Our Experience With Sacubitril/Valsartan in Chronic Heart Failure Management - HFrEF in the Ambulatory Setting.

Background: The prevalence of chronic heart failure (CHF) is up to 1-2% of the adult population in developed countries, rising to >10% after the age of 70. Heart failure with reduced ejection fraction (HFrEF) remains a prevalent clinical syndrome associated with significant morbidity and mortality. Objective: The aim of this study was to evaluate the clinical efficacy of sacubitril/valsartan in a group of ambulatory patients with heart failure with reduced ejection fraction (HFrEF) and its effect on the hemodynamic, metabolic, renal, and cardiac remodeling parameters.
Methods: From January 2018 to May 2021, 106 patients with chronic heart failure with reduced ejection fraction (HFrEF) were prospectively enrolled. Patients treated with sacubitril/valsartan (ARNI) were compared with an arm of the same size (n = 53) and matched by age and gender who were taking a standard optimal medical therapy for HFrEF.
Results: The 106 patients completing the study were characterized by age: 69.5 ± 8.0, 64% are male gender. The mean duration of follow-up in the 2 treatment arms was 12 months. In the ARNI arm, we evaluate the hemodynamic, metabolic, renal, and cardiac remodeling parameters upon the initial evaluation and at the end of the follow-up after 12 months treatment with sacubitril/valsartan. The LVEF values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm, 42.1 % vs. 30.1%. The LVMI decreased from a baseline value of 153.1 g/m2 to 147.8 g/m2 with significant improvement only in the arm treated with ARNI. The eGFR values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm 70.1 vs. 64.9 mL/min/1.73 m2. Initiation and titration of sacubitril-valsartan was associated with a reduction in NT-pro-BNP concentration, the values of NT-pro-BNP improved significantly only in the arm treated with ARNI 3107.1 vs. 5678.2. Mortality and re-hospitalization due to HF were lower in the arm treated with ARNI compared to the control (20.3 vs. 32.4 % and 25.3 vs. 46.6 %, respectively; p < 0.05).
Conclusion: Sacubitril/valsartan is an important advancement in the treatment of HFrEF. Sacubitril/valsartan induce "hemodynamic recovery". This study provides real-world data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan in ambulatory setting.

BACKGROUND

The new universal definition of heart failure indicates that heart failure is not a single pathological diagnosis, but 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). It is 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. The prevalence of chronic heart failure (CHF) is up to 1-2% of the adult population in developed countries, rising to >10% after the age of 70. Heart failure with reduced ejection fraction (HFrEF) remains a prevalent clinical syndrome associated with significant morbidity and mortality. Despite significant advances in heart failure with reduced ejection fraction pharmacotherapy, 5-year mortality remains 50%. %. The primary goals of treatment include improving functional capacity, quality of life, preventing hospital admissions, and reducing mortality. In 2015, a novel angiotensin receptor-nephrilysin inhibitor (ARNI) sacubitril/valsartan was approved by European Medicines Agency (EMA) and Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic HFrEF. Sacubitril/valsartan is recognized as a significant therapeutic advancement and endorsed by international guidelines. PARADIGM-HF is the landmark clinical trial comparing the long-term efficacy and safety of sacubitril/valsartan 97 to 103 mg twice daily to enalapril 10 mg twice daily in over 8,000 patient’s ambulatory outpatients with chronic HFrEF. Current guidelines recommend switching angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARBs) to sacubitril/valsartan (ARNI) in stable outpatients affected by heart failure with reduced ejection fraction (HFrEF) who remain symptomatic (Class II-III of the New York Health Association (NYHA) classification) despite being on optimal medical therapy. Sacubitril/valsartan has been shown to improve mortality and reduce hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF).

OBJECTIVE

The aim of this study was to evaluate the clinical efficacy of sacubitril/valsartan in a group of ambulatory patients with heart failure with reduced ejection fraction (HFrEF) and its effect on the hemodynamic, metabolic, renal, and cardiac remodeling parameters.

