use of ARNI in heart failure is well establish though when to start has been debatable.now there is data to show that use of inhospital arni early after stabilization is safe & saves more lives

1. Initiation of ARNi in hospital – How early is early?
1. Introduction --- HF A STATE OF NEUROHUMORAL IMBALANCE –
2. Natural history and Pathophysiology of ADHF
3. Patient’s journey – Optimizing the treatment
4. Management of Acute HF and Discharge Plan
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. Side effects comparison and dosages
10. Initiation of an ARNI De Novo Without Prior Exposure to an ACEI
or ARB –Preferred
12. Conclusion

4. PATHOPHYSIOLOGY OF ADHF

6. ESC Congress Munich 2018

9. How Do You Know When the Patient Is Decongested and
Ready For Discharge?
a Singer AJ, et al. Circ Heart Fail. 2009;2:287-293.

11. ESC Congress Munich 2018

12. Management of acute HF
ESC Congress Munich
2018

13. TABLE Important Pathophysiological Targets in Chronic, Hemodynamically Stable HFrEF
and Treatments
Target Therapy
Renin-angiotensin-aldosterone system ARNIs/ACEIs/ARBs, aldosterone Antagonists
Sympathetic nervous system Beta-blockers
Natriuretic and other vasodilator peptides Neprilysin inhibitor (ARNI)
Sodium-glucose cotransporter-2 SGLT2 inhibitors
Balanced vasodilation and oxidative stress
modulation
HYD/ISDN
Elevated heart rate Beta-blocker, ivabradine
Guanylyl cyclase Soluble guanylyl cyclase stimulators
Relief of congestion Diuretic agents
Ventricular arrhythmias Implantable cardioverter defibrillators
Ventricular dyssynchrony due to
conduction abnormalities
Cardiac resynchronization therapy
Mitral regurgitation Surgical or percutaneous mitral valve repair
Reduced aerobic capacity Aerobic exercise training

17. 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:
-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
• Over a median of 27 months
Courtesy of S. Solomon 2019

18. PARADIGM-HF : Limitations
• Limited experience with hospitalized ADHF patients (excluded by protocol)
• No prior hospitalization at baseline — 37.20/o
• At baseline 8O/o With rales and 21 0/o With LEE
• Enrollment of black patients low — 5.1 0/o
• Low rate of HF hospitalization (14.20/o) 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
• E: 15 days (IQR 14 -21); 10.5 0/o drop out (5.60/o AEs)
• S/V: 29 days (IQR 26-35); 10.40/o drop out (5.90/o AEs)

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

20. The initiation of ARNI in hospitalized ADHF pts feasible after the
patient has been hemodynamically stabilized and not volume –depleted.
In patients with Borderline blood pressure (e.g., SBP <=100 mm Hg),
careful administration and follow-up are advised.
Renal function and potassium should be checked within 1-2 weeks of
initiation or dose up-titration of ACEI/ARB/ARNI.
In non congested patients with otherwise stable clinical profiles,
empiric modest lowering of loop diuretic agents has been found to
mitigate the hypotensive effects of sacubitril/valsartan.
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)- issue
?

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

22. Nesiritide
(ASCEND)
Tolvaptan
(EVEREST)
Serelaxin (RELAX)
1. Contrast of evidence for acute versus chronic
HFrEF Rx
Ambulatory Hospitalized
The Need for PIONEER
Enalapril (SOLVD)
Carvedilol
(COPERNICUS)
Spironolactone (RALES)

23. • 70% of care
• Captive audience
• Transitions fragile
Action
1. Contrast of evidence for acute versus chronic
HFrEF Rx
Ambulatory Hospitalized
The Need for PIONEER
Data

24. 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

25. 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

26. 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

27. PIONEERing Success
1. Safe:
• Renal parameters (similar)
• Blood pressure (14% hypotension, <2%
difference)

28. PIONEERing Success
2. Effective
• NT-proBNP ↓ 29%
• Serious event composite: ↓ 46% at 8 weeks
HF Readmission:
Death:
13.8% to 8.0% = 5.8% ARR
(p=0.005)
3.4% to 2.3% = 1.1% ARR (NS)

29. Background
 Acute decompensated heart failure (ADHF)
accounts for over 1M hospitalizations in
the US annually
 Guideline-directed therapy for ADHF is limited
• Decongestion with diuretics and hemodynamic
support with vasodilators remain the standards
of care

30. Rationale
 PARADIGM-HF trial in chronic HFrEF:
sacubitril/valsartan
↓ CV death or HF hospitalization compared to
enalapril
• Patients with ADHF requiring IV therapy were
excluded
• Stable HF therapy with adequate doses for >4
weeks
• Required sequential run-in with high dose
enalapril and sacubitril/valsartan before
randomization
McMurray JJ. NEJM. 2014;371:993-1004.

