Heart failure (HF) is a major public health concern due to its high rates of morbidity and mortality. In industrialised countries, the prevalence of HF is reported to be 11.8% in people aged ≥60 years, and approximately 1% among those aged <60 years. Individuals with HF experience a significantly diminished quality of life (QoL), which is associated with increased risk for HF-related hospitalisations and overall mortality.1 Recent advancements in the treatment of HF with reduced ejection fraction (HFrEF) hold promise to improve prognosis, and reduce both HF hospitalisations and the number of deaths.2,3
Clinical trial data demonstrated the significant benefits of angiotensin II receptor–neprilysin inhibitors (ARNI; sacubitril/valsartan) over angiotensin-converting enzyme inhibitors (ACEi) in reducing the risks of cardiovascular death and HF hospitalisation.4,5 Given these results, the 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic HF introduced several updates regarding the use of ARNI. In the 2016 guidelines, ARNI was recommended primarily for patients who remained symptomatic despite treatment with ACEi or angiotensin II receptor blockers (ARBs), β-blockers and mineralocorticoid receptor antagonists (MRA). The ESC 2021 guidelines prompt the use of ARNI as a first-line therapy for patients with HFrEF, with strong evidence and consensus on its benefits, highlighting its superiority over ACEi and ARBs (class of recommendation 1b).6 In addition, the use of ARNI with respect to ACEi in de novo patients received a class of recommendation 2b, level of evidence B.6 The 2022 American Heart Association (AHA) and the American College of Cardiology recommend ARNI as de novo treatment in hospitalised patients with acute HF before discharge due to its benefits compared with ACEi/ARB, and in symptomatic chronic HFrEF patients (class of recommendation 1a).7
Besides ARNI, the current guideline-recommended disease-modifying therapies (GDMTs) for HFrEF include β-blockers, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and MRA, collectively known as the ‘four pillars’ of treatment. When using the four medications, the hazard of cardiovascular death or HF hospitalisation was reduced significantly (HR 0.38; 95% CI [0.3–0.47]), compared to therapy with only ACEi/ARBs and a β-blocker.8,9
However, despite the data supporting the ‘four pillars’ benefits, real-world data show a suboptimal use of these therapies among patients with HFrEF.9 The reasons for not achieving this therapeutic goal are multiple and differ for each type of patient.
In this article, Italian experts in the management of HFrEF discuss the challenges in implementing the ‘four pillars’ considering the different types of HFrEF patients. The discussion aims to propose practical solutions for overcoming these barriers and effectively executing the recommended treatment in clinical practice.
Maximising Outcomes: Achieving Optimal Therapy with the Four Pillars
The 2021 ESC guidelines, and even more so the 2022 AHA/ACC guidelines (class 1a), highlighted the value of replacing ACEi with ARNI to achieve better outcomes for patients.6,7 Moreover, the ESC 2023 focused update of the 2021 guidelines indicated the urgency of implementing ARNI together with β-blockers, SGLT2i and MRA – the ‘four pillars’– to maximise the early benefits of the treatment, significantly enhancing patients’ life expectancies, with the risk of death decreased to 50%.2
Furthermore, the treatment with the four guideline-recommended medications was estimated to reduce the hazard of HF hospitalisation and all-cause mortality to 68% and 47%, respectively.8 In line with what was shown for ARNI initiation, rapid uptitration of the ‘four pillars’ during pre-discharge of patients is safe, feasible and beneficial in terms of prognosis, and should reach the full dose in the 6 weeks following the discharge (class of recommendation 1b).2,10 Patients with optimised therapy can experience a better QoL, fewer symptoms and reduced risk of all-cause death or HF re-hospitalisation in comparison with usual care.10,11
The guidelines do not specify an optimal order for initiating and/or titrating the four treatments. However, they recommend starting all four treatments as soon as possible and gradually reaching the target or maximally tolerated doses.2
These drugs not only offer independent and additive benefits, but may also enhance each other’s tolerance.9,12 Moreover, there is a growing consensus that sequencing or simultaneously initiating the ‘four pillars’ provides greater protection for patients.9
Current Adoption of the Four Pillars and Barriers to Optimal Implementation
Although the guidelines emphasise the urgent need to implement the ‘four pillars’ in clinical practice, a large proportion of patients with HFrEF are not treated with these therapies, despite having no medical contraindication. Furthermore, even when the therapy is provided, its initiation is often largely delayed.13
