1) LCZ696, which inhibits neprilysin and blocks angiotensin receptors, reduced the risks of cardiovascular death and heart failure hospitalization compared to enalapril in patients with heart failure with reduced ejection fraction. 2) LCZ696 also reduced the risks of all-cause mortality and worsened heart failure compared to enalapril. 3) Patients receiving LCZ696 experienced greater improvements in quality of life and functional status measures compared to those receiving enalapril.

1. John McMurray
BHF Cardiovascular Research Centre
University of Glasgow
Scotland
UK
Angiotensin receptor-neprilysin
inhibition (ARNI): The new fronteir?

2. HF-REF: The building blocks of therapy
T
x
V
A
D
C
R
T
I
C
D
Beta-blocker MRAACEI/ARB
Digoxin Ivabradine
H-ISDNCABG

3. Can we change the paradigm?
• Harness endogenous protective systems as
well as inhibit the harmful ones?
• Replacing an existing treatment and not
adding a new one?

4. Heart failure: a state of
“neurohumoral imbalance”
Vasoconstrictor/
anti-natriuretic
/pro-mitotic
mediators
Vasodilator/
natriuretic/
anti-mitotic
mediators

5. A paradigm shift: from “neuro-humoral
inhibition” to “neuro-humoral modulation”
Vasoconstrictor/
anti-natriuretic
/pro-mitotic
mediators
Vasodilator/
natriuretic/
anti-mitotic
mediators

6. Natriuretic peptides: How the
heart protects itself
· The heart is an endocrine organ
· It secretes A and B type
natriuretic peptides into the
circulation where they act on the
blood vessels, kidneys, adrenal
glands, brain etc
· These peptides protect the heart
from volume and pressure
overolad

7. Natriuretic peptides
BK, ADM
Subs-P, VIP, CGRP
Angiotensin II
• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy
Degradation
products
Neprilysin AT1Receptor
Angiotensin Receptor Neprilysin
Inhibition (ARNI): LCZ696
• Vasodilation
• Natriuresis
• Diuresis
• Inhibition of pathologic
growth/fibrosis
LCZ696
sacubitril valsartan

8. PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial

9. LCZ696 200 mg BID (n=4187)
Enalapril 10 mg BID (n=4212)
Outcome driven (CV death): Stopped early for benefit
Median follow-up = 27 months
1-2 weeks
Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid
1-2 weeks 2 weeks
Prior ACEi/ARB use discontinued
Single-blind period Double-blind period
N = 8442 (1:1 randomization)
PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
• Age ≥18 years. NYHA class II-IV. LVEF ≤0.40 (amended to ≤0.35).
• BNP ≥150 pg/ml (NTpro-BNP ≥600 pg/ml) or if HF hosp. within12 mo. BNP
≥100 pg/ml (NTpro-BNP ≥400 pg/ml)
• Background RAS blocker therapy equivalent to enalapril ≥10 mg/d
• Beta-blocker and MRA as recommended by guidelines
• SBP ≥100 mmHg run-in/ ≥95 mmHg at randomization
• eGFR ≥30 ml/min/1.73m2 /no decrease >25% (amended to 35%)
• Potassium ≤5.2 mmol/l run-in/ ≤5.2 mmol/l at randomization

10. 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 (885-3154) 1594 (886-3305)
B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)
History of diabetes 35% 35%
Digitalis 29.3% 31.2%
Beta-adrenergic blockers 93.1% 92.9%
Mineralocorticoid antagonists 54.2% 57.0%
CRT 7.0% 6.7%
ICD 15% 15%
PARADIGM-HF: Baseline Characteristics

11. Trial N
Target dose,
mg
Mean daily
dose, mg
CONSENSUS (1987)* 127 20 bid 18.4
SOLVD-T (1991)† 1284 10 bid 16.6
SOLVD-P (1992) 2111 10 bid 16.7
V-HeFT II (1991) 403 10 bid 15.0
OVERTURE (2002) 2884 10 bid 17.7
CARMEN (2004) 190 E only
191 E+Carv
10 bid
10 bid
16.8
14.9
CIBIS-3 (2005) 190 E first
191 Bisop first
10 bid
10 bid
17.2
15.8
Dose of ACE Inhibitor (enalapril) achieved in
randomized outcome trials using forced titration
† N.B. active run-in; 49% reached target dose.*22% reached target dose
PARADIGM-HF 4212 10 bid 18.9

12. NT pro BNP and BNP
Cardiomyocyte
Blood

13. PARADIGM-HF: NT-proBNP and BNP
0 2 4 6 8
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
0
50
100
150
200
250
300
350
400
450
500
NT-proBNPpg/ml
Months
BNPpg/ml
LCZ696
Enalapril
NT-proBNP
BNP

