Sacubitril/valsartan

Sacubitril/valsartan, sold under the brand

name Entresto among others, is a
combination drug for use in heart failure
developed by Novartis. It consists of the
neprilysin inhibitor sacubitril and the
angiotensin receptor blocker valsartan, in
a 1:1 mixture by molecule count. It is
recommended for use as a replacement
for an ACE inhibitor or an angiotensin
receptor blocker in people with heart
failure with reduced ejection fraction.[1]
Sacubitril/valsartan

Combination of
Sacubitril Neprilysin inhibitor
Valsartan Angiotensin II receptor
antagonist

Clinical data
Trade names Entresto, Azmarda, other
Synonyms LCZ696
AHFS/Drugs.com entresto
License data EU EMA: by INN
Routes of By mouth
administration
ATC code C09DX04 (WHO )

Legal status
Legal status In general:
℞ (Prescription only)

Identifiers
CAS Number 936623-90-4
PubChem CID 24755604
KEGG D10226

Potential side effects include angioedema,

kidney problems, and low blood
pressure.[1] The risk of kidney problems
and increased levels of serum potassium
with sacubitril/valsartan is lower than that
of an ACE inhibitor or angiotensin receptor
blocker. The combination is sometimes
described as an "angiotensin receptor-
neprilysin inhibitor" (ARNi).

It was approved under the FDA's priority

review process on July 7, 2015.[2] It is also
approved in Europe.[3] In the USA, the
wholesale cost for a year of
sacubitril/valsartan is $4,560 per person
as of 2015.[4] Similar class generic drugs
without sacubitril, such as valsartan alone,
cost approximately $48 a year.[5] One
industry-funded analysis found a cost of
$45,017 per QALY.[6] The wholesale cost to
the National Health Service in the UK is
approximately £1,200 per person per
year.[7]

Medical uses
Sacubitril/valsartan can be used instead
of an ACE inhibitor or an angiotensin
receptor blocker in people with heart
failure and a reduced left ventricular
ejection fraction (LVEF), alongside other
standard therapies (e.g. beta-blockers) for
heart failure.[1][2][8] It is not known whether
sacubitril/valsartan is useful for the
treatment of heart failure in people with
normal LVEF.[8] The level of evidence to
support its use is less than that for ACE
inhibitors and ARBs.[1] In those with class
2 or 3 failure who do well with an ACE
inhibitor or ARB but still have symptoms,
changing to sacubitril/valsartan decreases
the risk of death.[1] It has not been
compared directly to ARBs as of 2016.[1]

Changing 100 people from an ACE

inhibitor or angiotensin II receptor
antagonist to sacubitril/valsartan for 2.3
years would prevent 3 deaths, 5
hospitalizations for heart failure, and 11
hospitalizations overall.[8]

Adverse effects
Common adverse effects in the main
study were cough, hyperkalemia (high
potassium levels in the blood, which can
be caused by valsartan), kidney
dysfunction, and hypotension (low blood
pressure, a common side effect of
vasodilators and ECF volume reducers).
12% of the patients withdrew from the
study during the run-in phase because of
such events.[8]

Sacubitril/valsartan is contraindicated in
pregnancy because it contains valsartan, a
known risk for birth defects.[9]

Pharmacology
Valsartan blocks the angiotensin II
receptor type 1 (AT1). This receptor is
found on both vascular smooth muscle
cells, and on the zona glomerulosa cells of
the adrenal gland which are responsible
for aldosterone secretion. In the absence
of AT1 blockade, angiotensin causes both
direct vasoconstriction and adrenal
aldosterone secretion, the aldosterone
then acting on the distal tubular cells of
the kidney to promote sodium
reabsorption which expands extracellular
fluid (ECF) volume. Blockade of (AT1) thus
causes blood vessel dilation and reduction
of ECF volume.[10][11]
Sacubitril is a prodrug that is activated to
sacubitrilat (LBQ657) by de-ethylation via
esterases.[12] Sacubitrilat inhibits the
enzyme neprilysin,[13] a neutral
endopeptidase that degrades vasoactive
peptides, including natriuretic peptides,
bradykinin, and adrenomedullin. Thus,
sacubitril increases the levels of these
peptides, causing blood vessel dilation
and reduction of ECF volume via sodium
excretion.[14]

Neprilysin also has a role in clearing the

protein amyloid beta from the
cerebrospinal fluid, and its inhibition by
sacubitril has shown increased levels of
AB1-38 in healthy subjects (Entresto
194/206 for two weeks). Amyloid beta is
considered to contribute to the
development of Alzheimer's disease.[9]

