Sacubitril/valsartan in heart failure: latest evidence and place in therapy

Abstract

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk for HF progression and death. Sacubitril/valsartan (previously known as LCZ696) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor (sacubitril) and an angiotensin II (Ang-II) receptor blocker (valsartan). NEP is an endopeptidase that metabolizes different vasoactive peptides including natriuretic peptides, bradykinin and Ang-II. In consequence, its inhibition increases mainly the levels of both, natriuretic peptides (promoting diuresis, natriuresis and vasodilatation) and Ang-II whose effects are blocked by the angiotensin receptor blocker, valsartan (reducing vasoconstriction and aldosterone release). Results from the 8442 patient PARADIGM-HF study showed in patients with New York Heart Association (NYHA) class II–IV and reduced ejection fraction treated with LCZ696 (versus enalapril), the following benefits: reduction of the risk of death from cardiovascular causes by 20%; reduction of HF hospitalizations by 21%; reduction of the risk of all-cause mortality by 16%. Overall there was a 20% risk reduction on the primary endpoint, composite measure of cardiovascular (CV) death or time to first HF hospitalization. PARADIGM-HF was stopped early after a median follow up of 27 months. Post hoc analyses of PARADIGM-HF as well as the place in therapy of sacubitril/valsartan, including future directions, are included in the present review.

Introduction

Heart failure (HF) is a complex syndrome whose pathophysiology is based on a progressive neurohormonal activation and alteration in the autonomic control. These mechanisms provide helpful support for the heart under physiological conditions and as transitory compensation when the myocardium starts to fail but their sustained activation play a detrimental role in HF clinical progression [Francis et al. 1990, 1993].

Stimulation of the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction (via angiotensin II; Ang-II) and salt and water retention (via aldosterone). In addition, RAAS has an important profibrotic effect on cardiac tissue and promoting endothelial dysfunction. Activation of the sympathetic nervous system (SNS) increases heart rate, myocardial contractility and arterial tone in order to maintain cardiac output but its prolonged activity finally ends raising afterload due to sustained vasocostriction, contributing to RAAS stimulation and boosting cardiomyocyte hypertrophy and apoptosis [Goldsmith, 2004].

On the other hand, several peptides like natriuretic peptides (NPs), bradykinin or adrenomedullin, try to ameliorate all these harmful effects (RAAS and SNS) attenuating vasoconstriction, sodium retention and retarding cardiac and vascular remodeling. However, normally, these compensatory actions are not sufficient enough to prevent or stop HF development [Magri et al. 1998; Levin et al. 1998].

Natriuretic peptides in heart failure: role of neprilysin

The family of NPs contains three main polypeptides, atrial (ANP), brain (BNP) and C-type (CNP) NPs. ANP (28 amino acids) is produced by cardiac atrial cells, BNP (32 amino acids) is predominantly from a cardiac ventricular myocardium origin (much less atrial) and CNP (22 amino acids) is mainly expressed in the central nervous system, bones, and endothelial tissue [Krupicka et al. 2009].

Overall, three NP receptors (NPRs) have been detected in mammals (NPR-A, NPR-B and NPR-C). NPs operate by binding NPR-A and NPR-B which are guanylate cyclase receptors leading to the production of cyclic guanosine monophosphate (cGMP), a classic intracellular second messenger responsible for all their known biological effects (RAAS antagonism). On the other hand, NPR-C does not have any known intrinsic enzymatic activity and its primary role is connected with the clearance of NPs (it binds ANP, BNP and CNP) by a receptor-mediated internalization and degradation process (lysosomal hydrolysis). All three NPs are metabolized through two main processes, the above mentioned NPR-C-mediated clearance and, by an enzymatic breakdown (neprilysin; NEP) [Volpe et al. 2014].

ANP and BNP synthesis and release is stimulated by the increase of cardiac wall stress during volume or pressure overload; levels of NPs are considerably higher in patients with HF and correlate closely with the severity of the disease and other parameters of left ventricular dysfunction like ejection fraction (EF), pulmonary capillary wedge pressure, and left ventricular end-diastolic pressure [Krupicka et al. 2009].

Physiological actions of ANP and BNP include, direct vasodilation, glomerular filtration increase, natriuresis and diuresis promotion, reduction of renin secretion (kidneys) and antihypertrophic and antifibrotic myocardial effects. CNP has an important local paracrine and autocrine role which is still not entirely understood [Levin et al. 1998; Krupicka et al. 2009].

In recent years, substantial interest has been generated about the therapeutic potential use of NPs, considering their biological actions and the increased circulating concentrations that ANP and BNP have in HF patients [Volpe et al. 2014]. In this context, one particular way to enhance NP levels and, in consequence, their beneficial effects, is the possibility to inhibit NEP, the enzyme that metabolizes NPs [Vardeny et al. 2014].

