1. Entresto (sacubitril/valsartan): A novel agent in Heart Failure Treatment

2. Disclosure Statement
Philip Leong
Potential conflicts of interest: none
Sponsorship: none
Speaker’s presentation is educational in nature and indicates agreement to abide by non- commercialism guidelines provided

3. Philip Leong
PGY1 Pharmacy Resident Centura St. Anthony Hospital

4. Learning Objectives
Understand the mechanism of action behind Entresto
Identify the clinical implications and limitations of the PARADIGM-HF trial
Determine the safety profile of Entresto
Identify the role of Entresto in heart failure management

5. Pre-test Questions
1. What is neprilysin and why is it an effective drug target?
2. Name one limitation of the PARADIGM-HF trial.
3. T/F: Patients already optimized on guideline-directed therapy should add on Entresto as a salvage option.

6. Entresto (sacubitril/valsartan)
Approved by FDA in July, 2015
Indication: Chronic heart failure NYHA class II-IV
Novartis Pharmaceuticals
Found to be superior to enalapril (ACE-inhibitor) in reducing risk of death and hospitalization in heart failure (PARADIGM-HF)
Cost: $ for 100 tablets
Understanding Heart Failure with Reduced Ejection Fraction. HelpRx. April 29th, 2016.
Understanding Heart Failure with Reduced Ejection Fraction. HelpRx. April 29th, 2016.

7. Valsartan: ARB (angiotensin-receptor blocker)
Mechanism of Action
Valsartan: ARB (angiotensin-receptor blocker)
Sacubitril: neprilysin-inhibitor
Modulation of two neurohormonal pathways, Renin-angiotensin-aldosterone system (RAAS) and the natriuretic peptide (NP) system.
Heart failure is caused by any condition which reduces the efficiency of the heart muscle, through damage or overloading. As such, it can be caused by a wide number of conditions, including myocardial infarction (in which the heart muscle is starved of oxygen and dies), hypertension (which increases the force of contraction needed to pump blood) and amyloidosis (in which misfolded proteins are deposited in the heart muscle, causing it to stiffen). Over time these increases in workload will produce changes to the heart itself:
The heart of a person with heart failure may have a reduced force of contraction due to overloading of the ventricle. In a healthy heart, increased filling of the ventricle results in increased contraction force (by the Frank–Starling law of the heart) and thus a rise in cardiac output. In heart failure this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin filaments in over-stretched heart muscle
N Engl J Med, Vol. 371, No. 11 (2014), pp

8. Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I
Angiotensin II: increase sympathetic activity, increase water-sodium-cl retention, arteriole vasoconstriction, blood pressure increase Angiotensin II: also activates aldosterone secretion (water and sodium retention), and ADH secretion (more water reabsorption in collecting duct)
A. Rad - Own work, CC BY-SA 3.0,
A. Rad - Own work, CC BY-SA 3.0,

9. Natriuretic-peptide system
Plays an important part in homeostasis
Three major components: atrial natriuretic peptide (ANP) 2. brain natriuretic peptide (BNP) C-type natriuretic peptide (CNP)
Causes natriuresis and diuresis, works against the RAAS system
NPs are secreted once the heart can no longer increase stroke volume in response to an increasing preload (Frank-Starling law)
BNP > 400 pg/ml in acute HF patients
ANP is released from atria BNP is released from ventricles CNP is released from endothelium (vasculature)

10. Natriuretic-peptide system
Neprilysin:
Neutral endopeptidase (NEP)
Responsible for degrading NPs and other substances
Inhibited by sacubitril component

11. ANP is released from atria BNP is released from ventricles CNP is released from endothelium (vasculature)
Kor Cir J, Vol. 38, No. 10 (2014), pp

12. Entresto (sacubitril/valsartan)
Why not NEP inhibition with ACE inhibition?:
Omapatrilat (inhibits NEP, ACE, aminopeptidase P)
Significant increases in angioedema
Increases in angioedema thought to be related to uninhibited bradykinin levels
No significant difference in clinical outcomes vs. enalapril
Omapatrilat was not approved by FDA
Normally ACE, neprilysin, and aminopeptidase P all degrade bradykinin. Since all 3 were inhibited, bradykinin levels were uncontrolled – and it acts as a potent vasodilator and contracts smooth muscle and increases vascular permeability
European J Heart Failure, No. 15 (2013), pp

13. PARADIGM-HF
Address which stage of heart failure, this drug was most effective in? – no correlation with outcomes and class of HF. Most pts fell into class II

14. PARADIGM-HF Study Design
Randomized, double-blinded parallel group, active-controlled study
Treatment Arms
LCZ mg BID (sacubitril 97 mg/valsartan 103 mg)
enalapril 10 mg BID
Primary Outcome
Composite of death from cardiovascular causes or a first-hospitalization for HF
The authors report that 200 mg of LCZ696 delivers the equivalent of 160 mg of valsartan. This has to do with achieved serum concentrations and systemic exposure. Neprilysin inhibition was not sustained with once daily omapatrilat so this study decided to dose the medication BID to maintain neprilysin inhibition during a 24 hour period.
N Engl J Med, Vol. 371, No. 11 (2014), pp