Among the 3,518 patients included in the prospective CHAMP-HF registry in the US, only 1% of the eligible patients were prescribed triple therapy (ACE/ARB/ARNI, β-blocker and MRA). Moreover, although <2% of patients reported an absolute contraindication to these therapies, the prescription of each guideline medication was <75%. ARNI and MRA therapies were the least prescribed, with 86% and 66% of patients left untreated, respectively, despite the absence of clinical contraindications.9
In another real-world study, prescription of the GDMTs was assessed in 305 patients with HFrEF and a first episode of HF hospitalisation. At discharge, only 21.6 and 2.6% of patients were prescribed the triple and quadruple therapies, respectively. In these patients, the prescription of ARNI was also low, with only 42.3% of patients being on treatment. The study found that approximately 46% of patients could have been prescribed the ‘four pillars’ at discharge. Renal dysfunction was identified as the main limiting factor that prevented this approach.14
The clinical characteristics of the patients are the main barriers to the use of these treatments. These conditions include hyperkalaemia, arterial hypotension and renal dysfunction. In addition, ‘clinical inertia’ and the costs of treatments also play a pivotal role in delaying treatment initiation. These barriers determine an underuse of the therapies, causing patients to miss out on the significant morbidity and mortality benefits they offer.13,14 Therefore, detailed investigations to better understand these challenges are needed to find potential strategies for optimising therapy in patients with HFrEF.
The Benefits of Angiotensin Receptor–Neprilysin Inhibitor Initiation
Numerous studies have demonstrated the efficacy and safety of ARNI, along with high patient adherence and persistence rates. ARNI treatment is associated with improved New York Heart Association (NYHA) class, levels of natriuretic peptides and left ventricular ejection fraction (EF).15–18 The cardiopulmonary capacity of patients with HFrEF is also enhanced.19 ARNI also reduces HF-related hospitalisation and death rates, indicating a promising therapeutic response, despite the chronic and progressive nature of the disease.4
While no randomised controlled trial has been specifically designed to demonstrate the superior efficacy of early ARNI initiation, existing evidence suggests that this therapeutic strategy is effective.
In hospitalised patients, ARNI showed better outcomes in terms of N-terminal prohormone of brain natriuretic peptide reduction compared with the ACEi, enalapril, without increasing the risk of adverse events.5,20 Of note, N-terminal prohormone of brain natriuretic peptide declined more in de novo patients compared with worsening chronic HF patients.20 Patients treated with ARNI during hospitalisation also experienced a significantly lower occurrence of cardiovascular death or re-hospitalisation (clinical endpoint) for HF. Several studies showed a feasible initiation of the treatment in the hospital or shortly after discharge, with half of the patients achieving the target dose within 10 weeks.20,21
Furthermore, the use of ARNI proved to be more cost-effective than enalapril when initiated before discharge compared with initiation 2 months after hospitalisation for patients with HFrEF, although cost-effectiveness may vary depending on differences across healthcare systems. These findings support the benefits of hospital initiation of ARNI and the advantages of switching from ACEi in terms of reducing hospitalisations, improving quality-adjusted life expectancy and cost savings.11,20,22
Real-world data also revealed a feasible rapid titration to the target dose (6.9 weeks) and high therapeutic adherence to ARNI (59.6%), demonstrating the manageability of the treatment in both non-hospitalised and hospitalised patients.15,16 Although the TRANSITION study was not powered to demonstrate clinical outcome benefits of early versus delayed initiation, early initiation with ARNI in patients with de novo HFrEF was associated with positive effects in slowing the disease progression.21,23 Considering the beneficial effects of ARNI on de novo patients, the ESC 2023 update and AHA/ACC guidelines recommend its use for this type of patient, indicating the need for close follow-up and attention to the risk of angioedema or hypotension (class of recommendation 2b, level b recommendation, and 1a).2,6,7,21
In addition, ARNI use reduces the loop diuretic dose more than enalapril, suggesting that this treatment may lower the requirement for loop diuretics in patients with HFrEF.24
ARNI treatment is associated with more frequent arterial hypotension compared with ACEi enalapril. However, this does not lead to permanent discontinuation of the treatment.25
Challenges in the Implementation of the Four Pillars
The challenges limiting the optimal implementation of the ‘four pillars’ differ with the type of patient and the clinical characteristics, such as age, clinical setting, comorbidities, polypharmacy and so on. An overview of the different clinical traits of patients and the corresponding challenges that hinder the implementation of the ‘four pillars’ can be found in Table 1.