NEP is a zinc-dependent metallopeptidase found in many tissues which is composed of a large extracellular catalytic domain, a single transmembrane region, and a short cytoplasmic N-terminal domain [Erdos and Skidgel, 1989; Maguer-Satta et al. 2011]. NEP catalyzes the degradation of a heterogeneous group of vasodilator peptides, including NPs, Ang-II, bradykinin, substance P, adrenomedullin, vasoactive intestinal polypeptide, calcitonin gene-related peptide and endothelin-1 [Stephenson et al. 1987; Kenny et al. 1993; Vijayaraghavan et al. 1990; Matsas et al. 1985; Wilkinson et al. 2001]. In consequence, inhibition of NEP would increase circulating levels of NPs which in turn stimulate the synthesis of cGMP (via guanylate cyclase receptors) promoting natriuresis, diuresis, vasodilation, and reducing cardiac hypertrophy [Krupicka et al. 2009].

Regardless of its enzymatic function, circulating soluble NEP levels have been positively associated with cardiovascular (CV) mortality and morbidity in HF patients. Soluble NEP was measured (by immunoassay) in 1069 consecutive ambulatory HF patients who were followed up for 4.1 years. NEP median concentration was 0.642 ng/ml (0.385–1.219) but there were 165 patients (14.6%) whose levels were below the analytic measurement range. Regression analyses showed that the median value of NEP concentration was significantly associated with the composite endpoints of CV death [hazard ratio (HR) 1.19; 95% confidence interval (CI) 1.06–1.32; p = 0.002] or HF hospitalization (HFH; HR 1.17; 95% CI 1.06–1.29; p = 0.001) [Bayés-Genis et al. 2015].

Apart from augmenting circulating levels of NPs, inhibition of NEP increases levels of Ang-II whose over-activation contributes to vasoconstriction, sodium retention and cardiac fibrosis stimulation [Goldsmith, 2004]. Therefore, the benefits of increasing the NP system may be lost by increasing Ang-II, so a simultaneous suppression of the RAAS is necessary. Consequently, this fact gives a clear pharmacological justification for agents that block both NEP and Ang-II [Vardeny et al. 2014].

Neprilysin inhibition: from candoxatril to sacubitril/valsartan

Candoxatril, was the first available oral pure NEP inhibitor but it was a failure from a clinical point of view since it concomitantly promoted a dose-dependent increase of both ANP (natriuresis) and Ang-II (breakdown inhibition). Consequently, candoxatril was not able to reduce blood pressure (BP) in hypertensive patients and vascular resistances (systemic and pulmonary) in HF patients [Ando et al. 1995; Kentsch et al. 1996]. The same destiny was then followed by ecadotril (another NEP inhibitor) whose expansion was stopped after a lack of efficacy documented in a dose-ranging study in systolic HF (n = 279). There were more deaths and side effects in patients receiving ecadotril and although plasma and urinary cGMP rose (dose-dependent), other markers (renin activity, Ang-II or N-terminal ANP) did not change significantly [Cleland et al. 1998].

Omapatrilat, the first inhibitor of NEP and the angiotensin-converting enzyme (ACE) had an initially very promising experience showing a better profile than candoxatril regarding BP and reduction of vascular resistance. It was checked in HF patients in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) in which 5770 patients (NYHA class II–IV) were randomized to receive (added to conventional therapy) enalapril 10 mg twice daily or omapatrilat 40 mg once daily. The primary endpoint (combined risk of death or HFH) was not different for the two groups. A slightly higher incidence of angioedema was reported in the omapatrilat group (0.8% versus 0.5% enalapril) but this difference was unfortunately more marked in another trial, the OCTAVE study in hypertensive patients (2.2% versus 0.7% enalapril). Taking into account the high occurrence of angioedema (favored by increased levels of bradykinin) and the lack of substantial benefit of omapatrilat in comparison with enalapril in HF patients, its clinical development was stopped [Packer et al. 2002; Kostis et al. 2004].

Sacubitril/valsartan is the first angiotensin receptor NEP inhibitor (ARNI) that contains the NEP inhibitor prodrug sacubitril (AHU377) and the Ang-II receptor antagonist valsartan in anionic forms (molar ratio 1:1). After oral administration, sacubitril/valsartan dissociates into valsartan and sacubitril (prodrug) which is subsequently metabolized to LBQ657 (active form; Figure 1). Peak concentrations of both are reached at about the same time (1.5–4.5 h) and steady-state levels of sacubitril, LBQ657 and valsartan are achieved in 3 days [Gu et al. 2010].

Figure 1.

