Advertisement

American Journal of Cardiovascular Drugs

, Volume 19, Issue 1, pp 21–36 | Cite as

Neprilysin Inhibitors: Filling a Gap in Heart Failure Management, Albeit Amidst Controversy and at a Significant Cost

  • Antonis S. ManolisEmail author
  • Theodora A. Manolis
  • Antonis A. Manolis
  • Helen Melita
Review Article
  • 192 Downloads

Abstract

Dual angiotensin and neprilysin inhibition using the combination drug sacubitril–valsartan has ushered in a new era in the treatment of heart failure (HF). The randomized controlled PARADIGM-HF trial, which randomized 8399 patients with HF to enalapril or sacubitril–valsartan, showed a 20% reduction in mortality and HF hospitalization with the new drug. This has been heralded as a step toward filling a crucial gap in HF management by providing strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin–angiotensin system alone in stable patients with chronic HF as it negates the deleterious effects of angiotensin while concomitantly augmenting the beneficial effects of the endogenous natriuretic peptide system. This new therapy is costly, and other confirmatory studies have been lacking for over 2 years since its approval by major regulatory authorities. As such, controversy and heated discussions have amassed, as has detailed information from a plethora of secondary analyses of this pivotal trial about the pros and cons of this promising new therapeutic strategy in HF management. The aim of this review was to provide a critical assessment of all these aspects.

Notes

Compliance with ethical standards

Conflict of interest

ASM, TAM, AAM, and HM have no conflicts of interest that might be relevant to the contents of this manuscript.

Funding

No external funding was used in the preparation of this manuscript.

