Biomedicine & Pharmacotherapy 130 (2020) 110596

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Original article

The role of sacubitril/valsartan in the treatment of chronic heart failure with T

reduced ejection fraction in hypertensive patients with comorbidities: From
clinical trials to real-world settings
Alberto Mazzaa,*, Danyelle M. Townsendb, Gioia Torina,c, Laura Schiavona,c,
Alessandro Camerottod, Gianluca Rigatellie, Stefano Cuppinic, Pietro Minuzf,
Domenico Rubellog,**
a
ESH Excellence Hypertension Centre, Internal Medicine Unit, S. Maria della Misericordia General Hospital, AULSS 5 Polesana, Rovigo, Italy
b
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, USA
c
Unit of Internal Medicine, S. Maria della Misericordia General Hospital, AULSS 5 Polesana, Rovigo, Italy
d
Department of Diagnosis and Care, Clinical Laboratory, S. Maria della Misericordia General Hospital, Rovigo, Italy
e
Interventional Cardiology Unit, Division of Cardiology, S. Maria della Misericordia General Hospital, AULSS 5 Polesana, Rovigo, Italy
f
Unit of Internal Medicine C, Department of Medicine, University of Verona, Verona, Italy
g
Nuclear Medicine Unit, Santa Maria della Misericordia Hospital, Rovigo, Italy

ARTICLE INFO ABSTRACT

Keywords: Background: Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin re­
Ejection fraction ceptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity com­
Chronic heart failure pared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection
Hypertension fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive
Internal medicine
patients with HFrEF and comorbidities.
Mortality
Sacubitril/valsartan
Methods: In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 %
male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned
to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were
gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for
HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glo­
merular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular
ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-
up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected.
Results: NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting
from class III to II, and 55.4 vs. 25.2 %, from class II to I, p < 0.05 for all). A significant improvement in LVEF
and eGFR levels was found in the ARNI arm compared to controls (42.4 vs. 34.2 %, 73.8 vs. 61.2 mL/min,
respectively; p < 0.001 for all). NT-proBNP, clinic systolic and diastolic BP, blood glucose, HbA1c and UA
values were reduced in both treatment arms, but they were lower in the ARNI arm compared controls (3107 vs.
4552 pg/mL, 112.2 vs. 120.4 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9 vs. 6.4 mg/
dL, respectively, p < 0.05). Mortality and re-hospitalization for HF was lower in the ARNI arm than controls
(20.1 vs. 33.6 % and 27.7 vs. 46.3 % respectively; p < 0.05 for all). Gender differences were not found in either
arm. No patients refused to continue the study, and no side effects to the ARNI treatment were observed.
Conclusions: In elderly patients with HFrEF and comorbidities, ARNI treatment seems effective and safe. The
improvement in LVEF and cardiac remodeling, BP, eGFR, serum glucose, UA and HbA1c could be the me­
chanisms by which ARNIs play their beneficial role on clinical outcomes. However, these results need to be
confirmed in studies involving a greater number of subjects, and with a longer follow-up.

⁎
Corresponding author at: Department of Internal Medicine, Santa Maria della Misericordia Hospital, Viale Tre Martiri 140, 45100, Rovigo, Italy.
⁎⁎
Corresponding author.
E-mail addresses: Xalberto.mazza@aulss5.veneto.it (A. Mazza), domenico.rubello@libero.it (D. Rubello).

https://doi.org/10.1016/j.biopha.2020.110596
Received 16 April 2020; Received in revised form 13 July 2020; Accepted 28 July 2020
Available online 21 August 2020
0753-3322/ © 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