Sacubitril/valsartan mode of action

Sacubitril/valsartan (LCZ696): simultaneous NEP inhibition (LBQ657) and AT1 receptor blockade (valsartan). NEP substrates may have biological opposing actions and the total effect of the inhibition depends on the net effect of the individual metabolized substrates. The benefits of increasing the NP system may be lost by increasing Ang-II, so a simultaneous suppression of the RAAS is necessary. Figure only shows effects on BNP but other metabolites are affected [Gu et al. 2010; Vardeny et al. 2014; Stephenson et al. 1987; Kenny et al. 1993; Vijayaraghavan et al. 1990; Matsas et al. 1985; Wilkinson et al. 2001].

Ang-II, angiotensin-II; AT1, angiotensin II receptor type 1; BNP, brain natriuretic peptide; NEP, neprilysin; NP, natriuretic peptide; N-terminal pro-B type natriuretic peptide; NT-pro-BNP; pro-B type natriuretic peptide; Pro-BNP; RAAS, renin angiotensin aldosterone system

The pharmacodynamic effects of sacubitril/valsartan in HF patients are consistent with simultaneous NEP inhibition and RAAS blockade. In a 7-day controlled study, sacubitril/valsartan administration (versus valsartan) resulted in a significant nonsustained increase in natriuresis, increased urine cGMP, and decreased plasma midregional proANP (MR-proANP) and N-terminal proBNP (NT-proBNP; expressions of NEP inhibition) [www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdf]. In a 21-day open-label phase II study, sacubitril/valsartan causes a dose-dependent increase in ANP, plasma and urinary cGMP as a consequence of NEP inhibition while on the other hand, blockade of AT1 receptor increases renin concentration and activity and Ang-II levels [Kobalava et al. 2011]. In the PARAMOUNT study which was a phase II, randomized, parallel-group, double-blind trial (patients in NYHA class II–III, preserved left ventricular ejection fraction (LVEF) ⩾ 45% and NT-proBNP > 400 pg/m); sacubitril/valsartan reduced NT-proBNP to a greater extent than valsartan at 12 weeks (primary endpoint) [Solomon et al. 2012]. In PARADIGM-HF, patients taking sacubitril/valsartan showed an early reduction of NT-proBNP and troponin levels (myocardial wall stress and injury reduction) while urinary cGMP and plasma BNP increased (NEP inhibition) [Packer et al. 2015].

Sacubitril/valsartan is available in tablets containing 24 mg of sacubitril and 26 mg of valsartan, 49 mg of sacubitril and 51 mg of valsartan and 97 mg of sacubitril and 103 mg of valsartan. Bioavailability of valsartan in combination is higher than valsartan given alone, with an exposure approximately 40% superior. Therefore, 26 mg, 51 mg and 103 mg of valsartan in sacubitril/valsartan is equivalent to 40 mg, 80 mg and 160 mg of valsartan in a common tablet formulation. Sacubitril is principally eliminated in urine (52–68%) while valsartan is eliminated mainly via feces (86%) [Gu et al. 2010].

PARADIGM-HF

The Prospective Comparison of ARNI with ACE inhibitors (ACEi) to Determine Impact on Global Mortality and Morbidity in Hart Failure Trial (PARADIGM-HF) is a randomized, double-blind and event-driven trial designed to investigate the effect of sacubitril/valsartan compared with enalapril in patients with chronic and symptomatic HF. The run-in period started in December 2009 and the study was stopped in March 2014 after a median follow up of 27 months due to an overwhelming performance with sacubitril/valsartan.

Sacubitril/valsartan (200 mg, twice daily) was compared with enalapril (10 mg, twice daily) in patients with systolic HF (NYHA functional class II–IV), previously treated with an ACEi or angiotensin receptor blocker (ARB; equivalent to at least 10 mg of enalapril), LVEF ⩽ 40% (⩽35% by amendment) and increased levels of BNP or NT-proBNP. Patients were required to have a plasma BNP level ⩾ 150 pg/ml (or NT-proBNP ⩾ 600 pg/ml) or, if they had been hospitalized for HF (within the previous 12 months), a BNP level ⩾ 100 pg/ml (or NT-proBNP ⩾ 400 pg/ml; Table 1).

Table 1.

PARADIGM-HF population at baseline.

Main characteristics	Sacubitril/valsartan (n = 4187)	Enalapril (n = 4212)
Age (years)	63.8 (11.5)	63.8 (11.3)
Female sex (n/%)	879 (21)	953 (22.6)
SBP (mmHg)	122 ± 15	121 ± 15
HR (beats/min)	72 ± 12	73 ± 12
NYHA functional class (%)	I, II, III, IV (4.3/71.6/23.1/0.8)	I, II, III, IV (5.0/69.3/24.9/0.6)
Creatinine (mg/dl)	1.13 ± 0.3/29	1.12 ± 0.3
LVEF (%)	6 ± 6.1	29.4 ± 6.3
Median BNP, pg/ml (IQR)	255 (155–474)	251 (153–465)
Median NT-proBNP, pg/ml (IQR)	1631 (8815–3154)	1594 (886–3305)
Ischemic cardiomyopathy (n/%)	2506 (59.9)	2530 (60.1)
Atrial fibrillation (n/%)	1517 (36.2)	1574 (37.4)
Hypertension (n/%)	2969 (70.9)	2971 (70.5)
Diabetes (n/%)	1451 (34.7)	1456 (34.6)
HF hospitalization (n/%)	2607 (62.3)	2667 (63.3)
Pretrial use ACEi (%)	78	77.5
Pretrial use ARB (%)	22.2	22.9
Beta-blocker	93.1	92.9
MRA (%)	54.2	57

