Heart Failure Management -in light of Evidence Based Medicine and Guidelines . Focus on ARNI

1. Heart Failure Management – in
light of Evidence Based
Medicine and Guidelines
Dr Syed Raza
MD, MRCP, FRCP, CCT(UK), FESC, FACC, FAECVI
Consultant Cardiologist
Awali Hospital
Bahrain

2. Which of the following does not improve CV
mortality ?
1. ACE Inhibitor
2. ARNI
3. MRA
4. B- Blocker
5. SGLT2 Inhibitors
6. Ivabradine
7. Vericiguat

3. As per new ESC-HF guideline , what does
HFmrEF mean to you ?
1.HF with moderately reduced EF
2. HF with mildly reduced EF
3. HF with mid range EF
4. HF with massively reduced EF
5. HF with mainly reduced EF

4. Objectives
1. Evolving management strategies in HF
2. What is the evidence ?
3. What is new in 2021 ESC HF guideline ?
4. ARNI in light of PARADIGM-HF
5. My personal experience with ARNI

8. Medication Efficacy & Patient Safety

9. Evidence Based Medicine and Guidelines

12. 2016 ESC Guideline for HF

17. What is the
position of
Vericiguat ?

18. VERICIGUAT - guanylate cyclase stimulator

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

23. ARNI –mechanism of action

24. PARADIGM-HF – Key inclusion and
exclusion criteria
• Chronic HF NYHA FC II–IV with LVEF
≤40%*
• BNP (or NT-proBNP) levels as
follows:
• ≥150 (or ≥600 pg/mL), or
• ≥100 (or ≥400 pg/mL) and a
hospitalization for HFrEF within the
last 12 months
• ≥4 weeks’ stable treatment with an
ACEI or an ARB, and a β-blocker
• Aldosterone antagonist should be
considered for all patients (with
treatment with a stable dose for ≥4
weeks, if given)
*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment.
ACE=angiotensin-converting enzyme; ACEI=ACE inhibitor; ARB=angiotensin-receptor-blocker; BNP=B-type natriuretic peptide; CV=cardiovascular;
eGFR=estimate glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal
pro-brain natriuretic peptide; PCI=percutaneous coronary intervention; SBP=systolic blood pressure
McMurray et al. Eur J Heart Fail 2013;15:1062–73
• History of angioedema
• eGFR <30 mL/min/1.73 m2
• Serum potassium >5.2 mmol/L at screening OR
>5.4 mmol/L at the end of the enalapril run-in or
end of the sacubitril/valsartan run-in
• Requirement for treatment with both ACEI and
ARBs
• Symptomatic hypotension, SBP <100 mmHg at
screening, OR SBP <95 mmHg at end of enalapril
run-in or at randomization
• Current acute decompensated HF
• History of severe pulmonary disease
• Acute coronary syndrome, stroke, transient
ischemic attack, cardiac, carotid, or other major CV
surgery, PCI, or carotid angioplasty within the 3
months prior to screening
Key exclusion criteria
Key inclusion criteria
24

25. 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
25

26. *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
26

27. *Time to cardiovascular 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)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; CV=cardiovascular; HR=hazard ratio
McMurray et al. N Engl J Med 2014;371:993–1004
Cumulative
probability
Months since randomization
0.3
0.2
0.1
0
RELATIVE RISK REDUCTION OF
CARDIOVASCULAR MORTALITY
Sacubitril/valsartan significantly reduced CV 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
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
6
p<0.001
HR: 0.80
(95 % CI: 0.71–0.89)
ARR: 3.2 %
12 18 24 30 36 42
Primary endpoint
27

