This document discusses the rationale for early initiation of angiotensin receptor-neprilysin inhibitor (ARNI) therapy after an episode of acute decompensated heart failure (ADHF). It provides evidence that starting ARNI therapy within days or weeks of an ADHF hospitalization leads to faster clinical improvements and better outcomes compared to starting an ACE inhibitor. Specifically, it references clinical trials that show ARNI initiated early after ADHF leads to greater short-term reductions in biomarkers like NT-proBNP, faster improvements in quality of life, lower rates of heart failure hospitalizations, and greater reductions in left ventricular volumes. The document argues for initiating ARNI in the vulnerable period after ADHF to improve outcomes,

1. Early Initiation of ARNI after ADHF

2. HF-rEF is a chronic progressive disease
Kemp CD et al. Cardiovasc Pathol 2012;21:365
Neurohormonal activation never turns OFF in HF. These systems are constantly ON in an attempt to
compensate for the failing heart's inability to maintain normal CV homeostasis. The chronic presence of these
circulating neurohormones exacerbates the hemodynamic abnormalities which encourage further remodeling
and neurohormone release and further hemodynamic deterioration.

3. Inversion Point
to End-of-Life
Care:
Relief of suffering
and quality of life
outweigh extending
quantity of life
Time
Disease-
modifying
therapies
Symptom
palliation
therapies
Decompensations
Onset of CHF
Intensity
of
Care
Pump Failure
Sudden Death
Quality
of
Life
Transition to
Advanced Heart
Failure:
Oral therapies failing;
consider MCS and/or
transplantation, if
eligible
Clinical
Course
Depiction of the Clinical Course of HF With Associated Types and Intensities of
Available Therapies Over Time
CHF indicates congestive heart failure;
HF, heart failure; and MCS, mechanical
circulatory support.
Heidenreich PA, et al. J Card Fail 2022

4. The Vulnerable Phase of Heart Failure
U-shaped distribution
of readmission
associated with heart
failure management
Am J Ther. 2018 ; 25(4): e456–e464

5. The 3-phase terrain of readmission risk after heart
failure hospitalization
Approximately 30% of all readmissions
occurred within the first 2 months of hospital
discharge & 50% occurred within the 2
months before death with much lower
admission rates (15%–20%) during the
intercurrent “plateau phase
Circ Heart Fail. 2012;5:398-400

6. Admissions are a critical stage in treating HF, and provide a unique
opportunity to improve care for patients with this condition
Circ Heart Fail. 2012;5:398-400

7. Risk and challenge of ADHF
CHALLENGES IN PREDICTING HEART FAILURE READMISSION
• One in 6 patients admitted for HF die within 30 days of hospitalization
• Patients with readmission for cardiovascular disease within 90 days of discharge for
HF hospitalization have a higher risk of mortality independent of the exact amount of
time from discharge
• Levels of cardiac biomarkers including natriuretic peptides and cardiac troponins may
also anticipate readmission risk, particularly if they remain high at hospital discharge.
Joyce N. Njoroge. Circulation Research. Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure, Volume: 128, Issue: 10, Pages:
1468-1486, DOI: (10.1161/CIRCRESAHA.121.318186)

8. High risk features in patients hospitalized with ADHF
(acute decompensated heart failure)
Lower systolic blood pressure
Elevated BUN
Hyponatremia
History of prior heart failure hospitalization
Elevated BNP or NT-proBNP
Elevated Troponin T or I

9. Comparison of risk for
death arising from deferral
of medical therapy for heart
failure for 1 year
European Journal of Heart Failure (2017) 19, 1401–1409

10. Multiple reasons for the delay in the initiation and
optimization of medical therapy
• Patient-related issues
• Inability to closely follow-up
• Self-care efficacy
• Insurance-related concerns
• Physician-related issues
• Knowledge of & comfort with providing optimal therapy
• Healthcare system–related issues like the need for
previous authorization or the lack of clinic availability
• Difficulty in establishing frequent encounters between
HCPs and patients also acts as another barrier to
achieving GDMT
• Time constraints, transportation limitations, or
financial burdens on patient and caregivers
Circulation. 2019;140:621–623.

11. GDMT at discharge in ADHF
Indian Heart Journal 72 (2020) 27e31

12. Treatment goals for ADHF
Improve symptoms of congestion
Optimize volume status
Identify and address triggers for decompensation
Optimize chronic oral therapy
Minimize side effects
Identify patients who benefits from revascularization
Educate patients concerning medications and disease management

13. HF algorithmic treatment
• The primordial goals of HF therapy are the
following:
• Mitigate symptoms and signs
• Prevent first hospital admission and
subsequent readmissions
• Improve survival as well as quality of life.
• Since ADHF corresponds to worsening HF, the
main goal is to compensate the patient, i.e.
treat volume overload and promote transition
towards stabilization.
• On the other hand, the challenging
fundamental strategy in chronic HF is to
maintain stability and avoid decompensation
Rocha BML, Menezes Falcão L. Acute decompensated heart failure (ADHF): A comprehensive contemporary review on
preventing early readmissions and postdischarge death. Int J Cardiol. 2016 Nov 15;223:1035-1044. doi:
10.1016/j.ijcard.2016.07.259. Epub 2016 Aug 3. PMID: 27592046.

