Role of Angiotensin Receptor Neprilysin Inhinitor in Congestive Heart Failure

This powerpoint presentation describes in detail about heart failure and the role of angiotensin receptor neprilysin inhibitors in treatment of congestive heart failure.

1. Angiotensin receptor neprilysin inhibitor in CCF Presenter: Dr. Chitranshi Hyanki (JR 3) Moderator: Dr. Shoebul Haque (SR) Peer Support: Dr. Anto Rajiv (JR 3) Department of Pharmacology & Therapeutics, King George’s Medical University Lucknow, Uttar Pradesh, India 226003 Email - [email protected]

2. Contents Introduction Pathophysiology of heart failure Natriuretic peptides ARNIs Mechanism of Action Current guidelines References

3. Learning objectives At the end of this teaching-learning session, the audience will be able to: Enumerate the diagnostic criteria for heart failure Enumerate signs and symptoms Understand the various group of drugs used in the treatment Understand ARNIs (Angiotensin receptor neprilysin inhibitors) and their role in managing CHF

4. Abbreviations AHA - American heart association HF - Heart failure EF - Ejection fraction NYHA - New York Heart Association HIV - Human immunodeficiency virus ARNI - Angiotensin receptor neprilysin inhibitor NP - Natriuretic peptide ACE - Angiotensin converting enzyme ARB - Angiotensin receptor blocker SGLT - Sodium glucose co-transporter ANP - Atrial natriuretic peptide BNP - Brain natriuretic peptide GBMT - Guideline based medical therapy

5. Introduction According to AHA , Heart failure (HF) is defined as a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood leading to cardinal manifestations of dyspnea , fatigue, and fluid retention. Source- Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal , A., Drazner , M. H., Dunlay , S. M., Evers, L. R., Fang, J. C., Fedson , S. E., Fonarow , G. C., Hayek, S. S., Hernandez, A. F., Khazanie , P., Kittleson , M. M., Lee, C. S., Link, M. S., … Yancy, C. W. (2022). 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. In  Circulation  (Vol. 145, Issue 18). https:// doi.org /10.1161/CIR.0000000000001063

6. Types of heart failure On the basis of ejection fraction HFrEF - Heart failure with reduced ejection fraction (<40%) HFmrEF - Heart failure with moderately reduced ejection fraction (40-49%) HFpEF - Heart failure with preserved ejection fraction (>=50%)

7. On the basis of severity of symptom The New York Heart Association (NYHA) defines four classes of HF Class I : No physical limitation; ordinary physical activity does not cause HF symptoms Class II : No symptoms at rest, but ordinary physical activities cause HF symptoms Class III : No symptoms at rest, but less-than-ordinary physical activities cause HF symptoms Class IV : Symptoms of HF at rest

8. 3. On the basis of anatomy of heart Left sided heart failure The left ventricular pump failure leads to pulmonary congestion It presents as- shortness of breath, orthopnea, and dyspnea Right sided heart failure The right ventricular pump failure leads to congestion of systemic veins It presents as – peripheral edema, hepatomegaly and jugular venous distension

9. 4. On the basis of cardiac output High output heart failure - elevated cardiac output because of high metabolic demand Low output heart failure – metabolic demand is within normal limits but the heart is not able to meet it

10. Etiology HRrEF HRpEF Coronary artery disease Hypertension Valvular heart disease Obesity Congenital heart disease Amyloidosis Infectious diseases- Chaga’s, HIV Sarcoidosis Toxic cardiomyopathy - drug induced Constructive pericarditis Cor pulmonale Aging Source- Jameson, J.L. (ed), Fauci, S.A. and Kasper, L.D. (ed, ) (2022)  Harrison’s principles of Medicine: Volume 1  (2 vols). 21st edn . New York: McGraw Hill. 

11. Pathophysiology Initial insult Neurohormonal activation Ventricular remodeling Progression to congestion Source- Jameson, J.L. (ed), Fauci, S.A. and Kasper, L.D. (ed, ) (2022)  Harrison’s principles of Medicine: Volume 1  (2 vols). 21st edn . New York: McGraw Hill. 

12. Clinical features Source- McDonagh TA, Metra M, Adamo M  et al ; ESC Scientific Document Group. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.  Eur Heart J  2023; 44 :3627–39.  https://doi.org/10.1093/eurheartj/ehad195  Erratum in:  Eur Heart J  2024; 45 :53.

13. Diagnostic algorithm for patients with heart failure Assessment Clinical history, Physical examination , ECG, Labs Natriuretic peptide NT-Pro BNP > 125 pg/ml BNP >= 35 pg/ml Transthoracic echocardiography Additional testing, if necessary HF diagnosis confirmed Determine cause and classify Evaluate for precipitating factors Initiate treatment HRpEF HFmrEF HRrEF

14. Treatment Inotropic drugs Diuretics RAAS inhibitors Vasodilators Synthetic BNPs Beta-blockers ACE inhibitors Aldosterone antagonists Neprilysin inhibitors

15. Natriuretic peptides Cyclic peptides having natriuretic, diuretic and vasodilator property – ANP : produced by atrial myocytes , ventricles and certain neurons BNP : produced by ventricles and the brain C-type : produced by the vascular endothelium

