ARNI ( sacubitril /valsartan ) in heart failure ,congenital heart disease, paediatric heart failure, adult CHD,Research

1. Sacubitril / valsartan
Dr Pankaj Bhosale
Consultant Paediatric Cardiac Anaesthesia / Intensive care
Wockhardt hospital,mumbai

2. Overview
Introduction
Physiology related to heart failure
Pharmacology
Trials related to ARNI
Use in adult heart failure
Use in paediatric heart failure
Our experience

3. Heart failure and neurohumoral response

4. Physiology related to heart failure
Natriuretic peptides
- reduced reabsorption of sodium and fluid
- increase in GFR
- prevention of RAAS activation
- reduced aldosterone secretion
- relaxation of vascular smooth muscles
- prevention of ventricular hypertrophy

5. Pharmacology
ARNI ( Angiotensin receptor blocker
Neprilysin inhibitors )
- combination of sacubitril and valsartan
- for heart failure with reduced ejection
fraction

6. Sacubitril
Neprilysin NUP
• Reduction of blood pressure
• Decrease in preload
• Decrease in after load

7. Sacubitril without valsartan
Over activation of RAAS Inc in aldosterone level

8. Valsartan
- angiotensin 2 receptor blocker
:- vasodilation
dec sodium and fluid retention
dec preload and after load

9. Indications and usage
1.1 Adult Heart Failure
ENTRESTO is indicated to reduce the risk of cardiovascular death and
hospitalization for heart failure in patients with chronic heart failure
(NYHA Class II-IV) and reduced ejection fraction.
ENTRESTO is usually administered in conjunction with other heart
failure therapies, in place of an ACE inhibitor or other ARB.
1.2 Pediatric Heart Failure
ENTRESTO is indicated for the treatment of symptomatic heart failure
with systemic left ventricular systolic dysfunction in pediatric patients
aged one year and older.
ENTRESTO reduces NT-proBNP and is expected to improve
cardiovascular outcomes.

12. Why should sacubitril not be combined with ace
inhibitors ?
Bradykinin Inactive peptides
Neprilysin ACE
Angioedema

13. ARNI : side effects
Hyperkalemia
Hypotension
Inc serum creatinine
Dizziness
Cough
Decreased hematocrit
Contraindicated in pregnancy and in impaired renal function

14. Contraindications
In patients with hypersensitivity to any
component
In patients with history of angioedema related
to previous ACEi therapy
Concomitant use of ACEi
Concomitant useo aliskiren in diabetics

15. Warnings and precautions
Fetal toxicity – when administered to a pregnant
woman
Angioedema
Hypotension – correct volume depletion,adjust
diuretic dose,salt depletion
Impaired renal fucntion- inhibition of RAAS
Hyperkalemia

16. Drug interactions
Avoid using with ace inhibitors
Pottasium sparing diuretics - hyperkalemia
NSAIDS- may result in worsening of renal
function
Lithium – lithium toxicity

17. Guidelines on use of ARNI in heart failure

18. Type to enter a caption.

19. PANORAMA HF TRIAL
PANORAMA-HF is a two-part study. Part 1 is an open-
label dose determination study. Part 2 is a randomized,
double-blind, 52-week study comparing Entresto to the
active comparator enalapril in patients aged 1 month to
<18 years old with HF (NYHA/Ross Class II-IV) due to
systemic left ventricular systolic dysfunction (LVEF
<40% or fractional shortening ≤20%)
Employs primary endpoint- clinical events
encompassing death
- initiation of mechanical life support,
- listing for urgent heart transplant,
- worsening HF,
- measures of functional capacity (NYHA/Ross scores)
and patient-reported HF symptoms

20. The trial is ongoing and is being conducted in
approximately 39 countries and 129 clinical
sites across North America, Europe, Asia and
Latin America.9 Each of 360 planned
participants will be followed for 52 weeks
after his or her respective enrollment.9 The
trial is expected to be completed in 2021.

21. The reductions from baseline in NT-proBNP
for Entresto (44 %) enalapril (33%), were
similar to or greater than those observed in
adults, but the difference between treatment
groups was not statistically significant.1
Safety and tolerability of Entresto in pediatric
patients were consistent with that observed in
adult patients.1,3

22. Fda approval
Novartis Entresto receives FDA approval for
pediatric heart failure, helping to address
critical unmet need for treatment options –
OCTOBER 2019

23. The approval was based on an analysis at 12
WEEKS FROM THE 52-WEEK PANORAMA-HF TRIAL
which demonstrated reductions in the cardiac
biomarker N-terminal pro-B-type natriuretic peptide
(NT-proBNP) in pediatric patients 1 to <18 years
with heart failure due to systemic left ventricular
systolic dysfunction.
Entresto improved outcomes and reduced NT-
proBNP in adult patients in PARADIGM-HF, this
effect on NT-proBNP was considered a reasonable
basis to infer improved cardiovascular outcomes in
pediatric patients

24. Published dec -2019

25. 205 patients were administered sacubitril/valsartan
Mean age 59 ± 10 years, 46% with ischemic heart disease
the % of patients in NYHA class III changed from 40% to 17% (p <
0.001)
Median (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205
pg/mL, (p = 0.01)
Ejection fraction (from 27 ± 5.9% to 30 ± 7.7% (p < 0.001) and E/A
ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p = 0.002)) improved.
Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p =
0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/s to 2.64 ±
0.59 m/s (p < 0.014)
Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p =
0.047)
Conclusions: Sacubitril/valsartan induce “hemodynamic recovery”
and, consistently with reduction in Nt-proBNP concentrations, improve
NYHA class despite diuretic dose reduction.

