1. The document discusses initiation of ARNi (angiotensin receptor-neprilysin inhibitor) therapy in hospitalized patients with acute heart failure. 2. It reviews the limitations of prior trials that excluded hospitalized patients and required run-in periods on ACEi/ARB therapy. The PIONEER trial demonstrated the safety and efficacy of initiating sacubitril/valsartan in stabilized hospitalized patients. 3. A sub-analysis found greater reductions in NT-proBNP levels and comparable safety with pre-discharge versus post-discharge initiation. Patients with no prior HF diagnosis had higher rates of achieving target sacubitril/valsartan doses with similar

1. Initiation of ARNi in hospital – How early is early?
1. Introduction and HF Stages
2. Natural history and Pathophysiology of ADHF
3. Patient’s journey – Optimizing the treatment
4. Basic tenets of Management of hospitalized Acute HF patient
5. Why not initiate ARNI at the time of discharge ? – Experience
from clinical trial
6. Pioneer –HF
7. Transition Trial
8. Clinical Interpretation from recent trials
9. Initiation of an ARNI in De Novo HF vs chronic heart failure with
or Without Prior Exposure to an ACEI or ARB
10. Conclusion

2. Larry A. Allen. Circulation. Decision Making in Advanced Heart
Failure, Volume: 125, Issue: 15, Pages: 1928-1952, DOI:
(10.1161/CIR.0b013e31824f2173)
© 2012 American Heart Association, Inc.

7. Pathway to improve outcomes in HF begins
with admission , continues through
admission and transition to oral therapies
before discharge

8. Clinical trajectory should be assessed
Key risk factors and comorbities assessed
at hospitalisation
Review and communicate at discharge day

9. First follow up visit – address specific
issues such as volume status, h/d stability,
kidney function, electrolytes, regimen of
recommended therapies, adherence
challenges and goals of care

11. When possible continuation of GDMT through hospitalization or initiation before discharge
Hospitalization provides a key opportunity to decrease risk and improve clinical trajectory in
In patients who respond to diuretics and and have not previously received adequate trial of
GDMT
Hence introduction of GDMT is a key target during hospitalization for HFrEF to reduce risk.
This has been shown for ACEI , Beta Blockers and most recently for ARNIs.
General tenets of acute heart failure hospitalisation
management

12. What we learned from PARADIGM - HF
• In stable outpatients with HFrEF already tolerating high doses of ACE or ARB therapy,
PARADIGM-HF demonstrated that sacubitril/valsartan reduced cardiovascular death, heart failure
hospitalization and all- cause mortality compared with the gold standard enalapril.
• Switching 1000 patients from an ACE inhibitor/ARB to sacubitril valsartan avoided(over a
median duration of 27 months):
- 47 primary endpoints of CVD or hospitalized HF
- 31 cardiovascular deaths
- 28 patients hospitalized for HF
- 37 patients hospitalized for any reason
- 53 total admissions for HF
- 111 total admissions for any reason
Courtesy - S. Solomon 2019

13. PARADIGM-HF : Limitations
• Limited experience with hospitalized ADHF patients (excluded by protocol)
• No prior hospitalization at baseline — 37.2 %
• At baseline 8% patients With rales and 21 % With LEE
• Low rate of HF hospitalization (14.2%) in follow-up
• Stable dose of ACEI/ARB (equivalent to Enalapril 10 mg daily) and BB required for at least 4 weeks prior to entry
• Design required sequential single blind periods

14. Why Not Initiate an ARNI In-Hospital for HFrEF?
• Unclear efficacy in a broad ADHF population?
• Increased risk of in hospital adverse events
• Compared to ACEi?
• Compared to later initiation?
• Increased risk of early discontinuations (affect on long- term adherence)?
• No difference in short-term clinical outcomes?
• No rationale for an early clinical effect?