28. *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
28

29. *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 %
29

30. *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
30

31. 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
31

32. *In surviving patients
HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire
Treatment with sacubitril/valsartan provides sustainable
improvement of patients’ quality of life*
• Treatment with sacubitril/valsartan improves patients’ quality of life*, including HF symptoms and physical
limitations (as measured based on the KCCQ)
• The effect of sacubitril/valsartan on quality of life is sustained for up to 36 months; over the same treatment
period, patients treated with enalapril experience a quality of life decline
• Sacubitril/valsartan had similar improvements as were seen with cardiac resynchronization therapy
Lewis et al. Circ Heart Fail 2017;10:e003430
-2
-1
0
1
2
Randomization
Month 4 Month 8 Month 12 Month 24 Month 36
Entresto
Enalapril
Change in KCCQ-Overall Summary Scores vs. baseline
KCCQ-OS
Time from
randomization
Sacubitril/valsarta
n
Enalapril
32

33. Lower proportion of sacubitril/valsartan-treated patients
required intravenous positive inotropic support , CRT , LVAD
compared with enalapril
Event
Sacubitril/
valsartan§
n (%)
Enalapril¶
n (%)
Rate ratio
(95% CI) p value
Relative risk
reduction¶
Patients receiving i.v.
positive inotropic drugs
161 (3.9) 229 (5.4)
0.69
(0.57–0.85)
<0.001 31%
Patients requiring
cardiac
resynchronization,
ventricular assist device
implantation or cardiac
transplantation*
94 (2.3) 119 (2.8)
0.78
(0.60–1.02)
0.07
22%
(non-
significant)
*Number of patients who received a left ventricular assist device or underwent cardiac transplantation was 23 in the enalapril group and 13 in the sacubitril/valsartan group; ‡With
sacubitril/valsartan, compared with enalapril; §N=4,187; ¶N=4,212.
CI=confidence interval; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio; i.v.=intravenous
Packer et al. Circulation 2015;131:54–61
33

34. Sacubitril/valsartan had fewer adverse events leading to
permanent study drug discontinuation
76% of patients remained on the target dose of sacubitril/valsartan (200 mg 2x daily) until
the end of the study2
*Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy)
1. McMurray et al. N Engl J Med 2014;371:993–1004; 2. Packer et al. Circulation 2015;131:54–61
15
Therapy
discontinuation
(%)
10
5
0
10.7
p=0.03
Any adverse event Hypotension Renal impairment Hyperkalemia
12.3
0.9 0.7 0.3 0.4
p=0.56
0.7 1.4
p=0.002
p=0.38
Sacubitril/valsartan (N=4,187)
Enalapril* (N=4,212)
34

35. The majority of patients achieved and maintained the target
dose of sacubitril/valsartan throughout PARADIGM-HF
OF PATIENTS REMAINED AT THE TARGET DOSE OF
SACUBITRIL/VALSARTAN 97 MG/103 MG* TWICE DAILY AT
THE END OF THE STUDY1
76%
• There were fewer discontinuations due to
adverse events with sacubitril/valsartan vs
enalapril (mean daily dose of 375 mg and 18.9
mg, respectively)2
*In PARADIGM-HF, sacubitril/valsartan 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
1. Sacubitril/valsartan Core Data Sheet, version 1.2. Novartis Pharmaceuticals, July 2017;
2. McMurray et al. N Engl J Med 2014;371:993–1004
35

36. 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.
36

39. Dosing and titration of ARNI

40. ARNI

41. SGLT2 Inhibitors – rational for benefit in HF

50. 2021 ESC HF Guidelines – What is new?
1.Simplified HF treatment algorithm
2.Early treatment with four medications with class I recommendation.
3.Tailored treatment as per underlying etiology and co-morbidities.
4. Initiation of ARNI in ACEi naïve (de novo ) patients
5. SGLT2 Inhibitors - class 1 recommendation.
6. Vericiguat to be considered.
7. (HFmrEF) the term has changed to heart failure with mildly reduced ejection
fraction (NOT mid range)
8. DOAC preferred to VKA in patients with AF and HF. PV isolation for PAF
9. AVR and MVR
10. Tafamidis is recommended for treatment of transthyretin (TTR) cardiac
amyloidosis

51. Patient Education

52. Summary
1. Heart Failure is a major health problem.
2. Management strategy in HF has witnessed major breakthrough in the last
few years.
3. Recent guidelines in HF has evolved based on high impact evidence from
recent robust clinical trials.
4. Being well informed with updates is key to successful patient management
and utilization of resources.

