The introduction of sacubitril + valsartan as therapy in heart failure. Which patients can benefit the most from this novel drug? Review article
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Published:
Mar 31, 2017
Keywords:
heart failure, PARADIGM-HF, sacubitril, valsartan
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Abstract
Niewydolność serca stanowi w krajach rozwiniętych istotną przyczynę zwiększonej chorobowości i śmiertelności. Przewlekła aktywacja układu RAAS (renin–angiotensin–aldosterone system) jest związana z przebudową serca i pogorszeniem jego funkcji. Wcześniejsze interwencje farmakologiczne polegały na zahamowaniu układu RAAS poprzez zastosowanie β-adrenolityków, inhibitorów konwertazy oraz antagonistów receptora dla aldosteronu. W ciągu ostatnich dekad dowiedziono protekcyjnego działania przedsionkowego peptydu natriuretycznego (ANP, atrial natriuretic peptide) i mózgowego peptydu natriuretycznego (BNP, brain natriuretic peptide) w niewydolności serca i rozpoczęto badania mające wyłonić leki hamujące uszkodzenie serca u chorych z jego niewydolnością. Początkowo stosowano rekombinowane peptydy natriuretyczne, jednak wyniki badań były niekorzystne. Kolejne badania dotyczyły neprylizyny, enzymu degradującego peptydy natriuretyczne. Wcześniej prowadzone badania nie wykazały przewagi leków hamujących neprylizynę względem inhibitorów konwertazy oraz sartanów. Przełom nastąpił po badaniu PARADIGM-HF. Wykazano w nim , że u chorych ze skurczową niewydolnością serca połączenie antagonisty receptora dla angiotensyny i inhibitora neprylizyny zmniejsza istotnie bardziej niż enalapryl śmiertelność całkowitą, sercowo-naczyniową i liczbę hospitalizacji. Chociaż wymienione połączenie zostało zarejestrowane przez FDA (US Food and Drug Administration), to użycie leku jest ograniczone z powodu małego doświadczenia z jego stosowaniem oraz działań ubocznych, m.in. obrzęku naczynioruchowego. Lek jest zalecany w niewydolności skurczowej serca zamiast inhibitorów konwertazy u chorych objawowych mimo optymalnego leczenia. Niezależnie od wyników badania PARADIGM-HF nadal pozostaje wiele pytań o skuteczność połączenia i jego bezpieczeństwo w różnych populacjach chorych z niewydolnością serca.
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Hussain , R. S., Kumar , M. S., Saka-Patrick , K., & Rezaee , A. J. (2017). The introduction of sacubitril + valsartan as therapy in heart failure. Which patients can benefit the most from this novel drug?. Cardiology in Practice, 11(1), 30-39. Retrieved from https://journalsmededu.pl/index.php/kwp/article/view/1264
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References
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4. McMurray J.J., Adamopoulos S., Anker S.D. et al.: ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur. Heart J. 2012; 33(14): 1787-1847.
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7. Cohn J.N., Ferrari R., Sharpe N.: Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J. Am. Coll. Cardiol. 2000; 35(3): 569-582.
8. Andersen S., Andersen A., Nielsen-Kudsk J.E.: The Renin–Angiotensin–Aldosterone-System And Right Heart Failure In Congenital Heart Disease. IJC Heart & Vasculature 2016; 11: 59-65.
9. Yan W., Sheng N., Seto M. et al.: Corin, a Mosaic Transmembrane Serine Protease Encoded by a Novel cDNA from Human Heart. J. Biol. Chem. 1999; 274(21): 14926-14935.
10. O’Connor C.M., Starling R.C., Hernandez A.F.: Effect Of Nesiritide In Patients With Acute Decompensated Heart Failure. N. Engl. J. Med. 2011; 365: 32-43.
11. Konishi M., Ishida J., Springer J. et al.: Heart Failure Epidemiology And Novel Treatments In Japan: Facts And Numbers. ESC Heart Failure 2016; 3(3): 145-151.
12. Bevan E.G., Connell J.M., Doyle J. et al.: Candoxatril, A Neutral Endopeptidase Inhibitor. J. Hypertens. 1992; 10(7): 607-614.
13. Packer M., Califf R.M., Konstam M.A. 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): 920-926.
14. Ruilope L.M., Dukat A., Böhm M. et al.: 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(9722): 1255-1266.
15. Gu J., Noe A., Chandra P. et al.: Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor-Neprilysin Inhibitor (ARN-I). J. Clin. Pharmacol. 2010; 50(4): 401-414.
16. Hegde L.G., Yu C., Renner T. et al.: Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat. J. Cardiovasc. Pharmacol. 2011; 57(4): 495-504.
