Angiotensin Receptor Blocker -Neprilysin Inhibitor combination has an important role to play in patients with Heart Failure with reduced ejection fraction. ARNI is now first line medication in HRrEF

1. ARNI as new standard of care in
HFrEF management in light of
Clinical Evidence
Dr Syed Raza
MD, MRCP, FRCP, CCT(UK), FESC, FACC, FAECVI
Consultant Cardiologist
Awali Hospital
Bahrain

2. Objectives
1. Role and place of
ARNI in management
of Heart Failure
2. Evidence that
supports its role and
benefits

4. ARNI –mechanism of action

5. Prospective comparison of ARNI with ACEI to Determine
Impact on Global Mortality and morbidity in Heart Failure

6. 2 weeks 1–2 weeks 2–4 weeks Median of 27 months’ follow-up
Sacubitril/valsartan200 mg BID
(N=4,209)
Enalapril* 10 mg BID
(N=4,233)
1:1 RANDOMIZATION
Double-blind
treatment period
Single-blind active
run-in period
Sacubitril/
valsartan
100 mg BID
Sacubitril/
valsartan
200 mg BID
ACE-inhibitor*
10 mg BID
*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with
ARBs or with a low dose of ACEI
ACE=angiotensin-converting enzyme; ARB=angiotensin-receptor-blocker; BID=twice daily; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association;
TDD=total daily dose
1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. McMurray et al. N Engl J Med 2014;371:993–1004;
3. Sacubitril/valsartan Core Data Sheet, version 1.2. Novartis Pharmaceuticals, July 2017
PARADIGM-HF
Over 8400 patients with chronic heart failure with systolic dysfunction (LVEF ≤40%)
in NYHA classes II–IV2,3
6

7. *Compared with enalapril, as assessed via time until cardiovascular death or first hospitalization for HF.1 ‡Enalapril 10 mg 2x daily as comparator vs
sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection
fraction; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
Cumulative
probability
0.4 Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
6
Months since randomization
0.3
0.2
0.1
0
p<0.0001
HR: 0.80
(95 % CI: 0.73–0.87)
ARR: 4.7 %
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF PRIMARY ENDPOINT
Sacubitril/valsartan significantly reduced death from
CV causes or first hospitalization for HF*
4,187 3,922 3,663 3,018 2,257 1,544 896 249
4,212 3,883 3,579 2,922 2,123 1,488 853 236
No. at risk
Sacubitril/
valsartan
Enalapril
Composite primary endpoint
7

8. *Compared with enalapril, as assessed via time to first hospitalization for HF (single component of primary endpoint). ‡Enalapril 10 mg 2x daily as
comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection
fraction; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004g
Cumulative
probability
Months since randomization
0.3
0.2
0.1
RELATIVE RISK REDUCTION OF
FIRST HOSPITALIZATION FOR HF
Sacubitril/valsartan significantly reduces the risk of first HF
hospitalization, keeping HFrEF patients out of the hospital*
4,187 3,922 3,663 3,018 2,257 1,544 896 249
4,212 3,883 3,579 2,922 2,123 1,488 853 236
No. at risk
Sacubitril/
valsartan
Enalapril
6
0
12 18 24 30 36 42
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p<0.001
HR: 0.79
(95 % CI: 0.71–0.89)
ARR: 2.8 %
Primary endpoint
8

9. *Time to all-cause death. ‡Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard
therapy).
§27 months since randomization (median)
ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
Cumulative
probability
6
Months since randomization
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF ALL-CAUSE MORTALITY
Sacubitril/valsartan significantly reduced all-cause mortality*
4,187 4,056 3,891 3,282 2,478 1,716 1,005 280
4,212 4,051 3,860 3,231 2,410 1,726 994 279
No. at risk
Sacubitril/
valsartan
Enalapril
0.3
0.2
0.1
0
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p<0.01
HR: 0.84
(95 % CI: 0.76–0.93)
ARR: 2.8 %
9

10. *Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ARR=absolute risk reduction; CI=confidence interval; HR=Hazard Ratio; NNT=number needed to treat
1. Desai et al. Eur Heart J 2015;36:1990–7
Cumulative
probability
6
Months since randomization
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF SUDDEN DEATH
Sacubitril/valsartan significantly reduced the risk of sudden death1
4,187 3,891 2,478 1,005
4,212 3,860 2,410 994
No. at risk
Sacubitril/
valsartan
Enalapril
0.10
0.06
0.02
0
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p=0.008
HR: 0.80
(95 % CI: 0.68–0.94)
ARR: 1.4 %
0.08
0.04
10