15. Recent Trials With Sacubitril / Valsartan
Dr. K.M. Nisamudeen

16. • 70% of care
• Transitions fragile
1. Contrast of evidence for acute versus chronic
HFrEF Rx
Ambulatory Hospitalized
The Need for PIONEER
Data

17. 1. Contrast of evidence for acute versus chronic HFrEF
Rx
2. Limitations of PARADIGM-HF
• Stable ambulatory patients
• Run-in phase
• <2% NYHA IV
• Concerns about hypotension
The Need for PIONEER
McMurray et al. NEJM 2014

18. 1. Contrast of evidence for acute versus chronic HFrEF
Rx
2. Limitations of PARADIGM-HF
3. Sacubitril/valsartan use low:
The Need for PIONEER
<15%
eligible
patients in
CHAMP
Greene et al. CHAMP. JACC 2018

19. 1. Contrast of evidence for acute versus
chronic HFrEF Rx
2. Limitations of PARADIGM-HF
3. Sacubitril/valsartan use low:
The Need for PIONEER
WHY?
• Not trust a single trial?
• Switching complicated?
• Background Rx complicated?
• Cost?
• Clinical intertia?!
Greene et al. CHAMP. JACC 2018

20. PIONEER – Patient profile

21. 9
Primary Endpoint : % Change in
NT-proBNP
29% greater reduction with
sacubitril/valsartan
CI 19%, 37%; P < 0.0001
10
0
–10
–20
–30
–40
–50
–60
–70
Percent
Change
from
Baseline
2 3 4 5 6
Week since Randomization
Baseline 1 7 8
enalapril
sacubitril/valsartan

22. PIONEER- safety
1. Safe:
• Renal parameters (similar)
• Blood pressure (14% hypotension, <2%
difference)
2. Effective
• NT-proBNP ↓ 29%
• Serious event composite: ↓ 46% at 8
weeks

23. Safety Events(%) sacubitr
il/valsa
rtn
(n=440)
enalapr
l
(n=441)
RR
(95% CI)
Worsening renal function* 13.6 14.7 0.93 (0.67-1.28)
Hyperkalemia† 11.6 9.3 1.25 (0.84-1.84)
Symptomatic hypotension 15.0 12.7 1.18 (0.85-1.64)
Angioedema event 1 (0.2%) 6 (1.4%) 0.17 (0.02-1.38)
Safety
10
*Cr ≥0.5 with simultaneous reduction in eGFR of ≥25%
†K+ >5.5 mg/dl
P = NS for all safety
events

24. Serious Composite Clinical
Endpoint
HR = 0.54; 95% CI 0.37, 0.79
P = 0.001
NNT = 13
20
Event
Rate
(%)
10
0
0 7
sacubitril/valsartan
9.3%
enalapril
N =
441
N = 440
24 28 35 42
Days since Randomization
14 49 56
Death, HF re-hosp, LVAD, Transplant listing
16.8%

25. sacubitril/
valsartan (n=440)
enalapri
l
(n=441)
HR P-value
Serious Composite, % 9.3 16.8 0.54 0.001
Death, % 2.3 3.4 0.66 0.311
Re-hosp for HF, % 8.0 13.8 0.56 0.005
LVAD, % 0.2 0.2 0.99 0.999
Cardiac Transplant, % 0 0 - -
Expanded Composite*, % 56.6 59.9 0.93 0.369
Unplanned IV diuretics, % 0.5 0.5 0.99 0.997
Addition of HF med, % 17.7 19.1 0.92 0.58
>50% diuretic increase, % 49.6 50.3 0.98 0.812
Exploratory Clinical
Endpoints
*Serious composite + addition of HF med, no unplanned outpatient IV diuretics or >50% increase in dose

26. Conclusions
Among hemodynamically stabilized acute heart failure
patients with reduced EF, compared with enalapril,
sacubitril/valsartan administered over 8 weeks …
 Led to greater reduction in NT-proBNP
 Reduced re-hospitalization for heart failure
 Was well tolerated with comparable rates of worsening
renal function, hyperkalemia, symptomatic hypotension,
and angioedema

31. Clinical predictors of NT-
proBNP response to early
initiation of
sacubitril/valsartan
after hospitalisation for
decompensated heart failure : A
sub analysis of the TRANSITION
study

32. TRANSITION study
39
Aims
• Identify patterns of NT-proBNP levels during the study
• Identify clinical predictors of NT-proBNP response to sacubitril/valsartan
Rationale
• NT-proBNP levels reflect cardiac wall stress and its reduction is related to improved outcomes
16-week
follow-up
1-
14
day
s
Hospital
admission
for ADHF
Pre-discharge sac/val
initiation
Post-discharge sac/val
initiati
on
10-week
treatment
OMT
Stratification
ACEi
ARB
ACEi/ARB-naïve
Patient
stabilised †
1–3 days screening
Sac/va
l
Sac/va
l
Randomisation Discharge Week 26
Week 10
Biomarker collection week 4
= 36 hours ACEi washout
OMT = optimised medical treatment
†Patients’ haemodynamically stable = no need for intravenous diuretics (in 24 h prior to screening)
and SBP >110 mmHg (for ≥6 h prior to randomisation)

