REVIEW published: 11 November 2021 doi: 10.3389/fcvm.2021.754499 Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review Domingo Pascual-Figal 1,2*† , Antoni Bayés-Genis 3,4,5† , Paola Beltrán-Troncoso 6† , Pedro Caravaca-Pérez 5,7,8† , Alicia Conde-Martel 9† , Maria G. Crespo-Leiro 10,11† , Juan F. Delgado 5,7,8† , Javier Díez 5,12,13,14† , Francesc Formiga 15 and Nicolás Manito 16*† 1 Cardiology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, 2 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, 3 Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, Edited by: 4 Department of Medicine, Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Autonomous Gaetano Ruocco, University of Barcelona, Barcelona, Spain, 5 Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Regina Montis Regalis Hospital, Italy Carlos III Institute of Health, Madrid, Spain, 6 Hospital de Viladecans, Barcelona, Spain, 7 Cardiology Service, Hospital Reviewed by: Universitario 12 de Octubre, Madrid, Spain, 8 Faculty of Medicine, Complutense University of Madrid, Madrid, Spain, 9 Guido Pastorini, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain, 10 Advanced Heart Failure and Heart Transplant Unit, Regina Montis Regalis Hospital, Italy Cardiology Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain, 11 Institute of Biomedical Research Mauro Feola, (INIBIC), A Coruña, Spain, 12 Cardiovascular Diseases Programme, Centre of Applied Medical Research, University of Regina Montis Regalis Hospital, Italy Navarra, Pamplona, Spain, 13 Departments of Nephrology, Cardiology, and Cardiac Surgery, University of Navarra Clinic, Francesca Valentini, Pamplona, Spain, 14 Navarra Institute for Health Research, Pamplona, Spain, 15 Internal Medicine Department, Hospital Azienda USL Toscana Sud Est, Italy Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain, 16 Heart Failure and Heart Transplantation Unit, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain *Correspondence: Domingo Pascual-Figal dpascual@um.es Heart failure (HF) is a clinical syndrome characterized by the presence of Nicolás Manito nml@bellvitgehospital.cat dyspnea or limited exertion due to impaired cardiac ventricular filling and/or blood † These ejection. Because of its high prevalence, it is a major health and economic authors have contributed equally to this work burden worldwide. Several mechanisms are involved in the pathophysiology of HF. First, the renin-angiotensin-aldosterone system (RAAS) is over-activated, causing Specialty section: vasoconstriction, hypertension, elevated aldosterone levels and sympathetic tone, and This article was submitted to Heart Failure and Transplantation, eventually cardiac remodeling. Second, an endogenous compensatory mechanism, a section of the journal the natriuretic peptide (NP) system is also activated, albeit insufficiently to counteract Frontiers in Cardiovascular Medicine the RAAS effects. Since NPs are degraded by the enzyme neprilysin, it was Received: 06 August 2021 hypothesized that its inhibition could be an important therapeutic target in HF. Accepted: 06 October 2021 Published: 11 November 2021 Sacubitril/valsartan is the first of the class of dual neprilysin and angiotensin receptor Citation: inhibitors (ARNI). In patients with HFrEF, treatment with sacubitril/valsartan has Pascual-Figal D, Bayés-Genis A, demonstrated to significantly reduce mortality and the rates of hospitalization and Beltrán-Troncoso P, Caravaca-Pérez P, Conde-Martel A, rehospitalization for HF when compared to enalapril. This communication reviews in Crespo-Leiro MG, Delgado JF, Díez J, detail the demonstrated benefits of sacubitril/valsartan in the treatment of patients Formiga F and Manito N (2021) with HFrEF, including reduction of mortality and disease progression as well as Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in improvement in cardiac remodeling and quality of life. The hemodynamic and Heart Failure With Reduced Ejection organic effects arising from its dual mechanism of action, including the impact of Fraction. A Review. Front. Cardiovasc. Med. 8:754499. neprilysin inhibition at the renal level, especially relevant in patients with type 2 doi: 10.3389/fcvm.2021.754499 diabetes mellitus, are also reviewed. Finally, the evidence on the demonstrated safety Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF and tolerability profile of sacubitril/valsartan in the different subpopulations studied has been compiled. The review of this evidence, together with the recommendations of the latest clinical guidelines, position sacubitril/valsartan as a fundamental pillar in the treatment of patients with HFrEF. Keywords: heart failure, heart failure with reduced ejection fraction, sacubitril/valsartan, ARNI, neprilysin inhibition INTRODUCTION markers and reduces the risk of rehospitalization relative to enalapril (7, 8). Accordingly, the latest guideline updates Heart failure (HF) is a clinical syndrome characterized by from academic associations, such as the American College the presence of dyspnea or limited exertion due to impaired of Cardiology in January 2021 or the Canadian Society of cardiac ventricular filling and/or blood ejection (1). Because of Cardiology, recommend sacubitril/valsartan as the angiotensin its high prevalence, it is a major health and economic burden antagonist of choice in HF patients with HFrEF (9–11). In worldwide (2, 3). the recent HF Congress 2021 from the European Society of Within neurohormonal regulation, there are different Cardiology, a novel framework for treatment implementation mechanisms that contribute to and modulate the key pathways has been proposed, recommending the four “pharmacological that trigger HF: the autonomic nervous system, the renin- pillars” [sacubitril/valsartan, beta blockers, mineralocorticoid angiotensin-aldosterone system (RAAS) and the natriuretic receptor antagonists (MRA) and sodium-glucose co-transporter peptide (NP) system (4). In patients with HF, the RAAS is 2 inhibitors] for the treatment of HFrEF to be introduced over-activated, causing vasoconstriction, hypertension, elevated in parallel, early in the patient pathway (12, 13). In terms of aldosterone levels and sympathetic tone, and eventually cardiac pharmacoeconomic value, in most countries sacubitril/valsartan remodeling (4). However, an endogenous compensatory has shown to be a better cost-effective therapy for HFrEF than mechanism, the NP system is also activated, albeit insufficiently the comparator (14). to counteract the RAAS effects. Since NPs are degraded by the This article reviews in detail the demonstrated benefits enzyme neprilysin, it was hypothesized that its inhibition could of sacubitril/valsartan in the treatment of patients with be an important therapeutic target in HF (5). However, inhibition HFrEF, both in terms of mortality reduction and disease of neprilysin alone results in reflex activation of the RAAS, so progression, cardiac remodeling and quality of life (5, 7, 8). pharmacological development of neprilysin inhibition has The hemodynamic and organic effects arising from been carried out in combination with simultaneous inhibition its dual mechanism of action, including the impact of of the RAAS (5). neprilysin inhibition at the renal level, especially relevant Sacubitril/valsartan is the first of the class of dual neprilysin in patients with type 2 diabetes mellitus (T2DM), are also and angiotensin receptor inhibitors (ARNI) (6). Its efficacy reviewed (15). Finally, the evidence on the demonstrated in reducing the combined risk of death from cardiovascular safety and tolerability profile of sacubitril/valsartan in (CV) causes or hospitalization for HF was demonstrated the different subpopulations studied has been compiled in the PARADIGM-HF study [Prospective Comparison of (7, 8, 16–18). ARNI with Angiotensin-Converting Enzyme Inhibitors (ACEI) to Determine Impact on Global Mortality and Morbidity MORTALITY, SUDDEN DEATH, AND in HF], a randomized, double-blind study involving 8,442 outpatients with symptomatic HF [New York Heart Association VENTRICULAR ARRHYTHMIAS (NYHA) class II–IV] in patients with left ventricular ejection Reduced Mortality in HF Patients fraction (LVEF) ≤40% (5). Patients were randomized to The PARADIGM-HF study demonstrated a clear and early receive sacubitril/valsartan 200 mg/12 h or enalapril 10 benefit of sacubitril/valsartan compared to enalapril, with a mg/12 h, in addition to treatment considered optimal in 20% relative risk reduction in the combined primary endpoint systolic HF. The study was stopped prematurely after a mean of CV death and HF hospitalization (HR 0.80 95% CI 0.73– follow-up of 27 months, due to the overwhelming clinical 0.87 p < 0.001), as well as in the individual components of benefit of sacubitril/valsartan over enalapril found in the pre- the primary endpoint. These results contrast with those of specified interim analysis (5). More recently, the PIONEER-HF many pivotal studies of ACEI/angiotensin II receptor antagonists [Comparison of Sacubitril/Valsartan vs. Enalapril on Effect on N- (ARA II) (SOLVD-T, CHARM-Alternative, EMPHASIS-HF, terminal pro b-type natriuretic peptide (NT-proBNP) in Patients ATLAS, HEAAL) where the reduction is more pronounced Stabilized from an Acute HF Episode] and TRANSITION in HF hospitalizations than in CV death (19). In addition, [Comparison of Pre- and Post-discharge Initiation of ARNI reduced the risk of death from any cause by 16% Sacubitril/Valsartan Therapy in HF With Reduced Ejection [Hazard ratio (HR) 0.84 95% CI 0.76–0.93 p < 0.009] Fraction (HFrEF) Patients After an Acute Decompensation and improved quality of life. The benefits were consistent Event] trials demonstrated that early administration of across all pre-specified subgroups analyzed (5), including sacubitril/valsartan during hospitalization improves prognostic age groups (17). Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF Reduction of CV Mortality Due to Sudden and < 30 s) and an 80% reduction in appropriate ICD shocks (0.8 Death vs. 6.6% p < 0.002). Additionally, patients had fewer ventricular Following the initial publication of PARADIGM-HF, a specific premature beats, leading to an increase in the percentage of and very detailed analysis of the mode of death was conducted biventricular pacing (from 95% ± 6% to 99% ±1%, p < 0.02) in and adjudicated by a blinded independent committee (19). patients on cardiac resynchronization therapy (21). Causes of death were initially classified as CV, non-CV and Conversely, patients with ventricular arrhythmias had higher unknown. CV deaths were subclassified into sudden death, death NT-proBNP levels (p < 0.0001), and the reduction of arrhythmic due to myocardial infarction, worsening HF, stroke or other cause load correlated with the grade of NT-proBNP improvement of death. Sudden death was defined as unexpected death in a (21). Previous studies have shown that elevated NP levels are stable patient and was subclassified according to whether patients independent predictors of sustained ventricular arrhythmias were seen alive 1 h or between 1 and 24 h before death. Sudden and ICD shocks. Likewise, appropriate ICD shocks have been deaths in patients who were last seen alive >24 h before death associated with increased mortality, so ARNI would be beneficial were categorized separately as “apparent sudden deaths.” in both cases. Of the total 1,546 patients who died in the study, there were 1,251 deaths that were considered CV (80.9%), with a Mechanism of Action of ARNIs in Mortality 20% risk reduction observed in the ARNI vs. enalapril group Reduction (13.30 vs. 16.5%, respectively; HR 0.80 CI 9% 0.72–0.89 p < There are two main mechanisms that can lead to sudden 0.001). Most CV deaths were sudden death (44.8%) (also in death. The first is sustained ventricular tachycardia, that patients considered “stable” in NYHA class I and II) or HF- is typically presented in patients with mild HF symptoms related (26.5%). In both cases, a reduction in the risk of death and underlying ischemic etiology, which can be treated of 20 and 21%, respectively, was observed in the ARNI group vs. by ICD implantation. The second mechanism is an acute enalapril (HR 0.80 95% CI 0.68–0.94 p = 0.008 and HR 0.79 95% mechanical failure of the left ventricle (LV), which manifests CI 0.64–0.98 p = 0.034) (19). on the electrocardiogram as bradyarrhythmia, asystole or For sudden deaths (both resuscitated and non-resuscitated), electromechanical dissociation. Regardless of the mechanism, a 22% risk reduction was observed in patients in the ARNI a common underlying pathogenesis involves adverse left treatment arm compared to enalapril. The magnitude of this ventricular remodeling with interstitial fibrosis and myocardial effect did not differ in patients with or without an implantable distension, which promotes a pro-arrhythmic substrate and defibrillator (ICD). Notably, this incremental benefit in reducing may trigger cascade failure, ending in electrical storm or sudden death with ARNI over the active comparator enalapril mechanical collapse (22). was also observed in patients receiving optimal treatment with It has been reported that treatment with an ARNI can reduce beta-blockers (93%) and MRA (55%). Both drugs are known mortality beyond treatment with beta-blockers, ACEI and MRAs, to reduce all-cause mortality and sudden death (20), and mainly due to the beneficial effects of neprilysin inhibition in interestingly, in patients with an ICD, in whom the reduction reducing myocardial fibrosis and improving cardiac remodeling of sudden death with ARNI reached 50% (19). Additionally, this (wall stress, inflammation, hypertrophy and cell death), as well protective effect on sudden death had not been observed with as its anti-arrhythmic effect through sympathetic inhibition ACEIs or ARA II. Thus, the SOLVD study showed a reduction and the increase of enkephalins, endorphins and bradykinin in mortality from HF progression with enalapril vs. placebo, but (Figure 1) (23–25). not of sudden death (20). Thus, in patients with HFrEF, sacubitril/valsartan has shown vs. enalapril a further reduction in all-cause mortality, CV mortality (including sudden death) and HF hospitalization, as Effect on Ventricular Arrhythmias well as improving patient quality of life, irrespective of age The effect of ARNIs on ventricular arrhythmias was evaluated (5, 17, 19). In addition, switching from treatment with ramipril in a prospective, observational study in a cohort of 120 patients or valsartan to treatment with an ARNI has been shown to reduce with HFrEF and an ICD with remote monitoring capability episodes of both SVT and NSVT, as well as ventricular premature (21). Patients in the study were treated with an ARNI for 9 beats (21). The beneficial effects observed with ARNIs on months after having previously been on ramipril or valsartan for cardiac remodeling, as well as their anti-arrhythmic effect, would 9 months. All arrhythmic events during the 9 months before and stem from their primary mechanism of action by inhibiting 9 months after the switch to ARNI were analyzed: appropriate neprilysin (23, 24). shocks, non-sustained ventricular tachycardia (NSVT) and supraventricular tachycardia (SVT), ventricular extrasystolic load and percentage of biventricular pacing, where indicated. The CLINICAL PROGRESSION: patients, most of whom were in NYHA class II, experienced HOSPITALIZATION AND clinical improvement, reduced NT-proBNP levels, improved REHOSPITALIZATION left ventricular remodeling (increase in ejection fraction of ∼5 points), and a significant reduction in arrhythmic load after HF is a chronic and progressive disease, in which related switching to ARNI. Specifically, patients had fewer episodes of hospitalizations represent a symptomatic event that identifies SVT (≥ 30 beats or treated with the ICD) or NSVT (≥ 4 beats disease progression and impaired prognosis, with an increased Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 1 | Summary of mechanisms involved in reducing the sudden death rate demonstrated by sacubitril/valsartan. AT1R-, angiotensin type 1 receptor inhibition; NEP-, neprilysin inhibition. risk of death in both the short and long-term (26, 27). sacubitril/valsartan had lower rates of early readmission for After the first hospitalization for HF, patients enter in a HF, which was already significant in the early phase after vulnerable phase in which they are prone to readmissions. Having discharge: at 30 days (risk reduction of 38%, p = 0.006) and overcome this early vulnerable period, patients may enter in at 60 days (risk reduction 32%, p = 0.013) (32). Consequently, an apparent “stable” phase. However, after a variable amount sacubitril/valsartan – compared with enalapril – reduced the of time, patients will suffer recurrent episodes of worsening risk of recurrent hospitalizations for HF by 33% (p < 0.001), HF leading to readmissions that anticipate death. Indeed, the which was more prominent in the early vulnerable period higher the number of hospitalizations, the shorter the survival after discharge (33). time. Therefore, hospitalizations due to worsening HF are the main signal of disease progression and impaired prognosis. This lifetime course is well-observed in registries in different Prevention of Hospitalization in Acutely populations (27–29). Decompensated HF The PIONEER-HF study included patients hospitalized with HFrEF, who were randomized to sacubitril/valsartan or enalapril Prevention of Hospitalizations in Chronic soon after admission (median of 68 h). After discharge, fewer HFrEF patients treated with sacubitril/valsartan were readmitted for HF In the PARADIGM-HF trial, after a median follow-up of 27 at 8 weeks (8.0%) compared to enalapril (13.8%). This meant a months, patients in the sacubitril/valsartan group had 23% fewer risk reduction of 44% (p = 0.005) with a number necessary to hospitalizations for worsening HF (P < 0.001). This reduction treat of 13 to prevent 1 HF readmission at 8 weeks (7). This study was irrespective of baseline patient characteristics, including provided the first evidence about the tolerability and safety of prior HF hospitalization, and sacubitril/valsartan prevented both initiating sacubitril/valsartan in hospital. Indeed, there were no the first HF hospitalization and recurrent HF hospitalizations differences between sacubitril/valsartan and enalapril in terms (30). It is significant that such reduction in risk was observed of secondary side effects, including hypotension. Tolerability of shortly after initiating sacubitril/valsartan, and the reduction sacubitril/valsartan initiated in hospital has also been confirmed in HF hospitalization was evident within the first 30 days in the TRANSITION study. This trial compared pre-discharge after randomization (40% risk reduction, P = 0.027) (31). In and post-discharge initiation of sacubitril/valsartan, and no case of hospitalization for HF during the study, patients on differences were found in