11. Secondary outcomes – summary
Outcome, n %
Sacubitril/
valsartan
(n=4,187)
Enalapril
(n=4,212)
Hazard ratio*
(95% CI) p value‡
Death from any cause, n (%) 711 (17.0) 835 (19.8)
0.84
(0.76–0.93)
<0.001
Change in KCCQ clinical summary
score§ at 8 months, mean ± SD
–2.99 ± 0.36 –4.63 ± 0.36
1.64
(0.63–2.65)
0.001
New onset atrial fibrillation¶,
n (%)
84 (3.1) 83 (3.1)
0.97
(0.72–1.31)
0.83
Decline in renal function#,
n (%)
94 (2.2) 108 (2.6)
0.86
(0.65–1.13)
0.28
*Calculated with the use of stratified cox proportional-hazard models; ‡Two-sided p values calculated by means of a stratified log-rank test without adjustment for
multiple comparisons; §KCCQ scores range from 0 to 100 – higher scores indicate fewer symptoms and physical limitations associated with HF; ¶2,670 patients in the
sacubitril/valsartan and 2,638 in the enalapril group who did not have atrial fibrillation at randomization were evaluated; #Defined as: (a) ≥50% decline in eGFR from
randomization; (b) >30 mL/min/1.73 m2 decline in eGFR from randomization or to a value of <60 mL/min/1.73 m2, or (c) progression to end-stage renal disease.
CI=confidence interval; eGFR=estimated glomerular filtration rate; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; SD=standard deviation
McMurray et al. N Engl J Med 2014;371:993–1004
11

12. Conclusions
• HEART FAILURE remains a chronic disease with unmet needs despite current available
treatment.
• In the PARADIGM-HF trial, the superiority of
sacubitril/valsartan vs enalapril was demonstrated
as follows:2*
• 20% reduction‡ in CV mortality or first HF hospitalization
(primary composite endpoint)
• 20% reduction‡ in CV mortality
• 20% reduction in risk of sudden cardiac death
• 21% reduction‡ in first HF hospitalization
• 16% reduction‡ in all-cause mortality (secondary endpoint)
• The superiority of sacubitril/valsartan over enalapril was
not accompanied by important safety concerns
• Implications for clinical practice
#For the full safety profile of sacubitril/valsartan please see
actual approved label; *Enalapril 10 mg 2x daily as comparator
vs sacubitril/valsartan 200 mg 2x daily in
the *PARADIGM-HF study (in addition of standard therapy);
‡Relative risk reduction
CV=cardiovascular; HF=heart failure
1. Langenickel and Dole. Drug Discov Today: Ther Strateg
2012;9:e131–9; 2. McMurray et al. N Engl J Med 2014;371:993–
1004.
12

14. Cardiac remodeling
1.Thinning of heart
muscle walls
2.Stretch of heart
muscle
3. Dilatation of chambers
of heart
4. Decrease in systolic
and diastolic function

15. 30 day NTproBNP in PARADIGM-HF

16. Effect of Sacubitril-Valsartan Compared with Enalapril on
Arterial Hemodynamics and Cardiac Remodeling in Heart
Failure and Reduced Ejection Fraction
Primary Results of the EVALUATE-HF Trial
Akshay S. Desai1, Scott D. Solomon1, Amil M. Shah1, Brian L. Claggett1, James C. Fang2, Joseph Izzo3, Kevin McCague
MA4, Cheryl A. Abbas PharmD4, Ricardo Rocha MD4, Gary F. Mitchell MD5 for the EVALUATE-HF Investigators
(1)Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA; (2) Cardiovascular Medicine, University of
Utah, Salt Lake City, UT; (3) Department of Medicine, State University of New York at Buffalo, Buffalo, NY;
(4) Novartis Pharmaceuticals, East Hanover, NJ; (5) Cardiovascular Engineering, Inc., Norwood MA

17. Key Entry Criteria
• Age ≥ 50 yrs
• Chronic HF with EF≤40%
• NYHA I-III
• History of hypertension
• Stable doses of GDMT
• SBP > 105 mm Hg at
randomization
• Prior treatment with
sacubitril/valsartan
• Persistent atrial fibrillation at
screening or randomization
• Inadequate baseline
hemodynamic study
Included Excluded
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843

18. Study Design
Sac/Val
24/26 mg bid
Enalapril
2.5 mg bid
Day 1 Week 2 Week 12
Week 4
Sac/val
49/51 mg bid
Enalapril
5 mg bid
Sacubitril/valsartan
97/103 mg bid
Enalapril 10 mg bid
Double-blind, double-dummy
treatment period
12 weeks
Screening period
n=465
Randomization
1:1
Week 1 Week 24
12 weeks
Open-label
treatment period
Week 14
Sac/val
49/51 mg bid
Sac/val
97/103 mg bid
Week -6
Hemodynamic Assessment
Echocardiography
Cardiac Biomarkers
KCCQ-12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