55. 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

56. 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

57. 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

60. Baseline Characteristics
Sacubitril/Valsartan (N=231) Enalapril (N=233)
Age, mean (SD), yr 68 (10) 67 (9)
Female Sex, % 26% 21%
Black Race, % 27% 23%
Systolic Blood Pressure, mean (SD), mm Hg 131 (15) 130 (13)
Diastolic Blood Pressure, mean (SD), mm Hg 77 (10) 78 (10)
Body Mass Index, mean (SD), kg/m2 30.0 (5.7) 30.1 (5.8)
Estimated GFR, mean (SD), mL/min/1.73 m2 70 (22) 69 (20)
Left Ventricular Ejection Fraction, mean (SD), % 34 (10) 33 (10)
NTproBNP, median (IQR), pg/mL 595 (244, 1438) 560 (254,1498)
Prior HF Hospitalization, % 55% 49%
Functional Class, %
NYHA Class I 14% 12%
NYHA Class 2 66% 69%
NYHA Class 3 20% 19%
On ACEi/ARB Prior To Randomization, % 81% 88%
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

61. 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

62. 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

63. 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

64. 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

65. 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

66. Correlation between changes from baseline to week 12 in LVEDVI, KCCQ,
and NTproBNP
Change
in
NTproBNP
+50%
0%
-30%
-50%
-40% -20% 0% 20%
Change in LVEDVi
P < 0.001
Change
in
KCCQ
Overall
Summary
Score
20
10
0
-5
-90% -80% +50% +200%
Change in NTproBNP
P = 0.001
15
5
0%
-50%
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

67. Adverse Events of Interest
Sacubitril/Valsartan
(N=231)
Enalapril
(N=233)
RR* [95% CI]
Hyperkalemia (K>5.3 meq/L), n (%) 37 (16) 30 (12.9) 1.24 (0.80,1.94)
Worsening renal function**, n (%) 12 (5.2) 14 (6.0) 0.86 (0.41, 1.83)
Hypotension (SBP< 90 mm Hg), n (%) 9 (3.9) 4 (1.7) 2.27 (0.71, 7.27)
Angioedema, n (%) 0 (0.0) 1 (0.4) --
* sacubitril/valsartan vs. enalapril
**worsening renal function defined as decrease in eGFR of >=35% or increase in serum creatinine of >= 0.5 mg/dL
from baseline AND decrease in eGFR of >=25% from baseline.
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

68. Conclusions
• Among patients with HFrEF, sacubitril/valsartan did not reduce Zc at 12
weeks compared with enalapril
• Significant reductions were seen with sacubitril/valsartan in left
ventricular and left atrial volumes as well as mitral E/e’ suggesting a
favorable impact on ventricular remodeling and filling pressure
• Cardiac structural changes mirrored significant reductions in cardiac
biomarkers and improvement in overall quality of life
Akshay S. Desai et al
JAMA. doi:10.1001/jama.2019.12843 Published online September 2, 2019

69. 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

70. Methods
• Adult patients with symptomatic HFrEF
(LVEF ≤40%) eligible for on-label
treatment with S/V were enrolled
• Following discontinuation of ACEI/ARB,
S/V was initiated and titrated
• 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.

71. 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.

