1. Entresto® (sacubitril & valsartan)
Manufacturer: Novartis Pharmaceuticals Corporation
FDA Approval Date: July

2. Entresto® - sacubitril/valsartan Clinical Application
Indications:
Neprilysin inhibitor and angiotensin II receptor blocker combination to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction
Place in therapy:
Patient who have progressed in severity of their heart failure on optimum ACE inhibitor therapy

3. Entresto® - sacubitril/valsartan Clinical Application
Contraindications
Hypersensitivity to any component
History of angioedema related to previous ACE inhibitor or ARB therapy
Concomitant use with ACE inhibitors
Concomitant use with aliskiren in patients with diabetes

4. Entresto® - sacubitril/valsartan Clinical Application
Warnings & precautions
Observe for signs and symptoms of angioedema and hypotension
Monitor renal function and potassium in susceptible patients

5. Entresto® - sacubitril/valsartan Clinical Application
Pregnancy – contraindicated
Lactation – not recommended
Pregnancy
When pregnancy is detected, discontinue Entresto as soon as possible
Direct RAAS agent that can cause injury and death to the fetus
Lactation
Not recommended
Crosses into breast milk of rats
Potential for serious adverse reactions

6. Entresto® - sacubitril/valsartan Drug Facts
Pharmacology:
Sacubitril – prodrug metabolized to active metabolite (LBQ657), which inhibits neprilysin
Neprilisyn – neutral endopeptidase
Leads to increase in level of peptides, including natriuretic peptides
Valsartan – blocks the angiotensin II type-1 (AT1) receptor
Sacubitril MOA – increases concentration of natriuretic peptides
Natriuretic peptides induce natriuresis – lets sodium go, letting water go
In effect, sacubitril decreases blood volume

7. Entresto® - sacubitril/valsartan Drug Facts
Pharmacokinetics: A
Time to peak: 0.5 hrs
Time to peak of metabolite: 2 hrs D
Protein binding – 94-97%
Vd: 103 L M
Metabolized by esterases to active metabolite
Major metabolite is not metabolized E
T1/2 sacubitril: 1.4 hrs
T1/2 metabolite: 11.5 hrs

8. Entresto® - sacubitril/valsartan Drug Interactions
Precipitant
Object
Nature of interaction
Entresto*
Furosemide, levonorgestrel, HCTZ, metformin
Decrease AUC and Cmax
Atorvastatin
Increase AUC and Cmax
Entresto
ACE-I
Increased risk of angioedema
Aliskiren
Dual RAAS blockade
Potassium-sparing diuretics, ACE-I
Increased risk of hyperkalemia
NSAID
Decreased renal function
Lithium
Increased concentrations
Drug Interactions – Object Drugs:
Object drugs are affected by “the reviewed drug”
List ( ##%) if available
Ex: ASA (100%)

9. Entresto® - sacubitril/valsartan Adverse Effects
Side effect
Entresto
Enalapril
Angioedema
0.5%
0.2%
Hypotension
18%
12%
Impaired renal function 6% 5%
Hyperkalemia
14%
Cough 9%
13%
Angioedema
19 pts on Entresto, 10 pts on enalapril
No airway compromise or requirement for mechanical airway protection

10. Entresto® - sacubitril/valsartan Monitoring Parameters
Efficacy Monitoring:
Blood pressure at each visit and dose titration
Toxicity Monitoring:
Serum electrolytes (K+)
SCr

11. Entresto® - sacubitril/valsartan Prescription Information
Dosing: initial
Previous ACE-I or ARB – 49/51 mg bid
No ACE-I or ARB or low doses – 24/26 mg bid
Dosing: target
Titrate after 2-4 weeks to 97/103 mg bid as tolerated by the patient

12. Entresto® - sacubitril/valsartan Prescription Information
Renal impairment
Mild-moderate – no dose adjustment
Severe – 24/26 mg bid (initial)
Hepatic impairment
Mild – no adjustment
Moderate (Child-Pugh B) – 24/26 mg bid (initial)
Severe impairment – not recommended

13. Entresto® - sacubitril/valsartan Prescription Information
If switching from ACE-I to Entresto, 36 hour washout period is recommended
Cost – Source: NY Times; Accessed 8/21/15
$4,500/year
Novartis offers free 30-day supply and $10 co-pay cards

14. Entresto® - sacubitril/valsartan Literature Review
PARADIGM-HF
Purpose: To compare the combination of sacubitril/valsartan with enalapril in patients who have HFrEF
Design: randomized, double-blind, phase 3 trial
1043 sites in 47 countries
McMurray JJV, et al. N Engl J Med. 2014;371(11):

15. Entresto® - sacubitril/valsartan Literature Review
Inclusion Criteria
Exclusion Criteria
Inclusion Criteria
Exclusion Criteria
Age >18 years
NYHA class II-IV
Ejection fraction <40% (amended to <35%)
BNP >150 pg/mL or pro- BNP >600 pg/mL
Treatment with ACE-I or ARB
Symptomatic hypotension
SBP <100 mg
eGFR <30 ml/min/1.73 m2 or  eGFR >25%
Serum K+ >5.2 mEq/L
Hx of angioedema or unacceptable side effects during receipt of ACE-I or ARB
If the patient had been hospitalized, the BNP cut-off was >100 and pro-BNP >400
For at least 4 weeks prior to screening, pts had to be on a Beta-blocker plus an ACE-I or ARB dose equivalent to at least enalapril 10 mg daily
McMurray JJV, et al. N Engl J Med. 2014;371(11):