1. Introduction 2. Materials and methods

Heart failure (HF) is the main cause of hospitalization in Internal Three months after discharge from an Internal Medicine unit, 54
Medicine units, and HF patients have a 50 % reduction in 5-year sur­ hypertensive subjects, with an average age of 78.6 ± 8.2 years (75 %
vival, similar to that of patients with cancer [1]. The prevalence of HF male), with HF with reduced left ventricular EF (LVEF) and in NYHA
increases with age, and doubles with each decade, both due to the class II-III, were consecutively enrolled in an HF outpatient clinic, from
progressive aging of the population [2] and to the improvement in the April 2017 to April 2019. The diagnosis of HF was obtained by ana­
treatment of the main risk factors for HF [1]. lyzing the hospital discharge sheets (HDSs) and taking into account the
In the European general population, including Italy and North following codes, based on the 9th revision of the international statistical
America, although HF it is considered a typical condition of advanced classification of diseases (ICD-9) and related health problems: 398.91,
age [3,4], in other countries HF is diagnosed in younger subjects [5]. 420.1, 402.11, 420.91, 404.01, 404.03, 404.11, 404.13, 404.91,
This is one of the reasons why the average age of the subjects enrolled 404.93, 428.0, 428.1. The study protocol was approved by the local
in HF clinical trials is generally lower than patients with HF managed in Ethics Committee and conducted according to the “Guide to Good
an outpatient or Internal Medicine setting [5]. Furthermore, in order to Clinical Practice” established by the International Conference on
have the chance to obtain significant results in terms of efficacy and Harmonization of Technical Requirements for Registration of
safety, controlled interventional clinical studies on HF enrolled fre­ Pharmaceuticals for Human Use (ICH). All procedures were conducted,
quently younger subjects and with fewer comorbidities than those taking into consideration the ethical standards of the Commission re­
treated in real-world settings [6]. In fact, patients hospitalized for HF in sponsible for human experimentation and in compliance with the
Internal Medicine units or managed at an outpatient level, as well as Helsinki Declaration of 1964, revised in 2013. All subjects were in­
being very old, commonly have multiple comorbidities, take a poly­ formed of the study protocol and expressed their informed consent to
therapy and are fragile, so much so that they are only partially re­ participate in the same.
presentative of the patients enrolled in most HF clinical trials [7,8]. For
these reasons, in the absence of strong recommendations from the main
guidelines based mostly on subjects under the age of 70, “internistic” 2.1. Data collection
HF patients often receive sub-optimal medical treatment [9]. For­
tunately, the standard optimal medical treatment of HF with angio­ At the screening visit, blood pressure (BP) was measured 3 times in
tensin-converting enzyme inhibitors (ACEIs) or angiotensin-II receptor both clinostatism and orthostatism, with a mercury sphygmoman­
blockers (ARBs) (in case of ACEI intolerance), beta-blockers and mi­ ometer, at 10-minute intervals. The average of the last two measure­
neralocorticoid receptor antagonists (MRA) reduces the risk of mor­ ments was approximated by default to minimize the “white coat” effect,
tality and hospitalization due to HF by up to 37 % [10]. However, data and at the same time heart rate (HR) was also measured. Arterial hy­
from the ARNO study [11], the largest Italian registry that collects in­ pertension was defined as a systolic BP value > 140 mmHg and/or
formation on 41,413 H F patients from administrative databases (for the diastolic BP > 90 mmHg or any BP during antihypertensive treatment.
majority, patients managed in Internal Medicine), indicate that HF Body Mass Index (BMI) was calculated as the ratio of weight (in kilo­
mortality remains high. The analysis of these data also reveals a sig­ grams) to height (in meters) squared.
nificant under-prescribing of drugs for HF, where only 66 %, 49 %, and The N-terminal pro-B-type natriuretic peptide (NT-proBNP) was
42 % of patients underwent treatment with ACE inhibitors/ARBs, beta- analyzed with the electrochemiluminescence immunoassay on human
blockers and MRA, respectively [11]. Fortunately, the clinician has the plasma, according to the Elecsys pro-BNP II STAT system [13]. The
task of adapting therapeutic strategies considering the availability of values of total cholesterol (TC), triglycerides (TG), cholesterol asso­
new treatments for HF. In this context, sacubitril/valsartan is the pro­ ciated with high-density lipoproteins (HDL-C), glycemia, glycated he­
genitor of the inhibitors of the AT1 receptor of angiotensin-II and ne­ moglobin (HbA1c). The cholesterol values (in mg/dL) associated with
prilysin (ARNIs, angiotensin receptor neprilysin inhibitors) and, thanks low-density lipoproteins (LDL-C) were calculated with Friedewald’s
to the results of the “Prospective comparison of ARNI with ACEI to formula [14].
Determine Impact on Global Mortality and Morbidity in Heart Failure” The subjects, based on their smoking habit (or absence thereof),
(PARADIGM-HF) trial [12], ARNIs were approved by the US Food and were classified into non-smokers and smokers (> 1 cigarette/day).
Drug Administration (FDA) and by the European Medicines Agency Patients were considered diabetic if they had repeated blood glucose
(EMA) as a new pharmacological class for the treatment of HF. The values (in mg/dL) ≥ 126, or glycated hemoglobin (HbA1c) values >
results of PARADIGM-HF have shown in the short term that treatment 6.5 %, or if they were treated with hypoglycemic drugs, regardless of
with ARNI allowed the reduction of total and cardiovascular mortality their blood sugar values. Serum creatinine values (SCr, in mg/dL) were
and the number of hospitalizations for HF by 20 % and this trial was measured by means of an enzymatic method, using an auto-analyzer
suspended early for an excess of benefit, at a follow-up of 27 months. In (Hitachi Modular P, Roche diagnostic, USA). Estimated glomerular fil­
the PARADIGM-HF study, the elderly population was well represented; tration rate (eGFR, in mL/min) was obtained from the serum creatinine
23 % of the 8442 outpatients with HF with reduced ejection fraction value in both genders, using the Cockroft-Gault formula:
(HFrEF < 40 %) randomized to ARNI or enalapril treatment were 75
eGFR = [(140 – age (years) x weight (kg))]/(SCr mg/dL × 72, if male)
years or older [12].
Although treatment with ARNI has shown promising results, it is
still unclear whether it is applicable to the Internal Medicine setting, Chronic kidney disease (CKD) was diagnosed based on eGFR
consisting mostly of frail, elderly patients with multiple comorbidities values < 60 mL/min. Patients who, upon spirometry, showed a non-
and requiring a complex pharmacological and non-pharmacological reversible ratio between forced expiratory volume in one second (FEV1)
therapy for HF [9]. and forced vital capacity (FVC) < 0.7, or who were taking bronchodi­
The aim of this prospective study, conducted in hypertensive, el­ lator drugs, were considered to be suffering from chronic obstructive
derly and comorbid patients managed in an internistic setting, was to pulmonary disease (COPD). Finally, the clinical history of myocardial
evaluate whether treatment with ARNI compared to the standard drug infarction (confirmed by relevant medical documentation), angina
therapy for HF was able to improve the symptoms of HF with reduced pectoris confirmed by medical documentation or by treatment with
EF and have a positive impact on mortality and re-hospitalization due anti-anginal drugs, and the presence of positive cycle ergometer or
to HF. positive myocardial scintigraphy tests, classified the subjects as offi­
cially suffering from ischemic heart disease (IHD).

