currently allow for the inclusion of OM in standard HF therapy. However, although some obstacles remain, the modulation of heart function through myosin activators, especially OM, as broadly accepted by the medical domain, is potentially paving the way for future therapies that directly interact with contractile proteins to enhance myocardial force. Moreover, a precise patient selection process that identifies those likely to derive benefits from this medication is anticipated to be refined in the foreseeable future.39 Hopefully, further evidence will come from the on-going event-driven COMET-HF randomised trial (NCT06736574), the purpose of which is to determine if OM can reduce the risk of the effects of HF, such as hospitalisation, transplantation or death in patients with HF and severe systolic dysfunction (LVEF <30%).

Semaglutide and the New Era of ‘Cardiometabolic Drugs’ in Heart Failure Patients

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was initially introduced for diabetes management, showing efficacy in both weight loss and the reduction of major adverse CV events (MACE).40,41 In the SELECT trial, once-weekly subcutaneous semaglutide 2.4 mg reduced MACE by 20% compared with placebo in patients with pre-existing atherosclerotic CV disease, overweight or obesity (BMI ≥27 kg/m2) and without diabetes.42 Although treatment with GLP-1 receptor agonists in patients with HFrEF was discouraged by small studies,43,44 a prespecified analysis of the SELECT trial in those diagnosed with HFrEF, demonstrated a significant reduction in a composite HF endpoint – CV death, hospitalisation or urgent hospital visit for HF – with a HR of 0.65.45 Additionally, there was a notable decrease in MACE, defined as a composite of non-fatal MI, non-fatal stroke and CV death. Similar outcomes were observed in patients with HFpEF, although the absolute event rates were lower. These efficacy findings, together with an acceptable safety profile, support the use of semaglutide, in addition to usual care, to reduce the risk of MACE and HF in a broad population of patients with established atherosclerotic CV disease and overweight or obesity, irrespective of their type of HF.45

Patiromer and Sodium Zirconium Cyclosilicate

Renin–angiotensin–aldosterone system (RAAS) inhibitors reduce hospitalisations for HF and CV mortality in patients with HFrEF, but they tend to increase the rate of hyperkalaemia, which might be associated with an increased risk of arrhythmias and mortality, even if not in all clinical scenarios.46,47 Importantly, clinicians tend to withdraw important disease-modifying drugs or reduce their doses because of concerns of the risk of hyperkalaemia. The DIAMOND trial demonstrated that concurrent use of patiromer (a potassium-binder that exchanges potassium for calcium in the gastrointestinal tract) titrated up to maximum 25.2 g/day and high-dose MRAs, reduced the risk of recurrent hyperkalaemia, allowing a safe administration of MRAs.48 Although with a different mechanism of action, sodium zirconium has also proven effective in reducing hyperkalaemia in various settings. A large trial conducted to specifically study the effects of the drug in the context of HFrEF (PRIORITIZE-HF) was prematurely halted due to the on-going COVID-19 pandemic.49

The Role of Iron Supplementation

In HF patients, iron deficiency constitutes a frequent comorbidity.50 In AFFIRM-AHF trial, among patients with HF and an ejection fraction <50% and iron deficiency (defined as ferritin <100 μg/l or 100–299 μg/l with transferrin saturation <20%), iron supplementation with ferric carboxymaltose was safe and reduced the risk of HF hospitalisations.51 Similarly, the IRONMAN trial demonstrated that intravenous iron infusion in patients with HF and ejection fraction <45% reduces risk of hospital admissions for HF and CV death.52 Conversely, the HEART-FID trial failed to demonstrate a significant reduction in the hierarchical composite endpoint of death, hospitalisations for HF or 6-minute walk distance.53 Based on trials and recent meta-analyses, the European Society of Cardiology (ESC) task force upgraded recommendations of intravenous iron supplementation to class 1a to alleviate HF symptoms and improve quality of life and to class 2a to reduce the risk of HF hospitalisation.54,55

Newer Substances

Istaroxime, an intravenous inotropic agent with a dual mechanism – increasing both cardiomyocyte contractility and relaxation – has been proposed as a new therapy for acute HF. In a meta-analysis in 300 patients with HFrEF and acute HF, istaroxime improved haemodynamic and echocardiographic parameters, with no significant differences in clinical outcomes.56 Further large-scale phase III trials are needed.