References

  1. 1.
    Manolis AS, Varriale P, Nobile J. Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure. Pharmacotherapy. 1987;7:216–22.CrossRefGoogle Scholar
  2. 2.
    van Bilsen M, Patel HC, Bauersachs J, et al. The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2017;19:1361–78.CrossRefGoogle Scholar
  3. 3.
    von Lueder TG, Kotecha D, Atar D, Hopper I. Neurohormonal Blockade in Heart Failure. Card Fail Rev. 2017;3:19–24.CrossRefGoogle Scholar
  4. 4.
    von Lueder TG, Sangaralingham SJ, Wang BH, et al. Renin-angiotensin blockade combined with natriuretic peptide system augmentation: novel therapeutic concepts to combat heart failure. Circ Heart Fail. 2013;6:594–605.CrossRefGoogle Scholar
  5. 5.
    McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.CrossRefGoogle Scholar
  6. 6.
    Chrysant SG. Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan. J Am Soc Hypertens. 2017;11:461–8.CrossRefGoogle Scholar
  7. 7.
    Tajik AA, Dickstein K. What constitutes optimal neurohumoral antagonism in chronic heart failure? Heart. 2016;102:1922–32.CrossRefGoogle Scholar
  8. 8.
    Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.CrossRefGoogle Scholar
  9. 9.
    Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776–803.CrossRefGoogle Scholar
  10. 10.
    Singh JS, Lang CC. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond. Vasc Health Risk Manag. 2015;11:283–95.Google Scholar
  11. 11.
    Volterrani M, Iellamo F, Senni M, Piepoli MF. Therapeutic options of Angiotensin Receptor Neprilysin inhibitors (ARNis) in chronic heart failure with reduced ejection fraction: Beyond RAAS and sympathetic nervous system inhibition. Int J Cardiol. 2017;226:132–5.CrossRefGoogle Scholar
  12. 12.
    Arrigo M, Vodovar N, Nougue H, et al. The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin. Eur Heart J. 2018;39:1794–8.CrossRefGoogle Scholar
  13. 13.
    Maisel AS, Duran JM, Wettersten N. Natriuretic peptides in heart failure: Atrial and B-type natriuretic peptides. Heart Fail Clin. 2018;14:13–25.CrossRefGoogle Scholar
  14. 14.
    O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32–43.CrossRefGoogle Scholar
  15. 15.
    Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900–5.CrossRefGoogle Scholar
  16. 16.
    Singh JSS, Burrell LM, Cherif M, Squire IB, Clark AL, Lang CC. Sacubitril/valsartan: beyond natriuretic peptides. Heart. 2017;103:1569–77.CrossRefGoogle Scholar
  17. 17.
    Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2:663–70.CrossRefGoogle Scholar
  18. 18.
    Gori M, Volterrani M, Piepoli M, Senni M. Angiotensin receptor-neprilysin inhibitor (ARNi): clinical studies on a new class of drugs. Int J Cardiol. 2017;226:136–40.CrossRefGoogle Scholar
  19. 19.
    Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun. 1990;168:863–70.CrossRefGoogle Scholar
  20. 20.
    Del Ry S. C-type natriuretic peptide: a new cardiac mediator. Peptides. 2013;40:93–8.CrossRefGoogle Scholar
  21. 21.
    Lok DJ, Klip IT, Voors AA, et al. Prognostic value of N-terminal pro C-type natriuretic peptide in heart failure patients with preserved and reduced ejection fraction. Eur J Heart Fail. 2014;16:958–66.CrossRefGoogle Scholar
  22. 22.
    Sangaralingham SJ, McKie PM, Ichiki T, et al. Circulating C-type natriuretic peptide and its relationship to cardiovascular disease in the general population. Hypertension. 2015;65:1187–94.CrossRefGoogle Scholar
  23. 23.
    Wong PC, Guo J, Zhang A. The renal and cardiovascular effects of natriuretic peptides. Adv Physiol Educ. 2017;41:179–85.CrossRefGoogle Scholar
  24. 24.
    Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–95.CrossRefGoogle Scholar
  25. 25.
    Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF Trial. JACC Heart Fail. 2017;5:471–82.CrossRefGoogle Scholar
  26. 26.
    Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68:241–8.CrossRefGoogle Scholar
  27. 27.
    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;36:1990–7.CrossRefGoogle Scholar
  28. 28.
    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;131:54–61.CrossRefGoogle Scholar
  29. 29.
    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;36:434–9.CrossRefGoogle Scholar
  30. 30.
    Simpson J, Jhund PS, Silva Cardoso J, et al. Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol. 2015;66:2059–71.CrossRefGoogle Scholar
  31. 31.
    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;36:2576–84.CrossRefGoogle Scholar
  32. 32.
    Smith KR, Hsu CC, Berei TJ, et al. PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions. Pharmacotherapy. 2018;38:284–98.CrossRefGoogle Scholar