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A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

2.2. Study plan 2.5. Echocardiographic study of the systo-diastolic function

As recommended by the 2016 European guidelines on HF man­ Echocardiographic data were analyzed by two observers who were
agement, ARNI treatment [9] was started in patients with HF with re­ not aware of the patient’s arm, and consequently, of the current treat­
duced EF who remained symptomatic despite optimal treatment at 3 ment. M-mode and two-dimensional echocardiography was performed
months with ACEI, or ARB (in case of intolerance to ACEI), beta-blocker with the IE33 system tool (Philips Medical System, Bothell, WA, United
and MRA. The inclusion criteria for participating in the study were as States), in accordance with the recommendations of the American
follows: adult patients with LVEF < 40 %, NT-pro BNP ≥ 900 pg/mL, Society of Echocardiography [15]. The thicknesses of the septum and
eGFR > 30 mL/min, serum potassium < 5.2 mmol/L, systolic and/or the posterior wall, the size of the left ventricle (LV) in end-diastole and
diastolic BP ≥ 110/70 mmHg. The exclusion criteria were a history of the mass of the LV were measured. LV mass was calculated using the
hypersensitivity or intolerance to ACEI or ARB, history of angioedema, Devereux formula [16] and then indexed for body surface area (LVM).
symptomatic hypotension and/or systolic BP < 100 mmHg, serum LV hypertrophy was defined as an indexed LVM ≥ 115 g/m2 for males
potassium ≥ 5.3 mmol/L, presence of neoplasms or liver failure, de­ and ≥ 95 g/m2 for females. Left atrium volumes were obtained by the
mentia or inability to cooperate. disc method [17] and, where possible, the estimate of systolic BP in the
pulmonary artery was obtained by tricuspidal regurgitation jet [18]. All
information obtained from Doppler imaging was gained during normal
2.3. Active ARNI treatment breathing. From the apical vision in 4 chambers, the sample volume
was positioned at the mitral valve level, and 5−10 cardiac cycles were
Upon the initial visit, ARNI therapy was administered in patients recorded to obtain the pulsed Doppler. From the mitral inflow rate, the
presenting with clinical symptoms of HF despite standard optimal early (E = early) and late (A = late) peak filling rate, the deceleration
medical therapy (OMT). ARNI therapy was administered in addition to time of the E wave velocity and the atrial filling fraction were obtained
OMT twice a day at different dosages of sacubitril/valsartan, [19]. As regards the pulmonary veins, the systolic peak velocity (S), the
24−26 mg, 49−51 mg or 97−103 mg, respectively (Fig. 1), after the antegrade diastolic peak velocity (D), and the S/D ratio were calcu­
suspension of the treatment with ACEI or ARB. In detail, for patients lated; the Doppler imaging program was set to the pulsed wave mode.
taking ACEI therapy, ARNI treatment was administered at least 36 h The filters were set to exclude high-frequency signals and the Nyquist
after stopping the ACEI, while in patients taking ARBs, ARNI treatment limit was adjusted to a velocity range of 15–20 cm/s. Gains were
was administered 24 h after stopping the ARB. The choice of the initial minimized, to allow for a clear tissue signal, with minimal background
dose of ARNI was based on baseline systolic BP, eGFR, and potassium noise. The pulsed wave Doppler imaging was performed in apical vi­
values. sion, to acquire the mitral annular speeds [20], and the sample volume
was positioned at ± 1 cm inside the sites of septal and lateral insertion
of the mitral flaps, and adjusted as needed (usually 5−10 mm) to cover
2.4. Control arm the longitudinal excursions of the mitral ring in systole and diastole.
The main end-points of the echocardiographic study were the changes
Patients treated with ARNI were compared with an arm of the same in EF, end-systolic volume, end-diastolic volume and left ventricular
size (n = 54) and matched by age and gender, selected from our da­ mass index (LVMI) between the treatment groups.
tabase for HF before the marketing of ARNIs and who were taking a
standard OMT for HF with reduced EF, characterized by ACEI or ARB,
beta-blocker, and MRA. The posology adopted for the drugs included in 2.6. Statistical analysis
OMT and the type of ACEI or ARB and beta-blockers used is shown in
Table 2. Continuous variables were analyzed and expressed as mean ±
The mean duration of follow-up in the 2 treatment arms was 12 standard deviation and compared by means of the analysis of variance
months. To evaluate the effectiveness and the titration of the ARNI and (ANOVA). For the comparison between the categorical variables,
OMT treatment, the NYHA class and the values of systolic BP, serum Pearson’s chi-squared test was used. The analysis of variance for re­
potassium and creatinine were analyzed upon the initial visit, at Month peated measures was used to compare the differences in the values of
1 and 6, and at the end of the follow-up, while NT-proBNP and left NT-proBNP, systolic BP, eGFR, and potassium at baseline and at follow-
ventricle EF and cardiac remodeling parameters were assessed upon the up. To obtain an 80 % probability of finding a difference of at least
initial visit and at the end of follow-up in both arms (Fig. 1). Data on 1000 pg/mL of the NT-proBNP concentration between the two study
clinical outcomes of mortality and re-hospitalization due to HF were arms, a potency test was performed. Considering a significance level of
collected through the analysis of the HDSs or by contacting the General 5%, the sample size had to be at least 40 subjects. Statistical analyses
Practitioner, when the patient did not report at follow-up. were obtained using the SPPS package version 18.0 of Windows (SPSS,
Chicago, IL, USA). The null hypothesis was always rejected for values of
p < 0.05.

