Congestive heart failure angiotensin receptor-neprilysin inhibitor

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2],Seyedmahdi Pahlavani, M.D. [3]

Overview

The PARADIGM-HF study evaluated the efficacy of LCZ696, a concomitant inhibitor of neprilysin and angiotensin receptor, on the rate of mortality due to cardiovascular causes and hospitalization. Compared to enalapril, angiotensin receptor-neprilysin inhibitor significantly reduced the rate of hospitalization by 21% and decreased the rate of cardiovascular and hospitalization-related deaths from 26.5% to 21.8%. The administration of angiotensin receptor-neprilysin inhibitor reduced chronic heart failure symptoms and the associated limitation of physical activity.[1]

Angiotensin Receptor-Neprilysin Inhibitor

The inhibition of neprilysin, a neutral endopeptidase, has been associated with a decrease in vasoactive peptides among patients with heart failure. In fact, neprilysin inhibition decreases the breakdown of natriuretic peptide, bradykinin, and adrenomedullin leading to an attenuation of sodium retention and vasoconstriction observed in heart failure patients.[2][3][4]

Animal studies revealed that the effect of neprilysin inhibition is further potentiated with the concomitant inhibition of the renin angiotensin system by the administration of ACE inhibitors at the expense of an increased risk of angioedema.[5] The PARADIGM-HF study evaluated the efficacy of LCZ696, a concomitant inhibitor of neprilysin and angiotensin receptor, on the rate of mortality due to cardiovascular causes and hospitalizations. PARADIGM-HF randomized 8442 chronic heart failure patients with an ejection fraction inferior to 40% to either enalapril or angiotensin receptor-neprilysin inhibitor. Compared to enalapril, angiotensin receptor-neprilysin inhibitor significantly reduced the rate of hospitalization by 21% and decreased the rate of cardiovascular and hospitalization-related deaths from 26.5% to 21.8%. The administration of angiotensin receptor-neprilysin inhibitor reduced chronic heart failure symptoms and the associated limitation of physical activity.[1]

2022 AHA/ACC/HFSA Heart Failure Guideline (DO NOT EDIT) [6]

Renin-Angiotensin System Inhibition With ACEi or ARB or ARNi

Class I
"1. In patients with HFrEF and NYHA class II to III symptoms, the use of ARNi is recommended to reduce morbidity and mortality. [7][8][9][10][11](Level of Evidence: A) "
"2. In patients with previous or current symptoms of chronic HFrEF, the use of ACEi is beneficial to reduce morbidity and mortality when the use of ARNi is not feasible.[12][13][14][15][16][17][18][19] (Level of Evidence: A) "
"3. In patients with previous or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema and when the use of ARNi is not feasible, the use of ARB is recommended to reduce morbidity and mortality. [20][21][22][23][24] (Level of Evidence: A) "
"5. In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNi is recommended to further reduce morbidity and mortality. [7][8][9][10][11](Level of Evidence: B-R) "
Class Value Statement: High Value
"4. In patients with previous or current symptoms of chronic HFrEF, in whom ARNi is not feasible, treatment with an ACEi or ARB provides high economic value. [25][26][27][28][29][30][31](Level of Evidence: A) "
"6. In patients with chronic symptomatic HFrEF, treatment with an ARNi instead of an ACEi provides high economic value. [32][33][34][35] (Level of Evidence: A) "
Class III (Harm)
"7. ARNi should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi. [36][37] (Level of Evidence: B-R) "
"8. ARNi should not be administered to patients with any history of angioedema.[38][39][40][41] (Level of Evidence: C-LD) "
"9. ACEi should not be administered to patients with any history of angioedema. [42][43][44][45] (Level of Evidence: C-LD) "