72. Baseline characteristics (N=794)
Parameter N=794
Age, years; mean (SD) 65.1 (12.4)
Male sex; n (%) 568 (71.5)
NYHA Class II or III; n (%) 780 (98.2)
Race; n (%)
White
Black
581 (73.4)
180 (22.7)
Body-mass index, kg/m2, mean (SD) 31.3 (6.9)
Past Medical History; n (%)
Hypertension
Diabetes mellitus
Myocardial infarction
Atrial fibrillation/flutter
699 (88.0)
361 (45.5)
329 (41.4)
280 (35.3)
Guideline-directed HFrEF therapy; n (%)
Beta blocker
ACEI/ARB
MRA
CRT/CRT-ICD
ICD-alone
757 (95.3)
602 (75.8)
281 (35.4)
122 (15.4)
226 (28.5)
Cardiac measurements, median (interquartile range):
• LVEF = 28.2 (24.5, 32.7) %
• LVEDVi = 86.93 (76.17, 100.43) mL/m2
• LVESVi = 61.68 (51.95, 75.00) mL/m2
• LAVi = 37.76 (31.63, 46.09) mL/m2
• E/e' =11.70 (8.80, 16.00)
Subgroups of interest:
• New-onset HF and/or ACEI/ARB naïve: N = 118 (14.9%)
• BNP or NT-proBNP concentrations below PARADIGM-HF
inclusion criteria: N = 292 (36.8%)
• Following titration, 278 (35.0%) did not receive target dose
N (%) unless otherwise noted; SD, standard deviation; NYHA, New York Heart Association; ACEI, ACE inhibitor; ARB, angiotensin II receptor blocker;
MRA, mineralocorticoid receptor antagonist; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

73. NT-proBNP concentrations
Time point N Median NT-proBNP
(25th, 75th percentile), pg/mL
Baseline 760 816 (332, 1822)
Day 14 754 528 (226, 1378)
Day 30 740 546 (211, 1321)
Day 45 734 514 (192, 1297)
Month 2 721 535 (210, 1299)
Month 3 719 488 (211, 1315)
Month 6 699 473 (179, 1163)
Month 9 659 444 (170, 1153)
Month 12 638 455 (153, 1090)
Rapid and significant reduction of NT-proBNP was observed, with
majority of reduction within the first 2 weeks
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

74. Primary endpoint
• From baseline to 12 months, significant correlations were observed between the
change in NT-proBNP concentration and cardiac remodeling parameters.
• Parallel latent growth curve analyses demonstrated strong association between
early NT-proBNP change and subsequent reverse cardiac remodeling.
Parameter Pearson r (IQR) P value
NT-proBNP (pg/mL) / LVEF (%) -0.381 (-0.448, -0.310) <.0001
NT-proBNP (pg/mL) / LVEDVi (mL/m2) 0.320 (0.246, 0.391) <.0001
NT-proBNP (pg/mL) / LVESVi (mL/m2) 0.405 (0.335, 0.470) <.0001
NT-proBNP (pg/mL) / LAVi (mL/m2) 0.263 (0.186, 0.338) <.0001
NT-proBNP (pg/mL) / E/E’ 0.269 (0.182, 0.353) <.0001
IQR, interquartile range; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; mL, milliliter; LAVi,
left atrial volume index; E/E’, ratio of early diastolic filling velocity and early diastolic mitral annular velocity
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