PATIENTS AND METHODS

From January 2018 to May 2021, 106 patients with chronic heart failure with reduced ejection fraction (HFrEF) were prospectively enrolled. PARADIGM HF criteria were applied for patient inclusion. The inclusion criteria for participating in the study were as follows: adult patients with class II–III of the New York Health Association (NYHA) classification symptoms despite standard optimal medical therapy (OMT), left ventricle ejection fraction (LVEF) of ≤40%, terminal pro-brain natriuretic peptide (NT-pro-BNP) ≥ 900 pg/mL, estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2, serum potassium <5.2 mmol/L, systolic and/or diastolic BP ≥ 110/70 mmHg. The exclusion criteria were a history of hypersensitivity or intolerance to ACEI or ARB, history of angioedema, symptomatic hypotension and/or systolic BP < 100 mmHg, serum potassium ≥5.3 mmol/L, eGFR <30 mL/min/1.73 m2, correctable valvulopathy, acute coronary syndrome within < 3 months, recent coronary revascularization within the last 3 months, dementia or inability to cooperate.

Patients treated with Sacubitril/Valsartan (ARNI) were compared with an arm of the same size (n = 53) and matched by age and gender who remained symptomatic despite optimal medical treatment (OMT) at 3 months with ACEI, or ARB (in case of intolerance to ACEI), beta-blocker and MRA. We conducted a complete medical history, physical examination, electrocardiogram, transthoracic echocardiogram, blood analysis including potassium, renal function and NT-pro-BNP for each participant at baseline and during follow-up period. The mean duration of follow-up in the 2 treatment arms was 12 months. Sacubitril/Valsartan (ARNI) therapy was administered in addition to OMT twice a day at different dosages of 50mg, 100mg or 200mg, respectively, after the suspension of the treatment with ACEI or ARB. In detail, for patients taking ACEI therapy, ARNI treatment was administered at least 72h after stopping the ACEI, while in patients taking ARBs, ARNI treatment was administered 36h after stopping the ARB. The choice of the initial dose of sacubitril/valsartan was based on baseline systolic BP, eGFR, and potassium values. To evaluate the effectiveness and the titration of the ARNI and OMT treatment, the NYHA class and the values of systolic BP, serum potassium and creatinine were analyzed upon the initial visit, at month 1 and 6, and at the end of the follow-up, while NT-pro-BNP and left ventricle EF and cardiac remodeling parameters were assessed upon the initial visit after 6 months and at the end of follow-up in both arms.

Echocardiography represents the key investigation for the assessment of cardiac function. As well as the determination of the LVEF and other important parameters. Transthoracic echocardiography was systematically performed 24-72 h prior to sacubitril/valsartan introduction using a commercially available system (Philips Epic 7, Vivid E9, GE Healthcare) and repeated at the end of follow up period of 12 months after optimal sacubitril/valsartan treatment. Echocardiographic examinations were performed by an experienced sonographer who acquired a complete 2-dimensional (2D) TTE including 4 and 2-chamber apical LV views. We measured LV dimensions (LVEDD, LVESD, IVS, and LVPW) using two-dimensional guided M-mode with the parasternal long axis view at the papillary muscle level, and thereafter the biplane (modified Simpson's) method to measure LVEDV and LVESV. Left ventricle ejection fraction (LVEF) was estimated by Simpson's method using the apical four (A4C) and apical two (A2C) chamber views using LV end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) estimates as follows: LVEF = (LVEDV - LVESV)/LVEDV according to guidelines. LV diastolic dysfunction was graded in each patient according to the latest guidelines. Mitral regurgitation was evaluated according to the criteria of the European Association for Cardiovascular Imaging (EACVI). Based on previous studies, an (absolute) improvement in LVEF ≥ 5% was considered to be a significant response to sacubitril/valsartan. All statistical analyses were performed using SAS StatView 5.0® software.

RESULTS

Demographic and general characteristics of 106 enrolled patients upon initial assessment, by treatment arms are summarized in Table 1. The 106 patients completing the study were characterized by age: 69.5 ± 8.0, 64% are male gender, 74% of all patients with ischemic heart disease, 61% with arterial hypertension, 56% with chronic kidney disease, ≈40% with chronic obstructive pulmonary disease and ≈37% with diabetes mellitus. eGFR (mL/min/1.73 m2) 64.6 ± 23.3, NT-pro-BNP (pg/mL) 5439.1 ± 3487.9. NYHA Classes: II in 55% and III in 45% of patients. The proportion of patients taking ACEIs or ARBs, diuretics, beta-blockers, mineralocorticoid antagonist, CRT and ICD is shown in Table 1. The Echocardiographic parameters in all patients and in both OMT and ARNI arms are shown in Table 2. The left ventricle mass index (LVMI kg/m2) in all patients was 152.8 ± 11.4, left ventricle ejection fraction (LVEF %) for all patients was 29.0 ± 5.2%, mitral regurgitation ≥ II Grade was found in 54%.