26. New researches
A post hoc analysis from the PARADIGM HF-
dose reduction study was performed.
This study compared the efficacy of SAC/VAL or
enalapril if the patients were administered a
dose lower than the target dose of respective
drug
The results of this study showed that efficacy of
SAC/VAL over enalapril was similar among
patients with dose reduction

27. Rate of hospital readmission at 30 days were
compared following treatment with SV and
enalapril
The results of this study showed that the
rates of all-cause and heart-failure
readmissions at 30 days during treatment
with SAC/VAL were fewer relative to enalapril

28. Another trial comparing SAC/VAL with
valsartan reported that SAC/VAL was
associated with short-term increases in
natriuresis and diuresis, superior office and
ambulatory blood pressure control, and
significantly reduced N-terminal pro B-type
natriuretic peptide levels in Asian patients
with salt-sensitive hypertension
A randomized, double-blind, placebo-
controlled study SAC/VAL was compared to
sacubitril alone.
results showed SAC/VAL showing better
perfomance and additive effects in reducing
diastolic pressure compared to SAC alone

29. Post hoc analysis - No evidence to show that
SAC/VAL increases dementia-related side
effects. Hence, SAC/VAL was similar in
safety with enalapril in terms of adverse
cognitive effects

30. PharmacoeconomicsCosteffectiveness :- Though SAC/VAL is an
expensive than the traditional drugs for patients
with HFrEF, but better efficacy, comparably less
adverse events, and reduced number of
hospitalizations makes it cost-effective than other
drugs in long term therapy.
Health-related quality of life (HRQL) of patients
from PARADIGM- HF trial showed promising
HRQL in surviving patients with heart failure on
SAC/VAL therapy
SAC/VAL significantly improved nearly all KCCQ
physical and social activities compared to
enalapril.

31. ARNI in Adult congenital heart
disease

32. *15 patients with ACHD were prescribed sacubitril/valsartan -June 2017 and June
2018.
baseline characteristics and clinical and laboratory changes after initiation of
sacubitril/valsartan.
*Adverse events, including renal function, medication intolerance, and worsening
HF were documented.

33. The median age was 53.2 (27.6-83.6) years, with a median
follow-up duration of 69 (8-419) days.
10 patients NYHA II , 5 patients NYHA III
No patients reported clinical deterioration; four NYHA class III
patients with complex CHD, pulmonary hypertension, and
cyanosis reported significant improvement to NYHA class II.
Baseline creatinine was 1.1 (0.9-1.7) and two weeks after
starting sacubitril/valsartan it was 1.3 (0.8-2.5, P = .22
Conclusion: Sacubitril/valsartan seems to be well tolerated in
patients with ACHD who present with refractory HF
symptoms. Patients with complex CHD associated with
cyanosis and pulmonary hypertension could benefit the most,
but larger studies are needed to assess the safety as well as
the effectiveness of sacubitril/valsartan in this patient
population.

34. Prospective cohort analysis study done between dec 2016 to dec 2017 in 5
patients with ACHD with chronic heart failure
6 month outcome was measured
Conclusion: sacubitril/valsartan therapy is well tolerated in ACHD heart failure
patients and is associated with improvement in functional class.

36. Retrospective review of 10 patients who were prescribed S/V
Identified and followed up
Males , 6 systemic lv, 4 systemic rv, 90% were able to
achieve target conc , 1 readmission for heart failure and
transplant
S/V in ACHD is feasible and safe in medium term follow up
with significant improvement in NYHA class and without side
effects including renal dysfunction or dyse- lectrolytemia.

37. •Retrospective study of ACHD pts with CHD with
moderate and severe complexity treated with ARNI
•Sample size 23- nt probnp,systolic and diastolic bp,
serum creatinine was monitored
•Conclusion: In this small group of patients with ACHD
treatment with ARNI did not improve systemic
ventricular function or functional status

38. 5 patients with HFrEF -inotrope dependent heart
failure, PDP > PCWP
Listed inactive on heart tx list, on pulmonary
vasodilators ,inotropes
Started on ARNI,pulmonary vasodilators
stopped,inotropes continued

40. UPCOMING
RESEARCHES(PARAGON-HF) trial is set to explore role of SAC/VAL in
HFpEF. The primary endpoint of this trial is to compare
SAC/VAL to valsartan in reducing the rate of the cardiovascular
death and total (first and recurrent) HF hospitalizations, in
HFpEF patients
The PARALLAX trial is another ongoing 24-week, a randomized,
double-blind controlled study to evaluate the effect of SAC/VAL
on NT-proBNP, symptoms, exercise function, and safety
compared to individualized medical management of
comorbidities in patients with HFpEF
ENTRESTO-SAS trial will be a 3-month, multicentric,
prospective, open-label real-life cohort study. This study will
evaluate whether SAC/VAL could improve the outcome of sleep-
disordered breathing in chronic HF patients