33. Changes in NT-proBNP during sac/val
treatment
40
*Change from baseline is p<0.05;
mixed model with repeated measures
Pre-
discharge
initiation (n) 478 430 446 444
Post-
discharge
initiation (n)
473 310 450 439
-40
-30
-20
-10
0
At Week
10
-
28.1
*p<0.001
-
25.1*
-
22.0*
p=0.377
-
38.0*
-
33.7*
p=0.250
At discharge At Week
4
-3.5
Changes
in
NT-proBNP
(%)
Plasma NT-proBNP levels Reductions in NT-proBNP from baseline
Pre-discharge initiation (N=493) Post-discharge initiation (N=489)
Randomisation Discharge Week 10
Geometric
mean
plasma
NT-proBNP
(pg/mL)
2200
2000
1800
1600
1400
1200
1000
800
p=0.29
3
p<0.00
1 p<0.001
p<0.001
p<0.00
1
p<0.000
1
Week 4
Visit

34. Discharge
199/430
Week 4
206/446
187/450
Week 10
227/444
211/439
10
0
20
40
30
50
60
46.
3
46.
2
18.
1
41.
6
48.
1
Pre-discharge
initiation
Post-discharge
initiation
51.4
Patients
(%)
Proportion of patients with NT-proBNP favorable
response (reduction ≤1000 pg/mL, or > 30% from
baseline)
41
Pre-discharge initiation
(m/N)
Post-discharge initiation (m/N)
56/310
m: number of patients with NT-proBNP assessments ≤1000 pg/mL or >30% reduction from baseline
N: number of patients with non-missing NT-proBNP assessments at both baseline and corresponding post-baseline time
point

35. TRANSITION : conclusions
Wachter R, et al. Abstract P6531.
European Society of Cardiology Congress; Aug. 25-29, 2018;Munich.

36. DE-NOVO vs Prior CHF – Post hoc analysis of
TRANSITION

43. DE-NOVO vs Prior CHF – Post hoc analysis of
TRANSITION
• After 10 weeks, 56% de novo HFrEF patients received target dose of sacubitril/valsartan (97/103 mg)
vs. 45% in prior HFrEF patients (P<0.001).
• Proportion of patients on 49/51 mg or 97/103 mg sacubitril/valsartan was also higher in de novoHFrEF
patients compared to prior diagnosed patients (72% vs. 63%, P=0.002).
• There was no difference between groups for percentage patients who discontinued sacubitril/valsartan
due to adverse events (3% in de novo group vs. 7% in the prior diagnosed group).
• Most relevant adverse events were hyperkalemia, hypotension, and cardiac failure, with no difference in
number of AEs between groups.
• Use of betablockers, MRAs and diuretics were similar for both groups.
• At week 4 and 10, NT-proBNP and hs-Troponin T were lower in de novo group vs. the prior diagnosed
group (for both markers and both time points P<0.001).

44. De-Novo Vs Prior CHF –PIONEER Substudy

46. Initiation of an ARNI De Novo
Without Prior Exposure to an ACEI or
ARB –Preferred :-
1. Recent data suggests that directly initiating an ARNI, rather than a
pretreatment
period ACEI or ARB, is a safe and effective strategy.
2. Patients with de novo HF who underwent in-hospital initiation of an
ARNI had a
greater reduction in NP concentrations, a comparable safety profile,
and a
significant improvement in early clinical outcomes compared with those
on enalapril .
3. When de novo initiation of ARNI is performed, close follow-up and
serial assessments
(blood pressure, electrolytes, and renal function) should be
considered, and any such
usage should consider concerns regarding the risk of angioedema or

47. ARNI -- The final outcome

48. Conclusion
The 2019 ACC Expert Consensus Statement on the Management of Patients
Hospitalized with HF recommends ARNI based on the PIONEER-HF study
for patients with HFrEF hospitalized for ADHF who are in the
trajectory phase toward stabilization, who have stabilized after
initial diuresis, or who are in the transition to discharge period.
When initiated in the hospital after stabilization of ADHF, it is
recommended that patients are clinically stable( no symptoms of
hypotension; no increase of IV diuretics, vasodilators, or nitrate
therapy in the prior 6 hours; and no IV inotropes for the prior 24
hours).

49. Thank you