Fig. 1. Study plan of patient follow-up after hospital discharge for the ARNI (active treatment) group and the OMT (control) group. ARNI angiotensin receptor
neprilysin inhibitor; OMT standard optimal medical treatment.

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A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

Table 1
General characteristics of patients upon initial assessment, by treatment arms.
Items All (N = 108) OMT (N = 54) ARNI (N = 54) P

Age (years) 78.6 ± 8.2 78.6 ± 8.2 78.6 ± 8.2 1.000

Male gender (%) 75 75 75 1.000
Body Mass Index (g/m2) 27.1 ± 3.6 26.8 ± 2.7 27.3 ± 4.3 0.655
Creatinine (mg/dL) 1.23 ± 0.45 1.24 ± 0.45 1.23 ± 0.44 0.906
eGFR (mL/min/1.73 m2) 62.5 ± 23.4 63.8 ± 22.3 61.2 ± 24.6 0.571
SBP (mmHg) 125.0 ± 10.3 126.2 ± 8.9 123.8 ± 11.5 0.384
DBP (mmHg) 75.6 ± 10.1 75.2 ± 9.6 74.0 ± 10.6 0.638
HR (bpm) 66.7 ± 8.9 68.5 ± 9.1 65.1 ± 8.5 0.156
Glycemia (mg/dL) 115.1 ± 31.3 112.7 ± 28.5 115.4 ± 34.1 0.583
HbA1c (%) 5.7 5.6 5.8 0.169
Uricemia (mg/dL) 6.3 ± 0.59 6.4 ± 0.58 6.2 ± 0.62 0.169
Potassium (mmol/L) 4.0 ± 0.5 4.1 ± 0.4 4.0 ± 0.5 0.645
Sodium (mg/dL) 139.1 ± 6.8 141.2 ± 7.7 137.2 ± 5.3 0.025
Hemoglobin (g/L) 12.8 ± 1.4 13.0 ± 1.6 12.6 ± 1.7 0.319
Cardiac parameters
LVMI (kg/m2) 152.2 ± 10.8 151.9 ± 9.5 152.4 ± 12.1 0.884
EF (%) 30.1 ± 5.1 29.8 ± 4.3 30.4 ± 5.4 0.462
History of HF (years) 13.4 ± 2.2 12.9 ± 2.5 13.8 ± 1.7 0.091
NT-proBNP (pg/mL) 5437.4 ± 3450.5 5363.9 ± 3562.8 5503.1 ± 3402.5 0.878
NYHA Class (%)
II 55.4 57.1 53.6 0.072
III 44.6 42.9 46.4 0.064
CRT (%) 14.3 10.7 17.9 0.583
ICD (%) 21.4 21.4 21.4 0.627
Concomitant treatment
ACEIs (%) 87.1 57.1 71.4 0.310
ARBs (%) 12.6 14.8 11.1 0.120
Diuretics (%) 92.5 94.4 90.7 0.642
Beta-blockers (%) 71.4 67.9 75.0 0.384
Mineralocorticoid antagonists (%) 55.4 53.6 57.1 0.071
Digitalis (%) 32.1 28.6 35.7 0.388
Concomitant conditions
Ischemic heart disease (%) 72.2 70.3 74.1 0.202
CKD (%) 58.9 57.1 60.7 0.074
Atrial fibrillation (%) 35.7 32.1 39.3 0.390
COPD (%) 42.0 32.5 48.1 0.226
Diabetes mellitus (%) 35.7 32.1 39.3 0.390
History of stroke (%) 19.6 21.4 17.9 0.500

Values are percent of patients or mean ± standard deviation (SD).

OMT, optimal medical therapy; ARNI, angiotensin receptor-neprilysin inhibitor; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, glomerular
filtration rate; LVMI, left ventricle mass index; LVEF, left ventricle ejection fraction; LV, left ventricle; EF, ejection fraction; HF, heart failure; NYHA, New York Heart
Association; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II
receptor blocker; MRA, mineralocorticoid antagonist; CHD, coronary heart disease; CKD, chronic kidney disease; AF, atrial fibrillation; COPD, chronic obstructive
pulmonary disease.

