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Entresto: added value in heart failure?

The combined sacubitril/valsartan molecule (Entresto®) has been authorised in Europe since 2015 for the treatment of symptomatic heart failure with reduced ejection fraction. Since Entresto is considerably more expensive than the generically available agents used in heart failure, treatment with Entresto should offer significant advantages over existing agents. As regards the authorised indication (chronic symptomatic heart failure with reduced ejection fraction), this has been investigated in one large randomised study with an actively treated control group. Entresto led to a convincing statistically significant and clinically relevant reduction of cardiovascular mortality or hospitalization due to heart failure (composite endpoint). However, critical questions about the quality of the study design have remained unanswered.

  • At a maximum dosage of 200 mg daily, Entresto is superior to enalapril at a maximum dosage of 10 mg twice daily to treat chronic symptomatic heart failure with reduced ejection fraction.
  • The available scientific evidence for the intended patient population has relevant shortcomings, limiting the applicability of Entresto.
  • One of the main points of criticism is that the control group in the authorisation study was not treated at the maximum dosage of enalapril recommended in the guidelines, 20 mg twice daily.
  • Treatment with Entresto should be reserved for patients who remain symptomatic despite receiving the optimal standard treatment titrated to the recommended maximum dosage. 

  1. Ponikowski P, Voors AA, Anker SD, et al. ESC Scientific Document Group. 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 Jul 14;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128. Epub 2016 May 20. Erratum in: Eur Heart J. 2016 Dec 30;: PMID: 27206819.
  2. 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 Apr;50(4):401-14. doi: 10.1177/0091270009343932. Epub 2009 Nov 23. PMID: 19934029.
  3. Schiering N, D'Arcy A, Villard F, Ramage P, et al. Structure of neprilysin in complex with the active metabolite of sacubitril. Sci Rep. 2016 Jun 15;6:27909. doi: 10.1038/srep27909. PMID: 27302413; PMCID: PMC4908401.
  4. CBG Geneesmiddeleninformatiebank. Summary of Product Characteristics Entresto. Via: op 20-07-2020.
  5. Dunselman PH. Replacement of Angiotensin Converting Enzyme Inhibition (REPLACE) Investigators. Effects of the replacement of the angiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patients with congestive heart failure. The replacement of angiotensin converting enzyme inhibition (REPLACE) investigators. Int J Cardiol. 2001 Feb;77(2-3):131-8; discussion 139-40. doi: 10.1016/s0167-5273(00)00426-5. PMID: 11182175.
  6. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997 Mar 15;349(9054):747-52. doi: 10.1016/s0140-6736(97)01187-2. PMID: 9074572.
  7. Campbell DJ. Long-term neprilysin inhibition - implications for ARNIs. Nat Rev Cardiol. 2017 Mar;14(3):171-186. doi: 10.1038/nrcardio.2016.200. Epub 2016 Dec 15. PMID: 27974807.
  8. Coats AJ. Omapatrilat--the story of Overture and Octave. Int J Cardiol. 2002 Nov;86(1):1-4. doi: 10.1016/s0167-5273(02)00389-3. PMID: 12243845.
  9. Campbell DJ. Neprilysin Inhibitors and Bradykinin. Front Med (Lausanne). 2018 Sep 19;5:257. doi: 10.3389/fmed.2018.00257. PMID: 30283782; PMCID: PMC6157573.
  10. EMA 2015. CHMP Assessment report Sacubitril/valsartan. EMA/671279/2015. Via: Geraadpleegd op 20-07-2020
  11. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015.
  12. Solomon SD, McMurray JJV, Anand IS, et al. PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1. PMID: 31475794.