Table 1.

Demographic and general characteristics of patients upon initial assessment, by treatment arms. eGFR: estimated glomerular filtration ratio, HbA1C: glycoside hemoglobin, ACEIs: angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA: mineralocorticoid antagonist; CRT: cardiac resynchronization therapy, ICD: Intracardiac defibrillator.

Items	All (N = 106)	OMT (N = 53)	ARNI (N = 53)	P value
Age (years)	69.5 ± 8.0	69.3 ± 7.9	69.7 ± 8.1	0.797
Male gender (%)	64	65	64	0.840
Body Mass Index (g/m2)	27.1 ± 3.9	26.8 ± 3.5	27.3 ± 4.4	0.519
Systolic blood pressure (mmHg)	130.9 ± 9.7	132.1 ± 9.1	129.7 ± 10.4	0.209
Diastolic blood pressure (mmHg)	74.8 ± 9.6	75.4 ± 9.5	74.3 ± 9.6	0.555
Heart rate (bpm)	67.9 ± 8.6	68.5 ± 8.4	67.4 ± 8.8	0.512
Creatinine (μmol/L)	110 ± 35	111 ± 34	109 ± 37	0.773
eGFR (mL/min/1.73 m2)	64.6 ± 23.3	64.5 ± 22.6	64.8 ± 23.9	0.947
Blood glucose (mmol/L)	6.3 ± 1.6	6.2 ± 1.5	6.4 ± 1.7	0.522
HbA1c (%)	6.3 ± 1.5	6.3 ± 1.7	6.4 ± 1.4	0.742
Potassium (mmol/L)	4.1 ± 0.7	4.1 ± 0.5	4.0 ± 0.8	0.442
NT-pro-BNP (pg/mL)	5439.1 ± 3487.9	5368.7 ± 3565.5	5509.4 ± 3410.4	0.836
NYHA Class (%)
II	55	45.3	54.7	0.776
III	45	46.2	53.8
Dyslipideamia (%)	65.4	65.2	65.6	0.985
Comorbidities
Arterial Hypertension	61.7	62.4	60.9	0.830
Ischemic heart disease (%)	72.2	70.3	74.1	0.682
Chronic kidney disease (%)	56.5	57.1	55.9	0.972
Chronic obstructive pulmonary disease (%)	39,9	36.4	43.3	0.342
Diabetes mellitus (%)	36.6	34.4	38.7	0.461
History of stroke (%)	20.5	21.5	19.4	0.799
Medications
ACEIs (%)	70.4	69.9	70.8	0.837
ARBs (%)	29.6	30.1	29.2	0.779
Diuretics (%)	92.9	94.5	91.3	0.689
Beta-blockers (%)	71.7	68.5	74.8	0.414
Mineralocorticoid antagonists (%)	55.2	53.9	56.5	0.827
Digoxin (%)	31.9	28.4	35.3	0.308
CRT (%)	14.6	11.4	17.5	0.295
ICD (%)	11.7	11.6	11.8	0,946

Table 2.

Echocardiographic parameters in all patients and in both OMT and ARNI arms. LVMI: Left ventricle mass index, LVEF: left ventricular ejection fraction, LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; TAPSE: Tricuspid annular plane systolic excursion.