75. 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

76. 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

77. Subgroups of interest
• Reverse cardiac remodeling was comparable in each subgroup of interest
New-onset HF/ACEI-ARB naïve (N=118)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +12.8 (+11.05, +14.5)
LVEDVi (mL/m2) -13.81 (-15.78, -11.83)
LVESVi (mL/m2) -17.88 (-20.07, -15.68)
LAVi (mL/m2) -8.44 (-9.73, -7.15)
E/e’ -2.60 (-3.83, -1.37)
NP < PARADIGM incl criteria* (N=292)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +9.4 (+8.6, +10.3)
LVEDVi (mL/m2) -11.32 (-12.24, -10.40)
LVESVi (mL/m2) -14.15 (-15.15, -13.15)
LAVi (mL/m2) -7.06 (-7.54, -6.58)
E/e’ -0.93 (-1.43, -0.43)
Not reaching target dose (N=278)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +9.4 (+8.4, +10.3)
LVEDVi (mL/m2) -10.99 (-12.21, -9.77)
LVESVi (mL/m2) -14.32 (-15.67, -12.97)
LAVi (mL/m2) -7.23 (-7.97, -6.50)
E/e’ -0.46 (-1.32, +0.40); P =NS
All P <0.001 except where noted
*NT-proBNP < 600 pg/mL if not hospitalized or < 400 pg/mL if hospitalized within the past 12 months; BNP < 150 pg/mL if not hospitalized or < 100 pg/mL if hospitalized for HF within the past 12 months; BL,
baseline; LS, least-square; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; mL, milliliter; LAVi, left atrial volume index; E/E’, ratio of early diastolic filling velocity and
early diastolic mitral annular velocity; NP, natriuretic peptide.
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

78. 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

79. Adverse events by 12 months
• Adverse events rates were similar to
the PARADIGM-HF study, with the
exception of dizziness
• Positively-adjudicated angioedema
occurred in only 2 patients (0.3%), of
whom 1 was Black (0.56%)
• Both cases of angioedema were mild,
resolving with antihistamines or no
therapy
Event
N = 794;
n (%)
Hypotension (systolic blood pressure <90 mm mercury) 140 (17.6)
Dizziness 133 (16.8)
Hyperkalemia (potassium > 5.3 milliequivalents/liter) 105 (13.2)
Worsening kidney function* 98 (12.3)
Angioedema
No treatment or antihistamines only without hospitalization 2 (0.3)
*Worsening (decrease) in estimated glomerular filtration rate of ≥ 35% from baseline, or an
increase in creatinine of ≥ 0.5 mg/dL from baseline and a worsening (decrease) in estimated
glomerular filtration rate of ≥ 25% from baseline at a given visit.
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

80. Conclusions
• In this study of patients with HFrEF treated with sacubitril/valsartan,
reduction in NT-proBNP was significantly associated with reverse cardiac
remodeling
• The degree of reverse remodeling demonstrated may help to explain how
sacubitril/valsartan reduces morbidity and mortality in patients with HFrEF
• Analyses examining impact of sacubitril/valsartan on quality of life,
symptoms, and a broad range of mechanistic biomarkers are underway
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

82. The Rational Behind the New Position of ARNI
in the new 2021 ACC Consensus
82

83. Dual Mechanism of Action
(Inhibition of RAAS & Activation of Natriuretic peptide system)
83
Sympathetic
nervous system
Renin-angiotensin-
aldosterone system
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II AT1R
HF SYMPTOMS &
PROGRESSION
Natriuretic peptide
system
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
Levin et al. N Engl J Med 1998;339:321–8
Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 2009;341:577–85
Ang=angiotensin; AT1R=angiotensin II type 1 receptor;
HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-
angiotensin-aldosterone system

84. Sacubitril/valsartan: Proven Superiority over
Enalapril

85. Sacubitril/valsartan significantly reduced the
risk of sudden death compared with
enalapril
85
Hazard ratio=0.80
(95% CI: 0.68–0.94) p=0.008
Enalapril
Sacubitril/valsartan
0 180 360 540 720 900 1080 1260
0
0.02
0.04
0.06
0.08
0.10
Days since randomization
No. at risk
Sacubitril/valsartan 4187 3891 2478 1005
Enalapril 4212 3860 2410 994
Cumulative
probability
of
sudden
death
311/4187 died
(7.4% patients)
250/4212 died
(6.0% patients)
1. Desai et al. Eur Heart J 2015;36:1990-7; 2. McMurray, et al. New Engl J Med. 2014;371:993-1004
20%