Van Tassell et al. are investigating effects of interleukin-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalisation due to acute decompensated HFrEF (REDHART2 trial).57 Inflammation is highly prevalent in patients with HF, correlates with disease severity and appears to be more pronounced in patients with acute HF, suggesting that inflammation contributes to the pathogenesis and progression of HF. In the REDHEART2 trial, anakinra treatment for 12 weeks led to an improvement in peak oxygen uptake. Further studies with hard endpoints will provide more robust information.58

Genetic and Cellular Therapies

Treatments with mesenchymal precursor cells (MPCs) are showing promising signs of preventing irreversible heart and brain pathologies.59 Although the randomised, double-blind, controlled DREAM-HF study did not show a reduction in hard clinical endpoints, a single intra-myocardial injection of 150 million cells of rexlemestrocel-L (MPCs) improved LVEF from baseline to 12 months to a significantly greater extent than controls, with maximal benefit seen in patients with active inflammation as measured by the presence of baseline high sensitivity C-reactive protein ≥2 mg/l (p=0.008).60 These early discoveries are quite promising, but it is important to remember that the area of gene and cell treatments for HFrEF is still growing.59

A Quick Look at the Field of Devices Under Evaluation in HFrEF

No Pressure: Interatrial Shunting Devices

Increased left atrium (LA) pressure and pulmonary capillary wedge pressure (PCWP) in HF patients are associated with worsening symptoms, lower functional capacity and worse quality of life and prognosis.61 Patients with Lutembacher’s syndrome, characterised by mitral stenosis and a congenital atrial septal defect, exhibit fewer symptoms than those with isolated mitral stenosis of comparable severity due to offloading of LA pressure.62 This supports the hypothesis that reducing LA pressure via a left-to-right shunt may lower PCWP and alleviate pulmonary oedema symptoms. Thus, creating a shunt between the left and right atria may be a potential strategy for reducing LA pressure and relieving HF symptoms.61 One concern with left-to-right shunting is the potential for right ventricular overload and elevated pulmonary artery pressure. However, studies in congenital heart disease have demonstrated that small shunts (atrial septal defects <10 mm) do not lead to adverse haemodynamic effects in long-term follow-up.63 Consequently, devices have been developed to create a controlled, permanent left-to-right shunt in HF patients.64,65 In a recent small trial (RELIEVE-HF) among 97 patients with symptomatic HF, ≥1 HF hospitalisation in the prior year or elevated natriuretic peptides, interatrial shunting with the Ventura device (V-Wave) was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF, demonstrating improvements of quality of life, left- and right-ventricular structure and function, leading to a consistent reverse myocardial remodeling.66 The potential of this strategy needs to be assessed in large-scale studies with longer follow up.

Cardiac Contractility Modulation

During overload, cardiac myocytes stretch activates hypertrophic pathways, resulting in higher oxygen demand and leading to myocardial angiogenesis to prevent hypoxia and maintain function. Therefore, repeated overload cause heart remodelling and worsening of HF.66

Cardiac contractility modulation (CCM) applies electrical signals during the absolute myocardial refractory period to the right ventricular septal wall using a relatively high voltage (approximately 7.5 V) with a duration of approximately 20 ms, with the aim of enhancing calcium influx into cardiomyocytes, prolonging the action potential and increasing inotropism.66 Unlike cyclic adenosine monophosphate-dependent positive inotropic drugs, CCM therapy improves LV function without significantly increasing myocardial oxygen consumption.67 Recent meta-analyses and clinical trials have demonstrated that, although CCM may not reduce CV adverse events, it significantly improves cardiopulmonary function and capacity, suggesting it as a potential alternative treatment for patients with advanced HF, targeting CRT-non-responsive patients with a wide QRS duration.68–70 Despite its potential, no studies have been conducted on the effects of the procedure on the development of right ventricular failure and diastolic hypertension.66

Baroreflex Activation Therapy

Previous studies have demonstrated that HF is linked to excessive activation of the sympathetic nervous system and concurrent impairment of parasympathetic activity, even in the early stages of the disease.71 The disequilibrium of the autonomic nervous system in HF correlates with impaired heart rate variability, cardiomyocyte dysfunction and apoptosis, neurohumoral activation, impaired nitric oxide signalling, inflammation and susceptibility to arrhythmia and sudden death.72