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, b-type natriuretic peptide; HF, heart failure; HR, heart rate; IQR, interquartile range; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal proBNP; NYHA, New York Heart Association; SPB, systolic blood pressure.

^*In both groups white and black races were 66% and 5.1%, respectively. Body mass indexes were 28.1 ± 5.5 (sacubitril/valsartan) and 28.2 ± 5.5 (enalapril). Pre-use of implantable cardioverter defibrillators or resynchronization devices were as follows (%): 14.9/7 (LCZ696), 14.7/6.7 (enalapril) [McMurray et al. 2014].

The exclusion criteria included history of intolerance of ACEi or ARBs, symptomatic hypotension (or a systolic BP < 100 mmHg at screening or 95 mmHg at randomization), an estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m², a serum potassium concentration > 5.2 mmol/l at screening (>5.4 mmol/l at randomization) and a history of angioedema.

The primary endpoint was a composite of death from CV causes or HFH. Secondary endpoints included time to death from any cause, the change from baseline to 8 months in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire (KCCQ; on a scale of 0–100, with higher scores indicating fewer symptoms or physical limitations associated with HF) [Green et al. 2000], the time to a new onset of atrial fibrillation and time to worsening of renal function (which was defined as end-stage renal disease or a decrease in eGFR of at least 50% or a decrease of >30 ml/min per 1.73 m² from randomization to <60 ml/min per 1.73 m²).

PARADIGM-HF began with a single-blind run-in period (10,512 patients) to check drug tolerability; patients received enalapril 10 mg twice daily for 2 weeks, then sacubitril/valsartan 100 mg twice daily for 1–2 weeks and then, 200 mg twice daily for 2 weeks (200 mg of valsartan in sacubitril/valsartan is equivalent to 160 mg of valsartan alone). A 1-day washout period was followed in order to avoid a potential overlapping (enalapril-sacubitril/valsartan) to try to reduce the risk of angioedema. Those patients who did not present any unacceptable side effects of both medications at target doses (8442 patients), were randomized in a 1:1 ratio to a double-blind treatment (4187 with sacubitril/valsartan and 4212 with enalapril).

At the time of trial completion, 21.8% of the sacubitril/valsartan group and 26.5% of the enalapril group had reached the primary endpoint (HR 0.80; 95% CI 0.73–0.87; p < 0.001). Compared with enalapril, sacubitril/valsartan reduced the risk of death from any cause by 16% (p < 0.001) and the risk of hospitalization from HF by 21% (p < 0.001). Overall mortality was also lower in the sacubitril/valsartan arm (17.0% versus 19.8%; HR 0.84; 95% CI 0.76–0.93;p < 0.001). Mean change from baseline to month 8 in the KCCQ was a reduction of 2.99 points and 4.63 points in the sacubitril/valsartan and enalapril arms, respectively (p = 0.001). New onset atrial fibrillation was detected in 84 patients in the sacubitril/valsartan group and in 83 patients taking enalapril (p = 0.84), while protocol-defined worsening renal function was present in 94 patients of the sacubitril/valsartan group and 108 of the enalapril group (p = 0.28; Table 2). The effect of sacubitril/valsartan was consistent across all prespecified representative subgroups and its favorable difference was seen early in the trial and each interim analysis.

Table 2.

PARADIGM-HF: clinical endpoints.

Endpoints	Sacubitril/valsartan	Enalapril	Hazard ratio	p value
	(n = 4187)	(n = 4212)	(95% CI)
Primary composite outcome (n/%)
Death from CV cause/first HFH	914 (21.8)	1117 (26.5)	0.80 (0.73–0.87)	<0.001
Death from CV cause	558 (1.3)	693 (16.5)	0.80 (0.71–0.89)	<0.001
First HFH	537 (12.8)	658 (15.6)	0.79 (0.71–0.89)	<0.001
Secondary outcomes (n/%)
Death from any cause	711 (17)	835 (19.8)	0.84 (0.76–0.93)	<0.001
Change in KCCQ*	−2.99 ± 0.36	−4.63 ± 0.36	1.64 (0.63–2.65)	0.001
New-onset atrial fibrillation	84 (3.1)	83 (3.1)	0.97 (0.72–1.31)	0.83
Renal function deterioration	94 (2.2)	108 (2.6)	0.86 (0.65–1.13)	0.28

CI, confidence interval; CV, cardiovascular; HFH, heart failure hospitalization; KCCQ, Kansas City Cardiomyopathy Questionnaire.