17. Bavishi C., Messerli F.H., Kadosh B. et al.: Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur. Heart J. 2015; 36(30): 1967-1973. http://doi.org/10.1093/eurheartj/ehv142.
18. Novartis: Entresto (sacubitril and valsartan): US pescribing information. 2015. Online.
19. Cada D.J., Baker D.E., Leonard J.: Sacubitril/Valsartan. Hosp. Pharm. 2015; 50(11): 1025-1036.
20. Chaplin S.: Sacubitril/Valsartan For The Treatment Of Heart Failure. Prescriber 2016; 27(4): 56-57.
21. Ejection Fraction Heart Failure Measurement. Online: http://www.heart.org/HEARTORG/Conditions/HeartFailure/DiagnosingHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp#.WSrqDOvyiUk.
22. Fala L.: Entresto (Sacubitril/Valsartan): First-In-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved For Patients With Heart Failure. Am. Health Drug Benefits 2015; 8(6): 330-334.
23. Latini R., Masson S., Anand I. et al.: Effects Of Valsartan On Circulating Brain Natriuretic Peptide And Norepinephrine In Symptomatic Chronic Heart Failure: The Valsartan Heart Failure Trial (Val-Heft). Circulation 2002; 106(19): 2454-2458.
24. Lee D.S., Gona P., Vasan R.S. et al.: Relation Of Disease Pathogenesis And Risk Factors To Heart Failure With Preserved Or Reduced Ejection Fraction: Insights From The Framingham Heart Study Of The National Heart, Lung, And Blood Institute. Circulation 2009; 119(24): 3070-3077.
25. Makani H., Messerli F.H., Romero J. et al.: Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am. J. Cardiol. 2012; 110(3): 383-391. http://doi.org/10.1016/j.amjcard.2012.03.034.
26. McMurray J.J., Packer M., Desai A.S. et al.: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014; 371(11): 993-1004. http://doi.org/10.1056/NEJMoa1409077.
27. National institute for health and care excellence (NICE). Sacubitril Valsartan For Treating Symptomatic Chronic Heart Failure With Reduced Ejection Fraction. London: National institute for health and care excellence (NICE). Online: https://www.nice.org.uk/guidance/ta388.
28. 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(6): 768-778. http://doi.org/10.1002/ejhf.788.
29. Potter L.R., Abbey-Hosch S., Dickey D.M.: Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr. Rev. 2006; 27(1): 47-72.
30. Ramzy I.: Standards And New Drugs In The Treatment Of Heart Failure. E-journal of Cardiology Practice 2017; 14(39): 1-5.
31. Solomon S.D., 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(9851): 1387-1395.
32. Vardeny O., Miller R., Solomon S.D.: Combined Neprilysin And Renin-Angiotensin System Inhibition For The Treatment Of Heart Failure. JACC Heart Fail. 2014; 2(6): 663-670. http://doi.org/10.1016/j.jchf.2014.09.001.
33. Bayes-Genis A., Morant-Talamante N., Lupón J.: Neprilysin and natriuretic peptide regulation in heart failure. Curr. Heart Fail. Rep. 2016; 13(4): 151-157.
34. Chaplin S.: Sacubitril/valsartan for chronic heart failure: its future potential. Prescriber 2016; 27(11): 26-34.
35. Ponikowski P., Voors A.A., Anker S.D.: 2016 ESC Guidelines For The Diagnosis And Treatment Of Acute And Chronic Heart Failure – Web Addenda. Eur. Heart J. 2016. http://doi.org/10.1093/eurheartj/ehw128.
36. Feldman A.M., Haller J.A., DeKosky S.T.: Valsartan/Sacubitril for Heart Failure. JAMA 2016; 315(1): 25-26.
37. Iwata N., Tsubuki S., Takaki Y. et al.: Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 2000; 6(2): 143-150.
38. Jhund P.S., Claggett B., Packer M. et al.: Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur. J. Heart Fail. 2014; 16(6): 671-677. http://doi.org/10.1002/ejhf.76.
39. Paulus W.J., Tschöpe C.: A novel paradigm for heart failure with preserved ejection fraction. JACC 2013; 62(4): 263-271.
40. Ponikowski P., Voors A.A., Anker S.D. 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(27): 2129-2200.
41. Sacubitril/Valsartan For Chronic Heart Failure. Aust. Prescr. 2016; 39(6): 226-227.
42. Williams B., Cockcroft J.R., 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(3): 411-420. http://doi.org/10.1161/HYPERTENSIONAHA.116.08556.
43. Williams B., Cockcroft J.R., Kario K. et al.: Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study. BMJ Open 2014; 4(2): e004254. http://doi.org/10.1136/bmjopen-2013-004254.