16. Neprilysin inhibitor - Sacubitril Orally active neprilysin inhibitor that increases the blood levels of natriuretic peptides by inhibiting neutral endopeptidase enzymes resulting in : Natriuresis Diuresis Vascular relaxation It is a prodrug that is absorbed after oral ingestion and rapidly activated to sacubitrilat

17. Angiotensin receptor blocker - Valsartan It binds to angiotensin II type 1 (AT1) receptors present on blood vessels and cause vasodilation thus lowering the blood pressure More selective for AT1 receptor

18. Angiotensin receptor neprilysin inhibitor (ARNI) combination of an ARB and NI ( sacubitril and valsartan) Used for heart failure with reduced ejection fraction The starting dosage is 24/26 mg BD, with the target dose being 97/103 mg BD

19. ARNI Source- Upadhya , B.  et al.  (2022) ‘Newer drugs to reduce high blood pressure and mitigate hypertensive target organ damage’,  Current Hypertension Reports , 24(1), pp. 1–20. doi:10.1007/s11906-022-01166-9. 

20. Side effects Angioedema (infrequent) Cough Reduced hematocrit Hyperkalemia Hypotension Renal impairment

21. Contraindications P regnant / lactating Already taking an ACE inhibitor or ARB drug Liver disease H ypersensitivity to ARBs or ARNIs R enal dysfunction

22. Drug interactions ACE inhibitors + ARNI - angioedema Potassium sparing diuretics + ARNI - hyperkalemia NSAIDS + ARNI- worsening of renal functio n

23. Diuretic agent Hydralazine + Isosorbide dinitrate For persistently symptomatic African-American patients despite ARNI/ Beta-blocker/ mineralocorticoid antagonist For patients with resting heart rate ≥ 70, on maximally tolerated beta-blocker dose in sinus rhythm, NYHA class II-III For high-risk patients already on optimal GDMT with worsening HF as evidenced by a HF hospitalization or requirement for intravenous diuretics For patients with persistent volume overload, NYHA class II-IV Vericiguat Ivabradine ARNI + Evidence-based beta blocker + Mineralocorticoid antagonist + SGLT inhibitor Titrate Add Add Add HFrEF Stage C Treatment Maddox, T, Januzzi , J, Allen, L. et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.  JACC.  2024 Apr, 83 (15) 1444–1488.

24. ARNI If previously on ACE, ensure 36 hours off before initiation Select starting dose : 24/26 mg to 49/51 mg twice daily If patient is taking equivalent of <= 10 mg daily of enalapril or equivalent of <= 160 mg daily of valsartan 24/26 mg twice daily If patient is taking equivalent of > 10 mg daily of enalapril of equivalent of > 160 mg of valsartan 49/51 mg twice daily In 1-2 weeks, access tolerability If possible, increase dose stepwise to target of 97/103 mg twice daily Monitor BP , electrolytes and kidney function after initiation and during titration Maddox, T, Januzzi , J, Allen, L. et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.  JACC.  2024 Apr, 83 (15) 1444–1488.

25. CDSCO approval

26. Summary CCF is a condition where the heart fails to pump blood effectively, causing fluid overload Classes of drugs udes for the treatment of HF are - Inotropic drugs, Diuretics, RAAS inhibitors, Vasodilators, Synthetic BNPs, Beta-blockers, ACE inhibitors, Aldosterone antagonists, Neprilysin inhibitors ACEi/ARBs provide incomplete neurohormonal blockade, limiting their long-term effectiveness Sacubitril/Valsartan enhances natriuretic peptides (vasodilation, natriuresis) while blocking RAAS activation and inhibiting neprilysin Currently, the use of ARNIs as a first-line therapy for the management of HFrEF is recommended.

27. References Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal , A., Drazner , M. H., Dunlay , S. M., Evers, L. R., Fang, J. C., Fedson , S. E., Fonarow , G. C., Hayek, S. S., Hernandez, A. F., Khazanie , P., Kittleson , M. M., Lee, C. S., Link, M. S., … Yancy, C. W. (2022). 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. In  Circulation  (Vol. 145, Issue 18). https:// doi.org /10.1161/CIR.0000000000001063 Fauci AS, Kasper DL, Longo DL, et al., editors.  Harrison's principles of internal medicine . 21st ed. New York: McGraw-Hill Education; 2022. Upadhya , B., Kozak, P. M., Stacey, R. B., & Vasan, R. S. (2022). Newer Drugs to Reduce High Blood Pressure and Mitigate Hypertensive Target Organ Damage. In  Current Hypertension Reports  (Vol. 24, Issue 1). https:// doi.org /10.1007/s11906-022-01166-9 Maddox, T, Januzzi , J, Allen, L. et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.  JACC.  2024 Apr, 83 (15) 1444–1488. Brunton LL, Chabner BA, Knollmann BC, editors.  Goodman & Gilman's: The pharmacological basis of therapeutics . 14th ed. New York: McGraw-Hill Education; 2022. Tripathi KD.  Essentials of medical pharmacology . 9th ed. New Delhi: Jaypee Brothers Medical Publishers; 2024.

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