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Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction

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Abstract

Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II–IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.

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References

  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–322.

    Article  PubMed  Google Scholar 

  2. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J. 2012;33(14):1787–847.

    Article  PubMed  Google Scholar 

  3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240–327.

    Article  PubMed  Google Scholar 

  4. McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail. 2015;17(3):242–7.

    Article  CAS  PubMed  Google Scholar 

  5. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920–6.

    Article  CAS  PubMed  Google Scholar 

  6. Fryer RM, Segreti J, Banfor PN, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol. 2008;153(5):947–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Feng L, Karpinski PH, Sutton P, et al. LCZ696: a dual-acting sodium supramolecular complex. Tetrahedron Lett. 2012;53(3):275–6.

    Article  CAS  Google Scholar 

  8. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–14.

    Article  CAS  PubMed  Google Scholar 

  9. Novartis. Entresto™ (sacubitril and valsartan): US pescribing information. 2015. http://www.pharma.us.novartis.com. Accessed 24 Sep 2015.

  10. European Medicines Agency. Entresto (sacubitril/valsartan): summary of product characteristics. 2015. http://www.ema.europa.eu/. Accessed 12 Jan 2016.

  11. US FDA. Diovan (valsartan): US prescribing information. 2015. http://www.accessdata.fda.gov. Accessed 24 Sep 2015.

  12. Damman K, Andersen K, Belohlavek J, et al. Angiotensin receptor neprilysin inhibition and renal function in heart faulure: results from PARADIGM-HF [abstract no. 3301]. Eur Heart J. 2015;36(Suppl 1):545.

    Google Scholar 

  13. Gori M, Senni M, Claggett B, et al. Effect of LCZ696 on urinary albumin excretion and relation to outcomes in patients with heart failure [abstract no. 3302]. Eur Heart J. 2015;36(Suppl 1):545.

    Google Scholar 

  14. Gan L, Langenickel T, Petruck J, et al. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor. J Clin Pharmacol. 2016;56(1):78–86

    Article  CAS  PubMed  Google Scholar 

  15. Ayalasomayajula S, Jordaan P, Pal P, et al. Assessment of pharmacokinetic drug interaction between LCZ696 and digoxin [abstract no. 449]. Hypertension. 2013;62(3, Suppl):449.

  16. Ayalasomayajula S, Jordaan P, Pal P, et al. Assessment of drug interaction potential between LCZ696 and warfarin [abstract no. 448]. Hypertension. 2013;62(3, Suppl):448.

  17. Gan L, Jiang X, Mendonza A, et al. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects. Clin Pharmacol Drug Dev. 2016;5(1):27–39.

    Article  Google Scholar 

  18. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.

    Article  PubMed  Google Scholar 

  19. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15(9):1062–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  21. Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36(30):1990–7.

    Article  PubMed  Google Scholar 

  22. McMurray J, Jhund P, Gong J, et al. Prevention of progressive worsening of heart failure over time with the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) [abstract no. 19363]. Circulation. 2015;132(Suppl 3):A19363.

    Google Scholar 

  23. Solomon SD, Packer M, Zile M, et al. Reduction in 30-day rehospitalization after discharge from a heart failure admission in patients receiving LCZ696 versus enalapril: PARADIGM-HF [abstract no. 17955]. Circulation. 2015;132(Suppl 3):A17955.

    Google Scholar 

  24. Jhund P, Claggett B, Solomon S, et al. Elevated high sensitivity troponin is associated with poorer outcomes in patients with heart failure and reduced by LCZ696 [abstract no. P214]. Eur Heart J. 2015;36(Suppl 1):22.

    Google Scholar 

  25. Zile MR, McMurray JJ, Packer M, et al. Prognostic implications of achieving an N-terminal pro-B-type natriuretic peptide level <1000 pg/ml in patients with heart failure: data from PARADIGM-HF [abstract no. 248]. J Card Fail. 2015;21(8):S106–7.

    Article  Google Scholar 

  26. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015;36(38):2576–84.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Solomon S, Packer M, Zile M, et al. The angiotensin receptor neprilysin inhibitor LCZ696 is effective across the spectrum of ejection fraction in heart failure with reduced ejection fraction [abstract no. 088]. J Card Fail. 2015;21(8):S45–6.

    Article  Google Scholar 

  28. Bohm M, Refsgaard J, Ramires FJA, et al. Effect of the angiotensin receptor neprilysin inhibitor LCZ696 compared with enalapril according to systolic blood pressure in PARADIGM-HF [abstract no. P1794]. Eur J Heart Fail. 2015;17(Suppl 1):393.