  33. 33.
    Mogensen UM, Kober L, Kristensen SL, et al. The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF. Am Heart J. 2017;188:35–41.CrossRefGoogle Scholar
  34. 34.
    Claggett B, Packer M, McMurray JJ, et al. Estimating the long-term treatment benefits of sacubitril–valsartan. N Engl J Med. 2015;373:2289–90.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5:333–40.CrossRefGoogle Scholar
  37. 37.
    Packer M, Claggett B, Lefkowitz MP, et al. Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2018.  https://doi.org/10.1016/S2213-8587(18)30100-1 (Epub ahead of print).Google Scholar
  38. 38.
    Packer M. Does neprilysin inhibition potentiate or minimize the adverse effects of glucagon-like peptide-1 receptor agonists in chronic heart failure? J Card Fail. 2018;24:109–11.CrossRefGoogle Scholar
  39. 39.
    Yandrapalli S, Andries G, Biswas M, Khera S. Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives. Vasc Health Risk Manag. 2017;13:369–82.CrossRefGoogle Scholar
  40. 40.
    Ishii M, Kaikita K, Sato K, et al. Cardioprotective effects of LCZ696 (sacubitril/valsartan) after experimental acute myocardial infarction. JACC: Basic to Translational. Science. 2017;2:655–68.Google Scholar
  41. 41.
    Iborra-Egea O, Galvez-Monton C, Roura S, et al. Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. NPJ Syst Biol Appl. 2017;3:12.CrossRefGoogle Scholar
  42. 42.
    de Diego C, Gonzalez-Torres L, Nunez JM, et al. Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm. 2018;15:395–402.CrossRefGoogle Scholar
  43. 43.
    Kaluzna-Oleksy M, Kolasa J, Migaj J, et al. Initial clinical experience with the first drug (sacubitril/valsartan) in a new class—ARNIs in patients with heart failure with reduced left ventricular ejection fraction in Poland. Kardiol Pol. 2018;76(2):381–7.Google Scholar
  44. 44.
    Ali D, Riley F, Kirkland S, Hyland J, Banerjee P. Sacubitril/valsartan in chronic symptomatic heart failure with reduced ejection fraction: first clinical experience from a large UK tertiary centre. Heart. 2017;103:A1.CrossRefGoogle Scholar
  45. 45.
    Crawley R, Guha K, Kalra P, Morton G. Sacubitril/valsartan: real world experience of delivery and tolerability. Heart. 2017;103:A1–2.CrossRefGoogle Scholar
  46. 46.
    Antol DD, Casebeer AW, DeClue RW, Stemkowski S, Russo PA. An early view of real-world patient response to sacubitril/valsartan: a retrospective study of patients with heart failure with reduced ejection fraction. Adv Ther. 2018.  https://doi.org/10.1007/s12325-018-0710-4 (Epub ahead of print).Google Scholar
  47. 47.
    Fonarow GC, Hernandez AF, Solomon SD, Yancy CW. Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol. 2016;1:714–7.CrossRefGoogle Scholar
  48. 48.
    Luo N, Fonarow GC, Lippmann SJ, et al. Early adoption of sacubitril/valsartan for patients with heart failure with reduced ejection fraction: insights from get with the guidelines-heart failure (GWTG-HF). JACC Heart Fail. 2017;5:305–9.CrossRefGoogle Scholar
  49. 49.
    Di Tano G, Bettari L. Adoption of sacubitril/valsartan must take into account different heart failure patient types. JACC Heart Fail. 2017;5:688–9.CrossRefGoogle Scholar
  50. 50.
    Lodge FM, Phillips J, Groves T, Yousef ZR. Eligibility of patients for sacubitril/valsartan in a secondary care heart failure service. Br J Cardiol. 2016;23:148–50.Google Scholar
  51. 51.
    Pellicori P, Urbinati A, Shah P, et al. What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan? Eur J Heart Fail. 2017;19:768–78.CrossRefGoogle Scholar
  52. 52.
    Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 comprehensive update of the canadian cardiovascular society guidelines for the management of heart failure. Can J Cardiol. 2017;33:1342–433.CrossRefGoogle Scholar
  53. 53.
    Solomon SD, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan relative to a prior decompensation: the PARADIGM-HF trial. JACC Heart Fail. 2016;4:816–22.CrossRefGoogle Scholar
  54. 54.
    Luo N, Mentz RJ, O’Brien EC. Reply: adoption of sacubitril/valsartan must take into account different heart failure patient types. JACC Heart Fail. 2017;5:689.CrossRefGoogle Scholar
  55. 55.
    Velazquez EJ, Morrow DA, DeVore AD, et al. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018;198:145–51.CrossRefGoogle Scholar
  56. 56.
    Ambrosy AP, Mentz RJ, Fiuzat M, et al. The role of angiotensin receptor-neprilysin inhibitors in cardiovascular disease-existing evidence, knowledge gaps, and future directions. Eur J Heart Fail. 2018;20:963–72.CrossRefGoogle Scholar
  57. 57.