^*KCCQ at 8 months: range 0–100 with higher scores showing fewer limitations. Renal function declination was defined as end-stage renal disease or a decrease ⩾50% in the estimated glomerular filtration rate form the randomization value or a decrease >30 ml/min per 1.73 m², to <60 ml/min per 1.73 m² [McMurray et al. 2014].

During the run-in period, 12% of patients withdrew due to an adverse event (cough, hyperkalemia, renal dysfunction and hypotension) with a higher rate in the enalapril group. This 12% dropout is important from a practical point of view because it may imply a limit of PARADIGM-HF results generalization (only patients that tolerated the run-in period were randomized).

After randomization, symptomatic hypotension and nonserious angioedema were more common in the sacubitril/valsartan group but renal deterioration (creatinine level ⩾ 2.5 mg/dl), cough and hyperkalemia (serum potassium ⩾ 6.0 mmol/l) occurred more frequently with enalapril. Regarding angioedema, there were no cases in either group which resulted in airway compromise. Few patients in the sacubitril/valsartan arm needed to stop their medication due to an adverse event (10.7% versus 12.3%; p = 0.03) or because of renal impairment (0.7% versus 1.4%; p = 0.002) [McMurray et al. 2014].

Post hoc analysis

Age

A total of 8399 patients were validly randomized in PARADIGM-HF aged 18–96 years (median age 63.8 years). Prespecified efficacy and safety outcomes according to age were examined in the following categories: <55 (n = 1624), 55–64 (n = 2655), 65–74 (n = 2655), and ⩾75 (n = 1563). The rate (per 100 patients/year) of the primary outcome (CV death or HFH) increased from 13.4–14.8 across the age categories. HR of sacubitril/valsartan compared with enalapril (primary outcome) was consistent all across the spectrum of age (p interaction = 0.94) with an overall HR of 0.80 (0.73–0.87); p < 0.001. Safety outcomes of hypotension (more in sacubitril/valsartan), renal impairment, and hyperkalemia (both more in enalapril) increased logically with age.

For example, 5 patients <55 years and 14 patients ⩾75 years discontinued the study due to symptomatic hypotension in the sacubitril/valsartan arm while 9 patients <55 years and in 16 patients ⩾75 years did the same due to renal impairment in the enalapril arm [Jhund et al. 2015].

Left ventricular ejection fraction

LVEF ranged from 5–42% (mean 29.5 ± 6.2%) which for analysis, was divided into the following categories: <17.5%, ⩾17.5% to <22.5%, ⩾22.5% to <27.5%, ⩾27.5% to <32.5%, and ⩾32.5%. The risk of all outcomes increased with the decrease of LVEF and each five-point reduction was associated with a 9% increased risk of CV death or HF hospitalization (HR 1.09; 95% CI 1.05–1.13; p < 0.001), a 9% increased risk for CV death (HR 1.09; 95% CI 1.04–1.14), a 9% increased risk in HFH (HR 1.09; 95% CI 1.04–1.14), and a 7% increased risk in all-cause mortality (HR 1.07; 95% CI 1.03–1.12). LVEF was documented as a significant and independent predictor of all outcomes and sacubitril/valsartan was effective across its entire spectrum and there was no evidence of heterogeneity for the primary endpoint (p interaction = 0.87), CV death (p interaction = 0.55), HF hospitalization (p interaction = 0.78) and all-cause mortality (p interaction = 0.93) [Solomon et al. 2016].

Clinical progression and biomarkers

Prespecified standards of nonfatal clinical deterioration (Table 3) were studied and as expected, fewer sacubitril/valsartan-treated patients (versus enalapril) required: an intensification of their HF medical treatment, to visit an emergency department (worsening HF), intravenous positive inotropic support, implantation of a ventricular assist device or, to receive a heart transplantation. Patients treated with sacubitril/valsartan were less likely to be hospitalized for HF (one or multiple times) with 23% fewer hospitalizations for worsening HF (p < 0.001), 16% lesser hospitalizations for CV reason (p < 0.001), 15.6% lesser hospitalizations for any reason (p < 0.001) and 29% fewer HF hospitalizations (more than once; p = 0.001). Diminution in HFH with sacubitril/valsartan was patent within the first 30 days after randomization. Regarding biomarkers, sacubitril/valsartan (versus enalapril) led to an early and sustained reduction in plasma NT-proBNP and troponin as an expression of myocardial wall stress and injury reduction while levels of urinary cGMP and plasma BNP increased reflecting NEP inhibition [Packer et al. 2015].

Table 3.

PARADIGM-HF: sacubitril/valsartan versus enalapril in clinical progression of surviving HF patients.