14. Explaining the NT pro BNP and BNP
changes with LCZ696 (schematic)
Pro BNP/
NT proBNP
Pre- Post- Pre- Post-
BNP
Inhibition
of BNP
breakdown
Reduced
LV wall
stress
LCZ696 LCZ696

15. PARADIGM-HF: PARADIGM-HF: Geometric mean urinary Geometric mean urinary
cyclic GMP concentration cyclic GMP concentration by visitby visit
Cyclic GMP is the intracellular second messenger
stimulated by natriuretic peptides and other vasoactive
substances including nitric oxide

16. PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure
hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function

17. PARADIGM-HF: Primary outcome
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
At risk
Enalapril: 4212 3883 3579 2922 2123 1488 853 236
LCZ696: 4187 3922 3663 3018 2257 1544 896 249
CumulativeProportionofPatients
withPrimaryEndPoint(%)
Days after Randomization
0
10
20
30
40
0 180 360 540 720 900 1080 1260
HR: 0.80 (0.73, 0.87)
p = 0.0000004 1117
Enalapril
(n=4212)
LCZ696
(n=4187)
914

18. PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure
hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function

19. PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
Death from CV causes
20% risk reduction
HF hospitalization
21% risk reduction
693
558
658
537
McMurray, Packer et al NEJM 2014
P = 0.00008 P = 0.00008

20. PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure
hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function

21. PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
Death from any cause
0
10
20
30
40
0 180 360 540 720 900 1080 1260
16% risk reduction
Enalapril
(n=4212)
835
LCZ696
(n=4187)
711
Days after Randomization
CumulativeProportionofPatients
WhoDiedfromAnyCause(%)
HR: 0.84 (0.76, 0.93)
P = 0.0009

22. PARADIGM-HF: cause/
mode of death
0.80
0.00004
835
693
311
184
711
558
250
147
0
100
200
300
400
500
600
700
800
900
0.80
0.008
0.79
0.034
0.84
< 0.001
Number
Enalapril
LCZ696
HR
p =
All causes CV causes Worsening HFSudden
0.80
0.00008

23. PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure
hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function

24. LCZ696
(n=4187)
Enalapril
(n=4212)
Treatment
effect
P
Value
KCCQ clinical
summary score at
8 months
- 2.99
± 0.36
- 4.63
± 0.36
1.64
(0.63, 2.65)
0.001
New onset
atrial fibrillation
84/2670
(3.1%)
83/2638
(3.1%)
Hazard ratio
0.97
(0.72,1.31)
0.83
Protocol-defined
decline in renal
function*
94/4187
(2.2%)
108/4212
(2.6%)
Hazard ratio
0.86
(0.65, 1.13)
0.28
PARADIGM-HF: Effect of LCZ696 vs.
enalapril on other secondary endpoints
*1) ESRD or 2) a decrease ≥50% in eGFR from value at randomization or 3)
a decrease in eGFR >30 ml/min/1.73 m2 to <60 ml/min/1.73 m2

25. PARADIGM-HF: Percentage of patients with at least
5 points deterioration in KCCQ scores at month 8
Physicallim
itation
Sym
ptom
stability
Sym
ptom
frequency
Sym
ptom
burden
Totalsym
ptom
score
SelfefficacyQ
uality
oflifeSociallim
itation
O
verallsum
m
ary
score
C
linicalsum
m
ary
score
0
5
10
15
20
25
30
35
40
45
LCZ696 Enalapril
P=0.004 P=0.029 P<0.001 P<0.005 P<0.001 P<0.001 P=0.001 P=0.001 P<0.001 P<0.001
Clinical summary score based on the physical limitation and total symptom score domains.
Death imputed as zero. The analysis included all patients with at least one KCCQ data point
(N=3833) (N=3873)
%

26. LCZ696
N=3833*
n (%)
Enalapril
N=3825*
n (%)
P-value
Improved 639 (16.7) 569 (14.9) 0.0015
Unchanged 2989 (78.0) 2990 (78.2)
Worse 205 (5.4) 266 (7.0)
*Surviving patients with data (deaths excluded)
PARADIGM-HF: Physician assessment
Change in NYHA functional class
from baseline to month 8 (pre-specified time-point)