Echocardiographic item	All (N = 106)	OMT (N = 53)	ARNI (N = 53)	P Value
LVMI (kg/m2)	152.8 ± 11.4	152.6 ± 10.2	153.1 ± 12.7	0.824
LVEF (%)	29.0 ± 5.2	28.9 ± 4.9	29.2 ± 5.6	0.753
LVEDV (mL)	174 ± 46	173 ± 54	175 ± 38	0.826
LVESV (mL)	122 ± 45	121 ± 42	123 ± 48	0.820
LVED diameter (mm)	61 ± 6	62 ± 3	60 ± 9	0.128
LVES diameter (mm)	51 ± 6	52 ± 5	51 ± 7	0.399
Mitral regurgitation (≥ II Grade) (%)	54	25	29	0.660
Systolic pulmonary pressure (mmHg)	38 ± 8	37 ± 10	39 ± 6	0.215
Tricuspid regurg. velocity (m/s)	2.8 ± 0.55	2.8 ± 0.63	2.8 ± 0.55	0.984
TAPSE (mm)	18 ± 6	18 ± 8	19 ± 4	0.418

In the OMT arm, the patients received the maximum tolerated dose of ACEi or ARBs, MRA and beta blockers. In the patient with chronic HFrEF, the generally recommended starting dose of sacubitril/valsartan is one 24 mg/26 mg tablet twice daily unless the patient is frankly hypertensive and/or is taking a large dose of ACEi/ARB prior to ARNI initiation. The dose of sacubitril/valsartan should be doubled every 2–4 weeks until the optimal dose of one 97 mg/103 mg tablet twice daily is reached, based on patient tolerability. In the ARNI group the maximal dosage (200 mg) with sacubitril/valsartan was obtained in 41/53 pts (77.4%) and in the resting population studied 12/53 pts (22.6%) the mean dosage was 100 mg a day.

In the ARNI arm, the hemodynamic, metabolic, renal, and cardiac remodeling parameters upon the initial evaluation and at the end of the follow-up after 12 months treatment with sacubitril/valsartan are summarized in Table 3. The LVEF values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm, 42.1 % vs. 30.1%. (Figure 1A). The LVMI decreased from a baseline value of 153.1 g/m2 to 147.8 g/m2 with significant improvement only in the arm treated with ARNI (Figure 1B). The eGFR values increased significantly (p < 0.001) in the ARNI arm compared to the OMT arm 70.1 vs. 64.9 mL/min/1.73 m2. (Figure 1C). Initiation and titration of sacubitril-valsartan was associated with a reduction in NT-pro-BNP concentration, the values of NT-pro-BNP improved significantly only in the arm treated with ARNI 3107.1 vs. 5678.2 (Figure 1D).

Table 3.

Hemodynamic, metabolic, renal, and cardiac remodeling parameters upon the initial evaluation and at the end of the follow-up after 12 months treatment with sacubitril/valsartan.

Item	Baseline (N = 53)	Follow-up (N = 41)	P Value
Systolic blood pressure (mmHg)	129.7 ± 10.4	117.0 ± 14.9	0.001
Diastolic blood pressure (mmHg)	74.3 ± 9.6	67.4 ± 9.1	0.001
Heart rate (bpm)	67.4 ± 8.8	66.3 ± 5.7	0.450
Blood glucose (mmol/L)	6.4 ± 1.7	6.2 ± 1.3	0.500
HbA1c (%)	6.4 ± 1.4	5.7 ± 1.7	0.023
NT-pro BNP (pg/mL)	5503.8 ± 3487.9	3107.1± 2411.5	0.001
Creatinine (μmol/L)	109 ± 37	108 ± 32	0.883
Potassium (mmol/L)	4.0 ± 0.8	4.1 ± 0.7	0.497
eGFR (ml/min/1.73 m2)	64.8 ± 23.9	70.1 ± 12.7	0.042
LVMI (g/m2)	153.1 ± 12.7	147.8 ± 11.4	0.049
LVEF (%)	29.2 ± 5.6	42.1 ± 4.8	0.001
LVEDV (mL)	175 ± 38	144.2 ± 28	0.001
LVESV (mL)	123 ± 48	83.1 ± 25	0.001
Mitral regurgitation (≥ II Grade) (%)	29	15.4	0.099
Systolic pulmonary pressure (mmHg)	39 ± 6	32 ± 8	0,001
Tricuspid regurg. velocity (m/s)	2.8 ± 0.55	2.6 ± 0.59	0.075
TAPSE (mm)	19 ± 4	18 ± 8	0.418

Fig. 1.

Change in ARNI and OMT group from baseline to final follow-up. A) left ventricular ejection fraction (LVEF), B) Left ventricle Mass Index (LVMI), C) estimated glomerular filtration rate (eGFR), and D) N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentrations.