Nonfatal clinical deterioration: prespecified measures	Enalapril (n/%; n = 4212)	Sacubitril/valsartan (n/%; n = 4187)	Hazard/rate ratio (95% CI)	p value
Outpatient therapy intensification	604 (14.3)	520 (12.4)	0.84 (0.74–0.94)	0.003
Worsening NYHA (⩾1 class) 12 months	271 (7.4)	225 (6.1)	–	0.023
ED visit for HF	150 (3.6)	102 (2.4)	0.66 (0.52–0.85)	0.001
Patients hospitalized for HF	658 (15.6)	537 (12.8)	0.79 (0.71–0.89)	<0.001
Total number of HFHs	1,079	851	0.77 (0.67–0.89)	<0.001
Patients receiving IV inotropic drugs	229 (5.4)	161 (3.9)	0.69 (0.57–0.85)	<0.001
Patients requiring CRT, VAD or HT	119 (2.8)	94 (2.3)	0.78 (0.60–1.02)	0.07

Sacubitril/valsartan prevented more efficiently clinical progression of surviving patients with heart failure than enalapril. In addition, it led an early and sustained reduction in biomarkers of myocardial wall stress and injury [Packer et al. 2015].

CI, confidence interval; CRT, cardiac resynchronization therapy; ED, emergency department; HF, heart failure; HFH, heart failure hospitalization; HT, heart transplantation IV, intravenous; VAD, ventricular assist device.

Mode of death

An overall total of 1546 patients, considering 711 (17% of total) in the sacubitril/valsartan group and 833 patients (19.8%) in the enalapril group, died during the trial (HR 0.84; 95% CI 0.76–0.93 for all-cause mortality). The majority of causes of death were CV-related (80.9% of total) including 558 (13.3% of total) in the sacubitril/valsartan group and 693 (16.5%) in the enalapril group (HR 0.80; 95% CI 0.72–0.89; p < 0.001). In the context of CV death, 44.8% were considered sudden death and 26.5% pump failure-related, and both were reduced by sacubitril/valsartan compared with enalapril (HR 0.80; 95% CI 0.68–0.94; p = 0.008 for sudden death, and HR 0.79; 95% CI 0.64–0.98; p = 0.034 for HF). Death imputed to other CV causes (myocardial infarction or stroke) as well as non-CV death did not differ between both groups (HR 1.07; 95% CI 0.85–1.34; p = 0.95 for non-CV death) [Desai et al. 2015].

This important proportion of sudden death (SD) in PARADIGM-HF was quite similar to other trials like V-HEFT II [Cohn et al. 2001] or MERIT HF [MERIT HF Study Group, 1999] in which most of enrolled patients had mild-to-moderate symptoms, while other trials like CONSENSUS [CONSESUS Trial Study Group, 1987], RALES [Pitt et al. 1999] or EVEREST [O’Connor et al. 2010] that included more severe patients, exhibited a larger proportion of death due to progressive HF.

Place in therapy

After the PARADIGM results were known, sacubitril/valsartan was first incorporated into The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: Anemia, Biomarkers and Recent Therapeutic Trials Implications receiving a conditional recommendation of high quality evidence. Sacubitril/valsartan was suggested for use in place of an ACEi or ARB in patients with appropriate guideline-directed medical therapy and showing mild-to-moderate HF, LVEF < 40%, elevated NPs or hospitalization for HF in the past 12 months (like PARADIGM entry criteria) [Moe et al. 2015].

During 2015, sacubitril/valsartan was approved by the United States Food and Drug Administration [US FDA, 2015] and the European Medicine Agency [EMA, 2015a, 2015b] with a very general and similar indication: to reduce the risk of CV death and HFH in patients with chronic HF (NYHA Class II–IV) and reduced EF (FDA) or to be indicated in adult patients for treatment of symptomatic chronic HF with reduced EF (EMA).

Throughout May 2016, sacubitril/valsartan got a strong class I recommendation in both US and European HF guidelines (less than a year after regulatory approvals). In the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure [Yancy et al. 2016], sacubitril/valsartan received a recommendation I-BR that means a class of recommendation I ‘strong’ and level of evidence BR ‘moderate quality’ (evidence based on only one study). In consequence, an ARNI should be recommended to further reduce morbidity and mortality in patients with chronic symptomatic HF, reduced EF, NYHA class II or III and who tolerate an ACEi or ARB (replacement). It signifies that sacubitril/valsartan is incorporated into the standard therapy for HF with reduced EF as an alternative to an ACEi or an ARB, given together with a beta-blocker and a mineralocorticoid receptor antagonist (MRA). Is important to remark (in contrast with EU guidelines) that there is not a specific cut-off level of EF needed to indicate sacubitril/valsartan (only reduced EF) or the necessity, of a prior MRA utilization. US authors warn that ARNI use is associated with hypotension and a low-frequency incidence of angioedema and with some potential off-target effects of NEP inhibition [Yancy et al. 2016].