    Shaddy R, Canter C, Halnon N, et al. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J. 2017;193:23–34.CrossRefGoogle Scholar
  58. 58.
    Bohm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J. 2017;38:1132–43.CrossRefGoogle Scholar
  59. 59.
    Vardeny O, Claggett B, Kachadourian J, et al. Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circ Heart Fail. 2018;11:e004745.CrossRefGoogle Scholar
  60. 60.
    Zhao Y, Yu H, Zhao X, Ma R, Li N, Yu J. The effects of LCZ696 in patients with hypertension compared with angiotensin receptor blockers: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther. 2017;22:447–57.CrossRefGoogle Scholar
  61. 61.
    Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. 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. 2010;375:1255–66.CrossRefGoogle Scholar
  62. 62.
    Cheung DG, Aizenberg D, Gorbunov V, Hafeez K, Chen CW, Zhang J. Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: a randomized, double-blind, 8-week study. J Clin Hypertens (Greenwich). 2018;20:150–8.CrossRefGoogle Scholar
  63. 63.
    Supasyndh O, Wang J, Hafeez K, Zhang Y, Zhang J, Rakugi H. Efficacy and safety of sacubitril/valsartan (LCZ696) Compared with olmesartan in elderly Asian patients (>/=65 Years) with systolic hypertension. Am J Hypertens. 2017;30:1163–9.CrossRefGoogle Scholar
  64. 64.
    Supasyndh O, Sun N, Kario K, Hafeez K, Zhang J. Long-term (52-week) safety and efficacy of sacubitril/valsartan in Asian patients with hypertension. Hypertens Res. 2017;40:472–6.CrossRefGoogle Scholar
  65. 65.
    Williams B, Cockcroft JR, Kario K, et al. Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: The PARAMETER Study. Hypertension. 2017;69:411–20.CrossRefGoogle Scholar
  66. 66.
    Izzo JL Jr, Zappe DH, Jia Y, Hafeez K, Zhang J. Efficacy and safety of crystalline valsartan/sacubitril (LCZ696) compared with placebo and combinations of free valsartan and sacubitril in patients with systolic hypertension: the RATIO Study. J Cardiovasc Pharmacol. 2017;69:374–81.CrossRefGoogle Scholar
  67. 67.
    Chrysant SG. Benefits and pitfalls of sacubitril/valsartan treatment in patients with hypertension. J Clin Hypertens (Greenwich). 2018;20:351–5.CrossRefGoogle Scholar
  68. 68.
    Patel N, Gluck J. Is Entresto good for the brain? World J Cardiol. 2017;9:594–9.CrossRefGoogle Scholar
  69. 69.
    Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18:1193–202.CrossRefGoogle Scholar
  70. 70.
    Sacubitril/valsartan (Entresto) for heart failure. Med Lett Drugs Ther. 2015;57(1474):107–9.Google Scholar
  71. 71.
    Aronow WS, Shamliyan TA. Benefits and harms of sacubitril in adults with heart failure and reduced left ventricular ejection fraction. Am J Cardiol. 2017;120:1166–70.CrossRefGoogle Scholar
  72. 72.
    Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2017;2:79–85.CrossRefGoogle Scholar
  73. 73.
    Vardeny O, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail. 2016;18:1228–34.CrossRefGoogle Scholar
  74. 74.
    Owens RE, Oliphant CS. Angioedema spotlight: a closer examination of sacubitril/valsartan safety results. J Am Board Fam Med. 2017;30:556–7.CrossRefGoogle Scholar
  75. 75.
    Shi V, Senni M, Streefkerk H, Modgill V, Zhou W, Kaplan A. Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study. Int J Cardiol. 2018;264:118–23.CrossRefGoogle Scholar
  76. 76.
    Campbell DJ. Long-term neprilysin inhibition—implications for ARNIs. Nat Rev Cardiol. 2017;14:171–86.CrossRefGoogle Scholar
  77. 77.
    Feldman AM. Neprilysin Inhibition in the time of precision medicine. JACC Heart Fail. 2016;4:409–14.CrossRefGoogle Scholar
  78. 78.
    Cannon JA, Shen L, Jhund PS, et al. Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. Eur J Heart Fail. 2017;19:129–37.CrossRefGoogle Scholar
  79. 79.
    Bodey F, Hopper I, Krum H. Neprilysin inhibitors preserve renal function in heart failure. Int J Cardiol. 2015;179:329–30.CrossRefGoogle Scholar
  80. 80.
    Li B, Zhao Y, Yin B, et al. Safety of the neprilysin/renin-angiotensin system inhibitor LCZ696. Oncotarget. 2017;8:83323–33.Google Scholar
  81. 81.
    Richards AM. N-terminal B-type natriuretic peptide in heart failure. Heart Fail Clin. 2018;14:27–39.CrossRefGoogle Scholar
  82. 82.
    Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in N-terminal Pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68:2425–36.CrossRefGoogle Scholar
  83. 83.
    Nunez J, Nunez E, Barallat J, et al. Serum neprilysin and recurrent admissions in patients with heart failure. J Am Heart Assoc. 2017;6:e005712.CrossRefGoogle Scholar
  84. 84.
