Arni

ARNI

1. Dr. KAZI ALAM NOWAZ MD FINAL PART STUDENT CARDIOLOGY NHFH & RI

2. Sacubitril

3. 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.

4. ARNI

5. Therapeutic Targeting of Natriuretic Peptide (NP) System in Heart Failure

6. Mechanism of progression of Heart Failure Increased activity or response to maladaptive mechanism Decreased activity or response to adaptive mechanism Myocardial or vascular stress injury Evolution and progression of heart failure Angiotensin Receptor Blocker Inhibition of Neprilysin

7. Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides ( Natriuretic peptides, adrenomodulin , bradykinin , substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Inactive metabolites Neprilysin Neprilysin inhibition

8. Mechanism of action Systematic (IUPAC) name 4-{[(2 S ,4 R )-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de- ethylation via esterases . LBQ657

9. How to inhibit Neprilysin in Heart Failure Neprilysin Inhibition alone Ineffective due to angiotensin potension Neprilysin inhibition +ACE inhibition Potentially dangerous due to angioedema Neorilysin inhibition + Angiotensin receptor blockade

10. Sacubitril / valsartan Pharmacokinetics: A Time to peak: 0.5 hrs Time to peak of metabolite: 2 hrs D Protein binding – 94-97% Vd : 103 L M Metabolized by esterases to active metabolite Major metabolite is not metabolized E T 1/2 sacubitril : 1.4 hrs T 1/2 metabolite: 11.5 hrs

11. 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

12. 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 N ot recommended for patients with severe hepatic impairment.

13. 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

14. 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

15. 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

16. PREGNANCY ARBs should not be used during pregnancy because they can reduce fetal renal function and increase fetal and neonatal morbidity and death.

17. sacubitril / valsartan Adverse Effects Side effect Sacubitril / Valsartan Enalapril Angioedema 0.5% 0.2% Hypotension 18% 12% Impaired renal function 3.3% 4.5% Hyperkalemia 12% 14% Cough 9% 13%

18. 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.

19. 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

20. Sacubitril / valsartan ( LCZ696) Trials

21. 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.

22. 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

23. PARADIGM-HF: early termination

24. 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 I n 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

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

26. Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (contd...) 2013 ACCF/AHA Guideline 2016 ACC/AHA/HFSA Focused Update No recommendation about angiotensin receptor– neprilysin inhibitor (ARNI) COR : III:Harm LOE: B-R Recommendation : ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor

27. Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (contd...) 2013 ACCF/AHA Guideline 2016 ACC/AHA/HFSA Focused Update No recommendation about angiotensin receptor– neprilysin inhibitor (ARNI) COR : III:Harm LOE: B-R Recommendation : ARNI should not be administered to patients with a history of angioedema

28. Current and possible future evidence-based treatment of HFrEF

29. Conclusion RAAS blockade combined with NP System augmentation represent a novel approach for patients with HF Sacubitril /valsartan is i ndicated 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

30. THANKS TO ALL