In this context, there is an eventual and theoretical increased risk for Alzheimer’s disease, since NEP plays a central role in the degradation of beta-amyloid peptide and it means that NEP inhibition might lead to abnormal accumulation in the brain. An inverse relationship between NEP levels and beta-amyloid peptide levels, and between NEP levels and amyloid plaque formation has been observed in the human brain [Hersh et al. 2008]. Although, no signals of an increase in dementia or cognitive impairment were seen in the PARADIGM-HF trial, the effects of sacubitril/valsartan on cognitive function will be assessed in the ongoing PARAGON-HF trial [EMA, 2015a, 2015b]. In addition, a multicenter, randomized, double-blind, active-controlled study (CLCZ696B2320) is planned in order to specifically evaluate cognitive impairment and brain amyloid plaque deposition (using PET imaging) comparing sacubitril/valsartan with valsartan [EMA, 2015a, 2015b].

In the EU, the 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure [Ponikowski et al. 2016], sacubitril/valsartan got a recommendation IB which signifies class I (is recommended) and level of evidence B (data derived from one single trial). Therefore, sacubitril/valsartan is recommended as an ACEi replacement to further reduce the risk of HFH and death in ambulatory patients with HF and reduced EF who remain symptomatic despite optimal treatment with an ACEi, a beta-blocker and an MRA (Figure 2). Similarly, some safety considerations were formulated to be taken into account regarding initiation of sacubitril/valsartan in clinical practice. Symptomatic hypotension is an essential issue since it was more frequent in patients taking sacubitril/valsartan but in the case of those ⩾75 years of age (elderly patients), it reached an important 18% versus 12% in the enalapril arm. Another relevant matter is the risk of angioedema whose rate was low in PARADIGM-HF (0.4% sacubitril/valsartan versus 0.2% enalapril), a fact connected with the point that PARADIGM-HF only randomized patients who tolerated the target dose of both medications (without intolerable side effects) and with a small proportion (5%) of African American patients recruited (this race has a natural increased risk of angioedema) [Brown et al. 1996]. Therefore, and in order to minimize the risk of angioedema caused by overlapping ACE and NEP inhibition, the ACEi should be withheld for at least 36 h before initiating sacubitril/valsartan. Finally, the concern regarding a theoretical brain amyloid deposition secondary to NEP inhibition was also present in European guidelines.

Figure 2.

Place in therapy of ARNI according European Society of Cardiology guidelines.

ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BNP, b-type natriuretic peptide; bpm, beats per minute; ICD, Implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; EF, ejection fraction; HF, heart failure; HFrEF, HF with reduced EF; H-ISDN, hydralazine and isosorbide dinitrate; HR, heart rate; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B type natriuretic peptide; NYHA, New York Heart Association; OMT, optimal medical therapy; VF, ventricular fibrillation; VT, ventricular tachycardia.

^aSymptomatic (NYHA class II–IV).

^bHFrEF = LVEF < 40%.

^cIf ACEi not tolerated/contraindicated, use ARB.

^dIf MRA not tolerated/contra-indicated, use ARB.

^eWith a hospital admission for HF within the last 6 months or with elevated natriuretic peptides (BNP > 250 pg/ml or NT-proBNP > 500 pg/ml in men and > 750 pg/ml in women).

^fWith an elevated plasma natriuretic peptide level (BNP ⩾ 150 pg/ml or plasma NT-proBNP ⩾ 600 pg/ml, or if HF hospitalization within recent 12 months plasma BNP ⩾ 100 pg/ml or plasma NT-proBNP ⩾ 400 pg/ml).

^gIn doses equivalent to enalapril 10 mg twice daily.

^hWith a hospital admission for HF within the previous year.

ⁱCRT is recommended if QRS ⩾ 130 ms and LBBB (in sinus rhythm).

^jCRT should/may be considered if QRS ⩾ 130 ms with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure biventricular capture in place (individual decision).

^kDespite maximally-tolerated beta-blocker next to HR ⩾ 70 bpm.

Diuretics should be used to relieve symptoms and signs of congestion and a CDI should be implanted if LVEF ⩽ 35% despite OMT or history of symptomatic VT/VF [Ponikowski et al. 2016].

Conclusion

Sacubitril/valsartan has an ambitious investigational clinical program in HF that involves different scenarios such as, reduced EF, preserved EF, a real-life setting, biomarkers, pediatrics, elderly patients, Japanese population, acute HF, and post-acute decompensation. It implies that taking into account Paradigm’s results; sacubitril/valsartan has the potential to change the treatment of HF in all these scenarios (Table 4). One of these ongoing studies, PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction; ClinicalTrials.gov identifier: NCT01920711) has a transcendental importance, particularly given our current lack of proven clinical benefits in patients with HF and preserved EF. PARAGON-HF is designed to determine whether sacubitril/valsartan (versus valsartan alone) can reduce CV death or total HFH in patients (n = 4300) with the following criteria: LVEF ⩾ 45%, NYHA class II–IV, histories of HFH within 9 months or elevated NPs, and evidence of structural heart disease, demonstrated by left ventricular hypertrophy or left atrial enlargement.