The values of systolic and diastolic BP, HbA1c and creatinine decreased in both arms, but more significantly in the arm treated with ARNI compared to the control (117.0 vs. 120.2 and 67.4 vs. 74.5 mmHg, 5.7 vs. 5.9 % and 108 vs. 111.8 μmol/L) respectively; p < 0.05).

Mortality and re-hospitalization due to HF were lower in the arm treated with ARNI compared to the control (20.3 vs. 32.4% and 25.3 vs. 46.6%, respectively; p < 0.05). No patient left the study voluntarily or because of the onset of adverse events (Figure 2).

Fig. 2.

Rates of mortality and re-hospitalization for heart failure in ARNI and OMT group from baseline to final follow-up (p < 0.05).

At the final follow-up, 51% of patients in the ARNI treatment arm were taking the 97/103 mg dose of sacubitril/valsartan, 33% the 49/51 mg dose and 17% the 24/26 mg dose.

DISCUSSION

Currently, the incidence of HF in Europe is about 3/1000 person-years (all age-groups) or about 5/1000 person-years in adults. The prevalence of HF appears to be 1-2% of adults. The prognosis of patients with HF has improved considerably since the publication of the first treatment trials a few decades ago. However, it remains poor, and quality of life is also markedly reduced. The improvement in prognosis has been confined to those with HFrEF. Mortality rates are higher in observational studies than in clinical trials. The 1-year and 5-year mortality rates after diagnosis, for all types of HF patients, were 20% and 53%, respectively. According to the recently published universal definition of heart failure, recent ESC and ACC/AHA Guidelines for the diagnosis and treatment of acute and chronic heart failure, patients with HF are classified based on their LVEF in 4 categories: a) HFrEF = heart failure with reduced ejection fraction (LVEF ≤40%); b) HFmrEF = heart failure with mildly reduced ejection fraction (LVEF 41- 49%); c) HFpEF = heart failure with preserved ejection fraction (LVEF ≥ 50%), and d) HFimpEF = heart failure with improved EF: HF with a baseline LVEF of ≤40%, and follow-up measurement of LVEF >40% (1-4).

Despite optimal medical therapy with Angiotensin Converting Enzyme Inhibitors (ACE-I) or Angiotensin Receptor Blockers (ARB), Beta-blockers and Mineralocorticoid Receptor Antagonists (MRA), many heart failure patients with reduced ejection fraction (HFrEF) exhibit a residually depressed cardiac function, paralleled by an increased risk for heart failure hospitalization and cardiovascular mortality. In the PARADIGM-HF trial, sacubitril/valsartan, an ARNI, was shown to be superior to enalapril in reducing hospitalizations for worsening HF, CV mortality, and all-cause mortality in patients with ambulatory HFrEF with LVEF ≤40% (changed to ≤35% during the study) (2, 3). Additional benefits of sacubitril/valsartan included an improvement in symptoms and quality of life, a reduction in the incidence of diabetes requiring insulin treatment, and a reduction in the decline in eGFR, as well as a reduced rate of hyperkalaemia. Additionally, the use of sacubitril/valsartan may allow a reduction in loop diuretic requirement (5-10).

Remodeling of the myocardium is central to the progression of HF with reduced ejection fraction (HFrEF), and occurs in response to injury, hemodynamic changes, or neurohormonal activation. Remodeling consists of changes in cardiac geometry, function, or both, reflected by reduced left ventricular ejection fraction (LVEF) and increased LV volumes. Cardiac remodeling is associated with risk for cardiovascular events, including death and hospitalization for HF, and represents an important target for HF therapy (10, 11). Reduction in NT-proBNP during guidline directed medical therapy (GDMT) for HFrEF is associated with reverse LV remodeling (1, 2, 10).

The PROVE-HF study adds information regarding associations between ARNI therapy, change in NT-proBNP, and cardiac remodeling. Reduction in NT-proBNP following treatment with sacubitril-valsartan was associated with an increase in LVEF, and reductions in indexed LV and LA volumes as well as E/e′ ratio (9, 10). In line with these findings, the results of this study suggest that patients with NT-proBNP reduction following ARNI initiation are likely to experience reverse cardiac remodeling. Our study reports on the reverse remodeling response to therapy with sacubitril/valsartan. Importantly, an incremental improvement of ≥ 5% in LVEF was noticed after switching therapy from 1 Class I therapy (ACE-I or ARB) to another Class I therapy (sacubitril/valsartan). Analyses of changes in cardiac remodeling indices demonstrated a significant increase in LVEF and corresponding reduction in LV volumes as early as 6 months; such changes continued to 12 months. Reverse myocardial remodeling manifested by reduced LV size and improved function is central to the benefits of most HF treatments and is associated with an improved prognosis (7-10).