either the ability to attain target doses Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF of sacubitril/valsartan at 10 weeks or in the occurrence of side initiation and in the mid to long term (Figure 2). These effects (8). In fact, both trials included patients with de novo positive effects observed in clinical trials lead to the expert HF and those naïve for ACEI or ARA II for the first time; recommendation of initiating sacubitril/valsartan in patients populations not included in PARADIGM-HF. The observed hospitalized with HFrEF in order to prevent rehospitalizations clinical benefit for these populations was similar in PIONEER- and HF progression in this high-risk population (11). HF, and tolerability was similar or even better in terms of side effects and achieved doses. CARDIAC REMODELING AND NEPRILYSIN Considering the PIONEER-HF and TRANSITION studies together, an in-hospital initiation should be preferred to prevent INHIBITION readmissions in the early vulnerable period after discharge. Cardiac remodeling is intrinsically related to the progression of This recommendation is reinforced by the open-label extension HFrEF (38). It is secondary to the compensatory mechanisms of PIONEER-HF that showed that after both arms were on that are triggered by a myocardial injury or stress. Molecular, sacubitril/valsartan, the survival curves remained separate due genetic, cellular, and interstitial changes manifest as an increase to the significant reduction of rehospitalization risk in the early in volume, alteration of shape (from elliptical to spherical), and period after discharge. progressive dysfunction of the LV (38). Cardiac remodeling leads to an increase in CV morbidity and mortality: a 10% decrease in Relationship Between HF Hospitalization LVEF has been associated with a 73% increase in the risk of death from chronic HF (39). In contrast, patients with reverse cardiac and Disease Progression remodeling show a decrease in mortality: a 15% reduction in left Apart from the ability of sacubitril/valsartan to reduce the ventricular end systolic volume index has been associated with a risk of hospitalization for HF – the main feature of HF 68% reduction in mortality (40). progression – other findings also suggest an effect of the Because medical treatment effecting cardiac remodeling is ARNI in the severity of decompensations, the risk of outpatient key to preventing the progression of ventricular functional worsening HF and meaningful myocardial biomarkers. Indeed, impairment and in turn improving the prognosis of patients with fewer patients treated with sacubitril/valsartan experienced HFrEF (41), it should be initiated early. ACEI (42), angiotensin worsening HF episodes not requiring hospitalization, defined as receptor blocker II (ARB II) (43), and MRA (44) slow the intensification of medical treatment for HF (16% risk reduction, progression of damaging cardiac remodeling, whereas beta- P = 0.003) or an emergency department visit for worsening HF blockers (45), cardiac resynchronization therapy (46) and ARNI without hospitalization (34% risk reduction, P = 0.001) (31). (25) induce reverse cardiac remodeling, achieving a significant This protective effect is relevant because worsening HF in an decrease in ventricular volumes and an increase in LVEF. outpatient setting is associated with a worse prognosis, indicating HF progression (34). When hospitalization was required, patients receiving Effects of Sacubitril/Valsartan on the sacubitril/valsartan were less likely to require intensive care Pathophysiology of Myocardial (18% risk reduction, P = 0.005), to receive intravenous positive Remodeling inotropic agents (31% risk reduction, P < 0.001), and to need One of the key mechanisms of sacubitril/valsartan is increased implantation of a HF device or cardiac transplantation (22% risk bioavailability of circulatory and myocardial nitric oxide, which reduction, P = 0.07) (31). leads to an increase in cyclic guanosine monophosphate This protective effect is supported from a pathophysiological (cGMP) and the activation of the protein kinase G. The point of view, given that biomarkers reflecting myocardial stretch final effect is reduced systemic oxidative stress, apoptosis, and (NT-proBP) and necrosis [high-sensitivity Troponin T (hsTnT)] hypertrophy, accompanied by antiplatelet and antithrombotic were also reduced and related to the net clinical benefit (7, effects (47). Regarding protection in acute myocardial infarction, 35). Indeed, patients with an early phase of disease as well experimental studies have shown that sacubitril/valsartan offers as de novo HF patients seemed to obtain a greater benefit in superior benefits to valsartan in the short and long term. It terms of biomarkers, as suggested in a sub analysis from the significantly reduces the size of the infarction and the progression TRANSITION study (36). of post-acute myocardial infarction cardiac remodeling by Finally, as the main consequence of halting disease suppressing pro-inflammatory cytokines and the degradation progression, CV death (HR 0.80, 95% CI 0.72–0.89, P < of the extracellular matrix. This prevents LV dysfunction and 0.001), and specifically death due to worsening HF (HR reduces the associated symptoms of HF. 0.79, 95% CI 0.64–0.98, P = 0.034) were reduced in patients A systems biology analysis provided mechanistic data at the receiving sacubitril/valsartan compared to enalapril (19). molecular level on the synergistic activity of sacubitril/valsartan Nevertheless, this beneficial effect was not observed in patients in cardiac remodeling in HF and after acute myocardial with advanced HFrEF (37). infarction. This analysis showed effects on the reduction Therefore, the accumulated evidence supports of cell death, hypertrophy, contractile dysfunction, and sacubitril/valsartan compared to enalapril prevents HF extracellular matrix remodeling (Figure 3) (48). As previously progression based on its ability to reduce worsening HF, mentioned, extracellular matrix and fibrosis promote adverse hospitalizations and rehospitalizations, shortly after treatment ventricular remodeling and dysfunction, and trigger severe Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 2 | HF-related events prevented by the treatment with sacubitril/valsartan. HF, heart failure; WHF, worsening HF; HTX, heart transplantation. ventricular arrhythmias and sudden death in HF. A substudy of patients with chronic HFpEF previously optimally treated (100% PARADIGM-HF trials analyzed the effect of sacubitril/valsartan ACEI/ARB II, 95% beta-blockers, 82% MRA, 56% RCT). The on biomarkers of extracellular matrix homoeostasis and collagen mean increase in EF was greater than 5 points, along with synthesis and their relationship with clinical events. Increased significant reductions in LVESV and LVEDV and a reduction baseline profibrotic activity was observed in patients with HFrEF in the degree of mitral insufficiency (MI) and in the proportion and a greater reduction in CV death or hospitalization for HF, of patients with a restrictive filling pattern (52). Functional MI the greater the decrease in soluble tumorigenicity suppressor 2 is a direct consequence of cardiac remodeling due to worsening (sST2) or metallopeptidase inhibitor 1 (TIMP-1) compared to ventricular geometry. Additionally, it facilitates the progression baseline levels (49). Sacubitril/valsartan significantly reduced of cardiac remodeling, inducing worse clinical evolution and levels of aldosterone, soluble tumorigenicity suppressor, matrix prognosis. The PRIME study in patients with symptomatic metallopeptidase 9 (MMP-9), TIMP-1, and procollagen type HF and functional MI also showed a significant reduction 1 amino-terminal propeptide (P1NP) (Figure 3) at 8 months’ in MI and ventricular volumes without significant changes treatment compared to enalapril. To date, the only other in blood pressure at 12 months, in this case compared to treatment that has been shown to decrease any profibrotic valsartan (53). biomarker are MRAs (N-terminal propeptide of procollagen The open study PROVE-HF (54) included patients with de type III). Finally, a pre-specified secondary analysis of the novo HF, who had not been previously treated with ACEI/ARB PROVE-HF study showed that the initiation of treatment with II, with low levels of NT-proBNP, and with submaximal doses of sacubitril/valsartan produced a rapid (before 14 days) and sacubitril/valsartan, at a mean of 50 months (more than 4 years) significant increase in atrial natriuretic peptide (ANP) correlated from the diagnosis of HF. The mean baseline concentration of with a subsequent increase in urinary cGMP (50). NT-proBNP was 816 pg/ml and presented a rapid, early (mostly during the first 14 days) and sustained reduction, reaching 455 Effects of Sacubitril-Valsartan on Cardiac pg/ml at 12 months (25). The most relevant finding was a mean Geometry and Function increase of 9.4 points in LVEF at 12 months, from 28.2 to 37.8%, The earliest effect in chronic patients was recorded in the with 25% of patients presenting an increase ≥13.4 points. In the EVALUATE-HF study: a significant reduction in left ventricular subgroup of naïve or de novo patients, the mean increase was end systolic and end diastolic volumes (LVESV and LVEDV) of 12.8 points. Based on these findings, the recent American Heart the left atrial volume index (LAVI) and E/e’ ratio compared with Association/American College of Cardiology expert consensus enalapril was observed at 12 