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References

  1. ↑ 1.0 1.1 J. McMurray, M. Packer, M.D., A.S. Desai, M.D. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of Medicine. Epub ahead of print. Accessed on August 30, 2014.
  2. ↑ Cruden NL, Fox KA, Ludlam CA, Johnston NR, Newby DE (2004). "Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition". Hypertension. 44 (6): 913–8. doi:10.1161/01.HYP.0000146483.78994.56. PMID 15492133.
  3. ↑ Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T (1996). "Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure". Clin Sci (Lond). 91 (3): 283–91. PMID 8869410.
  4. ↑ Wilkinson IB, McEniery CM, Bongaerts KH, MacCallum H, Webb DJ, Cockcroft JR (2001). "Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP)". Br J Clin Pharmacol. 52 (2): 159–64. PMC 2014526. PMID 11488772.
  5. ↑ Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T (1998). "Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II". J Cardiovasc Pharmacol. 31 (1): 116–25. PMID 9456286.
  6. ↑ Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM; et al. (2022). "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 145 (18): e876–e894. doi:10.1161/CIR.0000000000001062. PMID 35363500 Check |pmid= value (help).
  7. ↑ 7.0 7.1 McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR; et al. (2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". N Engl J Med. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015. Review in: Evid Based Med. 2015 Apr;20(2):61 Review in: Ann Intern Med. 2015 Feb 17;162(4):JC2
  8. ↑ 8.0 8.1 Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z; et al. (2019). "Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study". Eur J Heart Fail. 21 (8): 998–1007. doi:10.1002/ejhf.1498. PMID 31134724.
  9. ↑ 9.0 9.1 Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K; et al. (2019). "Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure". N Engl J Med. 380 (6): 539–548. doi:10.1056/NEJMoa1812851. PMID 30415601.
  10. ↑ 10.0 10.1 Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J; et al. (2019). "Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial". JAMA. 322 (11): 1077–1084. doi:10.1001/jama.2019.12843. PMC 6749534 Check |pmc= value (help). PMID 31475296.
  11. ↑ 11.0 11.1 Wang Y, Zhou R, Lu C, Chen Q, Xu T, Li D (2019). "Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis". J Am Heart Assoc. 8 (13): e012272. doi:10.1161/JAHA.119.012272. PMC 6662364 Check |pmc= value (help). PMID 31240976.
  12. ↑ CONSENSUS Trial Study Group (1987). "Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)". N Engl J Med. 316 (23): 1429–35. doi:10.1056/NEJM198706043162301. PMID 2883575.
  13. ↑ SOLVD Investigators. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN (1991). "Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure". N Engl J Med. 325 (5): 293–302. doi:10.1056/NEJM199108013250501. PMID 2057034.
  14. ↑ Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM; et al. (1999). "Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group". Circulation. 100 (23): 2312–8. doi:10.1161/01.cir.100.23.2312. PMID 10587334.
  15. ↑ Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, Cuddy TE; et al. (1992). "Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators". N Engl J Med. 327 (10): 669–77. doi:10.1056/NEJM199209033271001. PMID 1386652.
  16. ↑ "Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators". Lancet. 342 (8875): 821–8. 1993. PMID 8104270.
  17. ↑ Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K; et al. (1995). "A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group". N Engl J Med. 333 (25): 1670–6. doi:10.1056/NEJM199512213332503. PMID 7477219.
  18. ↑ Garg R, Yusuf S (1995). "Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials". JAMA. 273 (18): 1450–6. PMID 7654275.
  19. ↑ Woodard-Grice AV, Lucisano AC, Byrd JB, Stone ER, Simmons WH, Brown NJ (2010). "Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema". Pharmacogenet Genomics. 20 (9): 532–6. doi:10.1097/FPC.0b013e32833d3acb. PMC 2945219. PMID 20625347.
  20. ↑ Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators (2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N Engl J Med. 345 (23): 1667–75. doi:10.1056/NEJMoa010713. PMID 11759645.
  21. ↑ Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP; et al. (2003). "Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both". N Engl J Med. 349 (20): 1893–906. doi:10.1056/NEJMoa032292. PMID 14610160. Review in: ACP J Club. 2004 Jul-Aug;141(1):3
  22. ↑ Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA; et al. (2009). "Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial". Lancet. 374 (9704): 1840–8. doi:10.1016/S0140-6736(09)61913-9. PMID 19922995. Review in: Evid Based Med. 2010 Apr;15(2):51-2
  23. ↑ Dominiak M (2008). "[Commentary to the article: ONTARGET Investigators, Yusuf S, Teo KK, Pogue J et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59]". Kardiol Pol. 66 (6): 705–6, discussion 707. PMID 18700309.
  24. ↑ Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L; et al. (2008). "Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial". Lancet. 372 (9644): 1174–83. doi:10.1016/S0140-6736(08)61242-8. PMID 18757085. Review in: Ann Intern Med. 2009 Feb 17;150(4):JC2-6