Baroreflex activation therapy (BAT) uses a pacemaker-like device with an extravascular lead to electronically stimulate the carotid baroreceptor, mimicking increased blood pressure and triggering parasympathetic activity.73 Initially developed for drug-resistant hypertension,71 BAT has been shown in the BeAT-HF trial to reduce NT-proBNP levels and improve NYHA class and exercise capacity in 120 patients (compared with 125 in the control group) with HFrEF.74 In a small open-label study by Blanco et al., mortality at 1 and 3 years in 30 patients treated with BAT was as expected by the Meta-Analysis Global Group in Chronic HF risk score, thus questioning its efficacy in improving life expectancy.71 Further study tailored to evaluate hard endpoints, with larger sample sizes and longer follow up, should be considered.

Getting Out of the Loop Diuretics Loop

Intravenous loop diuretics (LD) are the cornerstone of treatment for acute HF and are recommended as first-line therapy according to the ESC guidelines for HF.1 In acute HF, fluid retention and redistribution lead to systemic congestion, ultimately causing organ dysfunction due to hypoperfusion. Results from the DOSE trial support aggressive LD administration (2.5 times the patient’s oral maintenance dose), tailored to maximise fluid loss and to obtain better relief of symptoms at the cost of increasing risk of temporary worsening of renal function, yet without causing long-term deterioration of glomerular filtration.75

In the early stages of HF, patients usually respond well to single-LD therapy. As the disease progresses, other comorbidities such as renal failure appear, and patients are chronically exposed to LD, with diuretic efficiency consequently decreasing.76 This results in a substantial proportion (20%) of patients being discharged with residual congestion.77

Chronic diuretic treatment significantly enhances the capacity of the distal nephron to reabsorb delivered sodium chloride (NaCl), resulting in a secondary decline in natriuresis, known as the ‘braking phenomenon.’ This secondary increase in NaCl reabsorptive capacity is associated with substantial nephron remodelling, including hypertrophy of the distal convoluted tubule, connecting tubule and collecting duct. This remodelling effectively bypasses the proximal effects of LD, leading to increased sodium retention.78

Recently, Mullens et al. evaluated whether acetazolamide can improve the efficiency of LD in patients with acute decompensated HF with volume overload.79 Acetazolamide is a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption. In the ADVOR trial, 519 patients (<45% with HFrEF) were randomly assigned to receive either intravenous once-daily acetazolamide 500 mg (259 patients) or placebo (260 patients). The primary end point of successful decongestion after 72 hours occurred in 42.2% of patients in the acetazolamide group and in 30.5% in the placebo group (risk ratio 1.46; p<0.001). Death from any cause or rehospitalisation for HF occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (HR 1.07). It was reassuring that acetazolamide treatment was not associated with higher incidences of hypokalaemia, hypotension or renal end points. Given that residual congestion is linked to adverse outcomes, the beneficial effects of acetazolamide therapy are important, and combining it with LD should be considered when diuretic resistance is predicted. Similarly, the combination of hydrochlorothiazide with LD improved decongestion in the CLOROTIC trial, although patients with HFrEF accounted for just over one-third.80

The recent introduction of SGLT2Is into the landscape of HF medications has raised dilemmas regarding the potential benefits and implications of their use in management of acute HF.

In the EMPULSE trial, 530 patients hospitalised for acute HF (approximately 50% with HFrEF) were randomised once clinically stable to receive either empagliflozin 10 mg once daily or placebo for up to 90 days.81 Empagliflozin demonstrated a clinical benefit, assessed by a hierarchical composite outcome of all-cause mortality, number of HF events and time-to-first HF event or a ≥5-point improvement in the KCCQ-Total Symptom Score from baseline at 90 days. Furthermore, the initiation of empagliflozin in patients hospitalised for acute HF resulted in an improvement in all the decongestion endpoints (weight loss, weight loss adjusted for diuretic dose, change from baseline in NT-proBNP, haemoconcentration and clinical congestion score). Correspondingly, in the DICTATE-AHF trial, which enrolled approximately 60% of patients with HFrEF, dapagliflozin administration within 24 hours of hospital presentation was associated with reduced LD doses (560 versus 800 mg; p=0.006) and fewer intravenous diuretic up-titrations (p≤0.05) to achieve equivalent weight loss as usual care.81 Data from the aforementioned trials support the early initiation of an SGLT2I in acute HF to facilitate decongestion while rapidly and safely optimising recommended standard of therapy.