44. Pellicori P., Clark A.L.: Clinical Evidence To Support The Use Of Sacubitril/Valsartan (LCZ696). Br. J. Cardiol. 2016; 23(supl. 1): S1-S16.
45. Pellicori P., Clark A.L.: Clinical trials update from the European Society of Cardiology-Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure. Eur. J. Heart Fail. 2015; 17(9): 979-983. http://doi.org/10.1002/ejhf.340.
46. Madani R., Poirier R., Wolfer D.P. et al.: Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo. J. Neurosci. Res. 2006; 84(8): 1871-1878.
47. Iwata N., Tsubuki S., Takaki Y. et al.: Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 2000; 6(2): 143-150.
48. EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study) (HFN-LIFE). Online: https://clinicaltrials.gov/ct2/show/NCT02816736. Identification number: NCT02816736.
49. Prospective ARN-I vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) (2016). Online: https://clinicaltrials.gov/ct2/show/NCT02924727. Identification number: NCT02924727.
50. Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON- HF) (2013). Online: https://clinicaltrials.gov/ct2/show/NCT01920711. Identification number: NCT01920711.
2. Rywik T.M., Kołodziej P., Targoński R. et al.: Characteristics of the heart failure population in Poland: ZOPAN, a multicentre national programme. Kardiol. Pol. 2011; 69(1): 24-31.
3. McCormack P.L.: Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. Drugs 2016; 76(3): 387-396.
4. McMurray J.J., Adamopoulos S., Anker S.D. et al.: ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur. Heart J. 2012; 33(14): 1787-1847.
5. Jhund P.S., McMurray J.J.V.: The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016; 102(17): 1342-1347.
6. Cohn J.N., 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; 345(23): 1667-1675.
7. Cohn J.N., Ferrari R., Sharpe N.: Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J. Am. Coll. Cardiol. 2000; 35(3): 569-582.
8. Andersen S., Andersen A., Nielsen-Kudsk J.E.: The Renin–Angiotensin–Aldosterone-System And Right Heart Failure In Congenital Heart Disease. IJC Heart & Vasculature 2016; 11: 59-65.
9. Yan W., Sheng N., Seto M. et al.: Corin, a Mosaic Transmembrane Serine Protease Encoded by a Novel cDNA from Human Heart. J. Biol. Chem. 1999; 274(21): 14926-14935.
10. O’Connor C.M., Starling R.C., Hernandez A.F.: Effect Of Nesiritide In Patients With Acute Decompensated Heart Failure. N. Engl. J. Med. 2011; 365: 32-43.
11. Konishi M., Ishida J., Springer J. et al.: Heart Failure Epidemiology And Novel Treatments In Japan: Facts And Numbers. ESC Heart Failure 2016; 3(3): 145-151.
12. Bevan E.G., Connell J.M., Doyle J. et al.: Candoxatril, A Neutral Endopeptidase Inhibitor. J. Hypertens. 1992; 10(7): 607-614.
13. Packer M., Califf R.M., Konstam M.A. 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): 920-926.
14. Ruilope L.M., Dukat A., Böhm M. et al.: 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(9722): 1255-1266.
15. Gu J., Noe A., Chandra P. et al.: Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor-Neprilysin Inhibitor (ARN-I). J. Clin. Pharmacol. 2010; 50(4): 401-414.
16. Hegde L.G., Yu C., Renner T. et al.: Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat. J. Cardiovasc. Pharmacol. 2011; 57(4): 495-504.
17. Bavishi C., Messerli F.H., Kadosh B. et al.: Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur. Heart J. 2015; 36(30): 1967-1973. http://doi.org/10.1093/eurheartj/ehv142.
18. Novartis: Entresto (sacubitril and valsartan): US pescribing information. 2015. Online.
19. Cada D.J., Baker D.E., Leonard J.: Sacubitril/Valsartan. Hosp. Pharm. 2015; 50(11): 1025-1036.
20. Chaplin S.: Sacubitril/Valsartan For The Treatment Of Heart Failure. Prescriber 2016; 27(4): 56-57.
21. Ejection Fraction Heart Failure Measurement. Online: http://www.heart.org/HEARTORG/Conditions/HeartFailure/DiagnosingHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp#.WSrqDOvyiUk.
22. Fala L.: Entresto (Sacubitril/Valsartan): First-In-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved For Patients With Heart Failure. Am. Health Drug Benefits 2015; 8(6): 330-334.
23. Latini R., Masson S., Anand I. et al.: Effects Of Valsartan On Circulating Brain Natriuretic Peptide And Norepinephrine In Symptomatic Chronic Heart Failure: The Valsartan Heart Failure Trial (Val-Heft). Circulation 2002; 106(19): 2454-2458.