    Google Scholar 

  29. Simpson J, Squire IB, Martinez F, et al. Effect of the angiotensin receptor neprilysin inhibitor LCZ696 compared with enalapril according to baseline risk in PARADIGM-HF [abstract no. P1416]. Eur J Heart Fail. 2015;17(Suppl 1):295–6.

    Google Scholar 

  30. Kristensen SL, Preiss D, Jhund PS, et al. Risk related to pre–diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from prospective comparison of ARNI With ACEI to determine impact on global mortality and morbidity in heart failure trial. Circ Heart Fail. 2016;9(1):e002560.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Claggett B, Packer M, McMurray JJV, et al. Estimating the long-term treatment benefits of sacubitril–valsartan. N Engl J Med. 2015;373(23):2289–90.

    Article  PubMed  Google Scholar 

  32. Lewis E, Zile MR, Swedberg K, et al. Health-related quality of life outcomes in PARADIGM-HF [abstract no. 17912]. Circulation. 2015;132(Suppl 3):A17912.

    Google Scholar 

  33. McMurray J, Packer M, Desai A, et al. A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. Eur Heart J. 2015;36(7):434–9.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Cannon J, Boytsov S, Senni M, et al. Dementia-related adverse effects in the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF) [abstract no. P242]. Eur J Heart Fail. 2015;17(Suppl 1):49–50.

    Google Scholar 

  35. Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280(45):37644–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Senni M, Reyes A, Majercak I, et al. Results of the TITRATION study: a 12-week, multicenter, randomized, double-blind, safety evaluation of a 3- versus 6-week up-titration regimen of LCZ696 in patients with HFrEF [abstract no. P1795]. Eur J Heart Fail. 2015;17(Suppl 1):393.

    Google Scholar 

  37. Senni M, Gogia H, Martinez Selles M, et al. Effect of baseline ACEI/ARB use on the safety and tolerability of up-titrating LCZ696 over 3 vs. 6 weeks: results from the TITRATION study [abstract no. 1281]. Eur J Heart Fail. 2015;17(Suppl 1):265–6.

    Google Scholar 

  38. Novartis. Swissmedic approves Novartis’ new heart failure medicine Entresto™ [media release]. 18 Sep 2015. https://www.novartis.com/news. Accessed 2 Feb 2016.

  39. Novartis Pharmaceuticals Canada Inc. Heart failure treatment ENTRESTO™ (LCZ696) shown to reduce the risk of cardiovascular death and hospitalization approved by Health Canada [media release]. 6 Oct 2015. http://www.novartis.ca/. Accessed 2 Feb 2016.

  40. Novartis. Novartis’ new heart failure medicine LCZ696, now called Entresto™, approved by FDA to reduce risk of cardiovascular death and heart failure hospitalization [media release]. 7 Jul 2015. https://www.novartis.com. Accessed 2 Feb 2016.

  41. Lillyblad MP. Dual angiotensin receptor and neprilysin inhibition in chronic systolic heart failure: understanding the new PARADIGM. Ann Pharmacother. 2015;49(11):1237–51.

    Article  PubMed  Google Scholar 

  42. McMurray JJ, Packer M, Solomon SD. Neprilysin inhibition for heart failure. N Engl J Med. 2014;371(24):2336–7.

    PubMed  Google Scholar 

  43. California Technology Assessment Forum. CardioMEMS™ HF System (St. Jude Medical) and sacubitril/valsartan (Entresto™, Novartis) for management of congestive heart failure: effectiveness, value, and value-based price benchmarks (draft report). 2015. http://ctaf.org/sites/default/files/u148/CHF_Draft_Report_091115.pdf. Accessed 18 Sep 2015.

  44. The National Institute for Health and Care Excellence. NICE gives green light to innovative drug for common heart condition [media release]. 11 December 2015. http://www.nice.org.uk/news/press-and-media/nice-gives-green-light-to-innovative-drug-for-common-heart-condition. Accessed 2 Feb 2016.

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Acknowledgments

During the peer review process, the manufacturer of sacubitril/valsartan was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Paul L. McCormack

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  1. Paul L. McCormack
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Correspondence to Paul L. McCormack.

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The preparation of this review was not supported by any external funding.

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Paul L. McCormack is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: A. L. Clark, Department of Academic Cardiology, Hull York Medical School, Castle Hill Hospital, Hull, UK; P. S. Jhund, British Heart Foundation Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; J. J. V. McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

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McCormack, P.L. Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. Drugs 76, 387–396 (2016). https://doi.org/10.1007/s40265-016-0544-9

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