31. 4
Study Design
sacubitril/valsar
tan
enalapril
vs
In-hospital
initiation
Hospitalized with ADHF
(HFrEF)
Stabilized
 Evaluate biomarker surrogates of
efficacy
 Evaluate safety and tolerability
 Explore clinical outcomes
Titration algorithm over 8
weeks

32. Key Entry
Criteria
 Hospitalized for ADHF (signs and symptoms of fluid
overload)
 LVEF ≤40% within the last 6 months
 NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL (screening)
 Stabilized while still hospitalized
• In the prior 6 hours :
- SBP ≥100 mmHg, no symptomatic hypotension
- No increase in IV diuretics
- No IV vasodilators
• In the prior 24 hours: no IV inotropes

33. Key Endpoints
 Primary endpoint : Proportional change in NT-proBNP from baseline
to the mean of weeks 4 and 8
 Safety
• Worsening renal
function
• Hyperkalemia
 Exploratory Clinical Outcomes
• Serious clinical composite: death, re-hospitalization for HF, LVAD,
or listing for cardiac transplant
• Expanded composite: Serious composite + addition of HF med,
unplanned outpatient IV diuretics or >50% increase in dose
• Symptomatic hypotension
• Angioedema

34. SBP Dose Titration
Algorithm
 Starting dose level based on SBP
• If 100 to <120 mm Hg, sacubitril/valsartan 24/26 mg or
enalapril 2.5 mg twice daily
• If ≥120 mm Hg, sacubitril/valsartan 49/51 mg or enalapril
5 mg
twice daily
 Up-titration based on SBP (clinical judgement permitted)
 Target doses
• sacubitril/valsartan 97/103 mg twice daily or enalapril 10
mg
twice daily

35. Baseline
Characteristics
sacubitril/valsartan
(n=440)
enalapril
(n=441)
Age* (years) 61 (51, 71) 63 (54, 72)
Women (%) 25.7 30.2
Black (%) 35.9 35.8
No prior HF diagnosis (%) 32.3 37.0
No ACEi/ARB therapy (%) 52.7 51.5
LVEF* 0.24 (0.18, 0.30) 0.25 (0.20, 0.30)
SBP (mm Hg)* 118 (110, 133) 118 (109, 132)
NT-proBNP (pg/mL)* 2883 (1610, 5403) 2536 (1363, 4917)
*Median (interquartile range) .

36. 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

38. 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

39. 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%

40. 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

41. All
Patients
Prior
HF
No
Yes
Prior
ACEi/ARB
No
Yes
Subgroup
Change in NT-proBNP
sacubitril/valsar
tan vs.
enalapril mean
[95% CI]
0.1 0.3 0.5 0.7 0.9 1.1
1.3 1.5 1.7 1.9
Favors
sacubitril /
valsartan
Favors
enalapri
l
0.71 [0.63,
0.81]
0.65 [0.53,
0.81]
0.72 [0.63,
0.83]
0.72 [0.60,
0.86]
0.72 [0.61,
0.85]
Key Subgroup Analyses
P value (interaction) = NS Favors
enalapril
Serious Composite Endpoint
0.1 0.3 0.5 0.7 0.9 1.1
1.3 1.5 1.7 1.9
Favors
sacubitril /
valsartan
0.54 [0.37,
0.79]
0.37 [0.12,
1.15]
0.53 [0.35,
0.80]
0.52 [0.29,
0.95]
0.56 [0.34,
0.92]
Hazard
Ratio
[95% CI]
All
Patients
Prior
HF
No
Yes
Prior
ACEi/ARB
No
Yes
Subgroup

42. 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

43. Clinical Implications
15
These results support the in-hospital initiation
of sacubitril/valsartan in stabilized patients
with
acute decompensated heart failure and reduced
EF, irrespective of prior ACEi/ARB use, or prior
HF diagnosis.

45. The Post-PIONEER World
• Simple (simpler) algorithm for inpatient and subsequent
out patient HFrEF management
Better for clinicians
Better for patients
• Reinforces the importance and
• safety of aggressive GDMT in most patients

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

47. TRANSITION study
47
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)

48. Male, n (%) 371 (74.9) 373(75.2)
LVEF (%), mean (SD) 28.6 (7.5) 29.0 (7.6)
NYHA class II / III / IV, n% 64.6/33.5/1.4 63.5/34.9/0.8
eGFR* (mL/min/1.73m2), mean (SD) 62.0 (20.5) 62.0 (19.4)
De novo HF, n (%) 148 (29.9) 138 (27.8)
Median NT-proBNP* median (IQR), pg/mL 1902 (945–3847) 1669 (706–3599)
Hypertension, n (%) 372 (75.2) 375 (75.6)
Diabetes, n (%) 226 (45.7) 234 (47.2)
Atrial fibrillation, n (%) 243 (49.1) 237 (47.8)
*At randomisation
Baseline characteristics
Parameters
Pre-discharge
initiation
(N=495)
Post-discharge
initiation
(N=496)
Age (years), mean (SD) 66.7 (12.3) 66.9 (11.7)

