1. Inhibicion de neprelipsina y del receptor de angiotensina en pacientes con insuf. cardiaca. A proposito del estudio paradigm
Dr. Roberto Concepción

2. Magnitud del problema IC
26 millones casos IC en el mundo.
IC principal causa hospitalización USA y Europa.
1-2% de todas las hospitalizaciones.
Pacientes hospitalizados tienen una elevada mortalidad y tasa rehospitalizaciones.

3. EVOLUCION DE LA IC

4. HF SYMPTOMS & PROGRESSION
Sobreactivación del sistema RAA y del SNA es perjudicial en la IC con FE reducida.
Sympathetic nervous system
Epinephrine
Norepinephrine
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
Natriuretic peptide system
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
NPRs
NPs
HF SYMPTOMS & PROGRESSION
Renin angiotensin aldosterone system
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II
AT1R
Ang=angiotensin; AT1R=angiotensin II type 1 receptor; HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier & Abraham. N Engl J Med 2009;341:577–85

5. Bloqueo Neurohormonal en IC
Angiotensinogen
ACE
Inhibitors
Renin
Angiotensin I X
Bradykinin
ACE
Angiotensin II
Inactive peptides
Angiotensin receptor blockers X
Reduced NO and vasodilating PGs
AT1 Receptor stimulation
Aldosterone Release
Aldosterone
Antagonists X
Vasoconstriction, Na retention, myocyte hypertrophy and apoptosis, endothelial dysfunction, sympathetic activation, free radical generation, etc 5

6. Bloqueo Neurohormonal en IC
Angiotensinogen
ACE
Inhibitors
Active natriuretic peptides
Renin
Neprilysin X
Neprilysin
inhibitor X
Angiotensin I
Bradykinin
Inactive natriuretic
peptides
ACE
Angiotensin II
Inactive peptides
Angiotensin receptor blockers X
Reduced NO and vasodilating PGs
AT1 Receptor stimulation
Aldosterone Release
Aldosterone
Antagonists X
Vasoconstriction, Na retention, myocyte hypertrophy and apoptosis, endothelial dysfunction, sympathetic activation, free radical generation, etc 6

7. NEP Inhibition Must Be Accompanied By Simultaneous RAAS Blockade
NEP metabolizes Ang I and Ang II via several pathways1,2
Angiotensinogen
Ang I
Ang II
ACE
Renin
AT1 receptor
NEP
Ang-(1–7)
Inhibition of NEP alone is insufficient as it is associated with an increase in Ang II levels, counteracting the potential benefits of NEP inhibition2
NEP
Inactive fragments
NEP inhibition must be accompanied by simultaneous RAAS blockade
(e.g. AT1 receptor blockade)2
Signalling
cascades
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction Hypertrophy
Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
ACE=angiotensin converting enzyme; AT1 = angiotensin II type 1; Ang=angiotensin; NEP=neprilysin; RAAS=renin angiotensin aldosterone system
1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;
2. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9

8. ¿Se estudiaron antes los inhibidores de neprilysina?
Omapatrilat
combined neprilysin inhibitor/ACEi/aminopeptidase P
Studied in HF, hypertension
Unacceptably high incidence of angioedema
3-fold increase in risk
Increased life-threatening episodes
Kostis et al, OCTAVE Trial, Am J Hypertension 2004
Packer et al, OVERTURE Trial, Circulation 2002

9. % Decrease in Mortality
Drogas que reducen mortalidad en IC con FE reducida
Angiotensin
receptor
blocker
Mineralocorticoid
receptor
antagonist
ACE
inhibitor
Beta
blocker 0%
10%
% Decrease in Mortality
20%
Farmacos que inhiben el sistema renina-angiotensina tienen un efecto en la sobrevida
30%
40%
Based on results of SOLVD-Treatment, CHARM-Alternative,
COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10. Una enzima — Neprilysin — Degrada
Muchos Peptidos Endogenos Vasoactivos
Endogenous
vasoactive peptides
(natriuretic peptides, adrenomedullin,
bradykinin, substance P,
calcitonin gene-related peptide)
Neprilysin
Inactive metabolites

11. Inhibicion de Neprilysin Potencia la acción de
Peptidos EndogenosVasoactivos
Neurohormonal activation
Vascular tone
Cardiac fibrosis, hypertrophy
Sodium retention
Endogenous
vasoactive peptides
(natriuretic peptides, adrenomedullin,
bradykinin, substance P,
calcitonin gene-related peptide)
Neprilysin
inhibition
Neprilysin
Inactive metabolites