15. Symptomatic hypotension SBP < 100 mm Hg
PARADIGM-HF
Inclusion Criteria:
18 years old
NYHA class II-IV
EF < 35%
BNP > 150 pg/mL
Exclusion Criteria:
Symptomatic hypotension
SBP < 100 mm Hg
eGFR < 30 ml/min per 1.73 m2 of BSA
Serum K+ > 5.2 mmol/L
Hx of angioedema or intolerance to ACE inhibitors or ARBs
How many people in each group
N Engl J Med, Vol. 371, No. 11 (2014), pp

16. Enalapril: 1117 patients (26.5%) HR = 0.80, P < 0.001
Results
Death from cardiovascular causes or hospitalization for heart failure (composite)
LCZ696: 914 patients (21.8%)
Enalapril: 1117 patients (26.5%)
HR = 0.80, P < 0.001
Boundary of overwhelming benefit crossed, trial stopped prematurely
N Engl J Med, Vol. 371, No. 11 (2014), pp

17. Enalapril: 693 patients (16.5%) HR = 0.80, P < 0.001
Results
Death due to CV causes:
LCZ696: 558 patients (13.3%)
Enalapril: 693 patients (16.5%)
HR = 0.80, P < 0.001
Hospitalized for heart failure:
LCZ696: 537 patients (12.8%)
Enalapril: 658 (15.6%)
N Engl J Med, Vol. 371, No. 11 (2014), pp

18. Results
Change from baseline to 8 months in Kansas City Cardiomyopathy Questionnaire (KCCQ):
LCZ696: pts
enalapril: pts
P = 0.001
The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.
This instrument was developed and validated by John Spertus. John is Director of Cardiovascular Education and Outcomes Research at the Mid America Heart Institute, and he is also a Professor of Medicine at the University of Missouri – Kansas City.
In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. For brevity, only the performance characteristics of the overall summary score are presented in this discussion.
NYHA I lives around 80
NYHA IV lives around 20
N Engl J Med, Vol. 371, No. 11 (2014), pp

19. Might want a verbal expalanation here
Might want a verbal expalanation here. Significantly more hypotension due to larger vasodilatory effects but not significant enough for patients to withdraw or drop out of trail
N Engl J Med, Vol. 371, No. 11 (2014), pp

20. Discontinuation due to adverse event (AE):
Safety
Discontinuation due to adverse event (AE):
LCZ696: 10.7%
enalapril: 12.3%
P = 0.03
Most common AE associated with Entresto:
Hypotension (18%)
Hyperkalemia (12%)
Cough (9%)
Dizziness (6%)
renal failure/acute renal failure (5%)
N Engl J Med, Vol. 371, No. 11 (2014), pp

21. Limitations/Criticism:
PARADIGM-HF
Limitations/Criticism:
“Run-in” period not representative of real-life population
Was beta-blocker therapy optimized?
Not versus valsartan alone
Enalapril 20 mg BID would have been more optimal
Switching from physician-directed ACE-inhibitor choice to enalapril (cannot ensure equivalent dosing)
Difficult to assess whether the benefit is truly derived from the combination of neprilysin and RAAS inhibition
Elaborate on run-in period
Enalapril 20 bid is not what was cited in the ACCF guidelines anyways mg/day was average – so this point is moot. In clinical practice, you don’t get a run-in period…. The study actually achieved a daily dosage of enalapril of 18.9 mg
(P=0.44 for the interaction between the baseline beta-blocker dose and the effect of LCZ696).
Is benefit dervied from ARNI or the disparity in RAAS drug dosing.
N Engl J Med, Vol. 371, No. 11 (2014), pp

22. The intended role of Entresto is to replace the ACE-inhibitor.
ACCF/AHA Guidelines:
ACE-inhibitor (ARB if necessary)
Beta-blocker
Diuretic (if fluid retention)
Aldosterone antagonist (NYHA II-IV, LVEF < 35%)
Hydralazine/isosorbide dinitrate (African Americans)
Digoxin
Anticoagulation
The intended role of Entresto is to replace the ACE-inhibitor.
Alters the foundation of heart failure therapy.
2013 ACCF/AHA Guideline for Management of Heart Failure

23. MOA PARADIGM-HF ROLE In Summary Neprilysin-inhibition ARB NP System
RAAS system
PARADIGM-HF
Overwhelming benefit for death from CV causes and HF hospitalization
Symptomatic hypotension
ROLE
Disrupts guideline-directed therapy
Replaces ACE-i

24. Post-test Questions
1. What is neprilysin and why is it an effective drug target?

25. 1. What is neprilysin and why is it an effective drug target?
Post-test Questions
1. What is neprilysin and why is it an effective drug target?
Neprilysin normally degrades NPs  Inhibiting neprilysin allows for more natriuresis and diuresis, less cardiac remodeling

26. Post-test Questions
2. Name one limitation of the PARADIGM-HF trial.

27. Post-test Questions
2. Name one limitation of the PARADIGM-HF trial. “Run-in” period, Not compared to valsartan alone, suboptimal dosing of ace-inhibitor, etc.

28. Post-test Questions
3. T/F: Patients already optimized on guideline-directed therapy should add on Entresto as a salvage option.

29. Post-test Questions
3. T/F: Patients already optimized on guideline-directed therapy should add on Entresto as a salvage option. False, Entresto replaces ace-inhibitor therapy

30. Thanks!
ANY QUESTIONS?
Philip Leong, PharmD PGY1 Pharmacy Resident Centura St. Anthony Hospital