27. Too good to be true?

28. LCZ696
(n=4187)
Enalapril
(n=4212)
Treatment
effect
P
Value
KCCQ clinical
summary score at
8 months
- 2.99
± 0.36
- 4.63
± 0.36
1.64
(0.63, 2.65)
0.001
New onset
atrial fibrillation
84/2670
(3.1%)
83/2638
(3.1%)
Hazard ratio
0.97
(0.72,1.31)
0.83
Protocol-defined
decline in renal
function*
94/4187
(2.2%)
108/4212
(2.6%)
Hazard ratio
0.86
(0.65, 1.13)
0.28
PARADIGM-HF: Effect of LCZ696 vs.
enalapril on other secondary endpoints
*1) ESRD or 2) a decrease ≥50% in eGFR from value at randomization or 3)
a decrease in eGFR >30 ml/min/1.73 m2 to <60 ml/min/1.73 m2

29. Pre-specified exploratory
outcomes
Selected outcomes – reflecting disease
progression

30. PARADIGM-HF: Treatment failure*
0
5
10
15
Proportionofpatients
Enalapril
LCZ696
*Addition of a new drug for treatment of WHF, need for
intravenous therapy or increase in diuretic dose >1 month
HR 0.84 (0.74, 0.94)
p = 0.0029
(%)

31. PARADIGM-HF: Emergency
department visits for heart failure†
0
1
2
3
4
5
0
50
100
150
200
250
Proportion of patients Number of ED visits*
Enalapril LCZ696
Patients visiting ED ED Visits
HR 0.66 (0.52, 0.85)
p = 0.001
RR 0.70 (0.52, 0.94)
p = 0.017
(%)
*Includes repeat episodes†Not leading to hospital admission

32. PARADIGM-HF: Hospitalization
for heart failure
0
3
6
9
12
15
18
0
200
400
600
800
1000
1200
Proportion of patients Number of admissions*
Enalapril LCZ696
Patients hospitalized Hospitalizations
HR 0.79 (0.71, 0.89)
p < 0.0001
RR 0.77 (0.67, 0.89)
p = 0.0004
(%)
*Includes repeat episodes

33. PARADIGM-HF: Intensive care
management
LCZ696
N=4187
n (%)
Enalapril
N=4212
n (%)
P-value
Number of
patients requiring
intensive care
549 (13.1) 623 (14.8)
0.87 (0.78, 0.98)
P=0.019
Total number of
stays in intensive
care
768 879
0.82 (0.72, 0.94)
P=0.005
Patients receiving
IV positive
inotropic drugs
161 (3.8%) 229 (5.4%)
0.69 (0.57, 0.85)
P < 0.001
Intensive management in hospital

34. PARADIGM-HF: Hospitalization
for any cause
0
5
10
15
20
25
30
35
40
45
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Proportion of patients Number of admissions*
Enalapril LCZ696
Patients hospitalized Hospitalizations
HR 0.88 (0.82, 0.94)
p < 0.001
RR 0.84 (0.78, 0.91)
p < 0.001
(%)
*Includes repeat episodes

35. Do all-patients benefit from
treatment?
Consistency of benefit across
subgroups

36. PARADIGM-HF: Sub-group analysis
(primary endpoint and CV death)

37. PARADIGM-HF: Baseline mineralocorticoid
receptor (aldosterone) antagonist (MRA) use
Cardiovascular death
HR 0.80 (0.71, 0.89); p <0.0001
HR 0.75 (0.63, 0.89)* HR 0.84 (0.73, 0.98)*
MRA - No MRA - Yes
(%)
Enalapril
LCZ696
*Interaction p = 0.32

38. CV mortality: Baseline ICD use
(post hoc analysis)
ICD - No
Enalapril
LCZ696
ICD - Yes
Cardiovascular death
HR 0.80 (0.71, 0.89); p <0.0001
HR 0.80 (0.71, 0.90)* HR 0.76 (0.55, 1.05)*
*Interaction p = 0.92
(%)

39. < 55 55-64 65-74 ≥ 75
0
2
4
6
8
10
12
14
16
Age (years)
rateper100patientyears
< 55 55-64 65-74 ≥ 75
0
2
4
6
8
10
12
14
16
Age (years)
rateper100patientyears
enalapril LCZ696
HF hospitalization
< 55 55-64 65-74 ≥ 75
0
2
4
6
8
10
12
14
16
Age (years)
rateper100patientyears
All-cause death
< 55 55-64 65-74 ≥ 75
0
2
4
6
8
10
12
14
16
Age (years)
rateper100patientyears
CV death or HF hospitalization CV death
PARADIGM-HF: Effect of LCZ696
according to age category

