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Drug notes

Entresto (sacubitril/valsartan)
Introduction vascular resistance and increased
Catherine Russell1 Heart failure has a high prevalence and sodium and water retention. The
MRCP(UK), ST3 Endocrinology and Diabetes poor prognosis, with ~900000 patients RAAS as a target for treatment in
in the UK and 3040% of patients likely heart failure is well established
Miles Fisher1
MD, FRCP, Consultant Physician
to die within one year of diagnosis.1 It is with good evidence for therapeutic
caused by any structural or functional benefit from ACE inhibitors (ACEIs)
Gerry McKay1 abnormality that impairs the ability of and angiotensin II receptor blockers
BSc(Hons) FRCP, Consultant Physician the heart to pump effectively, most (A2RBs). Raised cardiac filling
commonly due to ischaemic heart pressures also cause increased
Glasgow Royal Infirmary, Glasgow, UK disease, but can also be as a result of mechanical stretch activating the
valvular, pericardial, endocardial or secretion of precursor natriuretic
conduction problems. One-third of peptides, which in their active form
Correspondence to: patients with heart failure have dia cause vasodilatation, natriuresis and
Dr Catherine Russell, Specialty Trainee, Department of
betes, where a combination of abnor- inhibit the RAAS. The natriuretic
Clinical Pharmacology, Diabetes and Endocrinology,
Glasgow Royal Infirmary, 84 Castle Street, Glasgow
mal systolic function and diastolic peptides that are significant in heart
G40SF, UK; email: filling abnormalities contribute to the failure are atrial natriuretic peptide
disorder. Entresto (a combination of (ANP), B natriuretic peptide (BNP)
sacubitril/valsartan) has demonstrated and C natriuretic peptide (CNP). In
efficacy in reducing morbidity and chronic heart failure (CHF), levels of
mortality in patients with heart failure. natriuretic peptide are reduced in
part due to the increased activity of
Pathophysiology neprilysin which enhances the rate of
Elevated cardiac filling pressures, their degradation.
decreased cardiac output and Previous attempts at increasing
reduced oxygen delivery cause an active BNP using the synthetic BNP
activation of the renin angiotensin nesiritide were unsuccessful due to
aldosterone system (RAAS) and sym- associated significant hypotension,
pathetic nervous systems leading over high cost, need for intravenous admin-
time to complications such as myocar- istration route and studies not showing
dial remodelling, increased systemic a reduction in death or hospitalisation

Natriuretic peptide (NP) Heart failure Renin angiotensin

system Cardiac output aldosterone system
Ventricular filling pressure
Fluid volume
Atrial NP (ANP) Atrial pressure Renin production
Brain/B-type NP (BNP)
C-type NP (CNP)
Angiotensinogen angiotensin I
Sacubitril/valsartan Angiotensin
Natriuresis converting enzyme
Sacubitril (prodrug) Valsartan
Renin release Angiotensin II
Cardiac remodelling LBQ657 (active)

X Neprilysin X
Inactive NPs AT1 receptor AT2 receptor
Vasoconstriction Vasodilation
Blood pressure Blood pressure
Aldosterone (H2O and Natriuresis
Na+ retention) Cardiac remodelling
Cardiac remodelling

Figure 1. Entresto works by a dual effect on the natriuretic system and the renin angiotensin aldosterone system

Drug notes
Entresto (sacubitril/valsartan)

