The natriuretic peptide system works antagonistically to the RAAS and has favorable effects on the pathogenesis of heart failure Natriuretic peptides are broken down by an enzyme called neprilysin Neprilysin is also responsible for the breakdown of other substances, including bradykinin and angiotensin II Sacubitril/valsartan is a combination product Sacubitril is a pro-drug that, upon activation, acts as a neprilysin inhibitor It works by blocking the action of neprilysin, thus preventing the breakdown of natriuretic peptides This leads to a prolonged duration of the favorable effects of these peptides

1. - Dr. Akif A.B

3. PATHOPHYSIOLOGY OF HEART
FAILURE
 Renin-angiotensin-aldosterone system (RAAS) is
activated
 RAAS activation leads to vasoconstriction,
hypertension, increased aldosterone levels,
increased sympathetic tone, and eventually,
cardiac remodeling, all of which are detrimental to
the progression of the disease
 By blocking these maladaptive elements, ACEIs
or ARBs play a major role in reducing morbidity
and mortality due to heart failure

5. NATRIURETIC SYSTEM
 Simultaneously, the natriuretic peptide system is
also activated, hence the elevated BNP and NT-
pro BNP seen in heart failure exacerbations

7. Natriuretic Peptides Action
Vasodilation
Natriuresis and diuresis
Lowers blood pressure (BP)
Lowers Sympathetic tone
Reduces aldosterone levels

11. PATHOPHYSIOLOGY OF ARNI
 The natriuretic peptide system works
antagonistically to the RAAS and has favorable
effects on the pathogenesis of heart failure
 Natriuretic peptides are broken down by an
enzyme called neprilysin
 Neprilysin is also responsible for the breakdown
of other substances, including bradykinin and
angiotensin II

12. SACUBITRIL
 Sacubitril/valsartan is a combination product
 Sacubitril is a pro-drug that, upon activation, acts
as a neprilysin inhibitor
 It works by blocking the action of neprilysin, thus
preventing the breakdown of natriuretic
peptides
 This leads to a prolonged duration of the
favorable effects of these peptides

14. VALSARTAN
 Valsartan is an angiotensin receptor blocker, and
it works on blocking the RAAS system
 Because neprilysin breaks down angiotensin II,
inhibiting neprilysin will result in an accumulation
of angiotensin II
 For this reason, a neprilysin inhibitor cannot be
used alone; it must always be combined with an
ARB to block the effect of the excess angiotensin
II

15. BRADYKININ & ARNI
 Another important substance broken down by
neprilysin is bradykinin
 Neprilysin inhibition will also cause a build-up of
bradykinin
 Therefore, sacubitril cannot be used with an ACEI
due to an increased risk of angioedema
 In fact, when switching between ACEI and
sacubitril/valsartan, the patient must undergo a 36-
hour washout period to lower the risk of
angioedema

16. MECHANISM OF ACTION

19. EVOLUTION OF ANGIOTENSIN
RECEPTOR NEPRILYSIN INHIBITION
(ARNI)
 Potential ameliorative benefits of NPS such as
natriuresis, vasodilatation, and diuresis on the
effects of RAAS overactivity and significantly high
morbidity and mortality associated with HF, despite
the use of disease-modifying drugs, led to several
lines of research in finding therapeutic use of these
peptides
 During initial research, exogenous NP were
administered at supra-physiological doses to
mimic the endogenous NP to the patients with
decompensated HF

20.  Carperitide, a synthetic analog of ANP, and
nesiritide, a human recombinant form of BNP,
both have been associated with vasodilatation,
diuresis with symptomatic improvement in HF
patients
 Both drugs need continuous infusion rather
than bolus administration due to their short
duration of action failed to show sustained
clinical benefits, which limited the clinical
application of these two agents in treating acute
decompensated HF

21.  The alternative approach was to augment the level of
endogenous NP, thereby its activity by reducing
elimination through an NP clearance receptor (NPRC
or NPRC3)
 Candoxatril, a selective neprilysin inhibitor, has been
reported to exert vasodilator and diuretic activity in
patients with HF and improved exercise duration
when combined with ACEI
 But this too did not show significant clinical benefit in
treating patients with chronic HF, due to sustained
hypotensive effect
 Hence, candoxatril drug development was