weeks (51). Another prospective recommends deferring the decision to implant an ICD in patients study carried out with a blind echocardiographic analysis in whom reverse remodeling is expected to continue to progress showed improvement in systolic and diastolic function after 4 beyond the usual 3 months (9). All other echocardiographic months of substituting ACEI/ARB II for sacubitril/valsartan in parameters (indexed LVESV and LVEDV, LAVI, E/e’ ratio, and Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 3 | Summary of mechanisms of sacubitril/valsartan enhancement of ventricular remodeling. AO, aorta; LA, left atrium; LV, left ventricle; MI, mitral insufficiency; cGMP, cyclic guanosine monophosphate; NO, nitric oxide; sST2, soluble suppression of tumorigenesis-2; Nt-proBNP, N-terminal pro-brain natriuretic peptide; SBP, systolic blood pressure; AMI, acute myocardial infarction; MMP-9, matrix metallopeptidase 9; TIMP-1, tissue inhibitor of metalloproteinase-1; PINP, aminoterminal propeptide of type I collagen. LV mass index) also progressively and significantly improved sacubitril/valsartan over ACEI since the rate of the composite (25). The speed and magnitude of the increase in ANP was primary endpoint was 10% lower (59). seen to be associated with a greater increase in LVEF and a In any case, an improvement in cardiac remodeling should not decrease in the LAVI Furthermore, the speed and magnitude of result in a dose reduction or termination of medical treatment, the reduction in NT-proBNP and the indexed LVESV showed an since it has been seen that the suspension of medical treatment impact on clinical prognosis: the probability of hospitalization leads to the reappearance of cardiac remodeling and HF (60). for HF or death was significantly higher in patients in whom In conclusion, cardiac remodeling is one of the determining these parameters did not fall below the mean at 3 and 6 months, pathophysiological mechanisms in the progression of HF respectively, compared to those that did (odds ratio = 2.03; CI and is intrinsically related to a HF prognosis (38). The 95%, 1.25–3.30; p < 0.001) (55). precocity and magnitude of reverse cardiac remodeling The effect on reverse cardiac remodeling when is related to reduced clinical events: hospitalization sacubitril/valsartan was used to treat hospitalized patients for HF and CV death (40). Because of its antifibrotic, compared to ACEI/ARB II was even more striking: there was a antihypertrophic, and antiapoptotic effect, sacubitril/valsartan mean increase in LVEF of 7.5 points at 3 months’ follow-up, an induces early, significant and clinically meaningful reverse improvement of 42% in Global Longitudinal Strain compared cardiac remodeling that is not seen in treatment with with 1% in ACEI/ARB II and a significant reduction in LVESV ACEI/ARB II – even in patients with several years of HF and LAVI (56). development (25, 55). Finally, significant changes were also found in the remodeling of the right ventricle 12 months after substituting ACEI/ARB II for sacubitril/valsartan (57). All this points to the effect of HEMODYNAMIC EFFECTS OF NEPRILYSIN reverse cardiac remodeling of sacubitril/valsartan in patients with INHIBITION HFrEF. In the PARADISE-MI study (58), sacubitril/valsartan did not significantly reduce the rate of MACE compared with The hemodynamic effects of neprilysin inhibition were ramipril following acute myocardial infarction, but there were first studied with candoxatrilate, an inhibitor that increases consistent findings that support incremental clinical benefits of endogenous levels of ANP. First studies showed that Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF administration of this peptide increased natriuresis and (64). The use of sacubitril/valsartan has also been associated inhibited the sympathetic nervous system, with transient with a beneficial effect on reverse remodeling in patients with reductions in plasma vasopressin, aldosterone levels, and plasma HFrEF, improving ejection fraction, left ventricular diameter and renin activity, improving the hemodynamic profile of patients volume compared to treatment with ACEI or ARA II in a meta- with HFrEF (61). Acute exposure to a dose of candoxatrilate in analysis (65) and more recently in the PROVE-HF with evident patients with severe HF resulted in reduced ventricular filling improvement after 12 months of treatment (25). pressures: decreased pulmonary capillary pressure, right atrial The potent systemic vasodilator effects produced by dual pressure and pulmonary pressures, and slightly increased cardiac inhibition with sacubitril/valsartan in patients with arterial output (61). These hemodynamic effects were mainly explained hypertension result in a marked reduction in blood pressure, by the greater reduction in preload vs. afterload, as there were with a preferential effect on systolic blood pressure (SBP) no significant changes in systemic vascular resistances (61). This compared to diastolic blood pressure, providing an additional neutral effect on systemic vascular resistance could be due to improvement in pulse pressure reduction. In addition, it shows the non-selective nature of neprilysin, which also inhibits the a good safety profile, making it a promising molecule to treat degradation of vasoconstrictor molecules such as angiotensin II, arterial hypertension (66). endothelin 1 and noradrenaline, with a consequent increase in In the presence of HFrEF, low SBP levels are associated their circulating levels that counteract the vasodilatory effects of with poor prognosis. In addition, patients with a low SBP NPs (62). These observations suggested that the combination number represent a high-risk group for adverse events, of neprilysin inhibition with RAAS inhibition could enhance so these patients often do not receive disease-modifying the beneficial effects of both molecules and avoid deleterious drugs (16). In a sub-analysis of the PARADIGM-HF study effects (4) (Figure 4). on the effect of sacubitril/valsartan on SBP (16), a more Omapatrilat was the first dual inhibitor of neprilysin and beneficial effect was observed with sacubitril/valsartan vs. angiotensin-converting enzyme (ACE). Its hemodynamic enalapril, which was cross-sectional across the different effects were investigated in a randomized, double-blind, prespecified SBP categories. It is important to note that placebo-controlled study in 369 patients with HFrEF in the effect on blood pressure was significantly lower in functional class II-IV (63). After the first dose, pulmonary patients with the lowest SBP < 110 mm Hg), while the capillary pressure and systemic vascular resistances were beneficial effect was more defined in these same patients significantly reduced, an effect that was maintained at 12 with lower SBP. While 25.5% of patients with SBP < 110 weeks of treatment. These acute vasodilatory effects were mmHg treated with sacubitril/valsartan experienced an accompanied by an increase in circulating levels of NPs such episode of hypotension (vs. 13.7% with enalapril), only as ANP, b-type natriuretic peptide (BNP) or adrenomedullin. 1.3% discontinued sacubitril/valsartan compared to 1% who Increased plasma levels of potentially deleterious hormones discontinued enalapril. In the overall SBP categories for the such as endothelin-1 and noradrenaline, possibly due to two treatments, ≤1% of patients discontinued the study (16). sympathetic release reflecting the reduction in blood pressure, Thus, the sacubitril/valsartan combination has been shown to were observed initially, but normalized with chronic use. improve prognosis, including patients with persistent low SBP Despite these favorable effects on ventricular preload and compared to enalapril, reducing mortality and morbidity in afterload, no significant acute or chronic changes on cardiac these patients (16). index were observed. The development of omapatrilat was These data suggest that, in patients with HFrEF, the discontinued due to safety concerns regarding an increased risk presence of hypotension not accompanied by evidence of of angioedema (63). poor perfusion (cerebral, renal or peripheral) does not Sacubitril/valsartan is the first of the ARNI class, in which represent a reason not to initiate treatment with drugs neprilysin inhibition is coupled with blockade of the angiotensin that may modify the prognosis of the disease, such as AT1 receptor. As previously discussed, its efficacy in reducing the sacubitril/valsartan. The lower limit of SBP for treatment combined risk of death from CV causes or hospitalization for HF with this combination established in the product datasheet is in patients with HFrEF was demonstrated in the PARADIGM- 100 mmHg, although in the PARADIGM-HF study it was 95 HF study, which was prematurely stopped because it exceeded mmHg, and in clinical practice it is used at even lower SBP in the threshold of a clearly significant benefit (5). selected patients (16). At the hemodynamic level, sacubitril/valsartan treatment In conclusion, sacubitril/valsartan treatment exerts beneficial causes vasodilation, reduction of blood volume and increases hemodynamic effects, including vasodilatation and blood volume renal sodium and water excretion by reducing aldosterone reduction, with increased renal sodium and water excretion production (4). The hemodynamic impact of sacubitril/valsartan (4). It also has a beneficial effect on cardiac remodeling, use was further evaluated in a prospective study by implanting improving ventricular preload and afterload (65). Its use leads a monitoring device in patients with HFrEF, which showed a to a reduction in blood pressure, preferentially SBP and a significant reduction in pulmonary diastolic pressure, a surrogate greater reduction the lower the initial SBP and has been marker of pulmonary capillary pressure, even at low doses of the shown to improve prognosis in all SBP groups, including drug, which did not change significantly with increasing dose patients with persistently low SBP, compared to enalapril (16). Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 4 | Summary of the hemodynamic effects of neprilysin/RAAS inhibition. SNS, sympathetic nervous system; NPs, natriuretic peptides; RAAS, renin-angiotensin-aldosterone system; PCP, pulmonary capillary pressure; DAP, diastolic arterial pressure; mPAP, mean pulmonary arterial pressure; CO, cardiac output; SVR, systemic vascular resistance. Therefore, low SBP levels should not be an obstacle to initiating will focus on NPs (indicative of myocardial stretch), cardiac sacubitril/valsartan treatment. troponins (reflective of myocyte injury), and circulating ST2 (a multidimensional biomarker surrogate of stretch, inflammation, and extracellular matrix remodeling that some investigators BIOMARKERS: NPS, TROPONINS, AND call the 3-in-1 biomarker) These three biomarkers are already ST2 incorporated into the American Heart Association/American College of Cardiology guidelines for HF: NPs and troponins with HF Biomarkers IA indication, and ST2 with IIb indication (69). HF biomarkers can be classified as prognostic, pharmacodynamic, or predictive; a single biomarker can be valuable in all three conditions. A prognostic biomarker provides NT-ProBNP information on the likely course of HF in an untreated individual As expected, the biomarker substudy of PARADIGM-HF or in an individual treated with conventional therapies. A revealed neprilysin inhibition with sacubitril/valsartan increased predictive biomarker is one that can be used to identify levels of both urinary cGMP and plasma BNP. In contrast, in individuals who are most likely to respond to a given therapy comparison with enalapril, patients receiving sacubitril/valsartan (e.g., sacubitril/valsartan). Lastly, pharmacodynamic biomarkers had consistently lower levels of NT-proBNP (reflecting reduced measure the effect of a drug on the disease state itself (67). cardiac wall stress) throughout the trial (31). The contrasting For example, changes in circulating NT-proBNP levels are effects of sacubitril/valsartan on the two types of NPs are a key reflective of HF severity, and therefore blood NT-proBNP levels finding, because the levels of the two peptides characteristically have been proposed as a surrogate endpoint to test the efficacy parallel each other during the course of HF. However, because of sacubitril/valsartan. BNP (but not NT-proBNP) is a substrate for neprilysin, levels of Several HF biomarkers have been proposed according to the BNP reflect the action of the drug, whereas levels of NT-proBNP pathologic process they indicate (68). In the current review, we will reflect the cardioprotective effect of the drug. Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF Zile et al. reported that 1 month after randomization, 24% and patients hospitalized with decompensated HF (PIONEER- of the baseline NT-proBNP levels >1,000 pg/ml had fallen HF trial). It should be highlighted that even very low levels to ≤1,000 pg/ml. Risk of the primary endpoint was 59% of troponin release reflect ongoing myocardial injury (possibly lower in patients with a decrease of NT-proBNP to ≤1,000 related to increased wall stress), and even small increases in the pg/ml than in those without such a reduction. One month levels of troponin reflect a higher risk of HF progression (31). after randomization, median NT-proBNP was significantly lower Therefore, sacubitril/valsartan initiation prevented myocardial in sacubitril/valsartan-treated patients than in enalapril-treated injury (as reflected by troponin release) and consequently patients and fell to ≤1,000 pg/ml in 31% of patients treated with HF progression. sacubitril/valsartan vs. 17% of enalapril-treated patients. Similar results were seen when the partition value was set at a reduction ST2 in NT-proBNP ≤750 and ≤500 pg/ml; sacubitril/valsartan was ST2 is a receptor from the interleukin-1 family with two gene nearly twice as likely as enalapril to cause a meaningful reduction forms – soluble (sST2) and transmembrane (ST2L). Like other in NT-proBNP (35). biomarkers, blood ST2 levels can predict mortality and new onset In the PIONEER-HF trial, the NT-proBNP was used as a HF (72, 73). Soluble ST2 is associated with cardiac remodeling candidate pharmacodynamic biomarker of neprilysin inhibition- and fibrosis. based therapy monitoring. The primary efficacy outcome In PARADIGM-HF, O’Meara et al. compared ST2 levels was the time-averaged proportional change in NT-proBNP between treatment groups (sacubitril/valsartan vs. enalapril) concentration from baseline through weeks one, four, and eight. at baseline and at 1 and 8 months post-randomization. The investigators found that among patients with HF with Sacubitril/valsartan reduced ST2 levels at both one and eight HFrEF who were hospitalized for acute decompensated HF, the months, whereas enalapril did not. This finding held when initiation of sacubitril/valsartan therapy led to a greater reduction ST2 was evaluated as a continuous variable, as well as in the NT-proBNP concentration than enalapril therapy (-46.7 when it was evaluated as the percentage of patients above vs.−25.3%, respectively), which was significant at 1 week after or below the FDA threshold of 35 ng/ml (or any other randomization (7). Further insight on the rapid NT-proBNP threshold evaluated). Changes in ST2 level from baseline response to sacubitril/valsartan has been recently provided by a to 1 month were associated with the subsequent risk of post-hoc analysis of the TRANSITION study, which showed a major outcomes, even when corrected for baseline ST2 statistically significant decline of NT-proBNP levels just within concentration, clinical covariates, NT-proBNP, hsTnT, and a few days after in-hospital initiation of sacubitril/valsartan randomized treatment (74). compared to those who initiated optimized standard of care Zile et al. extended these data to incorporate additional therapy (28 vs. 4% decrease) (70). We must point out two extracellular matrix regulation biomarkers. The authors issues regarding the effect of sacubitril/valsartan on NT-proBNP observed that at baseline, the profibrotic biomarkers concentrations: the precocity, few days in the TRANSITION aldosterone, ST2, tissue TIMP-1, galectin 3, PINP and N- post-hoc analysis, 1 week in PIONEER-HF and 4 weeks in terminal propeptide of procollagen type III were higher, PARADIGM, reflecting a rapid decrease of myocardial wall stress; and biomarkers associated with collagen degradation and the close association with a lower risk of adverse clinical such as MMP-2 and MMP-9, were lower than published events, reflecting the meaningful relationship between cardiac reference control values. Eight months after randomization, protection and clinical evolution. aldosterone, ST2, TIMP-1, MMP-9, PINP, and N-terminal Similarly, NT-proBNP was used as the surrogate endpoint in propeptide of procollagen type III had decreased more in the PARAMOUNT (Prospective comparison of ARNI with ARA the sacubitril/valsartan group than in the enalapril group. II on Management of HF with preserved ejection fraction) trial Changes from baseline to 8 months in ST2 and TIMP-1 were in patients with HF and preserved ejection fraction, in which associated with changes in outcomes. These data suggest that a sacubitril/valsartan reduced NT-proBNP to a greater extent than mechanism by which sacubitril/valsartan may exert a beneficial valsartan at 12 weeks and was well-tolerated (71). outcome in HFrEF patients may be related to a reduction in profibrotic signaling (49). HsTnT In summary, biomarker studies using PARADIGM-HF data Cardiomyocyte necrosis releases Troponin I or Troponin T showed that treatment with sacubitril/valsartan decreased those (cardiac isomers of proteins from the troponin-tropomyosin meaningful biomarkers in patients with HFrEF: NT-proBNP, complex) into the circulation, where they are typically useful in hsTnT, and ST2 (Figure 5). Remarkably, the recently developed the detection of myocardial ischemia. However, both troponins Barcelona Bio-HF risk calculator incorporates these three are also elevated in the blood of patients with HF, and therefore biomarkers in addition to clinical variables, comorbidities, have been appropriately studied regarding their ability to predict and treatments (drugs and devices). The 2.0 version of the HF and their utility in determining prognosis in patients with Barcelona Bio-HF risk calculator (bcnbiohfcalculator.org) is established HF. externally validated with the PARADIGM-HF cohort (75) and Patients receiving sacubitril/valsartan had significantly lower may be a valuable addition for doctors to incorporate these levels of hsTnT (reflecting reduced cardiac injury) compared to biomarkers into their daily clinical practice for the stratification enalapril, in both ambulatory patients (PARADIGM-HF trial) of patient risk. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF HF represents a state of reduced effectiveness of the renal (and extrarenal) NP system with potential implications for therapy with neprilysin inhibition (78). A meta-analysis using data from three HFrEF trials that compared combined neprilysin/RAAS inhibition with RAAS inhibition alone (IMPRESS [omapatrilat vs. lisinopril], OVERTURE [omapatrilat vs. enalapril], and PARADIGM-HF [sacubitril/valsartan vs. enalapril]) showed that combined neprilysin/RAAS inhibition was associated with a reduced incidence of renal dysfunction or elevation in serum creatinine, and less pronounced decline of glomerular filtration rate (GFR) (79). Although blood pressure dropped more in the neprilysin/RAAS inhibition groups in these studies than in the RAAS inhibition groups, GFR was better preserved. In the PARADIGM-HF trial, the decrease in eGFR during follow-up was lower with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m2 /year vs.−2.04 ml/min/1.73 m2 /year; p < 0.001). A greater increase in urinary albumin/creatinine ratio was observed, but in a range FIGURE 5 | Effect of the treatment with sacubitril/valsartan on HF biomarkers. not clinically meaningful (1.20 mg/mmol vs. 0.90 mg/mmol; p Nt-proBNP, N-terminal pro b-type natriuretic peptide; sST2, soluble < 0.001) (80). The benefit of sacubitril/valsartan on CV death tumorigenicity suppressor 2; hs-TnT, high-sensitivity troponin T; TIMP-1, or HF hospitalization was not modified by renal parameters metallopeptidase inhibitor 1; MMP-9, matrix metallopeptidase 9; PINP, and, compared to enalapril, sacubitril/valsartan led to a slower aminoterminal propeptide of type I collagen; PIIINP, N-terminal propeptide of rate of decrease in the eGFR and improved CV outcomes, even procollagen type III. in patients with chronic kidney disease (CKD). Of interest, in the PARADIGM-HF trial, levels of urinary cGMP were RENAL IMPACT OF NEPRILYSIN higher during treatment with sacubitril/valsartan than with enalapril (31). Furthermore, the incremental renal benefit INHIBITION of sacubitril/valsartan in patients with T2DM from the Mechanistic Effects of the Renal Impact of PARADIGM-HF trial, which was twice as large as in those Neprilysin Inhibition without T2DM, is not solely explained by the benefit on the The increased renal bioavailability of NPs secondary to neprilysin clinical course of HF and other not well-known mechanisms inhibition results in a number of effects: (1) (i) direct inhibition (18). This benefit is really relevant, given that patients without of sodium reabsorption in the inner medullary collecting duct; diabetes who have chronic HF experienced a decline in eGFR (ii) inhibition of angiotensin II stimulated sodium reabsorption that was twice as rapid as the general population, and the in the proximal tubule; (iii) direct vasodilatation of the afferent coexistence of diabetes further doubled the rate of deterioration arteriole; (iv) reversal of norepinephrine mediated afferent in eGFR (18). vasoconstriction; (v) attenuation of angiotensin II induced A potential interpretation of the major renal effects of vasoconstriction of the efferent arteriole; (vi) increase of the combined neprilysin/RAAS inhibition in stable HF can be the glomerular capillary ultrafiltration coefficient secondary to both following (81). Enhanced renal bioavailability of NP (as assessed relaxation of the contractile intraglomerular mesangial cells that by the increase in urinary cGMP) in addition to further reducing increases the filtration surface and enhancement of endothelial systemic blood pressure and renal perfusion pressure induces permeability and capillary hydraulic conductivity; (vii) direct a preferential vasorelaxation of the afferent arteriole and a inhibition of renin release from juxtaglomerular (granular) cells; relative vasoconstriction of the efferent arteriole. The consequent and (viii) inhibition of the V2 receptor mediated action of decrease in pre-glomerular resistances and increase in post- vasopressin in the collecting ducts (76). Other consequences of glomerular resistances contribute to increasing intracapillary increased renal bioavailability of NPs secondary to neprilysin hydraulic pressure despite decreased renal perfusion pressure, inhibition include reduction in renal damage (e.g., inflammation which in turn increases filtration fraction and preserves GFR in and cell death) and attenuation of renal remodeling (e.g., a reduced blood pressure setting. The increased intracapillary glomerulosclerosis and tubulointerstitial fibrosis) that develop in hydraulic pressure possibly combined with a direct effect of NP conditions of kidney injury (77). on the glomerular barrier may increase albumin ultrafiltration with consequent albuminuria. Additionally, the maintenance of GFR and the inhibition of tubular reabsorption by NP facilitate Clinical Consequences of the Renal Impact natriuresis and diuresis. of the Neprilysin Inhibition Heart Failure Chronic Kidney Disease Findings from several clinical studies support that, despite The UK HARP-III trial compared the effects of dramatic increases in circulating NP concentrations, chronic sacubitril/valsartan and irbesartan on renal function and Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF other outcomes among patients with CKD (82). Over 12 0.0023) (15). This greater reduction with sacubitril/valsartan months, sacubitril/valsartan had similar effects on GFR and treatment was maintained at the 3-year follow-up (p = 0.0055). albuminuria to irbesartan, but it had the additional effect of Also, 29% fewer patients in the sacubitril/valsartan group needed lowering blood pressure and cardiac biomarkers (troponin I to start insulin (7 vs. 10%, p = 0.0052) or oral antidiabetic and NT-proBNP). Allocation to sacubitril/valsartan produced treatment (p = 0.073) (15). a non-significant 9% reduction in study-average albuminuria. The PARADIGM-HF data have also made it possible to assess Although the renal effects were not encouraging, the effects on the effect of neprilysin inhibition on the course of kidney disease blood pressure and cardiac biomarkers supported the hypothesis in patients with T2DM (18). A sub-study showed that even in that sacubitril/valsartan might reduce the risk of CV events (and patients already receiving high doses of RAAS-blocking drugs, in particular those related to HF) among patients with CKD, additional neprilysin inhibition slows the decline in estimated irrespective of established CV disease. The safety outcomes GFR (follow-up of up to 44 months), especially in patients with in the UK HARP-III trial also support further investigation diabetes (0.6 mL/min per 1.73 m² yr vs. 0.3 mL/min per 1.73 m² of this hypothesis. More recently, a multicenter observational yr; p = 0.038). This more marked effect in patients with diabetes study evaluating the effects of the concomitant administration could not be explained by glycaemic control and occurred of sacubitril/valsartan and an sodium-glucose co-transporter despite a modest increase in proteinuria in patients treated 2 inhibitor on the renal function in patients with T2D and with sacubitril/valsartan (18). The clinical benefits described HFrEF, demonstrated a similar renal safety profile at mid-term would be justified by the role of neprilysin inhibition in glucose as reported with both drugs given separately, without any homeostasis (89–91), increasing plasma levels of various peptides significant or clinical relevant changes in eGFR (83). such as GLP-1 (neprisilin inactivates up to 50% of GLP-1 released In summary, neprilysin/RAAS inhibition and the associated into circulation), NP, cGMP and bradykinin, which can improve increase in NP availability determines a plethora of renal benefits insulin sensitivity (Figure 7). Additionally, NPs promote lipid in terms of functional adaptations and structural remodeling mobilization from adipose tissue, increase postprandial lipid (Figure 6). These effects would explain the lower decline of renal oxidation, promote adiponectin release and increase muscle function observed in patients with HF and represent a promising oxidative capacity (91). Increased urinary cGMP concentrations, approach in chronic renal insufficiency. especially low in diabetic patients, have also been linked to the renal benefits of NPs (18). In another study of 73 HF patients, 16 of whom had diabetes, METABOLIC EFFECTS: T2DM AND URIC switching from an ACEI or ARA II to an ARNI for 3 months ACID resulted in a decrease in plasma neprilysin activity. This was associated with a reduction in fructosamine levels, a marker of HF and T2DM protein glycation in diabetic and non-diabetic patients, indicating HF and T2DM share risk factors and pathophysiological rapid action on glycaemic control with the use of ARNI (90). mechanisms that favor coexistence (84–86). It has been However, in monotherapy, neprisilin inhibitors increase levels documented that patients with HF have a four times higher of angiotensin II and enzymes such as dipeptidyl peptidase-4, prevalence of T2DM than patients without HF, with the resulting in reduced efficacy of inhibition, or concomitant proportion being even higher in patients hospitalized for HF elevation of other neprisilin substrates (adrenomedullin, (86). In fact, the severity of HF, as defined by the daily dose of endothelin1, glucagon, etc.) which may promote insulin loop diuretics, has been directly related to the risk of developing resistance and pancreatic beta-cell dysfunction (91). For this T2DM (87), which leads to a worse prognosis, both in terms reason, it is preferable to administer neprisilin