12. Mecanismos de progresión en IC
Myocardial or vascular
stress or injury
Increased activity or response to maladaptive
mechanisms
Decreased activity or response to adaptive mechanisms
Evolution and progression
of heart failure

13. Mechanisms of Progression in Heart Failure
Myocardial or vascular
stress or injury
Increased activity or response to maladaptive
mechanisms
Decreased activity or response to adaptive mechanisms
Angiotensin
receptor blocker
Inhibition of neprilysin
Evolution and progression
of heart failure

14. LCZ696 LCZ696: Angiotensin Receptor Neprilysin Inhibition Angiotensin
receptor blocker
Inhibition of neprilysin

15. ENTRESTO (LCZ696) simultaneously inhibits NEP (via LBQ657) and blocks AT1 receptors (via valsartan)
ANP, BNP, CNP, other
vasoactive peptides*
RAAS
Angiotensinogen
(liver secretion)
Neprilysin
Sacubitril
(AHU377; pro-drug)
Ang I
Inactive fragments
LBQ657
(NEP inhibitor) OH O HN HO
Valsartan N NH O OH
Ang II
AT1 Receptor
Vasorelaxation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
Enhancing
Inhibiting
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks AT1 receptors (via valsartan)
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI). Following oral administration LCZ696 dissociates into the prodrug sacubitril (AHU377), which is further metabolized to LBQ657, and valsartan.1,2
LCZ696 delivers simultaneous neprilysin (NEP) inhibition and AT1 receptor blockade.1
As the neprilysin enzyme degrades NPs as well as other vasoactive peptides,1 inhibition of neprilysin enhances the effects of these peptides, including vasorelaxation, natriuresis and diuresis and inhibition of cardiac fibrosis and hypertrophy.1,3–7
Through simultaneous blockade of the AT1 receptor, LCZ696 also suppresses the long-term harmful effects of RAAS over-activation, such as increased blood pressure and sodium and water retention.1
In addition, since NEP is involved in the breakdown of angiotensin II (Ang II),1 simultaneous suppression of the RAAS by LCZ696 is important to offset any potential effects of an increase in Ang II resulting from neprilysin inhibition.1,8
Of note, the biologically inert NT-proBNP  is not a substrate for neprilysin, and as such still represents a marker of cardiac wall stress even in the setting of neprilysin inhibition.1
Abbreviations
ARNI=angiotensin receptor neprilysin inhibitor; NEP=neprilysin; NP=natriuretic peptide; RAAS=renin-angiotensin-aldosterone system
References
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Gu et al. J Clin Pharmacol 2010;50:401–14
Levin et al. N Engl J Med 1998;339;321–8
Gardner et al. Hypertension 2007;49:419–26
Molkentin. J Clin Invest 2003;111:1275–77
Nishikimi et al. Cardiovasc Res 2006;69:318–28
Volpe et al. J Cardiol 2014 [Epub ahead of print]
Von Lueder et al. Circ Heart Fail 2013;6:594–605
*Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier & Abraham N Engl J Med 1999;341:577–85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9;
Feng et al. Tetrahedron Letters 2012;53:275–6

16. PARADIGM-HF
Study design

18. A Comparison of Angiotensin Receptor-Neprilysin Inhibition (ARNI) With ACE Inhibition in the Long-Term Treatment of Chronic Heart Failure With a Reduced Ejection Fraction
Milton Packer, John J.V. McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg and Michael R. Zile for the PARADIGM-HF Investigators and Committees

19. PARADIGM-HF: The most geographically diverse trial in patients with HFrEF
8442 patients were randomized at 985 sites in 47 countries
References
McMurray et al. Eur J Heart Fail. 2014;16:817–25
McMurray et al. Eur J Heart Fail 2013;15:1062–73
1. McMurray et al. Eur J Heart Fail. 2014;16:817–25; 2. McMurray et al. Eur J Heart Fail 2013;15:1062–73

20. PARADIGM-HF: El mas grande trabajo de morbi-mortalidad en IC con FE reducida.
1000
3000
4000
2000
5000
6000
8000
9000
10,000
7000
Number of patients
N=8442
N=6505
N=3834
N=2569
N=2737
N=2548
N=1798
Abbreviations
CHARM-Added=Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial; EMPHASIS-HF=Eplerenone in Mild Patients Hospitalization And Survival study in Heart Failure; HEAAL=Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; RAFT=Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; SHIFT=Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial; SOLVD-T=Studies of Left Ventricular Dysfunction Treatment trial
Reference
McMurray et al. Eur J Heart Fail. 2014;16:817–25
SOLVD-T
CHARM-Added
HEAAL
RAFT
SHIFT
EMPHASIS-HF
PARADIGM-HF
2003–2009
2001–2005
1999–2001
1986–1989
2009–2013
2006–2010
2006–2009
Recruitment
McMurray et al. Eur J Heart Fail. 2014;16:817–25