3. Results in Table 2. Specifically, among patients on ACEIs, 75 % took enalapril,

20 % ramipril, and 5 % perindopril. Among those on ARBs, 70 % took
The general characteristics of the patients, distributed by treatment valsartan, 20 % candesartan and 10 % losartan. For beta-blockers, the
arm (OMT and ARNI) are summarized in Table 1. In the OMT group, the proportion was 30 % each for metoprolol and carvedilol and 20 % each
proportion of patients taking ACEIs or ARBs and beta-blockers is shown for atenolol and bisoprolol. The maximum tolerated dose of the dif­
ferent drugs used in OMT is also shown in Table 2. At 1 and 6 months of
Table 2 follow-up, there were no significant changes in the levels of ambulatory
Type and posology of drugs included in the optimal medical therapy (OMT). BP, creatinine, and potassium (data not shown) between the two arms.
At the final follow-up (Fig. 2), NYHA class improved significantly in
Type of drugs Prevalence (%) Maximum tolerated dose/daily (mg)
the arm treated with ARNI compared to the control, where 24.9 % vs.
ACEIs 6.4 % of the patients switched from class III to class II and 55.4 % vs.
Enalapril 75 20 25.2 % from class II to class I, respectively (p < 0.05). The LVEF and
Ramipril 20 10 eGFR values increased significantly (p < 0.001) in the ARNI arm
Perindopril 5 10
compared to the control arm, 42.4 % vs. 34.2 %; 73.8 vs. 61.2 mL/min,
ARBs
Valsartan 70 160 respectively (Fig. 3A and B). On the contrary, the values of NT-proBNP
Candesartan 20 16 (Fig. 3C), systolic and diastolic BP, HbA1c, blood sugar, and uricemia
Losartan 10 100 decreased in both arms, but more significantly in the arm treated with
Beta-blockers
ARNI compared to the control (3107 vs. 4552 pg/mL, 112.2 vs. 120.4
Metoprolol 30 200
Carvedilol 30 25 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9
Atenolol 20 100 vs. 6.4 mg/dL respectively; p < 0.05). Furthermore, the LVMI and
Bisoprolol 20 10 cardiac remodeling parameters improved significantly only in the arm
treated with ARNI (Table 3). At the final follow-up, 38.5 % of patients
ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor
in the ARNI treatment arm were taking the 24–26 mg dose of sacubitril/
blockers.

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A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

Fig. 2. Change in New York Heart Association (NYHA) class between baseline
and the final follow-up. ARNI angiotensin receptor neprilysin inhibitor; OMT
standard optimal medical treatment.

valsartan, 33 % the 49–51 mg dose and 28.5 % the 97–103 mg dose.

There was a favorable trend towards a reduction in the use of loop
diuretics in the ARNI arm compared to the OMT arm (74.2 % vs. 86.4
%, NS) which, however, was not significant.
Mortality and re-hospitalization due to HF (Fig. 4) were lower in the
arm treated with ARNI compared to the control (20.1 vs. 33.6 % and
27.7 vs. 46.3 %, respectively; p < 0.05). No patient left the study
voluntarily or because of the onset of adverse events.

4. Discussion

Over 12 years ago, the results of Comorbidities and Outcome in

patients with chronic heart Failure: a study in Internal Medicine units
(CONFINE) study, an observational epidemiological study conducted in
Italy in Internal Medicine patients [7], had shown a high prevalence of
HF patients over the age of seventy years (80 %) having multiple co­
morbidities. The frequent association of other disorders in HF patients
is not a new observation and has also emerged in a large American
study that recruited subjects with an average age of 76, who in 39 % of
cases suffered from 5 conditions [21].
In our study, conducted in elderly subjects with HF with reduced EF
and with comorbidities, treatment with ARNI compared to standard
optimal therapy was shown to be safe and effective in improving the
symptoms of HF and in reducing its rate of mortality and re-hospitali­
zation due to HF. These effects would appear to be attributable both to
the action of ARNI on cardiovascular hemodynamics for improvement
of cardiac function (EF and cardiac remodeling) and BP and to the
modulation of the renal filtrate and some metabolic parameters, such as
blood glucose (and HbA1c) and uricemia, which are described below.

4.1. ARNI and cardiovascular hemodynamics Fig. 3. Change from baseline to final follow-up in A) left ventricular ejection
fraction (EF), B) estimated glomerular filtration rate (eGFR), and C) N-terminal
Although the physiological mechanisms of ARNI are well known, pro-B-type natriuretic peptide (NT-proBNP) concentrations. (*p < 0.05, **
p < 0.001 vs. baseline), ARNI angiotensin receptor neprilysin inhibitor; OMT
their effects on the remodeling of the left ventricle (LV) and EF have
standard optimal medical treatment.
been poorly studied, especially in elderly patients with multiple co­
morbidities [9]. In arterial hypertension, the remodeling of the LV is the
main mechanism by which progression from sub-clinical cardiac injury treated with ARNI and an arm treated with OMT for HF. As regards the
secondary to arterial hypertension leads to the signs and symptoms of latter aspect, current guidelines [9] emphasize the role of OMT for HF,
HF [22]. As a result, the actions aimed at improving the left ventricular but at the same time recommend the role of adherence and persistence
end-diastolic volume (LVEDV), left ventricular end-systolic volume to treatment.
(LVESV), LVEF, and left ventricular hypertrophy (LVH) are the main However, in the real-world setting, although OMT is the basis of the
goals of medical treatment, since these parameters are closely related to management of HF, there is much evidence to show that many HF
the clinical outcomes and survival of HF patients. patients do not receive OMT, or that the therapy is sub-optimal [11,24].
In our study, ARNI therapy at 12 months resulted in an improve­ There are numerous reasons that can explain the failure of OMT in
ment in LVEDV, LVESV, EF, and LVH, as also demonstrated by Almufleh chronic HF, partly related to the patient, such as advanced age, co­
and colleagues [23]. However, in the latter observational study, the morbidities and polytherapy (which, as is known, affect compliance
absence of a control arm precluded a comparison between an arm with therapy), to the doctor (such as inertia or lack of knowledge of the