    Emrich IE, Vodovar N, Feuer L, et al. Do plasma neprilysin activity and plasma neprilysin concentration predict cardiac events in chronic kidney disease patients? Nephrol Dial Transplant. 2018.  https://doi.org/10.1093/ndt/gfy066 (Epub ahead of print).Google Scholar
  85. 85.
    O’Meara E, Prescott MF, Claggett B, et al. Independent Prognostic Value of Serum Soluble ST2 Measurements in Patients With Heart Failure and a Reduced Ejection Fraction in the PARADIGM-HF Trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circ Heart Fail. 2018;11:e004446.Google Scholar
  86. 86.
    Mogensen UM, Kober L, Jhund PS, et al. Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF. Eur J Heart Fail. 2018;20:514–22.CrossRefGoogle Scholar
  87. 87.
    Januzzi JL, Butler J, Fombu E, et al. Rationale and methods of the prospective study of biomarkers, symptom improvement, and ventricular remodeling during sacubitril/valsartan therapy for heart failure (PROVE-HF). Am Heart J. 2018;199:130–6.CrossRefGoogle Scholar
  88. 88.
    Ollendorf DA, Sandhu AT, Pearson SD. Sacubitril–valsartan for the treatment of heart failure: effectiveness and value. JAMA Intern Med. 2016;176:249–50.CrossRefGoogle Scholar
  89. 89.
    King JB, Shah RU, Bress AP, Nelson RE, Bellows BK. Cost-effectiveness of sacubitril–valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail. 2016;4:392–402.CrossRefGoogle Scholar
  90. 90.
    Gaziano TA, Fonarow GC, Claggett B, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1:666–72.CrossRefGoogle Scholar
  91. 91.
    Sandhu AT, Ollendorf DA, Chapman RH, Pearson SD, Heidenreich PA. Cost-effectiveness of sacubitril–valsartan in patients with heart failure with reduced ejection fraction. Ann Intern Med. 2016;165:681–9.CrossRefGoogle Scholar
  92. 92.
    Ademi Z, Pfeil AM, Hancock E, et al. Cost-effectiveness of sacubitril/valsartan in chronic heart-failure patients with reduced ejection fraction. Swiss Med Wkly. 2017;147:w14533.Google Scholar
  93. 93.
    McMurray JJV, Trueman D, Hancock E, et al. Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction. Heart. 2018;104:1006–13.CrossRefGoogle Scholar
  94. 94.
    Ramos IC, Versteegh MM, de Boer RA, et al. Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines. Value Health. 2017;20:1260–9.CrossRefGoogle Scholar
  95. 95.
    Yandrapalli S, Aronow WS, Mondal P, Chabbott DR. Limitations of sacubitril/valsartan in the management of heart failure. Am J Ther. 2017;24:e234–9.CrossRefGoogle Scholar
  96. 96.
    Pablos-Mendez A, Barr RG, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice. JAMA. 1998;279:222–5.CrossRefGoogle Scholar
  97. 97.
    Perez AL, Kittipibul V, Tang WHW, Starling RC. Patients not meeting PARADIGM-HF enrollment criteria are eligible for sacubitril/valsartan on the basis of FDA approval: the need to close the gap. JACC Heart Fail. 2017;5:460–3.CrossRefGoogle Scholar
  98. 98.
    Tsutsui H, Momomura S, Saito Y, et al. Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: rationale for and design of the randomized, double-blind PARALLEL-HF study. J Cardiol. 2016;70:225–31.CrossRefGoogle Scholar
  99. 99.
    National Institute for Health and Care Excellence. Sacubitril valsartan for treating symptomatic chronic hert failure with reduced ejection fraction. Technology appraisal guidance [TA388]. 2016. www.nice.org.uk/guidance/ta388. Accessed 22 Jan 2018.
  100. 100.
    Institute for Clinical and Economic Review. ICER draft report on CardioMEMS and Entresto for management of congestive heart failure posted for public comment [media release]. 2015. https://icer-review.org/announcements/chf-draft-report-posted/. Accessed 22 Jan 2018.
  101. 101.
    Prasad V. Let’s take a closer look at PARADIGM-HF [blog post] 1 September 2014. NEJM Journal Watch. 2014. https://blogs.jwatch.org/cardioexchange/2014/09/01/lets-scrutinize-paradigm-hf/. Accessed 22 Jan 2018.
  102. 102.
    CardioExchange Editors, Staff. Perspectives on PARADIGM-HF [blog post]. 5 Septembe 2014. NEJM Journal Watch. 2014. https://blogs.jwatch.org/cardioexchange/2014/09/05/perspectives-on-paradigm-hf/. Accessed 22 Jan 2018.
  103. 103.
    Entresto (sacubitril and valsartan) tablets: US prescribing information. New Jersey: Novartis Pharmaceuticals Corporation, 2017.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Antonis S. Manolis
    • 1
    Email author
  • Theodora A. Manolis
    • 2
  • Antonis A. Manolis
    • 3
  • Helen Melita
    • 4
  1. 1.Third Department of CardiologyAthens University School of MedicineAthensGreece
  2. 2.Zakynthos HospitalZakynthosGreece
  3. 3.Patras University School of MedicinePatrasGreece
  4. 4.Onassis Cardiac Surgery CenterAthensGreece

Personalised recommendations