14. Rationale for ARNi first in chronic HF-rEF
1. Velazquez EJ et al. N Engl J Med 2019;380:539. 2. Pina IL et al. JACC Heart Fail 2021;9:42.
3. Packer M et al. Circulation 2015;131:54. 4. Desai AS et al. JAMA 2019;322:1.
Superiority achieved within days to weeks of treatment initiation
• 7 days – greater reduction in NT-proBNP vs ACEi1(NT-proBNP change from baseline)
• 2 weeks – significant improvement in QoL vs baseline2 (KCCQ-overall summary score)
• 1 month – lower rate of HF hospitalizations vs ACEi3 (time to first HF hospitalization)
• 12 weeks – greater reductions in LV ESVi & EDVi vs ACEi4(LV volume changes from baseline)

15. Rationale for ARNi first in chronic HF-rEF
1. Januzzi JL et al. JAMA 2019;322:1085. 2. Felker GM et al. Circulation 2021;144:180.
Significant potential to impact ICD eligibility
PROVE-HF1,2: Open-label, single-arm study that enrolled 794 patients with chronic HFrEF and LV EF ≤40% who were then initiated and titrated on
ARNi (78 US sites). Patients with a baeline EF >35% were excluded from this analysis. Treatment included BB in 97% and MRA in 47% of patients.
Among a cohort of HF-rEF patients who met primary prevention ICD eligibility criteria at baseline,
32% improved their EF to >35% by 6 months and 62% to >35% by 12 months after initiation of ARNi therapy.
6 months
median 4.8 points
12 months
median 9.6 points

16. Acute/decompensated HF-rEF
Early initiation of ARNI

17. PIONEER HF: Rationale for ANRi first in acute/decompensated HFrEF
1. Velazquez EJ et al. Am Heart J 2018;198:145. 2. Velazquez EJ et al. N Engl J Med 2019;380:539. 3. Morrow DA et al. Circulation 2019;139:2285.
PIONEER-HF1,2: 881 medically stable patients hospitalized for decompensated HF (129 US sites) with LV EF ≤40% and BNP ≥400 or NT-proBNP ≥1600,
were randomized 24h-10d after admission. Hospitalization was for the first diagnosis of HF in 303 patients (34.4%).
459 Patients (52.1%) were RAASi naïve at the time of hospital admission.
Clinical events reported here were adjudicated.
0
–10
–20
%
Change
from
inclusion
–30
–40
–50
–60
–70
Inclusion 1 2 3 4 5 6
Weeks from randomization
7 8
enalapril
sacubitril/valsartan
Faster recovery and superior protection in the ‘vulnerable phase’
NT-proBNP2
Time-averaged reduction
was 29% greater
Cumulative
incidence
(%)
-46.7
-25.3
16

18. Randomized trial of hospitalized patients with NYHA class II-IV acute HFrEF
‒ ARNI started ≥ 24 hrs after admission, after patients had stabilized
Composite of Death, HF Readmission, LVAD, Listing for Cardiac Transplant With ARNI
Serious clinical composite endpoint was driven by a reduction in death and HF rehospitalizations
Morrow. Circulation. 2019;139:2285.
56
0 7 14 21 28 35 42 49
9.8%
16.3%
Enalapril
Sacubitril/valsartan
Cumulative
Incidence
of
Composite
Death,
HF
Readmission,
LVAD,
Listing
for
Cardiac
Transplant
(%)
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
Effect Through Wk 8
HR: 0.58
(95% CI: 0.40-0.85;
P = .005)
Days
PIONEER HF: Rationale for ANRi first in acute/decompensated HFrEF

19. Earlier is better … because ‘time is prognosis’
CV Death or HF rehospitalization3
PIONEER-HF1,2: 881 medically stable patients hospitalized for decompensated HF (129 US sites) with LV EF ≤40% and BNP ≥400 or NT-proBNP ≥1600,
were randomized 24h-10d after admission. Hospitalization was for the first diagnosis of HF in 303 patients (34.4%).
459 Patients (52.1%) were RAASi naïve at the time of hospital admission.
Clinical events reported here were adjudicated.
25
Cumulative
incidence
(%)
10
0
0 1 2 3 4
5
20
15
5 6 7 8 9 10 11
Weeks from randomization
12
to sacubitril/valsartan
enalapril
HR 0.69
(95% CI, 0.49-0.97)
P=0.032
! No time to lose !
to sacubitril/valsartan
sacubitril/valsartan
13.0%
18.1%
1. Velazquez EJ et al. Am Heart J 2018;198:145. 2. Velazquez EJ et al. N Engl J Med 2019;380:539. 3. DeVore AD et al. JAMA Cardiol 2020;5:202.
PIONEER HF: Rationale for ANRi first in acute/decompensated HFrEF

