Clinical Review & Education

From The Medical Letter on Drugs and Therapeutics

Sacubitril/Valsartan (Entresto) for Heart Failure

The FDA has approved Entresto (Novartis), an oral fixed-dose com- nomedullin. Inhibition of neprilysin by LBQ657, the active metabo-
bination of the neprilysin inhibitor sacubitril and the angiotensin re- lite of sacubitril, increases the levels of these peptides, decreasing
ceptor blocker (ARB) valsartan, to reduce the risk of cardiovascular vasoconstriction, sodium retention, and maladaptive remodeling.
death and heart failure hospitalization in patients with heart failure Valsartan blocks the angiotensin II type-1 (AT1) receptor, inhibiting
with reduced ejection fraction. Sacubitril is the first neprilysin in- angiotensin II and the release of aldosterone (Box).2
hibitor to become available in the US.
Clinical Studies
Standard Treatment Approval of Entresto was based on a double-blind trial (PARADIGM-
Patients with symptomatic heart failure with reduced ejection frac- HF) in 8442 patients with class II-IV heart failure and a reduced ejec-
tion generally take an angiotensin-converting enzyme (ACE) inhibi- tion fraction who were randomized to Entresto 200 mg (sacubitril
tor, a beta blocker, and an aldosterone antagonist (Table). If vol- 97 mg/valsartan 103 mg) twice daily or the ACE inhibitor enalapril
ume overloaded, they may take a diuretic as well. An ARB is (Vasotec, and generics) 10 mg twice daily, both in addition to other
recommended for patients who cannot tolerate an ACE inhibitor.1 drugs. The study was stopped early because a prespecified interim
analysis showed lower cardiovascular mortality in patients random-
Mechanism of Action ized to Entresto. After a median follow-up of 27 months, the pri-
Neprilysin is a neutral endopeptidase that degrades some vasoac- mary endpoint, a composite of first hospitalization for worsening
tive peptides, including natriuretic peptides, bradykinin, and adre- heart failure or cardiovascular death, occurred in significantly fewer

Table. Some Drugs for Heart Failure With Reduced Ejection Fractiona
Usual Initial Usual Maximum
Drug Some Oral Formulations Adult Dosageb Adult Dosageb Costc
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril generic 12.5, 25, 50, 100 mg 6.25 mg tid 50 mg tid $151.50
tabsd
Enalapril generic 2.5, 5, 10, 20 mg tabs 2.5 mg bid 20 mg bid 39.90
Vasotec (Valeant) 1311.60
Fosinopril generic 10, 20, 40 mg tabsd 5-10 mg once/d 40 mg once/d 10.40
Lisinopril generic 2.5, 5, 10, 20, 40 mg tabs 2.5-5 mg once/d 40 mg once/d 2.70
Abbreviations: ER, extended-release.
Prinivil (Merck) 5, 10, 20 mg tabs 94.10 a
A full version of this table appears in
Zestril (Almatica) 2.5, 5, 10, 20, 30, 40 mg 48.00 The Medical Letter on Drugs and
tabs
Therapeutics. August 3,
Perindopril erbuminee generic 2, 4, 8 mg tabs 2 mg once/d 16 mg once/d 37.30 2015;57(1474):107-109.
Aceon (Symplmed) 196.20 b
Dosage adjustment may be needed
Quinapril generic 5, 10, 20, 40 mg tabs 5 mg bid 20 mg bid 23.60 for hepatic or renal impairment.
c
Accupril (Pfizer) 185.10 Approximate WAC for 30 days
treatment at the lowest usual
Ramipril generic 1.25, 2.5, 5, 10 mg caps 1.25-2.5 mg 10 mg once/d 15.80
once/d maximum adult dosage. WAC =
wholesaler acquisition cost or
Altace (Merck) 139.90
manufacturers published price to
Trandolapril generic 1, 2, 4 mg tabs 1 mg once/d 4 mg once/d 16.20 wholesalers; WAC represents a
Mavik (Abbvie) 59.10 published catalogue or list price and
may not represent an actual
Angiotensin Receptor Blockers (ARBs)
transactional price. Source:
Azilsartan medoxomile Edarbi (Arbor) 40, 80 mg tabs 40-80 mg 80 mg once/d 162.60 AnalySource Monthly. July 5, 2015.
once/d Reprinted with permission by First
Candesartan cilexetil generic 4, 8, 16, 32 mg tabs 4-8 mg once/d 32 mg once/d 103.30 Databank, Inc. All rights reserved.
Atacand (AstraZeneca) 131.10 2015. http://www.fdbhealth.com
/policies/drug-pricing-policy.
Losartane generic 25, 50, 100 mg tabs 25-50 mg 150 mg once/d 16.20
d
once/d Available as scored tablets.
e
Cozaar (Merck) 297.40 Not approved by the FDA for
Valsartan generic 40, 80, 160, 320 mg tabsd 20-40 mg bid 160 mg bid 52.40 treatment of heart failure.
f
For patients with an eGFR
Diovan (Novartis) 319.20
<30 mL/min/1.73 m2 or for those
Angiotensin-Receptor Neprilysin Inhibitor with moderate hepatic impairment,
Sacubitril/valsartan Entresto 24/26, 49/51, 97/103 mg 49/51 mg bidf 97/103 mg bid 375.00g the dose is 24/26 mg bid.
(Novartis) tabs g
WAC according to the manufacturer.