Blood Pressure
Patients with low blood pressure necessitate careful attention upon ARNI initiation, considering hypotension, estimated glomerular filtration rate (eGFR) and K values.25,26
ARNI is also associated with an increased rate of arterial hypotension symptoms.25,26
Potassium Serum Levels
Hyperkalaemia might also limit the use of ARNI, especially in hospitalised patients, as this treatment can induce increased hyperkalaemia and symptomatic hypotension compared with enalapril.20 However, among MRA-treated patients with symptomatic HFrEF, severe hyperkalaemia was less likely to occur during treatment with ARNI than with enalapril, suggesting that neprilysin inhibition reduces the risk of hyperkalaemia when MRAs are combined with other inhibitors of the renin–angiotensin–aldosterone system in patients with HF.26
Renal Function
The management of diuretic therapy is a major concern for all types of HFrEF patients, as they frequently experience impaired kidney function. The use of ARNI is associated with a decrease in the eGFR and an increase in the urinary albumin:creatinine ratio in patients with HFrEF. The use of ARNI in HF is generally restricted to patients with an eGFR >30 ml/min/1.73m².27 Moreover, as acute kidney injury (an absolute increase in serum creatinine ≥0.3 mg/dl [26.5 µmol/l]) often occurs in HF patients and is associated with increased hospitalisation, careful consideration is necessary when ARNI is used.28–30
However, in comparison with enalapril, ARNI causes a slower decline in eGFR and enhances cardiovascular outcomes, even in patients with chronic kidney disease.31 These favourable properties of ARNI suggest that, although its use requires careful management in patients with renal dysfunction, this should not limit its broader application.
Renal Dysfunction and Hyperkalaemia
Hospitalised patients also tend to show more adverse effects, and a higher risk of renal dysfunction and hyperkalaemia compared with other patients.11,24,32,33 Consequently, hospitalised patients often face a suboptimal implementation and titration of GDMTs, which is further complicated by the typically short duration of hospitalisation.
Comorbidities
There can also be challenges in ensuring adequate follow-up in more complex patients (chronic or with worsening HF), or difficulties in managing multidrug therapy for these patients and those already undergoing multiple treatments.34–36
Physicians are more reluctant to adjust therapies in vulnerable patients, such as those with comorbidities, older age and renal dysfunction. Because these patients are more prone to experience treatment toxicities, their specific conditions must be carefully considered when initiating new drugs. For example, older patients typically have lower eGFR, making them more susceptible to the diuretic effects of GDMT.35 In the PARADIGM-HF trial, treatment with ARNI was no less effective in frail patients than in other patients.37 Moreover, in patients with HF with preserved EF, ARNI was associated with a greater reduction in the primary endpoint with increasing frailty.38
Patient Adherence
Patient adherence is an important barrier to the optimal implementation of GDMTs.39 Discontinuation to GDMTs is still high in HFrEF patients, despite evidence showing that adherence to medical treatments reduces the mortality risk by 10.6% in HF patients.34 Poor adherence is often caused by the occurrence of side-effects, a scarce perception of the benefits of treatments when patients do not perceive an improvement in the symptoms and the complexity of handling multiple medications for the rest of their lives.34,39 Patients with HFrEF are rarely new to pharmacological therapies, as they often suffer from several conditions, such as AF, arterial hypertension, ischaemic heart disease or other comorbidities. For these patients, it is often challenging to identify the most appropriate initiation and titration schedule based on the patient’s profile.35
Clinical Inertia
Clinical inertia is closely associated with patient adherence issues, and significantly undermines compliance with the ESC guidelines. It involves several factors, which are both patient- and physician-related, such as fear of adverse events, lack of awareness of the physician of the benefits of an optimised therapy and poor clinical experience in the use of GDMTs.34,36,39
Other factors contributing to clinical inertia include inadequate communication between healthcare professionals and patients, who lack assistance from multidisciplinary and team-based care. Chronic and stable patients are the most affected by clinical inertia because of the scarce proactivity of physicians in adjusting their therapy. In these individuals, clinical inertia can also manifest as a poor perception of risk, with physicians often overestimating the quality of care they already provide without considering the risk of worsening HF in 18% of the so-called ‘stable’ HFrEF patients by 18 months from diagnosis.34,40
