Dr.

KAZI ALAM NOWAZ

MD FINAL PART STUDENT CARDIOLOGY
NHFH & RI
Sacubitril
 Sacubitril
• Neprilysin Inhibitor (NI) (An antihypertensive drug)
• Used in combination with valsartan
• A Novel treatment option for heart failure.
• The combination drug, sacubitril/valsartan, known
during trials as LCZ696
• Approved under the FDA's priority review process
for use in heart failure on July 7, 2015.
ARNI
Therapeutic Targeting of Natriuretic
Peptide (NP) System in Heart Failure
 Mechanism of progression of Heart Failure

Myocardial or
vascular stress injury

• Increased activity or response • Decreased activity or

to maladaptive mechanism response to adaptive
mechanism

Angiotensin Receptor Inhibition of

Blocker Neprilysin

Evolution and progression of heart

failure
 Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive
Peptides That Counter Maladaptive Mechanisms in Heart Failure

• Endogenous Neurohormonal activation

vasoactive peptides Vascular tone
(Natriuretic peptides, adrenomodulin, Cardiac fibrosis, hypertrophy
bradykinin, substance P, calcitonin
gene-related peptide) Sodium retention

Neprilysin Neprilysin
inhibition

• Inactive metabolites
 Mechanism of action
• Sacubitril is a prodrug that is activated to sacubitrilat
(LBQ657) by de-ethylation via esterases.

Systematic (IUPAC) name

4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-
pentanyl]amino}-4-oxobutanoic acid
LBQ657
 How to inhibit Neprilysin in Heart Failure

Neprilysin Inhibition Ineffective due to angiotensin

alone potension

Neprilysin inhibition +ACE inhibition

Potentially dangerous due to Neorilysin inhibition + Angiotensin

angioedema receptor blockade
 Sacubitril/valsartan
• Pharmacokinetics:
Time to peak: 0.5 hrs
A Time to peak of metabolite: 2 hrs
Protein binding – 94-97%
D Vd: 103 L
Metabolized by esterases to active
M metabolite
Major metabolite is not metabolized
T1/2 sacubitril: 1.4 hrs
E T1/2 metabolite: 11.5 hrs
 sacubitril/valsartan

Indications:
• 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
 sacubitril/valsartan
Contraindications
• Hypersensitivity to any component
• History of angioedema related to previous
ACE inhibitor or ARB therapy
• Concomitant use with ACE inhibitors
• Concomitant use with aliskiren in patients with
diabetes
• Not recommended for patients with severe
hepatic impairment.
DOSAGE AND ADMINISTRATION
• The recommended starting dose of is 49/51 mg
(sacubitril/valsartan) twice-daily.
• Double the dose after 2 to 4 weeks to the target
maintenance dose of 97/103 mg (sacubitril/valsartan)
twice-daily, as tolerated by the patient.
• Reduce the starting dose to 24/26 mg
(sacubitril/valsartan) twice-daily for:
- pts not currently taking an ACEi or an ARB or
previously taking a low dose of these agents
 Renal impairment
• Mild-to-moderate (eGFR ≥30 mL/min/1.73
m²): No starting dose adjustment required

• Severe (eGFR <30 mL/min/1.73 m²): Reduce

starting dose to 24 mg/26 mg BID; double the
dose every 2-4 weeks to target maintenance
dose of 97 mg/103 mg BID as tolerated
 Hepatic impairment
• Mild (Child-Pugh A): No starting dose
adjustment required

• Moderate (Child-Pugh B): Reduce starting dose

to 24mg/26 mg BID; double the dose every 2-4
weeks to target maintenance dose of 97 mg/103
mg BID as tolerated

• Severe (Child-Pugh C): Not recommended

 PREGNANCY

ARBs should not be used during pregnancy

because they can reduce fetal renal function
and increase fetal and neonatal morbidity and
death.
 sacubitril/valsartan
Adverse Effects
Side effect Sacubitril/ Enalapril
Valsartan
Angioedema 0.5% 0.2%
Hypotension 18% 12%
Impaired renal function 3.3% 4.5%

Hyperkalemia 12% 14%

Cough 9% 13%
 DRUG INTERACTIONS
• Concurrent use with an ACE I : is
contraindicated because of the risk of serious
angioedema, more often in blacks..
• Potassium-sparing diuretics: May lead to
increased hyperkalemia, especially in patients
with renal impairment, diabetes, or
hypoaldosteronism.
• NSAIDs: May lead to increased risk of renal
impairment.
• Lithium: Increased risk of lithium toxicity.
 Cautions

• Observe for signs and symptoms of

angioedema

• Sacubitril/valsartan lowers blood pressure

and may cause symptomatic hypotension
especially in patients who are volume
depleted or salt-depleted.

• Monitor renal function and potassium

levels
Sacubitril/valsartan ( LCZ696)

Trials
 PARADIGM-HF
• The largest clinical trial ever conducted in
heart failure ( 8442 patients over 47
countries)

• Stopped early due to compelling efficacy:

risk of CV death was significantly reduced.
PARADIGM-HF: key efficacy outcomes
• Primary end point:
• Cardiovascular death
• Heart failure hospitalization

• Secondary end point:

• All-cause mortality
• Time to new onset of atrial fibrillation
• Time to first occurrence of a protocol-defined
decline in renal function
PARADIGM-HF: early termination
 Conclusion of the Article
• The results of PARADIGM-HF, showing
significant reductions in the primary
composite endpoint, cardiovascular death,
and all-cause mortality in pts receiving
LCZ696
• In comparison with those receiving enalapril,
suggest that this drug could replace ACE I
and ARBs as first-line therapy in HFrEF, once
regulatory approval is obtained
Renin-Angiotensin System Inhibition With
ACE Inhibitor or ARB or ARNI (contd...)
2013 ACCF/AHA 2016 ACC/AHA/HFSA Focused
Guideline Update

No recommendation COR: I
about angiotensin LOE:B-R
receptor–neprilysin recommendation: In patients
inhibitor (ARNI) with chronic symptomatic HFrEF
NYHA class II or III who tolerate
an ACE inhibitor or ARB,
replacement by an ARNI is
recommended to further reduce
morbidity and mortality
Renin-Angiotensin System Inhibition With
ACE Inhibitor or ARB or ARNI (contd...)
2013 ACCF/AHA 2016 ACC/AHA/HFSA
Guideline Focused Update

No recommendation about COR: III:Harm

angiotensin receptor– LOE:B-R
neprilysin inhibitor (ARNI) Recommendation: ARNI
should not be
administered
concomitantly with ACE
inhibitors or within 36
hours of the last dose of
an ACE inhibitor
Renin-Angiotensin System Inhibition With
ACE Inhibitor or ARB or ARNI (contd...)
2013 ACCF/AHA 2016 ACC/AHA/HFSA
Guideline Focused Update

No recommendation about COR:III:Harm

angiotensin receptor– LOE:B-R
neprilysin inhibitor (ARNI) Recommendation: ARNI
should not be
administered to patients
with a history of
angioedema
Current and possible future evidence-based
treatment of HFrEF
 Conclusion
• RAAS blockade combined with NP System
augmentation represent a novel approach for
patients with HF

• Sacubitril/valsartan is indicated to reduce the risk of

cardiovascular death and hospitalization in chronic
heart failure (NYHA Class II-IV) and reduced ejection
fraction

• It may be considered instead of an ACE I or an ARB

for first-line treatment of heart failure with reduced
ejection fraction

• Hypotension and angioedema could be problematic

THANKS TO ALL