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A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

Table 3
Hemodynamic, metabolic, renal, and cardiac remodeling parameters upon the initial evaluation and at the end of the follow-up after treatment with ARNI.
Items Baseline (N = 54) Follow-up (N = 42) Mean difference of values ± SD P

SBP (mmHg) 123.8 117.0 −6.9 ± 11.6 0.001

DBP (mmHg) 73.9 69.5 −4.1 ± 10.9 0.04
HR (bpm) 65.1 62.0 −2.57 ± 7.21 0.04
Glycemia (mg/dL) 115.3 101.5 −15.9 ± 21.3 0.001
HbA1c (%) 5.9 5.4 −0.36 ± 0.31 0.04
eGFR (ml/min/1.73 m2) 64.8 70.1 8.46 ± 7.9 0.04
NT-pro BNP (pg/mL) 5503.8 3107.1 −2740.2 ± 1760.1 0.001
Uricemia (mg/dL) 6.21 5.92 −0.31 ± 0.23 0.04
EF (%) 29.8 42.1 11.7 ± 6.1 0.001
End-systolic volume (mL) 123.12 83.1 −39.8 ± 25.1 0.014
End-diastolic volume (mL) 173.3 144.2 −29.3 ± 19.7 0.002
LVMI (g/m2) 152.4 147.8 −4.68 ± 2.19 0.001

ARNI, angiotensin receptor-neprilysin inhibitor; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HR, heart rate; eGFR,
glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; EF, ejection fraction; LVMI, left ventricular mass index.

treated with sacubitril/valsartan compared to the arm receiving OMT.

In fact, in addition to the known action of valsartan on the BP reduction
observed in the above studies, the inhibition of neprilysin with sacu­
bitril increases the plasma concentrations of the atrial natriuretic pep­
tide and the cerebral natriuretic peptide, which have the effect in
lowering BP mainly through a volume reduction [31] and natriuresis
[32]. Furthermore, the action of sacubitril (as discussed below) causes
an increase in the glomerular filtration rate and the renal blood flow,
with inhibition of the release of renin and aldosterone, which is asso­
ciated with a reduction in the activity of the ortho-sympathetic system
and an anti-hypertrophic and anti-fibrotic action. These mechanisms
explain the greater BP reduction observed in the arm being treated with
Fig. 4. Rates of mortality and re-hospitalization for heart failure in patients
the sacubitril/valsartan combination, compared to the anti-hyperten­
treated with angiotensin receptor neprilysin inhibitor (ARNI) or standard op­
timal medical treatment (OMT).
sive therapy with a single RAAS inhibitor present in the control arm
receiving OMT (ACEI or ARB).
On the other hand, the magnitude of the modulation/regression of
guidelines) and finally to the difficulty in using medical care due to a the LVH of the OMT over time has not yet been clearly defined and it
lack of resources of the health systems [25]. seems that it can take months or years to observe significant effects on
In this study, in accordance with current HF guidelines [9], patients cardiac remodeling. However, it is commonly held that it takes a few
with OMT achieved an improvement in EF, thus confirming that the months to observe a significant reduction in LV mass during an anti­
treatment with ACEI or ARB, beta-blocker, and MRA is effective and hypertensive treatment, which is compatible with the results of our
safe in changing the clinical history of patients with chronic HF. study [33]. In fact, in agreement with Thurmann and colleagues [34],
However, as already demonstrated in clinical studies and animal the antihypertensive treatment with valsartan for 6–8 months produces
models [26,27], the benefits observed in our study on EF and cardiac a significant regression of LVH, which in turn is associated with a re­
remodeling are mainly attributable to the treatment with ARNI. In duction in hospitalization for HF [30].
addition to the action on the remodeling of the LV, it is well known that
the OMT is able to interact with the physio-pathological mechanisms
that determine the onset of LVH, a known predictor of cardiovascular 4.2. ARNI and kidney function
morbidity and mortality, regardless of BP and the classic cardiovascular
risk factors [9]. The prevalence of LVH gradually increases with age, ARNI treatment also appears to improve renal function, due to the
and it is now established that the therapy with antihypertensive drugs, combined effect of the RAAS blockade, the increase in atrial natriuretic
which are also the cornerstone of the treatment of chronic HF, reduces peptides due to the inhibition of neprilysin and the reduction of the
LVMI in hypertensive patients compared to placebo [28]. The regres­ diuretic therapy [35]. In detail, valsartan, as a RAAS AT1 receptor
sion of LVMI, in particular thanks to the treatment with renin-angio­ antagonist, blocks the effects of angiotensin II, especially in the glo­
tensin-aldosterone system (RAAS) blockers, is significantly more ef­ merular efferent arterioles, producing a vasodilator effect, reducing
fective than other antihypertensive drugs, such as calcium channel glomerular filtration pressure and decreasing the extent of intra-glo­
blockers or beta-blockers. Among the RAAS blockers, the Valsartan merular filtration [36]. In addition, animal models have also shown
Antihypertensive Long-term Use Evaluation (VALUE) trial [29], which how atrial natriuretic peptides act directly on the kidney by dilating
included 7800 high-risk hypertensive subjects, showed that valsartan and constricting the afferent and efferent arterioles, respectively,
treatment resulted in less morbidity and mortality due to HF compared causing an increase in intra-glomerular capillary pressure and in­
to the control arm taking amlodipine. These data confirmed the pre­ creasing the glomerular filtration rate [37]. In healthy subjects, in fact,
vious results of the Valsartan in Heart Failure (Val-HeFT) trial, where the infusion of atrial natriuretic peptides determines an increase in
there was a 13.2 % reduction of the combined end-points in the glomerular filtrate [38] and the inhibition of neprilysin increases
5010 H F patients in the valsartan arm compared to the arm treated plasma levels not only of atrial natriuretic peptides but also of brady­
with placebo [30]. kinin and adrenomedullin [39]. The latter are modulating substances of
In the light of this evidence, it can be deduced that the reduction of renal hemodynamics which, at the level of the glomerulus, determine
LVH observed in this study is also due to a significant reduction in the an increase in natriuresis, with a consequent reduction of the circu­
values of the BP, in particular for systolic BP, as observed in the arm lating plasma flow which, by reduction of the renal flow, leads to a
reduction in perfusion and glomerular filtration [40]. In addition,