23.  Based on the findings of the landmark
Prospective Comparison of ARNI with ACEI to
Determine Impact on Global Mortality and
Morbidity in HF (PARADIGM-HF) trial, the U.S.
Food and Drug Administration approved
sacubitril/valsartan combination in July 2015 for
the treatment of patients with New York Heart
Association (NYHA) Class II through IV HF
symptoms and a reduced ejection fraction with
elevated BNP, NT-proBNP levels

24. PARADIGM-HF TRIAL -2014

25. PARADIGM-HF TRIAL -2014
- 20% reduction in CVD Mortality when compared to Enalapril

28. ESC-2016

32. PIONEER-HF -2019

33. PIONEER-HF -2019

35. PIONEER-HF -2019

36. ESC-2021
Initiation of sacubitril/valsartan in ACE-I naive (i.e.
de novo) patients with HFrEF may be considered
(class of recommendation IIb, level of evidence B)

37. PARAGON-HF TRIAL-2019

38. PARAGON-HF TRIAL-2019

39. PARAGON-HF TRIAL-2019

40. INDICATION
Indications Recommendation
Heart Failure with Reduced
Ejection Fraction (EF <40%)
Class I
Heart Failure with Mildly Reduced
Ejection Fraction (EF 40-50%)
Class II B
Heart Failure with reduced ejection
fraction not on ACE or ARBs prior
Class II B

41. Administration
 Sacubitril/valsartan is available as an oral tablet
in 3 dosage strengths containing: sacubitril (24
mg, 49 mg, or 97 mg) and valsartan (26 mg, 51
mg, or 103 mg)
 The valsartan component in this combination has
a higher bioavailability as compared to regular
valsartan tablets; therefore, valsartan 26 mg, 51
mg, and 103 mg in the brand-name combination
are equivalent to valsartan 40 mg, 80 mg, and
160 mg in other formulations, respectively

42.  Sacubitril/valsartan is to be taken twice a day
and may be administered without regard to meals
 Allow at least a 36-hour washout period when
switching from an ACEI before starting
sacubitril/valsartan
 Patients must be able to tolerate an ACEI or an
ARB prior to being started on sacubitril/valsartan

43. RECOMMENDED DOSING
 Patients on low-dose ACEI or ARB or not
previously on ACEI or ARB
 Start with sacubitril 24 mg/valsartan 26 mg twice
per day
 Double the dose every 2 to 4 weeks as tolerated, up
to sacubitril 97 mg/valsartan 103 mg orally twice per
day
 Patients on moderate to a high dose of ACEI or
ARB
 Start with sacubitril 49 mg/valsartan 51 mg twice
per day
 Double the dose every 2 to 4 weeks as tolerated, up

44. DOSING IN LIVER AND KIDNEY
DISEASE
 Patients with eGFR less than 30 or moderate
hepatic impairment (Child-Pugh class B) should
start with sacubitril 24 mg/valsartan 26 mg twice
per day
 Sacubitril/valsartan is not recommended for
patients with severe hepatic impairment (Child-
Pugh class C)

45. ADVERSE EFFECTS
 In the PARADIGM-HF trial comparing
sacubitril/valsartan to enalapril 10 mg
twice per day, sacubitril/valsartan was
associated with a higher incidence of
hypotension and symptomatic
hypotension
 Sacubitril/valsartan was associated
with a lower risk of elevation in serum
potassium or serum creatinine and a
lower risk of cough compared to
enalapril
 More patients experienced
angioedema in the sacubitril/valsartan
arm than in the enalapril arm;
however, this outcome did not reach
statistical significance
ADVERSE
EFFECTS
Hypotension
Hyperkalemia
Angioedema
Renal failure
Cough

46. Contraindications
 Hypersensitivity to any component of the
product
 A prior history of angioedema due to an ACEI or
ARB
 Patients receiving the renin inhibitor, aliskiren
and any ARB due to an increased risk of
hypotension, hyperkalemia, and renal
impairment.
 Patients who have received an ACE- within 36

47. ARNI & BNP
 Because sacubitril/valsartan therapy affects several
biomarkers and specifically inhibits the breakdown
of brain natriuretic peptide (BNP), BNP will be
elevated in patients taking this drug
 Therefore, BNP will not be a reliable marker of heart
failure exacerbations in these patients
 NT-pro-BNP is not a substrate for neprilysin, and
therefore not affected by sacubitril
 As such, NT-pro-BNP should be utilized in patients
on sacubitril/valsartan when a heart-failure
exacerbation is suspected