21. Primary Endpoint: Change in Zc from Baseline to Week 12
223.8 213.2
218.9 214.3
0
50
100
150
200
250
300
Sacubitril/Valsartan Enalapril
Baseline 12 Weeks Baseline 12 Weeks
Z
c
(dynes-sec/cm
5
)
-0.7 (-11.6, +10.1)
- 2.9 (-13.8, +8.0)
-2.2 (-17.6, +13.2) p = 0.78
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

22. Change in Cardiac Biomarkers from Baseline to 12 weeks, by
Treatment
-37%
-5%
-13%
34%
-5%
1%
5%
-6%
-50%
-40%
-30%
-20%
-10%
0%
10%
20%
30%
40%
NTproBNP sST2 hsTnT Urine cGMP/Cr
Sacubitril/Valsartan
Enalapril
p<0.001
p=0.006
p<0.001
p<0.001
%
change
from
baseline
to
12
weeks
*
Secondary Exploratory
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

23. Secondary Endpoints:
Change in Cardiac Structure from Baseline to 12 weeks, by Treatment
-5.2 -4.9
-2.2
-3.2 -3.3
+0.6
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
LVEDVI LVESVI LAVI
Sacubitril/Valsartan Enalapril
Change
from
baseline
to
12
Weeks
(mL/m
2
)
p=0.02 p=0.045 p=<0.001
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

24. Secondary Endpoints:
Change in Cardiac Function from Baseline to 12 weeks, by Treatment
+1.9
-0.3
+1.3
-0.2
-6
-5
-4
-3
-2
-1
0
1
2
3
LVEF GLS
Change
from
baseline
to
12
Weeks
(%)
-0.03
-1.4
+0.02
-0.003
+0.3
+0.03
-5
-4
-3
-2
-1
0
1
Mitral e’ Velocity,
cm/s
Mitral E/e’ Ea/Ees
Change
from
baseline
to
12
Weeks
Systolic Function Diastolic Function and
Ventricular-Vascular Coupling
p=0.24 p=0.58
p=0.86 p=0.001 p=0.82
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

25. Exploratory Endpoint: Change in KCCQ-12 Overall Score at
Week 12
64.7 67.7
73.8 71.2
0
10
20
30
40
50
60
70
80
90
100
Sacubitril/Valsartan Enalapril
Baseline 12 Weeks Baseline 12 Weeks
4.2 (2.2, 6.2)
8.7 (6.7, 10.7)
4.5 (1.7, 7.3), p = 0.002
KCCQ
Overall
Summary
Score
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

27. Prospective Study of Biomarkers, Symptom
improvement and Ventricular Remodeling
during Sacubitril/Valsartan Therapy for
Heart Failure
(PROVE-HF; NCT02887183)
James L. Januzzi MD1,2, Margaret F. Prescott PhD3, Javed Butler MD MPH MBA4,
G. Michael Felker MD MHS5, Alan S. Maisel MD6, Kevin McCague MA3, Alexander
Camacho PhD1, Ileana L. Piña MD MPH7, Ricardo A. Rocha MD3, Amil M. Shah
MD MPH8, Kristin M. Williamson PharmD3, and Scott D. Solomon MD8 on behalf
of the PROVE-HF Investigators
1Massachusetts General Hospital, 2Baim Institute for Clinical Research, Boston, MA, USA;
3Novartis Pharmaceuticals, East Hanover, NJ, USA; 4University of Mississippi Medical Center,
Jackson, MS, USA; 5Duke University Medical Center and Duke Clinical Research Institute,
Durham, NC, USA; 6University of California, San Diego School of Medicine, San Diego, CA, USA;
7Detroit Medical Center, Detroit, MI, USA; 8Brigham and Women’s Hospital, Boston, MA, USA

28. PROVE-HF
• US Study, multicentric , open label , single
arm prospective study
• 795 patients with HFrEF
• FU 52 weeks
METHODS
• Blood samples (x) were obtained at each
study visit for NT-proBNP measurement
• An echocardiogram was performed at
baseline, 6- and 12-months, and
interpreted by a core lab in a clinically and
temporally blinded fashion
X = Vital status/events (CV death, HF hospitalization, worsening HF), physical examination, blood
samples for safety chemistry and biomarkers, urine sampling, HF symptom assessment, KCCQ-23.
* Standard HF therapy was continued throughout the study with the exception of ACEI/ARB; †At Day 45,
KCCQ-23 was not administered.
CV denotes: cardiovascular; HF denotes: heart failure; KCCQ-23 denotes: Kansas City Cardiomyopathy
Questionnaire-23.
Key Inclusion Criteria Key Exclusion Criteria
 Aged ≥18 years
 Patients with HFrEF who are
candidates for on-label
sacubitril/valsartan treatment per
the standard of care
 NYHA functional class II, III, or IV
 LVEF ≤40% within the preceding 6
months according to any local
measurement, and no subsequent
documentation of EF >40%
 Stable dose of loop diuretic for
the 2 weeks preceding study start
 History of hypersensitivity/allergy or
suspected contraindication to ACEI,
ARB, or ARNI
 Any angioedema history
 Concomitant use of ACEI therapy,
nesiritide, aliskiren, or drugs that may
affect absorption of the study
medication
 Current or previous treatment with
sacubitril/valsartan
 Inadequate washout of other
investigational drugs before study
initiation
 Enrollment in another clinical trial
within 30 days of screening
 Potassium >5.2 mEq/L at screening
 History of malignancy within 1 year
 Pregnancy, lactation, or use of any
method of contraception that is not
highly effective
 Implantation of CRT/D within 6 months
 Prior or planned heart transplant or
LVAD
Januzzi JL, Butler J, Fombu E, et al; Am Heart J, 2018;199:130-136.