6
A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

different nephron-protective effects of bradykinin have also been de­ biomolecular mechanisms could in part explain the reduction in blood
scribed, including the inhibition of renal inflammation, apoptosis and glucose and glycated hemoglobin observed in our study in patients
glomerulosclerosis [41]. Consequently, ARNI treatment, by blocking treated with ARNI.
the action of angiotensin II and increasing the biological action of the
atrial natriuretic peptides, leads to an improvement in renal function 4.4. ARNI and uric acid
which is superior to treatment with RAAS antagonists alone, particu­
larly in diabetic subjects [42]. Although the benefit of ARNI treatment Uric acid (UA) is the final product of purine metabolism, and hy­
on renal function was more evident in subjects < 65 years old, Span­ peruricemia reflects the balance between the dietary intake of purines,
nella and colleagues [43] recently observed that it was preserved in the synthesis of UA by xanthine oxidase, and the renal excretion of UA
older subjects too. [55]. In this respect, diuretic therapy, often used in HF treatment, is
Finally, ARNI treatment has been associated with a reduction in the also associated with hyperuricemia, probably because diuretics alter
use of loop diuretics, suggesting that such therapy may decrease the the excretion of UA [55]. Indeed, hyperuricemia potentially reflects
need for diuretics in patients with chronic HF with reduced EF [44]. In oxidative stress as a consequence of the activity of xanthine oxidase, as
our study, after titration to the tolerated target dose of ARNI, while UA itself can have harmful effects, due to increased expression of cy­
observing a trend favorable to the reduction in the use of loop diuretics, tokines, induction of inflammation, impaired endothelial function and
patients showed an improvement in the hydro-electrolyte balance activation of the RAAS [56]. These mechanisms in part explain why
without a significant reduction in the diuretic. In hypertensive patients hyperuricemia is associated with worse clinical outcomes in patients
with chronic HF, especially the elderly and those with CKD, the re­ with acute and chronic HF [57].
duction or discontinuation of the diuretic therapy should be carefully Whether UA represents an independent predictor of outcomes in HF
evaluated, since there is a risk of creating a “rebound” effect, with re­ is still under debate, since the renal function and the use of diuretics
tention of sodium and water, and the consequent occurrence of per­ increase its plasma concentration [55,57]. However, in a sub-analysis of
ipheral edema [45]. the PARADIGM-HF study, ARNI treatment at 12 months significantly
On the other hand, when long-term trials on the treatment of hy­ reduced UA values by 0.24 mg/dL, and improved the outcomes, re­
pertension were examined to evaluate the effects of diuretics on the gardless of UA concentration [58]. This correlation between UA and HF
development of HF, diuretics were found to reduce the risk of HF by 52 prognosis is therefore still uncertain as hyperuricemia has been shown
% [46]. In particular, treatment with diuretics compared with calcium to be a marker of reduced excretion of UA, due to renal failure or to a
channel blockers or ACEI from the Antihypertensive in the Lipid-Low­ higher diuretic dose [59]. On the other hand, hyperuricemia seems to
ering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that increase oxidative stress (via xanthine oxidase activity) and endothelial
chlorthalidone was superior to amlodipine in preventing HF progres­ dysfunction, which play a harmful role in HF [60]. Whether the re­
sion and that the arm treated with amlodipine had a 38 % higher risk of duction in UA levels observed in the ARNI therapy contributed or not to
developing HF at 6 years of follow-up [47]. The results of our study the reduction in morbidity and mortality observed in the PARAD­
confirmed the beneficial clinical role of the use of diuretics (particularly IGM-HF study remains to be confirmed in controlled clinical trials.
loop diuretics) in the management of HF, the need for which is probably However, the possibility that the reduction in UA levels may have a role
reduced by the ARNI therapy [44]. in HF cannot be ruled out, as the sacubitril/valsartan mechanism on UA
is still unknown. In this respect, losartan has a well-known uricosuric
4.3. ARNI and glucose metabolism action [61], not observed for valsartan. On the other hand, it would
seem that inhibition of neprilysin may cause a small increase in urinary
Emerging data support a beneficial effect of ARNI treatment on excretion of UA [58].
glycemic control [42]. In detail, in a post-hoc analysis of the PARAD­
IGM-HF study [48], in 3778 patients with a known diagnosis of diabetes 4.5. ARNI, indicators of efficacy, comorbidity, and outcomes
or with a HbA1c > 6.5 %, ARNI treatment was associated with persis­
tently lower values of HbA1c than in the control arm. In addition, the As widely demonstrated, since atrial natriuretic peptides are de­
initiation of insulin therapy was 29 % less frequent in patients treated graded by neprilysin, treatment with ARNI increases the concentration
with ARNI than in those treated with enalapril, and there was lower use of the atrial natriuretic peptide, the type-B natriuretic peptide (BNP)
of oral antidiabetic agents in the ARNI arm. and the type-C natriuretic peptide [62]. On the contrary, neprilysin has
The potential mechanisms through which sacubitril/valsartan could no effect on the degradation of NT-proBNP and therefore the NT-
lead to an improvement in glycemic control are manifold. Natriuretic proBNP levels are not affected by the inhibition of neprilysin. In
peptides, which are increased by the inhibition of neprilysin by sacu­ agreement with the PARADIGM-HF study, in our study the NT-proBNP
bitril, could play a crucial role in insulin metabolism [49]. Serum glu­ levels decreased significantly during treatment with ARNI. In detail, a
cose concentrations have also been shown to decrease after natriuretic NT-proBNP level lower than 1000 pg/mL was associated with an im­
peptide infusion and higher concentrations of NT-proBNP are asso­ provement NYHA functional class. However, unlike the PARADIGM
ciated with a significantly reduced risk of diabetes, after adjustment for study, where 70 % of the enrolled subjects were in NYHA class I or II
the classic risk factors and the fasting blood glucose levels [50]. Fur­ [12], in our experience, 54 % of the subjects were in NYHA class II,
thermore, glucagon-like peptide-1 (GLP-1), a neuropeptide of the in­ therefore with a worse clinical picture of cardiac HF upon the initial
cretin family, a powerful hypoglycemic hormone with a very short visit. The improvement in the NYHA class observed in our study en­
circulating half-life, is partially degraded by neprilysin [51]. In animal courages the use of sacubitril/valsartan even in elderly people over the
models deficient in neprilysin, the improvement of glycemic control has age of 78 and with multiple comorbidities, since NYHA functional
been associated with high active concentrations of GLP-1, reduced ac­ classes, as recommended by international guidelines, are recognized as
tivity of plasma dipeptidyl peptidase-4 and an improvement in the indicators able to influence the therapeutic decisions on HF manage­
function of beta-cells, suggesting beneficial metabolic effects with the ment. In particular, comorbidities can worsen the management and
inhibition of neprilysin [52]. Furthermore, since angiotensin II pro­ prognosis of HF [63], in particular by promoting the patient’s func­
motes insulin resistance, the inhibition of RAAS with valsartan helps to tional decline, which in turn negatively affects compliance and long-
modulate glycemic control [53]. As a consequence, it is commonly term adherence to HF drug therapy. In our study, the positive effects of
believed that the improvement in glucose metabolism by RAAS in­ ARNIs on BP and blood glucose reflect in part the improvement of the
hibition alone is likely to be very modest, and that it is mainly due to two comorbidities most frequently associated with HF, i.e., arterial
the effects of sacubitril on glucose homeostasis [54]. These hypertension and diabetes, conditions which in turn, if not adequately