86. The reduction in HF hospitalization with Sacubitril/Valsartan was evident within the
first 30 days after randomization
HR 0.60 (95% CI: 0.38–0.94)
p=0.027
Days after randomization
Number of patients at risk
LCZ696 4,187 4,174 4,153 4,140
Enalapril 4,212 4,192 4,166 4,143
Kaplan-Meier
estimate
of
cumulative
rate
1.5
1.0
0.5
0
0 10 20 30
Enalapril (N=4,212)
Sacubitril/Valsartan (N=4,187)
Packer et al. Circulation 2014; epub ahead of print: DOI:
10.1161/CIRCULATIONAHA.114.013748
Shown is the Kaplan-Meier estimate of the cumulative probability of a first hospitalization for heart
failure during the first 30 days after randomization. The analysis at 30 days was prespecified and also
represented the earliest time point at which the difference between the LCZ696 and enalapril groups
was statistically significant.

87. Additional Reduction for ARNI in CV outcomes Vs ACEI
1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302.
3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
10
20
30
40
ACE
Inhibitor2
Angiotensin
Receptor
Blocker1
0
Decrease
in
Mortality
(%)
18%
20%
ARNI3
15%

88. Sacubitril/valsartan vs enalapril significantly improved most KCCQ
domains* in surviving patients
• Differences between the treatments
in score changes from baseline at 8
months favored sacubitril/valsartan
vs enalapril for all KCCQ domains
• Improvements in all scores with
sacubitril/valsartan treatment
• Decline# in most of the KCCQ
domains were observed in the
enalapril treatment group
88
KCCQ, Kansas City Cardiomyopathy Questionnaire, LSM,
least squares mean
Lewis E et al. Circ Heart Fail. 2017;10:e003430.
A prespecified HRQoL efficacy measure of PARADIGM-HF in surviving patients
*Improvements were noted in all the KCCQ domains except in symptom stability
#Decline in symptom stability scores observed in both treatment groups was significantly higher in the enalapril treatment group (a 4.3-point decline)
than that observed in sacubitril/valsartan group (2.9-point decline)

89. Differences in combined physical/social activity score between sacubitril/valsartan
and enalapril were comparable to 9 years of ageing
89
KCCQ, Kansas City Cardiomyopathy Questionnaire
Unadjusted age equivalency analysis at 8-month follow-up
80
75
70
85
65
80
75
70
65
60
55
50
45
40
35 85
Combined
KCCQ
physical
and
social
activities
mean
score
Enalapril
Sacubitril/valsartan
Age (years)
9 years
(95% CI: 4–13);
p<0.001)
Chandra A et al. JAMA Cardiol. 2018;
doi:10.1001/jamacardio.2018.0398.
A prespecified analysis

90. EVALUATE-HF:
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

91. PROVE-HF: Enhancement of EF%
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

92. PROVE-HF:
De novo / ACEI-ARB naïve HFrEF
Patients
• Reverse cardiac remodeling was comparable in each subgroup of interest
New-onset HF/ACEI-ARB naïve (N=118)
Parameter
LS Mean change,
BL to 12 months (95%
CI)
LVEF (%) +12.8 (+11.05, +14.5)
LVEDVi
(mL/m2)
-13.81 (-15.78, -11.83)
LVESVi
(mL/m2)
-17.88 (-20.07, -15.68)
LAVi (mL/m2) -8.44 (-9.73, -7.15)
E/e’ -2.60 (-3.83, -1.37)
NP < PARADIGM incl criteria* (N=292)
Parameter
LS Mean change,
BL to 12 months (95%
CI)
LVEF (%) +9.4 (+8.6, +10.3)
LVEDVi
(mL/m2)
-11.32 (-12.24, -10.40)
LVESVi
(mL/m2)
-14.15 (-15.15, -13.15)
LAVi (mL/m2) -7.06 (-7.54, -6.58)
E/e’ -0.93 (-1.43, -0.43)
Not reaching target dose (N=278)
Parameter
LS Mean change,
BL to 12 months (95%
CI)
LVEF (%) +9.4 (+8.4, +10.3)
LVEDVi
(mL/m2)
-10.99 (-12.21, -9.77)
LVESVi (mL/m2) -14.32 (-15.67, -12.97)
LAVi (mL/m2) -7.23 (-7.97, -6.50)
E/e’
-0.46 (-1.32, +0.40); P
=NS
All P <0.001 except where noted
*NT-proBNP < 600 pg/mL if not hospitalized or < 400 pg/mL if hospitalized within the past 12 months; BNP < 150 pg/mL if not hospitalized or < 100 pg/mL if hospitalized for HF within the past 12 months; BL,
baseline; LS, least-square; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; mL, milliliter; LAVi, left atrial volume index; E/E’, ratio of early diastolic filling velocity and
early diastolic mitral annular velocity; NP, natriuretic peptide.
James L. Januzzi et al
JAMA. doi:10.1001/jama.2019.12821 Published online September 2, 2019