29. Goals of the study
• Primary endpoint:
• Correlation between change in NT-proBNP
and remodeling at 12 months:
1) Left ventricular ejection fraction (LVEF)
2) LV end-diastolic volume index (LVEDVi)
3) LV end-systolic volume index (LVESVi)
4) Left atrial volume index (LAVi)
5) Ratio of early mitral diastolic filling
velocity/early diastolic mitral annular
velocity (E/e')
• Secondary endpoints:
• Association between change in NT-
proBNP and remodeling at 6 months
• Effect of S/V on cardiac remodeling in
specific patient subgroups not
represented in the PARADIGM-HF trial:
1) New-onset HF and/or ACEI/ARB naïve
2) Those with BNP or NT-proBNP
concentrations below PARADIGM-HF
inclusion criteria
3) Patients not reaching target doses of
S/V (97/103 mg twice daily)
Januzzi JL, Butler J, Fombu E, et al; Am Heart J, 2018;199:130-136.

31. Reverse cardiac remodeling (1)
0
5
10
15
20
25
30
35
40
45
LVEF
0
10
20
30
40
50
60
70
80
90
100
LVEDVi LVESVi
BL 6M 12M
LVEF
(%)
LV
volume
(mL/m
2
)
+5.2%
+9.4%
-6.65
-12.25
-8.67
-15.29
BL 6M 12M BL 6M 12M
Baseline to 12 months: all P <.001
28.2
86.93
61.68
25% of subjects
experienced an LVEF
increase of ≥13% at
12 months
BL, baseline; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; LVESVi, left ventricular end-systolic
volume index
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

32. 0
5
10
15
20
25
30
35
40
LAVi
Reverse cardiac remodeling (2)
0
2
4
6
8
10
12
14
E/e’
BL 6M 12M BL 6M 12M
-4.36
-7.57 -1.23 -1.30
LA
volume
(mL/m
2
)
E/e’
ratio
Baseline to 12 months: all P <.001
37.76
11.70
BL, baseline; mL, milliliter; LA, left atrial; LAVi, left atrial volume index; E/e’, ratio of early diastolic filling velocity and early diastolic mitral annular
velocity; LVMi, left ventricular mass index.
LVMi fell from
124.77 to 107.82 g/m2
(mean -16.00 g/m2; P <.001)
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

33. Death or HF hospitalization by 12 months
Patients with largest reduction in NT-proBNP and LVESVi by 6 months had
lowest rates of subsequent death or HF hospitalization by 12 months
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

36. In-Hospital Settings (after patients become hemodynamically stable)
Greater reduction in the NT-proBNP concentration from baseline to 4 and 8 weeks
and improved clinical outcomes with sac/val
ADHF, acute decompensated heart failure; CV,
cardiovascular; HFrEF, heart failure with reduced
ejection fraction; HF, heart failure; HR, hazard ratio; NT-
proBNP, N-terminal pro b-type natriuretic peptide;
sac/val, sacubitril/valsartan
36
HR: 0.58 (95% CI, 0.39 to 0.87) P=0.007
Change in NT-proBNP1 CV death or re-hospitalization for HF2
Enalapril
Sac/val
Change
in
NT-proBNP
from
baseline
(%)
Percent
of
patients
with
CV
death/HHF
15.2%
9.2%
HR 0.58 (95% CI: 0.39 − 0.87) p=0.007
Ratio of change 0.71 (95% CI: 0.63 − 0.81) p<0.001
Weeks since randomization
10
0
- 10
- 20
- 30
- 40
- 50
- 60
- 70
0 1 2 3 4 5 6 7 8
-25.3%
Weeks from randomization
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
0 1 2 3 4 5 6 7 8
-46.7%
1. Velazquez EJ, et al. NEJM
2019;380:539-548; 2. Morrow et al.
Circulation 2019;139:2285–2288.