In the published metanalysis of twenty studies enrolling 10,175 patients by Wang Y et al., ARNI improved functional capacity in patients with HFrEF, including increasing NYHA class and 6 minute walking distance. Moreover, ARNI outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of cardiac reverse remodeling with striking changes in left ventricular EF, diameter, and volume. Improving in filling pressure, mitral regurgitation degree, pulmonary systolic pressure and LVEF, that is “hemodynamic recovery”, effectively improved NYHA class and quality of life (12, 22).

Pharmacotherapy is the cornerstone of treatment for HFrEF and should be implemented before considering device therapy, and alongside non-pharmacological interventions. There are three major goals of treatment for patients with HFrEF: (i) reduction in mortality, (ii) prevention of recurrent hospitalizations due to worsening HF, and (iii) improvement in clinical status, functional capacity, and quality of life (8-11).

Modulation of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems with angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) has been shown to improve survival, reduce the risk of HF hospitalizations, and reduce symptoms in patients with HFrEF. These drugs serve as the foundations of pharmacotherapy for patients with HFrEF. Therefore, it is recommended that an ACE-I or ARB is replaced by sacubitril/valsartan in ambulatory patients with HFrEF, who remain symptomatic despite optimal medical treatment (1-6).

According to the recent 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure, Guide directed medicla therapy (GDMT) has expanded to include four classes: a) renin-angiotensin system inhibition (RASi) with angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi), or angiotensin (II) receptor blockers (ARB) alone; b) beta blockers; c) mineralocorticoid receptor antagonists (MRA); and d) sodium-glucose cotransporter-2 inhibitors (SGLT2i). ARNi is now recommended as first-line RASi to reduce morbidity and mortality in HFrEF (Class of Recommendation 1a). In symptomatic patients with HFrEF who tolerate ACEi or ARB, replacement with ARNi is recommended for further reduction in morbidity and mortality (2). The 2021 ESC published guidelines recommends the use of ARNI as a replacement for ACE-I in suitable patients who remain symptomatic on ACE-I, beta-blocker, and MRA therapies; however, an ARNI may be considered as a first-line therapy instead of an ACE-I - (Class of Recommendation 1B) in reducing the risks of cardiovascular death and hospitalization (1). In addition, a meta-analysis provided evidence that sacubitril/valsartan had fewer drug-risks compared with ACEIs/ARBs, such as angioedema, hyperkalemia, cough, dizziness, renal dysfunction and arterial hypotension (6, 7, 10-13).

In order to reduce hospitalizations and mortality, the use of multidisciplinary HF management programmes (HF-MPs), which enable patients to have the correct investigations, an accurate diagnosis, appropriate evidence-based therapy, education, and suitable follow-up (16, 17). Adequate patient self-care is essential in the effective management of HF and allows patients to understand what is beneficial, and to agree to self-monitoring and management plans. HF patients who report more effective self-care have a better quality of life, lower readmission rates, and reduced mortality (17, 18, 21). Patients with HF, even if symptoms are well controlled and stable, require follow-up to ensure continued optimization of therapy, to detect asymptomatic progression of HF or its comorbidities and to discuss any new advances in care. The new guidelines recommend follow-up at intervals no longer than 6 months to check symptoms, heart rate and rhythm, BP, full blood count, iron, electrolytes, and renal function (1-8).

CONCLUSION

This study provides real-world clinical practice data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan. Sacubitril/valsartan is an important advancement in the treatment of HFrEF. Sacubitril/valsartan induce “hemodynamic recovery”. The efficacy of sacubitril/valsartan in the treatment of HF can be summarized in the following 7 key perspectives: reduction in the risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvements in NYHA class, improvement of quality of life, improvement of renal function and regulation of metabolism in HF patients.