  13. Velazquez EJ, Morrow DA, DeVore AD, et al. PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11. Erratum in: N Engl J Med. 2019 Mar 14;380(11):1090. PMID: 30415601.
  14. Mogensen UM, Køber L, Kristensen SL, et al. PARADIGM-HF Investigators and Committees. The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF. Am Heart J. 2017 Jun;188:35-41. doi: 10.1016/j.ahj.2017.02.034. Epub 2017 Mar 14. PMID: 28577679.
  15. 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 May;5(5):333-340. doi: 10.1016/S2213-8587(17)30087-6. Epub 2017 Mar 18. PMID: 28330649; PMCID: PMC5534167.
  16. Myhre PL, Vaduganathan M, Claggett B, et al. B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial. J Am Coll Cardiol. 2019 Mar 26;73(11):1264-1272. doi: 10.1016/j.jacc.2019.01.018. Epub 2019 Mar 4. PMID: 30846338.
  17. Haynes R, Judge PK, Staplin N, et al. Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease. Circulation. 2018 Oct 9;138(15):1505-1514. doi: 10.1161/CIRCULATIONAHA.118.034818. PMID: 30002098. 
  18. Okumura N, Jhund PS, Gong J, et al. PARADIGM-HF Investigators and Committees*. Effects of Sacubitril/Valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) According to Background Therapy. Circ Heart Fail. 2016 Sep;9(9):e003212. doi: 10.1161/CIRCHEARTFAILURE.116.003212. PMID: 27618854.
  19. Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail. 2019 Mar;21(3):337-341. doi: 10.1002/ejhf.1402. Epub 2019 Feb 11. PMID: 30741494; PMCID: PMC6607492.
  20. Ter Maaten JM. Unravelling the effect of sacubitril/valsartan on loop diuretic dosing. Eur J Heart Fail. 2019 Mar;21(3):342-344. doi: 10.1002/ejhf.1410. Epub 2019 Feb 11. PMID: 30741487.
  21. Chen CH. Critical Questions about PARADIGM-HF and the Future. Acta Cardiol Sin. 2016 Jul;32(4):387-96. doi: 10.6515/acs20151120a. PMID: 27471351; PMCID: PMC4963414.
  22. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Committees and Investigators. 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 Sep;15(9):1062-73. doi: 10.1093/eurjhf/hft052. Epub 2013 Apr 5. PMID: 23563576; PMCID: PMC3746839. Correspondence: Doi 10.1056/NEJMc1412654 
  23. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75. doi: 10.1056/NEJMoa010713. PMID: 11759645. 
  24. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008 Oct;10(10):933-89. doi: 10.1016/j.ejheart.2008.08.005. Epub 2008 Sep 16. Erratum in: Eur J Heart Fail. 2009 Jan;11(1):110. Erratum in: Eur J Heart Fail. 2010 Apr;12(4):416. Dosage error in article text. PMID: 18826876.
  25. Hunt SA, Abraham WT, Chin MH, et al. American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009 Apr 14;53(15):e1-e90. doi: 10.1016/j.jacc.2008.11.013. Erratum in: J Am Coll Cardiol. 2009 Dec 15;54(25):2464. PMID: 19358937.
  26. 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. Circulation. 2017 Aug 8;136(6):e137-e161. doi: 10.1161/CIR.0000000000000509. Epub 2017 Apr 28. PMID: 28455343.
  27. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987 Jun 4;316(23):1429-35. doi: 10.1056/NEJM198706043162301. PMID: 2883575. 
  28. Bernardez-Pereira S, Ramires FJA, de Melo RFT, et al. Was the Enalapril Dose Too Low in the PARADIGM-HF Trial? Cardiol Rev. 2018 Jul/Aug;26(4):196-200. doi: 10.1097/CRD.0000000000000193. PMID: 29369824.
  29. Faris R, Flather M, Purcell H, et al. Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol. 2002 Feb;82(2):149-58. doi: 10.1016/s0167-5273(01)00600-3. PMID: 11853901.
  30. Yandrapalli S, Aronow WS, Mondal P, Chabbott DR. Limitations of Sacubitril/Valsartan in the Management of Heart Failure. Am J Ther. 2017 Mar/Apr;24(2):e234-e239. doi: 10.1097/MJT.0000000000000473. PMID: 27574931.


  • Sander van den Bogert, dr, pharmacist