Chemistry
Sacubitril/valsartan is co-crystallized
sacubitril and valsartan, in a one-to-one
molar ratio. One sacubitril/valsartan
complex consists of six sacubitril anions,
six valsartan anions, 18 sodium cations,
and 15 molecules of water, resulting in the
molecular formula
C288H330N36Na18O48·15H2O and a
molecular mass of 5748.03 g/mol.[15][16]
The substance is a white powder
consisting of thin hexagonal plates. It is
stable in solid form as well as in aqueous
(watery) solution with a pH of 5 to 7, and
has a melting point of about 138 °C
(280 °F).[16]

History
During its development by Novartis,
Entresto was known as LCZ696. It was
approved under the FDA's priority review
process on July 7, 2015.[2] It was also
approved in Europe in 2015.[3]

Society and culture

Trial design

There was controversy over the

PARADIGM-HF trial—the Phase III trial on
the basis of which the drug was approved
by the FDA. For example, both Richard
Lehman, a physician who writes a weekly
review of key medical articles for the BMJ
Blog and a December 2015 report from the
Institute for Clinical and Economic Review
(ICER) found that the risk–benefit ratio
was not adequately determined because
the design of the clinical trial was too
artificial and did not reflect people with
heart failure that doctors usually
encounter.[4]:28[17] On the other hand, in
December 2015 Steven Nissen and other
thought leaders in cardiology said that the
approval of sacubitril/valsartan had the
greatest impact on clinical practice in
cardiology in 2015, and Nissen called the
drug "a truly a breakthrough approach."[18]

One 2015 review stated that

sacubitril/valsartan represents "an
advancement in the chronic treatment of
heart failure with reduced ejection
fraction" but that widespread clinical
success with the drug will require taking
care to use it in appropriate patients,
specifically those with characteristics
similar to those in the clinical trial
population.[19] Another 2015 review called
the reductions in mortality and
hospitalization conferred by
sacubitril/valsartan "striking", but noted
that its effects in heart failure people with
hypertension, diabetes, chronic kidney
disease, and the elderly needed to be
evaluated further.[20]

Cost

The wholesale cost for a year of

sacubitril/valsartan in the USA is $4,560
per person as of 2015,[4] but the cost to
the NHS in the UK is less than £1,200 per
person per year.[7] Similar class generic
drugs without sacubitril, such as valsartan
alone, cost approximately $48 a year.[5]
One analysis found a cost of $45,017 per
QALY.[6]

Research
The PARADIGM-HF trial (in which Milton
Packer was one of the principal
investigators) compared treatment with
sacubitril/valsartan to treatment with
enalapril.[21] People with heart failure and
reduced LVEF (10,513) were sequentially
treated on a short-term basis with
enalapril and then with
sacubitril/valsartan. Those that were able
to tolerate both regimens (8442, 80%)
were randomly assigned to long-term
treatment with either enalapril or
sacubitril/valsartan. Participants were
mainly white (66%), male (78%), middle
aged (median 63.8 +/- 11 years) with
NYHA stage II (71.6%) or stage III (23.1%)
heart failure.[22]

The trial was stopped early after a

prespecified interim analysis revealed a
reduction in the primary endpoint of
cardiovascular death or heart failure in the
sacubitril/valsartan group relative to those
treated with enalapril. Taken individually,
the reductions in cardiovascular death and
heart failure hospitalizations retained
statistical significance.[8] Relative to
enalapril, sacubitril/valsartan provided
reductions[22] in

the composite endpoint of

cardiovascular death or hospitalization
for heart failure (incidence 21.8% vs
26.5%)
cardiovascular death (incidence 13.3%
vs 16.5%)
first hospitalization for worsening heart
failure (incidence 12.8% vs 15.6%), and
all-cause mortality (incidence 17.0% vs
19.8%)
The favorable effect of sacubitril/valsartan
was seen in all subgroups examined,
including those based on age, sex, weight,
race, NYHA class, presence or absence of
reduced kidney function, diabetes mellitus,
atrial fibrillation, hypertension, and prior
hospitalization.[9] Additional analyses of
the trial demonstrated a meaningful
representation of minority groups and well
as a benefit in patients with an implantable
cardiac device. Limitations of the trial
include scarce experience with initiation of
therapy in hospitalized patients and in
those with NYHA heart failure class IV
symptoms.[23][24]
References
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ACC/AHA/HFSA Focused Update on New
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Ejection Fraction" . Journal of
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the Pipeline" . Boston. p. 48. Retrieved
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22. King JB, Bress AP, Reese AD, Munger
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24. Perez AL, Kittipibul V, Tang WHW,
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JACC Heart Fail. 2017;5:460-463. doi:
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