49. Contraindications
 History of angioedema
 Known bilateral renal artery stenosis.
 Pregnancy/risk of pregnancy and breastfeeding
period.
 Known allergic reaction/other adverse reaction
(drug-specific).
 Symptoms of hypotension or a SBP <90 mmHg

50. Cautions/seek specialist
advice
 A washout period of at least 36 h after ACE-I therapy
is required in order to minimize the risk of
angioedema.
 Significant hyperkalaemia (K>5.0 mmol/L).
 Drug interactions to look out for:
 K supplements/K-sparing diuretics, e.g. amiloride and
triamterene (beware combination preparations with
furosemide).
 MRAs.
 Renin inhibitorsc
 NSAIDsd
 Trimethoprim/trimethoprim-sulfamethoxazole.
 ‘Low-salt’ substitutes with a high K content

51. HOW TO USE ??
 Check renal function and electrolytes
 Start with a low dose
 In some patients, one may consider a reduced
starting dose (24/26 mg b.i.d.), namely in those
with SBP 100-110 mmHg, ACE-I/ARB naive
patients, eGFR 30-60 mL/min/1.73 m2

52.  Double the dose at not less than 2-week
intervals in the community, monitoring tolerability
 Aim for the target dose or, failing that, the highest
tolerated dose.
 Re-check blood chemistry (urea/BUN, creatinine,
K) 12 weeks after initiation and 12 weeks after
final dose titration

53. Systemic Hypertension and
ARNI
 Efficacy of sacubitril/valsartan as an antihypertensive
agent has been studied mostly in comparison with a
single angiotensin II receptor type 1 blocker (ARB)
 Studies have demonstrated consistent blood pressure
reductions by sacubitril/valsartan that is superior to its
competitors
 The role of sacubitril/valsartan as add-on therapy in
uncontrolled hypertension has also been validated in
selected studies
 However, data comparing the effects of
sacubitril/valsartan to other drug classes (namely beta
blockers, thiazide diuretics, and calcium channel
blockers) are lacking

54. PROBLEM SOLVING

55. Asymptomatic low blood
pressure:
 Does not usually require any change in therapy

56. Symptomatic hypotension
 Dizziness/light-headedness is common and often
improves with time—patients should be
reassured.
 Reconsider need for any other vasodilators and
reduce dose/stop, if possible.
 If no signs or symptoms of congestion, consider
reducing diuretic dose.
 If these measures do not solve problem, seek
specialist advice.

57. Cough:
 Cough is common in patients with HF, many of
whom have smoking-related lung disease
 Cough is also a symptom of pulmonary oedema,
which should be excluded when a new worsening
cough develops
 When a troublesome cough does develop (e.g.
one stopping the patient from sleeping) and can
be proved to be due to ARNI and ACE-I (i.e.
recurs after the drugs withdrawal and re-
challenge), substitution of an ARB is

58. RF and hyperkalaemia:
 Some rise in urea (BUN), creatinine, and K is to
be expected after an ARNI; if an increase is small
and asymptomatic, no action is necessary
 A reduction in eGFR up to <30 mL/min/1.73 m2 is
acceptable
 An increase in K upto <5.5 mmol/L is acceptable

59.  If K rises to >5.5 mmol/L or eGFR lowers to <30
mL/min/1.73 m2, the ARNI should be stopped
and specialist advice sought
 Blood chemistry should be monitored frequently
and serially until K and creatinine have plateaued

60.  When RAAS inhibitors, ARNI or SGLT2 inhibitors are
started, the initial decrease in the glomerular filtration
pressure may decrease GFR and increase serum
creatinine
 However, these changes are generally transient and occur
despite improvement in patient outcomes and slower
worsening of renal function in the long term
 A transient decrease in renal function should not prompt
their interruption
 An increase in serum creatinine of <50% above baseline,
as long as it is <266 lmol/L (3 mg/dL), or a decrease in
eGFR of <10% from baseline, as long as eGFR is >25
mL/min/1.73 m2, can be considered as acceptable

61. PREGNANCY and ARNI
 Pre-pregnancy management includes the
modification of existing
 HF medications to avoid foetal harm. ACE-Is,
ARBs, ARNI, MRAs, ivabradine, and SGLT2
inhibitors are contraindicated and should be
stopped prior to conception with close clinical and
echocardiographic monitoring

70. HFrEF Treatment

71. Heart Failure with Mildly reduced
Ejection Fraction

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