40. Safety
Pre-defined safety assessments

41. LCZ696
(n=4187)
Enalapril
(n=4212)
p value
Hypotension (%)
symptoms
symptoms and SBP < 90 mmHg
14.0
2.7
9.2
1.4
< 0.001
<0.001
Renal impairment (%)
Cr ≥ 2.5 mg/dl
Cr ≥ 3.0 mg/dl
3.3
1.5
4.5
2.0
0.007
0.10
Hyperkalaemia (%)
K+ > 5.5 mmol/l
K+ > 6.0 mmol/l
16.2
4.3
17.4
5.6
0.15
0.007
Cough (%) 11.3 14.3 < 0.001
Angioedema:
Not hospitalized
No treatment/antihistamines n, (%)
Catecholamines/corticosteroids n, (%)
10 (0.2)
6 (0.1)
5 (0.1)
4 (0.1)
0.19
0.52
Hospitalized
No airway compromise n, (%)
Airway compromise n, (%)
3 (0.1)
0 (0.0)
1 (0.0)
0 (0.0)
0.31
-
PARADIGM-HF: Safety
McMurray et al. N Engl Med 2014;371:993-1004.

42. PARADIGM-HF: Adverse events leading to
permanent study drug discontinuation
Hypotension
p = 0.38
0
2
4
6
8
10
12
14
Renal reasons
p = 0.002
Hyperkalaemia
p = 0.56
Any adverse
event p = 0.03
(%)
Enalapril LCZ696
29
29
36
59
29
15 11
516
449

43. SMQ Dementia
LCZ696
N=4203
n (%)
Enalapril
N=4229
n (%)
LCZ696 vs Enalapril
Relative Risk
(95% CI)
Broad SMQ Dementia 86
(2.05)
83
(1.96)
1.029
(0.761, 1.391)
Narrow SMQ Dementia 12
(0.29)
15
(0.35)
0.793
(0.371, 1.695)
LCZ696 most frequently reported PTs
Broad SMQ Dementia
LCZ696
n (%)
Enalapril
n (%)
Confusional state 12 (0.29) 18 (0.43)
Somnolence 11 (0.26) 9 (0.21)
Amnesia 10 (0.24) 7 (0.17)
Delirium 10 (0.24) 8 (0.19)
Agitation 7 (0.17) 3 (0.07)
Memory impairment 6 (0.14) 6 (0.14)
Dementia 6 (0.14) 10 (0.24)
Disorientation 5 (0.12) 4 (0.09)
Mental status changes 5 (0.12) 1 (0.02)
Cerebral atrophy 4 (0.10) 0 (0.00)
LCZ696 most frequently reported PTs
Narrow SMQ
Dementia
LCZ
n (%)
Enalapril
N (%)
Dementia 6 (0.14) 10 (0.24)
Dementia
Alzheimer’s type
2 (0.05) 2 (0.05)
Vascular dementia 2 (0.05) 1 (0.02)
Hippocampal
sclerosis
1 (0.02) 0 (0.00)
Presenile dementia 1 (0.02) 0 (0.00)
Senile dementia 0 (0.00) 2 (0.05)
Dementia/cognition-related adverse
events (MedRA)

44. Consistent benefit of LCZ696 on all
measures of progression/worsening
Compared with enalapril, patients on LCZ696:
· Are less likely to show symptomatic deterioration
· Are less likely to need intensification of oral therapy/addition of
iv therapy
· Are less likely to visit the emergency department
· Are less likely to be admitted to hospital
· When admitted, are less likely to go to the ICU and less likely to
need iv inotropic therapy
· Are less likely to require devices/surgery for worsening/
end-stage heart failure (not statistically significant)
· Are less likely to die prematurely (either suddenly or from
worsening HF)
· Less likely to show biomarker evidence of cardiac wall-stress
and myocyte injury (data not shown – see Circulation)
Compared with enalapril, LCZ696 slows progression of heart
failure, delaying/preventing non-fatal and fatal worsening.

45. PARADIGM-HF: Absolute benefits
47 primary endpoints
31 cardiovascular deaths
28 patients hospitalized for HF
37 patients hospitalized for any reason
53 admissions for HF
111 admissions for any reason
Switching 1000 patients from an ACE inhibitor/ARB
to LCZ696 avoided:
over a median treatment period of 27 months

46. We are not as smart as we might like to
think we are!

47. HF-REF: The building blocks of therapy
T
x
V
A
D
C
R
T
I
C
D
Beta-blocker MRAACEI/ARB
Digoxin Ivabradine
H-ISDNCABG

48. HF-REF: The building blocks of therapy
T
x
V
A
D
C
R
T
I
C
D
Beta-blocker MRA
Digoxin Ivabradine
H-ISDNCABG
ARNI