20. 1. Fonarow GC et al. J Card Fail 2007;13:722. 2. Curtis LH et al. Am Heart J 2013;165:979. 3. Carnicelli AP et al. J Card Fail 2021;27:826.
Earlier is better … for short-term adherence and long-term persistence
OPTIMIZE-HF1: 2720 HFrEF patients discharged from 91
US hospitals, Mar ‘03 to Dec ‘04. 90.1% eligible for BB at
discharge, of whom 84.0% actually got BB at discharge.
Rationale for ANRi first in acute/decompensated HF-rEF
GWTG-HF2: 4666 HFrEF patients, age ≥65, ARNi eligible,
discharged from US hospitals, Oct ‘15 to Sep ‘17. At
discharge, only 9.2.9% actually taking ARNi.
GWTG-HF3: 2086 HFrEF patients, age ≥65, MRA eligible,
discharged from US hospitals, Jan ‘06 to Dec ‘08. At
discharge, only 26.9% actually taking MRA.
BB1
0
20
40
60
80
100 93.1
69.2
79.6
30.5
2.1
13
Proportion
with
postdischarge
medication
fill
(%)
80.5
85.5
7.7
22.3
60-90 day follow up 1-year follow up
ARNi2 MRA3
Not prescribed at hospital discharge
ARNi2 MRA3
Prescribed at hospital discharge

21. Initiation of ARNi in haemodynamically stabilised heart
failure patients in hospital or early after discharge:
TRANSITION study
European Journal of Heart Failure (2019)21, 998–1007

22. Discharge
199/430
Week 4
206/446
187/450
Week10
227/444
211/439
10
0
20
40
30
50
60
46.3
18.1
41. 6
48. 1
Pre-discharge
initiation
46.2
Post-discharge
initiation
51.4
Patients
(%)
Proportion of patients with NT-proBNP favorable response
(reduction ≤1000 pg/mL, or > 30% from baseline)
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
European Journal of Heart Failure (2019)21, 998–1007

23. DE-NOVO vs Prior CHF – Post hoc analysis of TRANSITION
Eur J Heart Fail. 2020 Feb;22(2):303-312

24. DE-NOVO vs Prior CHF – Post hoc analysis of TRANSITION
Eur J Heart Fail. 2020 Feb;22(2):303-312

25. 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.
• 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).
Eur J Heart Fail. 2020 Feb;22(2):303-312

26. Safety and efficacy of ARNI (valsartan/sacubitril) vs
ACEI (enalapril) in AHF
Comparison of various parameters at baseline & at 6-month follow-up
• ARNI study group showed better safety and efficacy outcomes at the end of 6 months follow-up in terms of death,
echocardiographic parameters, readmission rate due to HF, 6 min walk test compared to ACEI group
• KCCQ showed improvement in both the groups, however ARNI group had significant increased compared to ACEI group
Indian Heart Journal 74 (2022) 178e181

27. Relationship between ARNi Treatment, Echocardiographic
Parameters, & NT-proBNP Levels in HFpEF Pts with ADHF
Pre- and post-treatment NT-proBNP levels
Comput Math Methods Med. 2022;2022:4298644.

28. Acute Hemodynamic Effects of
ARNI In Heart Failure Patients
Receiving IV Vasodilator &
Inotropic Therapy
J Card Fail. 2021 Mar;27(3):368-372.
Patients maintained their significant
improvement in cardiac index and reduction in
SVR/PVR on transition from i.v. inotropic and
vasodilator therapy to oral S/V. There was an
increase in PAPi with S/V therapy compared
with the i.v. vasoactive phase of care.

29. Acute Hemodynamic Effects of ARNI Therapy in Low Cardiac
Output in HF Receiving IV Vasodilator/ Inotropic Therapy
Hemodynamic Factors in Successful Initiation of Sacubitril-Valsartan
J Card Fail. 2021 Mar;27(3):368-372.

30. Cureus 13(10): e18740

31. Recommendations for pre-discharge and early post- discharge
follow-up of patients hospitalized for acute HF
McDonagh TA et al. Eur Heart J 2021;42:3599
Recommendations Class Level
It is recommended that patients hospitalized for HF be carefully
evaluated to exclude persistent signs of congestion before
discharge and to optimize oral treatment
I C
It is recommended that evidence based oral medical treatment be
administered before discharge
I C
An early follow-up visit is recommended at 1-2 weeks after
discharge to assess signs of congestion, drugs’ tolerance and start
and/or uptitrate evidence-based therapy
I C
Ferric carboxymaltoseshould be considered in symptomatic HF
patients recently hospitalized for HF and with LVEF <50% and iron
deficiency, defined as serum ferritin <100 ng/mL or serum ferritin
100-299 ng/mL with TSAT <20%, to improve symptoms and reduce
the risk of HF hospitalization
IIa B
! No time to lose !

32. 2021 ACC
Expert
Consensus
Decision
Pathway for
Optimization
of Heart
Failure
Treatment

33. Treatment of HFrEF Stages C and
D
Treatment recommendations for patients with HFrEF are displayed. Step 1
medications may be started simultaneously at initial (low) doses
recommended for HFrEF. Alternatively, these medications may be started
sequentially, with sequence guided by clinical or other factors, without need
to achieve target dosing before initiating next medication. Medication doses
should be increased to target as tolerated.
2022 AHA/ACC/HFSA
Recommendations

34. Thank you…