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

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. 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. 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. 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). 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.

Naser N ，Kulić M ，Jatić Z 《-》

The role of sacubitril/valsartan in the treatment of chronic heart failure with reduced ejection fraction in hypertensive patients with comorbidities: From clinical trials to real-world settings.

Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities. 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 glomerular 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. 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. 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 mechanisms 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.

Mazza A ，Townsend DM ，Torin G ，Schiavon L ，Camerotto A ，Rigatelli G ，Cuppini S ，Minuz P ，Rubello D ... -  《-》

Effects of sacubitril/valsartan on clinical symptoms, echocardiographic parameters, and outcomes in HFrEF and HFmrEF patients with coronary heart disease and chronic kidney disease.

Raphael DM ，Liu Z ，Jin Z ，Cui X ，Han D ，He W ，Shangguan J ，Shen D ... -  《-》

Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: The ARIADNE registry.

ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively. This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Maggioni AP ，Clark AL ，Barrios V ，Damy T ，Drozdz J ，Fonseca C ，Lund LH ，Kalus S ，Ferber PC ，Hussain RI ，Koch C ，Zeymer U ，ARIADNE investigators ... -  《ESC Heart Failure》

Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF.

This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information. Through inhibition of neprilysin, Sac/Val may increase BNP concentrations. In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12. Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P < 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P < 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P < 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]). In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Myhre PL ，Prescott MF ，Murphy SP ，Fang JC ，Mitchell GF ，Ward JH ，Claggett B ，Desai AS ，Solomon SD ，Januzzi JL ... -  《-》