16. Entresto® - sacubitril/valsartan Literature Review
Intervention: LCZ mg bid vs. enalapril 10 mg bid
Primary endpoint: composite of death from cardiovascular causes or a first hospitalization for HF
Secondary endpoint:
Time to death from any cause
Change from baseline to 8 months in clinical summary score (KCCQ)
Time to new onset atrial fibrillation
Time to first occurrence of a decline in renal function
Dose of enalapril chosen based on CONSENSUS and SOLVD trials
Run in period – 2 weeks of enalapril and then 4-6 weeks of Entresto
Withheld each a day before switching treatments
Powered for cardiovascular death – not for primary endpoint in general or for their claim to fame of decreasing hospitalization by 21%
McMurray JJV, et al. N Engl J Med. 2014;371(11):

17. Entresto® - sacubitril/valsartan Literature Review
Baseline characteristics
Entresto (N=4187)
Enalapril (N=4212)
Age
63.8
Female
879 (21.0%)
953 (22.6%)
White
2763 (66.0%)
2781 (66.0%)
Medical History:
HTN
Afib
Hospitalization for HF MI
Pretrial use of ACE-I
Pretrial use of ARB
2969 (70.9%)
1517 (36.2%)
2607 (62.3%)
1818 (43.4%)
3266 (78.0%)
929 (22.2%)
2971 (70.5)
1574 (37.4%)
2667 (63.3%)
1816 (43.1%)
3266 (77.5%)
963 (22.9%)
Treatment at randomization:
Diuretic
Beta-blocker
Mineralocorticoid antagonist
3363 (80.3%)
3899 (93.1%)
2271 (54.2%)
3375 (80.1%)
3912 (92.9%)
2400 (57.0%)
NYHA class II
2998 (71.6%)
2921 (69.3%)
McMurray JJV, et al. N Engl J Med. 2014;371(11):

18. Entresto® - sacubitril/valsartan Literature Review
Results
Entresto (N=4187)
Enalapril (N=4212)
HR or Difference (95% CI)
P-value
Composite outcome
914 (21.8)
1117 (26.5)
0.80 ( )
<0.001
Death from cardio-vascular causes
558 (13.3)
693 (16.5)
0.80 ( )
1st hospitalization for worsening HF
537 (12.8)
658 (15.6)
0.79 ( )
Death from any cause
711 (17.0)
835 (19.8)
0.84 ( )
Change in KCCQ clinical summary score at 8 mo
-2.99
-4.63
1.64 ( )
0.001
New-onset afib
84 (3.1)
83 (3.1)
0.97 ( )
0.83
Decline in renal fxn
94 (2.2)
108 (2.6)
0.86 ( )
0.28
NNT – primary event – 21 pts
NNT – death from cardiovascular causes – 32 pts
NYHA class at randomization had an effect on primary endpoint (nominal; p=0.03)
Not seen for death from cardiovascular causes
McMurray JJV, et al. N Engl J Med. 2014;371(11):

19. Entresto® - sacubitril/valsartan Literature Review
Safety endpoints
Entresto (N=4187)
Enalapril (N=4212)
P-value
Hypotension
Symptomatic
588 (14.0)
388 (9.2)
<0.001
Symptomatic w/ SBP <90 mmHg
112 (2.7)
59 (1.4)
SCr > 2.5 mg/dl
139 (3.3)
188 (4.5)
0.007
Serum K >6.0 mmol/L
181 (4.3)
236 (5.6)
Cough
474 (11.3)
601 (14.3)
SCr >3.0 mg/dL not significant
Serum K >5.5 mmol/L not significant
Angioedema not significant
McMurray JJV, et al. N Engl J Med. 2014;371(11):

20. Entresto® - sacubitril/valsartan Literature Review
Conclusions
Entresto’s dual inhibition was more effective in reducing the risk of death from cardiovascular causes or hospitalization for HF than ACE inhibition with enalapril
The only significant side effect was symptomatic hypotension, though this did not increase the rate of discontinuation
McMurray JJV, et al. N Engl J Med. 2014;371(11):

21. Entresto™ - sacubitril/valsartan Summary
Entresto™ inhibits neprilysin and angiotensin receptors
Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction
Initial dose is based on receipt of ACE-I or ARB therapy prior to initiation
Avoid use in combination with an ACE-I or in patients with a history of angioedema
Most common side effect is hypotension

22. Entresto® - sacubitril/valsartan References
Entresto [sacubitril and valsartan] package insert. Novartis Pharmaceutical Corporation. July
McMurray, J, et al. PARADIGM-HF Study. New England Journal of Medicine. 2014;371;11:
Pollack, A. The New York Times Website. F.D.A. Approves Heart Drug Entresto Said to Cut Death Risk by 20%. rnational/fda-approves-heart-drug-entresto-after- promising-trial-results.html. Published July 7, Accessed August 21, 2015.