93. 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
93
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.

94. In-HospitalSettings(afterpatientsbecomehemodynamicallystable)
Sac/val led to a greater reduction in NT-proBNP
compared to ACEi - irrespective of prior HF history
ACEi, angiotensin converting enzyme inhibitor HF, heart failure; NT-proBNP, N-terminal pro b-type
natriuretic peptide; sac/val, sacubitril/valsartan
-42.0
-36.4
-31.2
-55.0
-59.2
-51.2
2 4 8
-60
Baseline
-50
-40
10
1
Time (weeks)
Time (weeks)
134
154
116
142
122
141
128
141
122
140
0
-10
-20
-30
2 4 8
-80
Baseline
-70
-60
-50
-40
-30
-20
-10
0
10
1
Percentage
change
from
baseline
-31.5 -30.4
-39.0
-56.2
-73.6
-19.3
-12.6
-11.2
-20.8
263
239
239
216
241
209
237
208
227
207
0
0
94
De novo HF Worsening chronic HF
-37.5
Sacubitril/Valsartan
Enalapril
Number at risk
Sac/val
Enalapril
Sac/val
Enalapril
Number at risk
Percentage
change
from
baseline
Change in NT-proBNP from baseline
Ambrosy et al., Oral Presentation
(#1135) at ESC 2019 Congress,
Paris, France
Sacubitril/Valsartan
Enalapril

95. Results (4/4)
Kaplan-Meier Estimated Cumulative Incidence of Cardiovascular Death or Rehospitalization for Heart Failure
20
10
0
Enalapril
Sacubitril/Valsartan
%
of
patients
with
clinical
endpoint
Sacubitril/
Valsartan*:
Enalapril*:
232
227
0 7 14 21 28 35 42 49 56
231
219
228
212
226
206
222
203
219
197
215
193
212
190
208
188
Time since randomization (days)
20
10
0
%
of
patients
with
clinical
endpoint
Sacubitril/
Valsartan*:
Enalapril*:
208
214
0 7 14 21 28 35 42 49 56
205
212
193
206
190
202
183
193
180
186
176
176
175
170
172
168
Time since randomization (days)
Enalapril
Sacubitril/Valsartan
No ACEi/ARB Yes ACEi/ARB
*N at Risk
P value for interaction = 0.880
ACEi, angiotensin converting-enzyme inhibitor; ARB, angiotensin receptor blocker
Source: Ambrosy AP, et al. Poster presented at: The American College of Cardiologists Meeting, New Orleans, Louisiana, USA; 16–18 March 2019..
In-Hospital Settings (after patients become hemodynamically stable)
Angiotensin Receptor-Neprilysin Inhibition in Acute Decompensated Heart Failure
Based on Prior Exposure to a Conventional Renin-Angiotensin System Antagonist:
A Pre-specified Subgroup Analysis of the PIONEER-HF Trial