49. Changes in NT-proBNP during sac/val
treatment
49
*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

50. 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)
50
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

51. Predictor Odds ratio (95% CI) p value
1.196 (0.899–
1.591)
Treatment group: pre-discharge vs post-discharge initiation 0.2193
Higher NT-proBNP at baseline*, Δ of 1000 pg/mL 1.175 (1.116–1.236)
<0.000
1
0.000
8
0.018
2
0.000
4
0.037
9
0.007
5
0.003
6
Higher serum creatinine at baseline*, Δ of 20 µmol/L 0.834 (0.751–
0.928)
De novo HF 1.548 (1.077–
2.226)
No atrial fibrillation at baseline 1.696 (1.267–
2.269)
Starting sac/val dose ≥49/51 mg b.i.d 1.550 (1.025–
2.344)
ACEi/ARB naïve 1.582 (1.130–
2.213)
No prior MI 1.617 (1.169–
2.235)
1 2 3
4 weeks predictors analysis of NT-proBNP favorable
response (reduction ≤1000 pg/mL, or >30% from
baseline)†
†Multivariate logistic regression analysis. Only predictors with p<0.05 included in the final model.
Treatment group and at baseline NT-proBNP per 1000 pg/mL change included as covariate in the model regardless of the p-value
* Baseline assessment taken at Randomisation visit

52. Predicto
r
Treatment group: pre-discharge vs post-discharge
initiation
Odds ratio (95% CI) p
value
1.034 (0.767–1.393)
0.8278
Higher NT-proBNP at baseline*, Δ of 1000
pg/mL
Higher serum creatinine at baseline*, Δ of
20 µmol/L
1.204 (1.134–1.277)
<0.000
1
0.822 (0.737–0.917)
0.0004
De novo
HF
No atrial fibrillation at
baseline
1.600 (1.075–2.382)
0.020
6
1.384 (1.022–1.873)
0.035
6
Starting sac/val dose ≥49/51 mg
b.i.d
ACEi/ARB naïve
No MRA before admission
Non-Ischemic HF aetiology
1.661 (1.075–2.566)
0.022
2
1.698 (1.193–2.418)
0.003
3
1.831 (1.302–2.575)
0.000
5
1.708 (1.244–2.344)
0.000
Weight group >100 kg 1.571 (1.082–2.282)
0.0176
1 2 3
10 weeks predictors analysis of NT-proBNP favorable
response (reduction ≤1000 pg/mL, or >30% from
baseline)†
†Multivariate logistic regression analysis. Only predictors with p<0.05
included
in the final model. Treatment group and at baseline NT-proBNP per 1000 pg/mL change included as covariate
in the model regardless of the p-value.
* Baseline assessment taken at Randomisation
visit

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

54. Conclusions
 Initiation of sacubitril/valsartan shortly after an ADHF event is
feasible and associated with early and sustained reductions in NT-
proBNP levels, proving pathophysiological benefits in a wide range
of hospitalised HFrEF patients:
 In-hospital initiation of sacubitril/valsartan rapidly reduced
NT-proBNP, which was statistically significant at discharge
 After discharge, once all patients were on sacubitril/valsartan,
significant reductions were observed at 4 and 10 weeks for both
initiation groups
 Among predictors to attain a favorable NT-proBNP response, we
identified: higher sac/val starting dose (>49/51 mg bid) and
baseline characteristics including higher NT-proBNP levels,
preserved renal function, non-ischemic etiology, no atrial
fibrillation, being de novo HF, and ACEi/ARB naïve .
Hypertensive patients were more likely to successfully
uptitrate to target dose

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

56. •PIONEER-HF address use of sacubitril/valsartan In the in-patient
setting.
•TRANSITION study addresses up titration of sacubitril/valsartan and
feasibility of starting the drug in the hospital or after discharge
within the first 2 weeks with
• No safety issues noted when comparing the 2 strategies
• At 10 weeks and then 2 months, only 6% of the patients who had
recently been admitted for HF had to discontinue the drug
permanently.
The findings OF PIONEER-HF bolster support for the strategy of initiating
sacubitril/valsartan in stabilized patients who had presented with acute
decompensated HF "regardless of prior ACE inhibitor use or prior HF
diagnosis.
TRANSITION study demonstrated the safety and feasibility of starting
sacubitril/valsartan during hospitalization for decompensated HF
associated with a 33% drop (P = .02) in 12-week risk for a composite
Clinical Interpretation

57. Side effects comparison

59. 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

60. ARNI -- The final outcome

61. 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).