In the last few years, the concept of multi-nephron segment diuretic therapy (MSDT) has been developed, defined as the simultaneous use of three to four diuretic classes with actions along the proximal tubule, the loop of Henle, the distal tubule and the collecting duct.78 Because of safety concerns, this approach is understudied. Recently, a small retrospective study evaluated treatment with a simultaneous regimen of diuretics comprising an oral carbonic anhydrase inhibitor, intravenous LD, oral or intravenous thiazide and oral MRA. In 167 patients hospitalised for acute HF with diuretic resistance and a median LVEF of 20%, treatment with a simultaneous regimen of diuretics comprising an oral carbonic anhydrase inhibitor, intravenous LD, oral or intravenous thiazide and oral MRA, was retrospectively associated with a significant diuretic response in approximately two-thirds of the total cohort and in half of the patients with severe diuretic resistance, without substantial changes in serum electrolytes, excessive electrolyte repletion or worsening renal function.82 Theoretically, multi-drug diuretic therapy (MSDT) could address the underlying pathophysiology of diuretic resistance. However, prospective and controlled studies are needed to better validate these findings. The evidence regarding the role of a new diuretic therapy approach, extending beyond LD, raises new questions about the appropriate chronic prescription of diuretics in HFrEF.

According to ESC guidelines on HF and American Heart Association HF guidelines, diuretics are recommended (class 1) in patients with signs and/or symptoms of congestion to alleviate HF symptoms.1,20 The primary meta-analysis of randomised controlled trials on diuretic therapy in patients with chronic HF included studies conducted between 1966 and 1999, preceding the recent advancements in gold standard medical therapies. The introduction of medications with mild diuretic effects (MRAs, sacubitril and SGLT2Is) raises new questions about the need to adjust diuretic therapy according to the patient’s current condition, highlighting the importance of dose reduction in cases of significant symptomatic improvement. As underlined in both the EMPEROR-Reduced and DAPA-HF trials, a weight reduction of 0.5–1 kg was observed within the first hours or days following the administration of SGLT2Is.21,22 Although generally no significant weight losses were reported in the first hours or days after initiating MRAs, their mechanism of action, including reduction in sodium and water retention, is more gradual and less pronounced.

Additionally, both thiazides and LD have hypotensive effects, meaning that excessive or inappropriate prescribing could hinder the up-titration of the four pillars of HF therapy, particularly ARNIs.15,83 Since symptomatic hypotension was reported in 12% of patients treated with ARNIs in the PARADIGM-HF trial, the suspension or dose reduction of ARNIs, influenced by inappropriate diuretic therapy, could compromise or even negate the positive effects of ARNIs in terms of reduced mortality and HF hospitalisations.10

Furthermore, because of increased survival associated with advanced therapies, HF patients are generally older and consequently more likely to experience adverse effects from diuretics, such as dehydration, electrolyte imbalances and falls.84,85 Moreover, activation of the RAAS is of pathophysiologic and prognostic importance in HF. By activating the RAAS, diuretics may reinforce fluid retention and peripheral vasoconstriction.86 Observational data suggest that HF patients managed chronically without a LD agent generally have a good prognosis.87,88

In the ReBIC trial, no significant difference in patients’ assessment of dyspnoea between furosemide withdrawal and continuous administration was found.89 Additionally, the incidence of HF-related events, including hospitalisations, emergency room visits, and deaths, was similar between patients without LDs and those receiving standard doses of LDs.86 Likewise, Romano et al. found a worsening of renal function tests in patients taking LD compared with withdrawal group.90

Okoye et al. proposed an algorithm for discontinuation of LDs in very elderly patients with HF.86 Following a successful decongestion period of 1–3 months and clinical stability in NYHA class I–II after an acute decompensated HF episode, down-titration of LDs may be considered based on frailty status and the burden of comorbidities. The LD dose should be reduced by 25–50% of the starting dose, following a comprehensive clinical evaluation, which includes blood tests, lung ultrasound and physical examinations. Down-titration of LDs could be followed by a brief re-evaluation after 1 week, including comprehensive assessments of NT-proBNP levels and electrolytes, with an outpatient visit scheduled at 3 months. For older, frail patients, after the down-titration attempt, follow-up visits should occur at least monthly for 3 months, as frail individuals are at a higher risk for adverse events and HF relapse. Weight changes can serve as an easy and practical metric for monitoring fluid volume overload.86