inhibitors in dual of mortality and readmissions (84–86). Moreover, the risk of therapy as ARNIs (91). developing HF is 2.5 times higher in patients with T2DM, and Recently, the DAPA-HF study has shown that dapagliflozin hospitalization for HF is higher in diabetic patients compared to administration in patients with HFrEF, with or without DM2, non-diabetic patients (86). results in a significant reduction vs. placebo in the risk of Moreover, the risk of developing HF is 2.5 times higher in worsening HF or CV death, which remains constant in patients patients with T2DM, and hospitalization for HF is higher in who received sacubitril/valsartan treatment (92). Similarly, diabetic patients compared to non-diabetic patients. Similarly, the EMPEROR-Reduced study has shown that empagliflozin in clinical trials, all HF drugs and devices were equally effective significantly reduces the primary composite endpoint of HF regardless of the presence or absence of T2DM (86). Interestingly, hospitalization rate and CV death vs. placebo, with no difference it was noted that dual inhibition of the RAAS and neprilysin may compared to the sacubitril/valsartan treatment group (93). These lead to better glycemic control (15, 88). results suggest that the two drugs have different and potentially This is suggested by the results of a post-hoc analysis synergistic biological effects. of the PARADIGM-HF study, which included 3,778 patients with HFrEF and known diabetes (98% T2DM) or an HbA1c HF and Uric Acid ≥6.5%, who were randomized to receive either enalapril or Uric acid is a marker of oxidative stress that induces sacubitril/valsartan. At a 1-year follow-up, a greater reduction in inflammation, impairs endothelial function, and activates the HbA1c concentrations was observed in the sacubitril/valsartan RAAS, which may be associated with myocardial damage and group compared to the enalapril group (0.26 vs. 0.16%, p = worse outcome in HF patients (94–96). Renal insufficiency and Frontiers in Cardiovascular Medicine | www.frontiersin.org 12 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 6 | Neprilysin/RAAS inhibition provides several renal benefits both in terms of functional adaptations and structural remodeling. RAAS, renin-angiotensin-aldosterone system; GFR, glomerular filtration rate; VP, vasopressin. the use of diuretics also increase the concentration of uric acid has been shown to reduce UA levels and the improved CV due to alterations in its excretion (94). In PARADIGM-HF, UA outcomes demonstrated in the PARADIGM-HF study compared was an independent predictor of worse outcomes. Compared to enalapril occurred independently from UA levels (96). with enalapril, sacubitril/valsartan reduced UA by 0.24 mg/dL and improved clinical outcomes irrespective of UA levels (96). QUALITY OF LIFE AND FUNCTIONAL In conclusion, the use of ARNI in HF patients has shown CAPACITY a better metabolic profile than enalapril treatment. In a sub- analysis of the PARADIGM-HF study with patients with HFrEF Quality of Life and T2DM, treatment with sacubitril/valsartan resulted in lower HF patients have a severely impaired health-related quality HbA1C concentrations and reduced need for both insulin of life (HRQOL). As the VIDA-IC (97) study demonstrated, and oral antidiabetic drugs compared to the group treated patients with HF and systolic dysfunction suffer from a higher with enalapril (15). Similarly, sacubitril/valsartan treatment limitation of mobility and a higher incidence of symptoms Frontiers in Cardiovascular Medicine | www.frontiersin.org 13 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 7 | The role of neprilysin inhibition in glucose homeostasis. GLP-1, glucagon-like peptide 1; GIP, glucose-dependent insulinotropic peptide; PYY, peptide YY; CCK, cholecystokinin; VIP, vasoactive intestinal polypeptide. Adapted from Esser and Zraika (91). such as pain/discomfort and anxiety/depression compared to with sacubitril/valsartan would be equivalent to a difference of other chronic diseases perceived as very disabling, e.g., cancer ∼9 years of aging compared to those treated with enalapril. In and Alzheimer’s disease. Therefore, understanding the impact of turn, a sub-analysis showed that non-fatal events worsen HRQOL therapeutic interventions beyond mortality or hospitalizations is (100), therefore preventing these events with sacubitril/valsartan a priority, especially from the patient’s perspective. would prevent the associated deterioration in HRQOL. In the PARADIGM-HF study, sacubitril/valsartan was shown In summary, we can state that improving HRQOL is a target to improve quality of life over enalapril from month 4 of increasing interest when evaluating new therapies in HF. post-randomization using the Kansas City Cardiomyopathy So far, the first-line drugs that have been shown to improve Questionnaire. This difference was sustained over 36 months of disease prognosis have had mixed results with respect to HRQOL, follow-up (98). This improvement was consistent across the 8 starting with beta-blockers, which do not improve HRQOL, domains explored. An important aspect was the buffering effect to the mixed results seen with ACEIs or ARA II. However, of sacubitril/valsartan on the decline in quality of life associated sacubitril/valsartan has been shown to improve quality of life with HF hospitalization compared to enalapril (98). in HF patients consistently over enalapril, especially in terms of Since physical and social activities are typically the most physical activity and social relationships. limited in HF patients, a specific secondary analysis was performed on the effect of sacubitril/valsartan relative to enalapril Functional Capacity on these aspects of quality of life. Patients on sacubitril/valsartan Quality of life is strongly associated with intolerance to physical had better adjusted scores on most physical and social activities exertion, a pivotal symptom of HF. The assessment of functional at 8 months compared to those on enalapril. These scores capacity in healthcare practice is routinely performed using the were sustained at 36 months (99). The greatest comparative NYHA functional classification, and significant improvements in improvements were found in domestic activities and sexual NYHA functional class were reported in PARADIGM-HF (5). relations (Figure 8). Overall, the improvement in patients treated Nevertheless, it has limitations due to its subjectivity and lack of Frontiers in Cardiovascular Medicine | www.frontiersin.org 14 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF FIGURE 8 | Effect of sacubitril/valsartan relative to enalapril on different components of quality of life99 . KCCQ, Kansas City cardiomyopathy questionnaire; MTS, meters; 6minWT, 6-minute walk test; VO2, Oxygen uptake. reproducibility compared to objective assessments using the 6- the year prior to starting sacubitril/valsartan (107). In turn, miwalk test (6MWT) (101) or the cardiopulmonary exercise test a significant reduction in depressive symptomatology related (102), the latter is considered to be the reference standard. to improvements in the 6MWT was observed independently The 6MWT is a simple and inexpensive tool that helps of other variables (age, sex, antidepressant treatment, VO2 predict morbidity and mortality. In the BIOSTAT-CHF study, maximum, NT-proBNP, systolic pulmonary artery pressure, walking 240 m or less at the baseline assessment was shown NYHA class) (107). The relationship between depression, a to be more predictive of mortality than age (>75 years), common problem in patients with CV disease, and increased diabetes, chronic renal failure or previous stroke. Conversely, mortality, excess disability, increased health expenditure, and for every 50 m “lost” at 9 months, the risk of mortality and reduced quality of life has been previously described (108). hospitalizations increased by 8% and the risk of mortality by 14%. In conclusion, there is sufficient evidence that Functional capacity gains of 30–50 m at 6MWT are considered sacubitril/valsartan has a positive and clinically significant clinically meaningful as they are associated with significant impact on quality of life and functional capacity. These measures improvements in NYHA functional class and HRQOL. Regarding are highly relevant from the patient perspective and may cardiopulmonary ergometry, a 6% increase in peak VO2 is also improve adherence to this life-saving therapy. It should associated with an 8% reduction in CV mortality or HF be a priority in clinical practice to incorporate the patient’s hospitalizations and a 7% reduction in all-cause mortality (103). perspective through objective assessments of these parameters, The effect of sacubitril/valsartan on objective functional both in the evaluation of new therapeutic interventions and in capacity has been explored in several observational studies. In day-to-day clinical care. a cohort of 58 patients, after 1 month with sacubitril/valsartan (104), patients were able to walk 41.8 meters further, which represented an increase of 14% over baseline (104). In SAFETY: RENAL FAILURE, another cohort of 16 patients treated with sacubitril/valsartan HYPERKALEMIA, HYPOTENSION, and assessed by cardiopulmonary ergometry (105), peak ANGIOEDEMA, IN OUTPATIENTS AND VO2 increased significantly at 30 days by 0.92 ml/min/kg, HOSPITALIZED PATIENTS corresponding to an increase of 7.9% compared to baseline, and respiratory efficiency also showed a significant improvement after The safety and