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 From The Medical Letter on Drugs and Therapeutics Clinical Review & Education

Drug Interactions
Box. Pharmacology Concurrent use of Entresto with an ACE inhibitor is contraindi-
Class: Angiotensin-receptor neprilysin inhibitor
cated because of the risk of serious angioedema, which occurs more
often in black patients. Concurrent use of the combination with po-
Formulation: Sacubitril/valsartan - 24/26 mg, 49/51 mg, 97/103 mg
tablets
tassium-sparing diuretics or potassium supplements could lead to
hyperkalemia, especially in patients with renal impairment, diabe-
Route: Oral
tes, or hypoaldosteronism. Worsening of renal function and acute
Tmax: 0.5 hrs (sacubitril); 2 hrs (LBQ657)a; 1.5 hrs (valsartan)
renal failure could occur in patients taking Entresto and NSAIDs con-
Elimination: Sacubitril (52-68% urine; 37-48% feces); valsartan currently. Lithium toxicity has occurred in patients taking lithium and
(~13% urine; 86% feces)
an ARB.
Half-life: 1.4 hrs (sacubitril); 11.5 hrs (LBQ657)a; 9.9 hrs (valsartan)
a
Active metabolite of sacubitril. Dosage and Administration
The valsartan salt in Entresto is different from the one in Diovan;
103 mg of valsartan in Entresto is equivalent to 160 mg of valsartan
patients taking the combination compared to those taking enal- in Diovan. The recommended starting dosage of Entresto is
april (21.8% vs 26.5%). The combination significantly reduced the 49/51 mg twice daily. The dose should be doubled after 2-4 weeks
risk of first hospitalization for worsening heart failure (12.8% vs as tolerated to reach the target maintenance dosage of 97/103 mg
15.6%), death from cardiovascular causes (13.3% vs 16.5%), and all- twice daily. ACE inhibitor treatment should be stopped for 36 hours
cause mortality (17.0% vs 19.8%).3 It also slowed the progression of before starting treatment with Entresto. For patients not currently
heart failure.4 taking an ACE inhibitor or an ARB, or for those with severe renal
impairment (eGFR <30 mL/min/1.73 m 2 ) or moderate hepatic
Adverse Effects impairment, the starting dosage of Entresto is 24/26 mg twice
Hypotension and hyperkalemia were the most common adverse ef- daily. The dose should be doubled every 2-4 weeks as tolerated to
fects in the clinical trial; symptomatic hypotension occurred in 14% reach a final dose of 97/103 mg. Entresto is not recommended for
of patients taking Entresto, even though the study excluded those patients with severe hepatic impairment.
with baseline hypotension. Cough (11.3%) and elevated serum cre-
atinine (3.3%) occurred in patients treated with the combination, Conclusion
but less frequently than with enalapril. Neprilysin inhibition can cause Entresto, a combination of the neprilysin inhibitor sacubitril and the
angioedema, which occurred in 0.5% of patients treated with the ARB valsartan, was significantly more effective than the ACE inhibi-
combination compared to 0.2% of those treated with enalapril. tor enalapril in reducing the rate of death from cardiovascular causes
or hospitalization for heart failure in patients with heart failure with
Pregnancy reduced ejection fraction. It should be considered for use instead
ARBs should not be used during pregnancy because they can re- of an ACE inhibitor or an ARB for first-line treatment of heart failure
duce fetal renal function and increase fetal and neonatal morbidity with reduced ejection fraction. Hypotension and angioedema could
and death. be problematic.

ARTICLE INFORMATION Financial support comes solely from sales of for the treatment of heart failure. JACC Heart Fail.
Once a month, JAMA selects for publication one subscriptions, books, software, continuing 2014;2(6):663-670.
article previously published in The Medical Letter. education materials, and licenses. 3. McMurray JJ, Packer M, Desai AS, et al;
Previous Publication: A full version of this article www.medicalletter.org PARADIGM-HF Investigators and Committees.
was previously published: The Medical Letter on Editors: Mark Abramowicz, MD, Editor in Chief; Angiotensin-neprilysin inhibition versus enalapril in
Drugs and Therapeutics. August 3, 2015;57(1474): Gianna Zuccotti, MD, MPH, Executive Editor; heart failure. N Engl J Med. 2014;371(11):993-1004.
107-109. Jean-Marie Pflomm, PharmD, Editor 4. Packer M, McMurray JJ, Desai AS, et al;
The Medical Letter Inc. PARADIGM-HF Investigators and Coordinators.
About The Medical Letter: The Medical Letter is a REFERENCES Angiotensin receptor neprilysin inhibition
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The Medical Letter does not accept Circulation. 2015;131(1):54-61.
2. Vardeny O, Miller R, Solomon SD. Combined
advertisements, gifts, grants, or donations. neprilysin and renin-angiotensin system inhibition

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