21. LCZ696 LCZ696: Angiotensin Receptor Neprilysin Inhibition Angiotensin
receptor blocker
Inhibition of neprilysin

22. Aim of the PARADIGM-HF Trial
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)
specifically designed to replace current use
of ACE inhibitors and angiotensin receptor blockers as the cornerstone of the
treatment of heart failure
LCZ696
400 mg daily
Enalapril
20 mg daily

23. PARADIGM-HF: Entry Criteria
• NYHA class II-IV heart failure
• LV ejection fraction ≤ 40%  35%
• BNP ≥ 150 (or NT-proBNP ≥ 600), but one-third if hospitalized for heart failure within 12 months
• Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks
• Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists
• Systolic BP ≥ 95 mm Hg, eGFR ≥ 30 ml/min/1.73 m2 and serum K ≤ 5.4 mEq/L at randomization

24. Single-blind run-in period
PARADIGM-HF: Study Design
Randomization
Single-blind run-in period
Double-blind period
LCZ mg BID
LCZ696
Enalapril
10 mg
BID
(1:1 randomization)
100 mg
BID
200 mg
BID
Enalapril 10 mg BID
2 weeks
1-2 weeks
2-4 weeks

25. PARADIGM-HF Was Designed to Show Incremental Effect on Cardiovascular Death
Primary endpoint was cardiovascular death or hospitalization for heart failure, but PARADIGM-HF was designed as a cardiovascular mortality trial

26. PARADIGM-HF: Secondary Endpoints
• All-cause mortality
• Change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire at 8 months
• Time to new onset of atrial fibrillation
• Time to first occurrence of a protocol-defined decline in renal function

27. PARADIGM-HF: Patient Disposition
10,521 patients screened at
1043 centers in 47 countries
Did not fulfill criteria
for randomization
(n=2079)
Randomized erroneously or at sites closed due to GCP violations (n=43)
8399 patients randomized for ITT analysis
LCZ696 (n=4187)
At last visit
375 mg daily
11 lost to follow-up
Enalapril (n=4212)
At last visit
18.9 mg daily
9 lost to follow-up
median 27 months
of follow-up

28. PARADIGM-HF: Baseline Characteristics
LCZ696
(n=4187)
Enalapril
(n=4212)
Age (years)
63.8 ± 11.5
63.8 ± 11.3
Women (%)
21.0%
22.6%
Ischemic cardiomyopathy (%)
59.9%
60.1%
LV ejection fraction (%)
29.6 ± 6.1
29.4 ± 6.3
NYHA functional class II / III (%)
71.6% / 23.1%
69.4% / 24.9%
Systolic blood pressure (mm Hg)
122 ± 15
121 ± 15
Heart rate (beats/min)
72 ± 12
73 ± 12
N-terminal pro-BNP (pg/ml)
1631 ( )
1594 ( )
B-type natriuretic peptide (pg/ml)
255 ( )
251 ( )
History of diabetes
35%
Digitalis
29.3%
31.2%
Beta-adrenergic blockers
93.1%
92.9%
Mineralocorticoid antagonists
54.2%
57.0%
ICD and/or CRT
16.5%
16.3%

30. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 40
Enalapril
(n=4212)
1117 32 24
Kaplan-Meier Estimate of
Cumulative Rates (%) 16 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236

31. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 40
Enalapril
(n=4212)
1117 32
914 24
LCZ696
(n=4187)
Kaplan-Meier Estimate of
Cumulative Rates (%) 16 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236

32. PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)40
Enalapril
(n=4212)
1117 32
914 24
LCZ696
(n=4187)
Kaplan-Meier Estimate of
Cumulative Rates (%) 16
HR = 0.80 ( )
P =
Number needed to treat = 21 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236

33. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: Cardiovascular Death 32
Enalapril
(n=4212) 24
693
Kaplan-Meier Estimate of
Cumulative Rates (%) 16 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279

34. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: Cardiovascular Death 32
Enalapril
(n=4212) 24
693
558
Kaplan-Meier Estimate of
Cumulative Rates (%) 16
LCZ696
(n=4187) 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279

35. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: Cardiovascular Death 32
Enalapril
(n=4212) 24
HR = 0.80 ( )
P =
Number need to treat = 32
693
558
Kaplan-Meier Estimate of
Cumulative Rates (%) 16
LCZ696
(n=4187) 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279

36. Hospitalization for heart failure
PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard Ratio
(95% CI) P
Value
Primary endpoint
914
(21.8%)
1117
(26.5%)
0.80
( )
Cardiovascular death
558
(13.3%)
693
(16.5%)
( )
Hospitalization for heart failure
537
(12.8%)
658
(15.6%)
0.79
( )

37. LCZ696 vs Enalapril on Primary Endpoint and on Cardiovascular Death, by Subgroups

38. Kaplan-Meier Estimate of Days After Randomization
PARADIGM-HF: All-Cause Mortality 32
Enalapril
(n=4212)
HR = 0.84 ( )
P<0.0001
835 24
711
Kaplan-Meier Estimate of
Cumulative Rates (%) 16
LCZ696
(n=4187) 8
180
360
540
720
900
1080
1260
Days After Randomization
Patients at Risk
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279

39. PARADIGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints
Treatment
effect P
Value
KCCQ clinical summary score at 8 months
– 2.99
± 0.36
– 4.63
1.64
(0.63, 2.65)
0.001
New onset
atrial fibrillation
84/2670
(3.2%)
83/2638
Hazard ratio
0.97
(0.72,1.31)
0.84
Protocol-defined decline in renal function
94/4187
(2.3%)
108/4212
(2.6%)
0.86
(0.65, 1.13)
0.28

40. PARADIGM-HF: Adverse Events
LCZ696
(n=4187)
Enalapril
(n=4212) P
Value
Prospectively identified adverse events
Symptomatic hypotension
Discontinuation for adverse event
Discontinuation for hypotension 36 29 NS

41. PARADIGM-HF: Adverse Events
LCZ696
(n=4187)
Enalapril
(n=4212) P
Value
Prospectively identified adverse events
Serum potassium > 6.0 mmol/l
181
236
0.007
Serum creatinine ≥ 2.5 mg/dl
139
188
Cough
474
601
< 0.001
Discontinuation for adverse event
449
516
0.02
Discontinuation for hyperkalemia 11 15 NS
Discontinuation for renal impairment 29 59
0.001

42. PARADIGM-HF: Adverse Events
LCZ696
(n=4187)
Enalapril
(n=4212) P
Value
Prospectively identified adverse events
Symptomatic hypotension
588
388
< 0.001
Serum potassium > 6.0 mmol/l
181
236
0.007
Serum creatinine ≥ 2.5 mg/dl
139
188
Cough
474
601
Discontinuation for adverse event
449
516
0.02
Discontinuation for hypotension 36 29 NS
Discontinuation for hyperkalemia 11 15
Discontinuation for renal impairment 59
0.001
Angioedema (adjudicated)
Medications, no hospitalization 16 9
Hospitalized; no airway compromise 3 1
Airway compromise
----

43. PARADIGM-HF: Conclusiones
En pacientes con IC y FE reducida
LCZ696 fue mas efectivo que enalapril en. . .
• Reducir riesgo de muerte CV y Hospitalización por IC
• Reducir mortalidad global
• Mejoria de sintomas
LCZ696 fue mejor tolerado que enalapril . . .
• Menos tos, hiperkalemia y disfunción renal
• Menos decontinuación del tratamiento
• Mas hipotensión pero no causa de discontinuación de •

44. % Decrease in Mortality
Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System
Angiotensin
receptor
blocker
Angiotensin
neprilysin
inhibition
ACE
inhibitor 0%
15%
18%
10%
% Decrease in Mortality
20%
20%
30%
Effect of ARB vs placebo derived from CHARM-Alternative trial
Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
40%

46. ES TODO COLOR ROSA?? Trabajo unico
12% pacientes se retiraron durante fase de “run-in”
Se lograra dosis target en el mundo real?
Bajo uso de DAI y TRC
Puede reducir el real beneficio de la droga
Mayor incidencia de hipotension vs. IECA
“Wash out” 36 h
Poca evidencia en IC “de novo”
Enalapril en desventaja vs. Valsartan???

47. Trabajo no representa los pacientes de mundo real:
Solo 310 pts (7.4%) con LCZ en Norte-America
Solo 213 pts (5.1%) con LCZ were Negros
Only 879 pts (21%) con LCZ Mujeres