7
A. Mazza, et al. Biomedicine & Pharmacotherapy 130 (2020) 110596

controlled, lead to a worsening of outcomes. appear to be attributable both to the action of the ARNIs on cardiac
In agreement with PARADIGM-HF [64], ARNIs had a positive im­ hemodynamics and BP and to the modulation of renal function and
pact on clinical outcomes in our study performed in elderly subjects. some metabolic parameters. However, these results must be confirmed
However, unlike PARADIGM-HF, where HF mortality was assessed with in studies involving a greater number of subjects, and with a longer
a composite end-point, together with cardiovascular mortality, only HF follow-up.
mortality was assessed in our study. The same applies to re-hospitali­
zation due to HF, which was assessed separately and not in combination Funding
with cardiovascular mortality, as occurred in PARADIGM-HF. In detail,
patients of our study who took ARNIs presented a significantly reduced The study was supported by an unrestricted grant from Novartis
HF mortality compared to those who received OMT. The data on the Farma SpA.
reduction in HF mortality observed in our study with ARNIs versus
OMT are encouraging but still remain high, as one in five patients died Declaration of Competing Interest
due to HF at 12 months. This is in part also due to the advanced age of
our patients, which was about 15 years greater than that of the patients The authors declare that there are no conflicts of interest.
enrolled in the PARADIGM-HF study, and to the greater prevalence of
comorbidities present in our study (i.e. hypertension, CKD and COPD, Acknowledgements
the latter not included in the PARADIGM-HF trial), which have a ne­
gative impact on the management of HF. We thank Ray Hill, an independent medical writer, who provided
Finally, the results on the hospitalizations due to HF were also very English-language editing and journal styling prior to submission on
interesting, since fewer than one patient out of three on ARNI treatment behalf of Springer Healthcare Communications. This assistance was
was re-admitted for HF. Conversely, re-hospitalization due to HF in the funded by Novartis Farma SpA.
arm treated with OMT was still very high (46.3 %). These data are quite
in line with that observed in clinical and pivotal studies involving HF References
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