A lack of strong symptoms or worsening in chronic and stable patients can be misinterpreted as a sign of a good prognosis, and can mislead clinicians on the need to optimise treatments. Currently, no existing guidelines define quantitative measures for assessing stability. Patients are often considered stable if they have no or mild symptoms and their functional condition (i.e. NYHA class) has not changed recently. However, patients with lower NYHA class have the highest risk of sudden cardiac death, and those with symptomatic HF at any time, but no symptoms at the clinic visit, exhibit a significant risk of death (22% mortality at 5 years). Thus, the misleading perception of ‘stability’ should not be interpreted as no need to improve treatment.41
Solutions to Overcome Challenges in the Implementation of the Four Pillars
Given the multiple barriers to the initiation and titration of the ‘four pillars’, healthcare professionals need to identify concrete actions that help to overcome the suboptimal implementation of these therapies in HFrEF patients. Considering the different clinical characteristics of patients, it is essential to create comprehensive profiles that will serve as operational manuals for managing therapies and identifying the most suitable treatment plans for each clinical scenario.
These profiles should consider the patient’s age, sex, cardiomyopathy, naïvety to treatment, worsening of HF, comorbidities, blood pressure, chronic renal dysfunction, hyperkalaemia and concurrent multiple therapies. Other factors to consider are blood pressure and concurrent multiple therapies. In these cases, fragile patients should be included in a structured follow-up system of care by HF specialists and clinical nurses, and regularly checked with laboratory investigations (Table 2).13,39
Recommended laboratory investigations include a check of kidney function (eGFR rate) and electrolytes within 4 weeks after ARNI and SGLT2i initiation. This is especially indicated for patients with chronic stable HFrEF, as they often show a high burden of comorbidities, including chronic kidney disease and type 2 diabetes.13 Renal function monitoring is also important to prevent potential adverse events.42
The collaboration and awareness of all medical specialists also need to be enhanced. HFrEF patients, especially the most vulnerable, should be managed by a multidisciplinary team of advanced practice professionals, general practitioners and clinical nurses, aiming at clear objectives and timelines.39
Including HFrEF patients in organised follow-ups is beneficial for improving patient adherence and addressing the issue of short hospitalisation, which often hinders the timely initiation and adjustment of GDMTs. To mitigate this challenge for hospitalised patients, rehabilitation and early post-discharge re-evaluation are also effective strategies.43
Considering the difficulties and costs of patient follow-up, telemonitoring and remote telerehabilitation could be a valuable strategy that should be further optimised and broadly implemented. Evidence showed the benefits of integrating telemonitoring into clinical practice, considering its ability to reduce mortality, HF hospitalisation and all-cause hospitalisation. The QoL of HF patients was also shown to be improved. Regular telemonitoring practices for HF patients could include physiological monitoring of blood pressure, heart rate, weight and ECGs.34,43
Additionally, counselling and positive interactions between physicians, clinical nurses and patients, along with enhanced patient awareness and engagement, assist with reaching the target therapeutic strategy and improving adherence, playing a crucial role in overcoming clinical inertia.36 Key actions to implement include raising awareness about the manageability of ARNI and educating all patients, caregivers and clinicians on the importance of reaching an effective therapy.34
It is crucial to better communicate that ARNI is a manageable treatment with an adequate tolerance and rapid titration to the target dose, as shown by the REAL.IT study and previous clinical trials.15,16,44 An excessive focus on its side-effects might have delayed the clinical implementation of ARNI, as its adoption has been gradual since 2018, but remains incomplete.45–50 A more realistic perception of ARNI’s manageability could improve its prescription rates. Additionally, ARNI tolerability can be enhanced with the use of potassium binders or a low-potassium diet, which is indicated especially for patients with hyperkalaemia.13,39