tolerability of sacubitril/valsartan is well- 1 month, with a 9.1% reduction in VE/VCO2 slope (Figure 8) established in both clinical trials and real-life clinical practice. (105). A third study in a larger cohort (n = 99) (106), showed The more relevant adverse events related to treatment with drugs a significant improvement of 17% in peak VO2 and a 7% in HF and with sacubitril/valsartan are discussed below (Table 1). reduction in VE/VCO2 slope. Finally, in a prospective study of 37 consecutive patients with advanced HF on the waiting Renal Insufficiency list for heart transplantation, significant improvement in NYHA Sacubitril/valsartan has shown a more favorable renal safety class, peak VO2 and 6MWT was observed after 1 year of profile than enalapril (5). The PARADIGM-HF study found that treatment, while no statistical differences were observed during both the elevation of serum creatinine ≥ 2.5 mg/dl and the Frontiers in Cardiovascular Medicine | www.frontiersin.org 15 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF TABLE 1 | Side effects in the PARADIGM-HF and PIONEER-HF trials. PARADIGM-HF (5) PIONEER-HF (7) n (%) n (%) S/V Enalapril P S/V Enalapril RR (CI 95 %) (N = 4,817) (N = 4,212) (N = 440) (N = 441) Symptomatic hypotension 588 (14.0) 388 (9.2) <0.001 66 (15.0) 56 (12.7) 1.18 (0.85–1.64) Elevated creatinine ≥2.5/mg/dL* or Impaired renal function =l 139 (3.3)* 188 (4.5)* 0.007 60 (13.6) =l 65 (14.7) =l 0.93 (0.67–1.28) Elevated K+ > 5.5 mmol/L 674 (16.1) 727 (17.3) 0.15 51 (11.6) 41 (9.3) 1.25 (0.84–1.84) Elevated K+ > 6 mmol/L 181 (4.3) 236 (5.6) 0.007 ___ ___ ___ Angioedema 19 (0.4) 10 (0.2) 0.13 1 (0.2) 6 (1.4) 0.17 (0.02–1.38) Discontinuation of treatment due to side effects (10.7) (12.3) 0.03 51 (11.5) 45 (10.1) NS eGFR, estimated glomerular filtration rate. =l Impaired renal function defined as an increase in creatinine concentration ≥ 0.5 mg/dL and decrease in estimated GFR ≥ 25%. NS, not significant. *Elevated creatinine in the PARADIGM study. progression of renal function deterioration were less frequent than those treated with enalapril (111). All these data suggest with sacubitril/valsartan vs. enalapril (80). The magnitude of that sacubitril/valsartan associates a lower risk of hyperkalemia, the benefit of sacubitril/valsartan on renal function was twice even when combined with ARM, compared with ACEI as high in patients with T2D vs. patients without T2D (18). or ARB (110). This nephroprotective effect was observed despite the fact that patients treated with sacubitril/valsartan had higher hypertension and increased albumin/creatinine ratio in urine (18, 80). The Arterial Hypotension Symptomatic hypotension was the most frequent adverse event number of patients who discontinued sacubitril/valsartan due reported with sacubitril/valsartan, in clinical trials (5, 7) and real to adverse renal events was half compared to enalapril (0.7 vs life (109). In the PARADIGM-HF trial (5), sacubitril/valsartan 1.4%; p = 0.002), and fewer than half in CKD patients (1.1 vs was associated with a higher frequency of symptomatic 2.6%; p = 0.008) (80). In patients hospitalized with acute HF hypotension (14 vs. 9.2% enalapril; p < 0.001), but did not result in the PIONEER-HF trial (7), the frequency of renal function in a higher rate of drug withdrawal (0.9 vs. 0.7%, p = 0.38). The impairment did not differ [13.6 vs. 14.7%; RR 0.93 (0.67–1.28)]. beneficial effect observed with sacubitril/valsartan vs. enalapril, Sacubitril/valsartan was also evaluated in patients with CKD however, was constant across the different pre-established SBP and albuminuria (but not HF) vs. irbesartan, including patients categories, and greater in those patients with lower SBP below with eGFR of 20 to 60 mL/min/1.73m2 . There were no differences 110 mm Hg (16). in eGFR at 12 months, but sacubitril/valsartan added significant Hypotension should not preclude initiation and titration of reductions in levels of cardiac biomarkers (82). Successful use sacubitril/valsartan in elderly patients (aged >75 years), as there of sacubitril/valsartan in eGFR of <30 mL/min/1.73m2 has also was no interaction between age and treatment on its rate, it been reported in real life patients (109). Sacubitril/valsartan did not lead to a higher rate of discontinuation and the benefit seems therefore safe in patients with more advanced CKD, a obtained was independent of age (17). scenario where the use of ACE inhibitors is very limited. In the PIONEER-HF study (82), symptomatic hypotension did not differ significantly between sacubitril/valsartan and Hyperkalemia enalapril [15% vs. 12.7%; RR 1.18 (0.85–1.64)] in hospitalized The PARADIGM-HF study (5) found that severe hyperkalemia patients, with similar low withdrawal rates in both groups (2.5%). (serum potassium of >6 mEq/L) was less frequent with Hypotension did not influence the benefits of sacubitril/valsartan sacubitril/valsartan than with enalapril (4.3 vs. 5.6%; p = vs. enalapril (80). A slower titration is recommended in the 0.007), while no significant differences were found in the presence of hypotension, as it is associated with a higher rate of PIONEER-HF study (7). achieving target doses (111). Concomitant use of MRA is recommended by clinical practice guidelines to reduce morbidity and mortality in patients with symptomatic HFrEF, but it associates an increased risk of Angioedema hyperkalemia. A sub-analysis of patients treated with MRA in Both in the PARADIGM-HF (5) (0.5% sacubitril/valsartan and the PARADIGM-HF study (110) found that the annual incidence 0.2% enalapril, p = 0.13), and the PIONEER-HF (82) studies of severe hyperkalemia was lower with sacubitril/valsartan vs. (0.2% sacubitril/valsartan and 1.4% with enalapril, RR 0.17; 0.02– enalapril, both in patients already receiving MRA (2.2 vs. 3.1%; 1.38), angioedema was rarely seen, with no significant differences p = 0.02) or those who initiated MRA (2.3 vs. 3.3%; p = 0.003). between groups. In all studies, sacubitril/valsartan was started at In addition, patients receiving sacubitril/valsartan and MRA least 36 h after discontinuation of enalapril to minimize the risk had fewer temporary or permanent discontinuations of MRA of angioedema. Frontiers in Cardiovascular Medicine | www.frontiersin.org 16 November 2021 | Volume 8 | Article 754499 Pascual-Figal et al. Sacubitril-Valsartan in HFrEF Tolerance of ARNI is also associated with an early significant benefit, In the PARADIGM-HF study drug tolerance was adequate, and compared to treatment with enalapril, in both the chronic and the permanent discontinuation due to adverse events was very low acute setting (7, 8). Sacubitril/valsartan administration has been and less frequent with sacubitril/valsartan vs. enalapril (10.7 shown to be safe and well-tolerated in a wide range of HFrEF vs. 12.3%, p = 0.03) (5). A recent meta-analysis affirmed that patients, and associated with a significant improvement in quality patients with HFpEF who received sacubitril/valsartan had a of life measures (99, 100). lower rate of serious adverse events vs. the ACEI/ARB control There are several related mechanisms that explain this wide group (RR 0.89; CI 95%, 0.86–0.93) (112). In patients with benefit, and they include both cardiac and extracardiac protective acute decompensated HF, early initiation of sacubitril-valsartan effects. At the cardiac level, a major mechanism is the modulation or enalapril were associated with similar rates of discontinuation of the NP system, leading to a reduction in myocardial stress, (11.5 vs. 10.1%, p not significant) (7) When initiated in stable inflammation and cell death, which in turn leads to improved patients before discharge, sacubitril/valsartan showed an even parameters of cardiac function and remodeling (24, 25, 65). At lower discontinuation rate (7.1%) (8). the extracardiac level, favorable vascular (4), metabolic (15, 96) To summarize, sacubitril/valsartan has been shown to be and renal effects (18, 80) also make a significant contribution, safe in patients with HFrEF, both in the outpatient and the leading to greater vascular protection and a lower risk of diabetes in-hospital settings, with a more favorable renal safety profile and renal impairment, as well as better tolerance and persistence vs. enalapril, including a lower risk of renal impairment and over other beneficial treatments (5, 7, 112). severe hyperkalemia. It should be expected a slightly higher In conclusion, there is sufficient evidence to affirm that risk of hypotension, but not severe hypotension. Considering sacubitril/valsartan is the first-line therapeutic option in patients the clinical benefits, initiation of sacubitril/valsartan must be with HFrEF, compared to isolated RAAS inhibition. recommended before discharge in hospitalized HFrEF patients. AUTHOR CONTRIBUTIONS DISCUSSION All authors listed have made a substantial, direct and intellectual In patients with HFrEF, treatment with sacubitril/valsartan has contribution to the work, and approved it for publication. been shown to be cost-effective (14) and superior to enalapril in reducing all-cause and cardiovascular mortality, including FUNDING sudden cardiac death and HF death, as well as in reducing the rate of HF hospitalization and rehospitalization (5). Initiation A non-conditioned grant by Novartis Spain was acknowledged. REFERENCES 8. Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, et al. Initiation of sacubitril/valsartan in haemodynamically 1. 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