rates.2 Trials of neprilysin inhibitors A total of 10521 were recruited

showed increases in ANP levels and with an NYHA class of II, III or IV, an Key points
natriuresis but also had associated ejection fraction of 40% (later
Heart failure has a high prevalence with
increased levels of angiotensin II as amended to 35%), plasma BNP level
a poor prognosis
neprilysin also has a role in angiotensin of >150pg/ml (or if hospitalised in
There are a number of medications
II degradation. The first neprilysin- the last 12 months with heart failure
available for use that have been shown
ACEI combination, omapatrilat, failed >100pg/ml). Eligible patients were
to improve prognosis in heart failure
to demonstrate superiority over switched from their usual ACEI or
including ACE inhibitors, A2RBs, beta
enalapril and was withdrawn due to the A2RB to single-blind treatment with
blockers and mineralocorticoid inhibitors
high occurrence and severity of enalapril 10mg bd for two weeks. If
T he combination of sacubitril/valsartan
angioedema thought to be due to tolerated, the regimen was switched to
(Entresto) has been shown to improve
increased levels of bradykinin and sub- Entresto for 46 weeks titrated up
morbidity and mortality in patients
stance P caused by the inhibition of from 100mg bd to 200mg bd. Patients
with heart failure, even in patients who
neprilysin, ACE and aminopeptidiase.3 were then randomly assigned to
would have previously been considered
Entresto (sacubitril/valsartan) is a first- double-blind treatment with either
to be on optimal treatment
in-class drug combining a neprilysin enalapril 10mg bd or Entresto 200mg
inhibitor and A2RB. bd. Enalapril was withheld a day
before initiation of treatment with Discussion
Pharmacology Entresto and Entresto was withheld a The superiority of Entresto over enal-
Figure 1 outlines the pharmacologi- day before randomisation to minimise april in reducing both morbidity and
cal actions of Entresto. It is adminis- the risk of angioedema. The primary mortality in chronic heart disease in
tered orally as a complex of sacubitril outcome was death from cardiovascu- the PARADIGM-HF trial demonstrates
and valsartan. Once ingested the lar causes and first hospitalisation for an exciting development in the treat-
complex dissociates. Sacubitril, a heart failure. There were significantly ment of CHF. This, coupled with a
prodrug, is metabolised by esterases fewer deaths due to cardiovascular lower incidence of adverse reaction in
to the active metabolite LBQ657. causes for those on Entresto (558 the Entresto group during the study,
This inhibits neprilysin which is [13.3%]) compared with those on raises the possibility that patients who
responsible for the breakdown of enalapril (693 [16.5%]); (hazard ratio have had an ACEI withdrawn due to
natriuretic peptides. This results in 0.80, 95% Cl 0.710.89; p<0.001). The hyperkalaemia, cough or renal dys-
increasing levels of endogenous Entresto-treated patients also demon- function may have another treatment
natriuretic peptide and therefore strated lower rates of hospitalisation option available to them. Current
increased benefit of natriuresis, diu- for heart failure (537 [12.8%] com- NICE guidance suggests Entresto is an
resis, vasodilatation and inhibition of pared with 658 [15.6%]) in those option for treating symptomatic CHF
RAAS. As neprilysin is also responsi- receiving enalapril (hazard ratio 0.79, with reduced ejection fraction, but
ble for the breakdown of angiotensin 95% Cl 0.710.89; p<0.001). Death only in patients with NYHA class II IV
II, an ACEI or A2RB is necessary to from any cause was also lower in those symptoms and a left ventricular ejec-
counteract this. Valsartan acts by treated with Entresto compared tion fraction of 35% and who are
selective blockade of the angiotensin with enalapril (711 [17.0%] vs 835 already taking a stable dose of ACEI or
II AT1 receptor thereby restricting [19.8%]; hazard ratio 0.84, 95% Cl A2RB. Treatment with sacubitril/
the stimulation of aldosterone secre- 0.760.93; p<0.001). Symptoms were valsartan should be started by a heart
tion and vasoconstriction while also assessed via the Kansas City failure specialist with access to a
allowing the stimulation of the angio- Cardiomyopathy Questionnaire. In multidisciplinary heart failure team.
tensin II AT2 receptor. This has the the first eight months, the Entresto- Similar advice is given by the Scottish
effect of decreased cell proliferation, treated patients performed better Medicines Consortium who approved
apoptosis and bradykinin and nitric with a reduction of 2.99 points versus its use.
oxide induced vasodilation. The a reduction of 4.63 points in the
mean elimination half-life of sacubi- enalapril-treated patients (between- Declaration of interests
tril, LBQ657 and valsartan ranges group difference 1.64 points; 95% Cl Professor Fisher has received honor
from 0.93.3, 12.314.7 and 1522.6 0.63 or 2.65; p=0.001). At the third aria for advisory boards and lectures
hours. The prodrug sacubitril is interim analysis the trial was halted as from Novartis.
hydrolysed by esterases but LBQ657 the prespecified stopping boundary
and valsartan do not undergo signifi- for an overwhelming benefit had References
cant hepatic metabolisation. been crossed. 1. NICE. Chronic heart failure in adults: management.
NICE guideline CG108. August 2010. https://www. [accessed 23 May
Trials of safety and efficacy Evidence specific to diabetes 2016].
The PARADIGM-HF study was a While there was no specific subgroup 2. OConnor CM, et al. Effect of nesiritide in patients
with acute decompensated heart failure. N Engl J
phase 3, randomised, double-blind analysis for those with diabetes in Med 2011;365:3243.
trial in 1043 centres across 47 coun- PARADIGM-HF, they contributed to 3. Pickering TG. The rise and fall of omapatrilat.
tries conducted with the aim of show- 34.7% of the Entresto group and Medscape News and Perspectives. www.medscape.
ing superiority over enalapril on 34.6% of the enalapril group making com/viewarticle/443224 [accessed 23 May 2016].
4. McMurray JJV, et al. Angiotensinneprilysin inhibi-
morbidity and mortality in patients a significant proportion of both tion versus enalapril in heart Failure. N Engl J Med
with CHF.4 study groups. 2014;371:9931004.