The early use of ARNI and SGLT2i also benefits patients with hyperkalaemia.51 Evidence shows that neprilysin inhibition exerted by ARNI reduces the risk of hyperkalaemia when MRAs are used in combination with other renin–angiotensin–aldosterone inhibitors in HF patients.26 However, since ARNI can induce a slight increase in hyperkalaemia and symptomatic hypotension, the initiation of SGLT2i before ARNI is preferable to reduce the risk of side-effects in this category of patients.20,51
The initiation of SGLT2i and ARNI is also indicated to facilitate the implementation of the other GDMTs and enhance the management of diuretics, as these treatments can reduce the requirement for loop diuretics.13,25 Adjusting the dosage of loop diuretics can also facilitate the initiation of GDMTs, if the patient does not show signs of congestion.24,52
The sequence of treatment initiation is closely linked to tolerability and should be tailored to the patient’s clinical condition. In chronic, stable and frail patients, a two-phase treatment initiation with low doses is recommended to reach the optimal therapy as soon as possible. Although there is no ‘standard’ sequence optimal for all patients, there are several key factors to consider when implementing the ‘four pillars’ treatment approach, including the timing of their introduction, the potential for a simultaneous initiation, the importance of teamwork, the speed of titration and patient tolerability.
For de novo patients, it is advised to start with ARNI therapy at a minimum dose (24/26 mg twice daily), and strictly monitor tolerability and possible side-effects. De novo patients showed a better response and tolerability when starting ARNI concurrently with other guideline-recommended treatments, better adherence to therapy and a higher rate of patients reaching higher doses of ARNI than patients with prior HFrEF. These results highlighted the importance of an early initiation of ARNI in HFrEF to improve patient outcomes.23 Regular follow-ups and periodical evaluations of blood pressure, electrolytes and kidney function, while also monitoring for initial potential risks, such as angioedema or hypotension, are suggested.43
All patients should start the treatment with a low dosage of GDMTs, and discontinue or reduce any unnecessary medications to enhance patient adherence.9,13 Starting all the ‘four pillars’ should be prioritised rather than reaching their maximal doses, as several clinical studies showed that a decrease in morbidity and mortality can be achieved even at low doses of GDMTs.13,26 Finally, removal or reduction of unnecessary medications without cardiovascular benefit should be considered to avoid polypharmacy and minimise the risk of adverse events.13,53
Conclusion
The growing body of data supporting the efficacy and safety of ARNI in managing HF led to its more prominent role in the updated ESC 2021 guidelines. However, there is still a high proportion of patients with HFrEF who fail to achieve therapeutic targets with the ‘four pillars’ and, as a result, do not experience the desired reductions in morbidity and mortality. Therefore, it is crucial in clinical practice to recognise the multiple barriers to the implementation of GDMT and tailor solutions to the specific clinical conditions of each patient to improve outcomes.
The early use of ARNI is a strong recommendation in multiple guidelines. These guidelines highlight the positive outcomes that patients can achieve from this treatment, and reinforce the need to prioritise its initiation in HF management. The optimal timing for ARNI initiation remains an area of ongoing research. The guidelines emphasise the importance of multidisciplinary team efforts in the management of HF. They pinpoint the need for coordinated and tailored care to ensure that all relevant aspects of the patient’s health are managed collaboratively. The US guidelines also provide more detailed guidance on integrating palliative care into the treatment plan.7
The US guidelines also introduce updated HF staging, which focuses on early identification and intervention, and de novo/ACE-naïve patients, whereas ESC classification of HF is more oriented towards EF.
Recommendations for specific patient populations are also included in the US guidelines, such as for different ethnic groups, which are not present in the ESC, and also provide more indications on patients that could potentially benefit from ARNI treatment. The guidelines recommend the use of ARNI to patients at risk of HF and pre-HF (i.e. patients with structural heart disease, but no current or prior symptoms of HF), and a subgroup of patients with improved EF, with mildly reduced EF and with preserved EF. Continued research and clinical trials will be essential to further refine these guidelines, and ensure that all HF patients receive the most effective and personalised care possible to effectively and significantly impact on their outcome.