24. Lee D.S., Gona P., Vasan R.S. et al.: Relation Of Disease Pathogenesis And Risk Factors To Heart Failure With Preserved Or Reduced Ejection Fraction: Insights From The Framingham Heart Study Of The National Heart, Lung, And Blood Institute. Circulation 2009; 119(24): 3070-3077.
25. Makani H., Messerli F.H., Romero J. et al.: Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am. J. Cardiol. 2012; 110(3): 383-391. http://doi.org/10.1016/j.amjcard.2012.03.034.
26. McMurray J.J., Packer M., Desai A.S. et al.: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014; 371(11): 993-1004. http://doi.org/10.1056/NEJMoa1409077.
27. National institute for health and care excellence (NICE). Sacubitril Valsartan For Treating Symptomatic Chronic Heart Failure With Reduced Ejection Fraction. London: National institute for health and care excellence (NICE). Online: https://www.nice.org.uk/guidance/ta388.
28. 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(6): 768-778. http://doi.org/10.1002/ejhf.788.
29. Potter L.R., Abbey-Hosch S., Dickey D.M.: Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr. Rev. 2006; 27(1): 47-72.
30. Ramzy I.: Standards And New Drugs In The Treatment Of Heart Failure. E-journal of Cardiology Practice 2017; 14(39): 1-5.
31. Solomon S.D., 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(9851): 1387-1395.
32. Vardeny O., Miller R., Solomon S.D.: Combined Neprilysin And Renin-Angiotensin System Inhibition For The Treatment Of Heart Failure. JACC Heart Fail. 2014; 2(6): 663-670. http://doi.org/10.1016/j.jchf.2014.09.001.
33. Bayes-Genis A., Morant-Talamante N., Lupón J.: Neprilysin and natriuretic peptide regulation in heart failure. Curr. Heart Fail. Rep. 2016; 13(4): 151-157.
34. Chaplin S.: Sacubitril/valsartan for chronic heart failure: its future potential. Prescriber 2016; 27(11): 26-34.
35. Ponikowski P., Voors A.A., Anker S.D.: 2016 ESC Guidelines For The Diagnosis And Treatment Of Acute And Chronic Heart Failure – Web Addenda. Eur. Heart J. 2016. http://doi.org/10.1093/eurheartj/ehw128.
36. Feldman A.M., Haller J.A., DeKosky S.T.: Valsartan/Sacubitril for Heart Failure. JAMA 2016; 315(1): 25-26.
37. Iwata N., Tsubuki S., Takaki Y. et al.: Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 2000; 6(2): 143-150.
38. Jhund P.S., Claggett B., Packer M. et al.: Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur. J. Heart Fail. 2014; 16(6): 671-677. http://doi.org/10.1002/ejhf.76.
39. Paulus W.J., Tschöpe C.: A novel paradigm for heart failure with preserved ejection fraction. JACC 2013; 62(4): 263-271.
40. Ponikowski P., Voors A.A., Anker S.D. 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(27): 2129-2200.
41. Sacubitril/Valsartan For Chronic Heart Failure. Aust. Prescr. 2016; 39(6): 226-227.
42. Williams B., Cockcroft J.R., 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(3): 411-420. http://doi.org/10.1161/HYPERTENSIONAHA.116.08556.
43. Williams B., Cockcroft J.R., Kario K. et al.: Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study. BMJ Open 2014; 4(2): e004254. http://doi.org/10.1136/bmjopen-2013-004254.
44. Pellicori P., Clark A.L.: Clinical Evidence To Support The Use Of Sacubitril/Valsartan (LCZ696). Br. J. Cardiol. 2016; 23(supl. 1): S1-S16.
45. Pellicori P., Clark A.L.: Clinical trials update from the European Society of Cardiology-Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure. Eur. J. Heart Fail. 2015; 17(9): 979-983. http://doi.org/10.1002/ejhf.340.
46. Madani R., Poirier R., Wolfer D.P. et al.: Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo. J. Neurosci. Res. 2006; 84(8): 1871-1878.
47. Iwata N., Tsubuki S., Takaki Y. et al.: Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 2000; 6(2): 143-150.
48. EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study) (HFN-LIFE). Online: https://clinicaltrials.gov/ct2/show/NCT02816736. Identification number: NCT02816736.
49. Prospective ARN-I vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) (2016). Online: https://clinicaltrials.gov/ct2/show/NCT02924727. Identification number: NCT02924727.
50. Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON- HF) (2013). Online: https://clinicaltrials.gov/ct2/show/NCT01920711. Identification number: NCT01920711.