In our opinion, similar recommendations should be extended to younger patients, with a greater willingness to reduce LDs doses when patient reliability, compliance and awareness of worsening HF red flags are evident. These red flags may include, for example, weight increase of >1 kg in one day or >2 kg in 1 week, peripheral oedema and worsening dyspnoea. It should also be mentioned how new ancillary therapies that have shown very favourable effects even in patients with HF are able to significantly reduce the LD required to maintain effective decongestion, as shown in the STEP-HF and STEP-HF-DM studies.91 Although these studies were conducted in patients with normal LV systolic function, it is reasonable to imagine a similar effect in HFrEF patients as well, with obvious implications for daily clinical practice.

Despite the discontinuation of diuretics following the initiation of SGLT2I, ARNI or MRA therapies, if the patient experiences a more pronounced weight loss or persistent symptomatic hypotension, a more permissive approach to daily fluid intake should be considered. This approach entails a shift from a traditional chronic therapy model to a more dynamic, symptom-guided treatment strategy. By focusing on the patient’s current clinical status and specific symptoms, healthcare providers can tailor the management of HF to be more responsive to individual needs. This flexible approach allows for adjustments in therapy based on the patient’s reported symptoms and signs of fluid overload, ensuring that treatment is not only effective but also aligned with the patient’s changing condition and overall quality of life. In other words, after decades of advising HF patients to avoid drinking to prevent fluid buildup, we now have to explain to selected patients – who show no signs of fluid retention – that they risk dehydration due to their diuretic (or diuretic-like) therapy beyond LDs (MRAs, SGLT2I, sacubitril).

HFrEF: Where Next?

In recent years, as documented in the excursus above, we have witnessed an abundance of innovations in the treatment of HFrEF, both pharmacological and non-pharmacological. However, despite these advances, many patients continue to face poor medium-term prognoses. One of the main issues remains the under-prescription of many life-saving HF therapies, patients’ access to these treatments and their long-term adherence. For example, a study analysing patients in the Swedish HF Registry who met the eligibility criteria for SGLT2Is – drugs known for their tolerability and ease of integration into treatment – found their use had tripled between 2020 and 2022.92 Despite this progress, therapy was still not initiated in over 40% of eligible patients, with discontinuation rates reaching 20% after a year.92

It is crucial to reconfigure our hospitals towards a more multidisciplinary approach, fostering continuous dialogue between specialised outpatient clinics, inpatient care (limited to when is absolutely necessary) and remote care strategies (i.e., dedicated nurses, monitoring devices and telemedicine). For instance, remote monitoring in HFrEF patients (including both telemedicine and implantable or wearable devices able to monitor impedance, pulmonary pressure or arrhythmias), is a well-demonstrated – but markedly under-used – beneficial strategy in this field.93,94 It is ineffective to summon stable patients to the clinic when remote monitoring, involving lab tests and vital parameters, can provide sufficient information, allowing them to be seen only once or twice a year.

Conclusion

Over the past decades, cardiology has become increasingly hyper-specialised, leading to fundamental innovations such as advancements in cardiac imaging, percutaneous techniques, ablation and in the understanding of the genetics of cardiomyopathies. However, it is essential that clinical cardiologists – especially those specialising in HF and cardiomyopathies – act as a real bridge between these complexities and patients, providing tailored diagnostic and therapeutic strategies. Currently, specialised centres for HF see only a fraction of patients, a small tip of the iceberg, making it vital to disseminate knowledge to help colleagues refer patients to tertiary centres as necessary and to prescribe widely available medications with a significant impact on prognosis. It is also imperative to raise awareness and establish dedicated structures for end-of-life care. HF, like many forms of cancer, exhibits a poor prognosis and requires proper management in the terminal phase.

Figure 3: Looking to the Future of Heart Failure Management

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Today, we possess a time machine of sorts, capable of improving our patients’ lives, extending their survival and enhancing their quality of life. However, we can fully capitalise on this opportunity only if we apply all our effort and leverage the evidence provided by well-conducted clinical studies. It is time to act, remaining vigilant and proactive in our approach to treating HF. Indeed, the future for this field will be filled with exciting innovations and we should view it with curious and hopeful eyes (Figure 3).

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