  25. ↑ Banka G, Heidenreich PA, Fonarow GC (2013). "Incremental cost-effectiveness of guideline-directed medical therapies for heart failure". J Am Coll Cardiol. 61 (13): 1440–6. doi:10.1016/j.jacc.2012.12.022. PMID 23433562.
  26. ↑ Dasbach EJ, Rich MW, Segal R, Gerth WC, Carides GW, Cook JR; et al. (1999). "The cost-effectiveness of losartan versus captopril in patients with symptomatic heart failure". Cardiology. 91 (3): 189–94. doi:10.1159/000006908. PMID 10516413.
  27. ↑ Glick H, Cook J, Kinosian B, Pitt B, Bourassa MG, Pouleur H; et al. (1995). "Costs and effects of enalapril therapy in patients with symptomatic heart failure: an economic analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial". J Card Fail. 1 (5): 371–80. doi:10.1016/s1071-9164(05)80006-5. PMID 12836712.
  28. ↑ Paul SD, Kuntz KM, Eagle KA, Weinstein MC (1994). "Costs and effectiveness of angiotensin converting enzyme inhibition in patients with congestive heart failure". Arch Intern Med. 154 (10): 1143–9. PMID 8185426.
  29. ↑ Reed SD, Friedman JY, Velazquez EJ, Gnanasakthy A, Califf RM, Schulman KA (2004). "Multinational economic evaluation of valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT)". Am Heart J. 148 (1): 122–8. doi:10.1016/j.ahj.2003.12.040. PMID 15215801.
  30. ↑ Shekelle P, Morton S, Atkinson S, Suttorp M, Tu W, Heidenreich P; et al. (2003). "Pharmacologic management of heart failure and left ventricular systolic dysfunction: effect in female, black, and diabetic patients, and cost-effectiveness". Evid Rep Technol Assess (Summ) (82): 1–6. PMC 4781559. PMID 14571595.
  31. ↑ Tsevat J, Duke D, Goldman L, Pfeffer MA, Lamas GA, Soukup JR; et al. (1995). "Cost-effectiveness of captopril therapy after myocardial infarction". J Am Coll Cardiol. 26 (4): 914–9. doi:10.1016/0735-1097(95)00284-1. PMID 7560617.
  32. ↑ Gaziano TA, Fonarow GC, Claggett B, Chan WW, Deschaseaux-Voinet C, Turner SJ; et al. (2016). "Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction". JAMA Cardiol. 1 (6): 666–72. doi:10.1001/jamacardio.2016.1747. PMID 27438344.
  33. ↑ Gaziano TA, Fonarow GC, Velazquez EJ, Morrow DA, Braunwald E, Solomon SD (2020). "Cost-effectiveness of Sacubitril-Valsartan in Hospitalized Patients Who Have Heart Failure With Reduced Ejection Fraction". JAMA Cardiol. 5 (11): 1236–1244. doi:10.1001/jamacardio.2020.2822. PMC 7675099 Check |pmc= value (help). PMID 32785628 Check |pmid= value (help).
  34. ↑ King JB, Shah RU, Bress AP, Nelson RE, Bellows BK (2016). "Cost-Effectiveness of Sacubitril-Valsartan Combination Therapy Compared With Enalapril for the Treatment of Heart Failure With Reduced Ejection Fraction". JACC Heart Fail. 4 (5): 392–402. doi:10.1016/j.jchf.2016.02.007. PMID 27039128.
  35. ↑ Sandhu AT, Ollendorf DA, Chapman RH, Pearson SD, Heidenreich PA (2016). "Cost-Effectiveness of Sacubitril-Valsartan in Patients With Heart Failure With Reduced Ejection Fraction". Ann Intern Med. 165 (10): 681–689. doi:10.7326/M16-0057. PMID 27571284.
  36. ↑ Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL; et al. (2002). "Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE)". Circulation. 106 (8): 920–6. doi:10.1161/01.cir.0000029801.86489.50. PMID 12186794.
  37. ↑ Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E (2004). "Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial". Am J Hypertens. 17 (2): 103–11. doi:10.1016/j.amjhyper.2003.09.014. PMID 14751650.
  38. ↑ Vardeny O, Miller R, Solomon SD (2014). "Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure". JACC Heart Fail. 2 (6): 663–70. doi:10.1016/j.jchf.2014.09.001. PMID 25306450.
  39. ↑ Messerli FH, Nussberger J (2000). "Vasopeptidase inhibition and angio-oedema". Lancet. 356 (9230): 608–9. doi:10.1016/S0140-6736(00)02596-4. PMID 10968427.
  40. ↑ Braunwald E (2015). "The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure". J Am Coll Cardiol. 65 (10): 1029–41. doi:10.1016/j.jacc.2015.01.033. PMID 25766951.
  41. ↑ Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP (2010). "Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study". Lancet. 375 (9722): 1255–66. doi:10.1016/S0140-6736(09)61966-8. PMID 20236700.
  42. ↑ Byrd JB, Adam A, Brown NJ (2006). "Angiotensin-converting enzyme inhibitor-associated angioedema". Immunol Allergy Clin North Am. 26 (4): 725–37. doi:10.1016/j.iac.2006.08.001. PMID 17085287.
  43. ↑ Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF; et al. (2012). "Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system". Arch Intern Med. 172 (20): 1582–9. doi:10.1001/2013.jamainternmed.34. PMID 23147456. Review in: Evid Based Med. 2013 Dec;18(6):e52
  44. ↑ Makani H, Messerli FH, Romero J, Wever-Pinzon O, Korniyenko A, Berrios RS; et al. (2012). "Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors". Am J Cardiol. 110 (3): 383–91. doi:10.1016/j.amjcard.2012.03.034. PMID 22521308.
  45. ↑ Rasmussen ER, Pottegård A, Bygum A, von Buchwald C, Homøe P, Hallas J (2019). "Angiotensin II receptor blockers are safe in patients with prior angioedema related to angiotensin-converting enzyme inhibitors - a nationwide registry-based cohort study". J Intern Med. 285 (5): 553–561. doi:10.1111/joim.12867. PMID 30618189.
  46. ↑ Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW (May 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". Circulation. 145 (18): e895–e1032. doi:10.1161/CIR.0000000000001063. PMID 35363499 Check |pmid= value (help).

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