Table 4.

Sacubitril/valsartan clinical development: phase III/IV and observational global studies.

Trial number	Focus	Brief title
NCT01922089	HFreEF	TITRATION: safety and tolerability of initiating LCZ696 in HF patients
NCT02661217	HFreEF	TRANSITION: comparison of pre- and post-discharge initiation of LCZ696 therapy in HFreF patients after an acute decompensation event
NCT02678312	HFreEF	Single-dose study to evaluate safety, tolerability and pharmacokinetics of LCZ696 followed by a 52-week study of LCZ696 compared with enalapril in pediatric patients with heart failure
NCT02226120	HFreEF	PARADIGM-OPEN LABEL: safety and tolerability during open-label treatment with LCZ696 in patients with HFreEF
NCT00887588	HFpEF	PRESERVED: LCZ696 compared with valsartan in patients with chronic HFpEF
NCT01920711	HFpEF	PARAGON-HF: efficacy and safety of LCZ696 compared with valsartan, on morbidity and mortality in HFpEF
NCT02690974	HFreEF	PARASAIL: tolerability of LCZ696 (sacubitril/valsartan) HFreEF treated in real life setting
NCT02468232	HFreEF	Efficacy and safety of LCZ696 in Japanese patients with chronic HFreEF
NCT02554890	NT-PROBNP	PIONEER-HF: sacubitril/valsartan versus enalapril on effect on NT-PROBNP in patients stabilized from an acute HF episode
NCT02682719	Asymptomatic patients	PARABLE: asymptomatic patients with elevated natriuretic peptide and elevated left atrial volume index
NCT02687932	Mitral regurgitation	PRIME: pharmacological reduction of functional ischemic mitral regurgitation
CLCZ696B2320**	Cognitive function	To evaluate the effects of Entresto* compared with valsartan on cognitive function as assessed by comprehensive neurocognitive battery and brain amyloid plaque deposition as assessed by PET imaging in HFpEF
Observational US Study**	Angioedema	Risk of serious angioedema with Entresto* (black patients with HF)
Post-authorization European Study**	Safety	Angioedema, hypotension, hyperkalemia, renal impairment, hepatotoxicity in HF patients newly starting treatment with Entresto*

From ClinicalTrials.gov and International Standard Controlled Trials Number (ISRCTN) Register.

HF, heart failure; HFreEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; PET, positron emission tomography.

^*Brand name of sacubitril/valsartan.

^**EMA [2015a, 2015b].

Meanwhile, sacubitril/valsartan has obtained a strong class I (I-BR or IB) recommendation with only one study behind it which in fact, PARADIGM-HF is the largest HF trial ever. This counsel has a very high value because ACEi/ARBs have a top 1A recommendation based on a large group of studies like CONSENSUS [CONSESUS Trial Study Group, 1987], SOLVD [SOLVD Investigators, 1991], SAVE [Pfeffer et al. 1992] and TRACE [Køber et al. 1995] for ACEi or, VAL-Heft [Cohn et al. 2001], HEAAL [Konstam et al. 2009] and CHARM [Pfeffer et al. 2003], in the case of ARBS. Beta-blockers share the same 1A recommendation with also an important number of studies like MERIT-HF [MERIT HF Study Group, 1999], CIBIS-II [CIBIS-II Investigators, 1999], COPERNICUS [Packer et al. 2002] or SENIORS [Flather et al. 2005]. On the other hand, ivabradine, which is one of the latest incorporations to the treatment of HF, has a modest IIa-B/IIa-C (European guidelines) or IIa-BR (American guidelines) recommendation with two supporting studies: SHIFT [Swedberg et al. 2010] and Beautiful [Fox et al. 2008].

In conclusion, ACEis have been the cornerstone of HF with reduced EF treatment for >25 years since enalapril was found to improve survival which was the beginning of an ‘effective disease-modifying drugs’ era [CONSESUS Trial Study Group, 1987; SOLVD Investigators, 1991]. Sacubitril/valsartan which consists of the NEP inhibitor sacubitril and the ARB valsartan has shown to be superior to the ACEi enalapril, reducing the risk of death and HFH, facts that were consistent all across different studied subgroups or populations. In addition, sacubitril/valsartan was more effective at improving symptoms and preventing clinical deterioration in surviving patients. So, having reached this point it is quite reasonable to assume that after PARADIGM-HF and with the appearance of the first ARNI (first-in-class medicine), the basis of our current HF treatment will irremediably change and in consequence, our clinical practice.