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Novel Blockers of the Renin-Angiotensin-Aldosterone System in Chronic Heart Failure

  • Pharmacologic Therapy (WHW Tang, Section Editor)
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Abstract

Because of the impressive record of ACE inhibitors in patients with heart failure with reduced ejection fraction, the renin-angiotensin-aldosterone system continues to be pursued as a therapeutic target. Furthermore, the optimal treatment of patients with heart failure with preserved ejection fraction remains unclear. Early trials of direct renin inhibitors suggested that they may have a role, but recent results have not been encouraging. Preliminary trials of angiotensin-receptor/neprilysin inhibitors look positive. Whether these or other drugs will alter current recommendations remains to be seen.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance

  1. •• Yancy CW, Jessup M, Bozkurt B, et al. 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. J Am Coll Cardiol. 2013. doi:10.1016/j.jacc.2013.05.019. Recently released clinical practice guidelines for the management of patients with HF.

    PubMed Central  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: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803–69.

    Article  CAS  PubMed  Google Scholar 

  3. McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med. 2010;362(3):228–38.

    Article  CAS  PubMed  Google Scholar 

  4. Bueno H, Ross JS, Wang Y, et al. Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993–2006. JAMA. 2010;303(21):2141–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Steinberg BA, Zhao X, Heidenreich PA, et al. Get With the Guidelines Scientific Advisory Committee and Investigators. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation. 2012;126(1):65–75. doi:10.1161/CIRCULATIONAHA.111.080770.

    Article  PubMed  Google Scholar 

  6. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670–9.

    Article  PubMed  Google Scholar 

  7. Investigators SOLVD. Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure. N Engl J Med. 1991;325(5):293–302.

    Article  Google Scholar 

  8. Consensus Trial Study Group. Effects of Enalapril on Mortality in Severe Congestive Heart Failure. N Engl J Med. 1987;316(23):1429–35.

    Article  Google Scholar 

  9. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction. N Engl J Med. 1992;327(10):669–77.

    Article  CAS  PubMed  Google Scholar 

  10. Koitabashi N, Kass DA. Reverse remodeling in heart failure – mechanisms and therapeutic opportunities. Nat Rev Cardiol. 2012;9(3):147–57.

    Article  CAS  Google Scholar 

  11. Konstam MA, Rousseau MF, Kronenberg MW, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation. 1992;86(2):431–8.

    Article  CAS  PubMed  Google Scholar 

  12. Goussev A, Sharov VG, Shimoyama H, et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol. 1998;275(2 Pt 2):H626–31.

    CAS  PubMed  Google Scholar 

  13. Pahor M, Bernabei R, Sgadari A, et al. Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats. Hypertension. 1991;18(2):148–57.

    Article  CAS  PubMed  Google Scholar 

  14. McMurray JJ, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation. 2004;110(20):3281–8.

    Article  PubMed  Google Scholar 

  15. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–906.

    Article  CAS  PubMed  Google Scholar 

  16. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355(9215):1582–7.

    Article  CAS  PubMed  Google Scholar 

  17. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–6.

    Article  CAS  PubMed  Google Scholar 

  18. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362(9386):767–71.

    Article  CAS  PubMed  Google Scholar 

  19. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–75.

    Article  CAS  PubMed  Google Scholar 

  20. 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(15):1547–59.

    Article  CAS  PubMed  Google Scholar 

  21. Kuenzli A, Bucher HC, Anand I, et al. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS One. 2010;5(4):e9946. doi:10.1371/journal.pone.0009946.

    Article  PubMed Central  PubMed  Google Scholar 

  22. National PBM Bulletin. Dual renin-angiotensin aldosterone system blockade in diabetic nephropathy and increased adverse events. 2013. December 2; Available at URL: http://www.pbm.va.gov/vacenterformedicationsafety/nationalpbmbulletin/DualRenin-AngiotensinAldosteroneSystemBlockadeandImpairedRenalFu.pdf. Accessed 4th September 2013.

  23. Zannad F. Angiotensin-converting enzyme inhibitor and spironolactone combination therapy. New objectives in congestive heart failure treatment. Am J Cardiol. 1993;71(3):34A–9.

    Article  CAS  PubMed  Google Scholar 

  24. MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart. 1999;82(1):57–61.

    CAS  PubMed  Google Scholar 

  25. Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol. 1994;26(7):809–20.

    Article  CAS  PubMed  Google Scholar 

  26. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995;76(17):1259–65.

    Article  CAS  PubMed  Google Scholar 

  27. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–17.

    Article  CAS  PubMed  Google Scholar 

  28. • Zannad F, McMurray JJ, Krum H, et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med. 2011;364:11–21. In patients with even NYHA Class II symptoms and EF < 35 % Eplerenone reduced a composite of death from cardiovascular causes or a first hospitalization for HF over placebo.

    Article  CAS  PubMed  Google Scholar 

  29. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–21.

    Article  CAS  PubMed  Google Scholar 

  30. Beygui F, Vicaut E, Ecollan P, et al. Rationale for an early aldosterone blockade in acute myocardial infarction and design of the ALBATROSS trial. Am Heart J. 2010;160(4):642–8.

    Article  CAS  PubMed  Google Scholar 

  31. Reminder Trial http://clinicaltrials.gov/ct2/show/NCT01176968. Accessed June 2013.

  32. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543–51.

    Article  CAS  PubMed  Google Scholar 

  33. Wei L, Struthers AD, Fahey T, Watson AD, Macdonald TM. Spironolactone use and renal toxicity: population based longitudinal analysis. BMJ. 2010;340:c1768.

    Article  PubMed  Google Scholar 

  34. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation. 2008;118(16):1643–50.

    Article  CAS  PubMed  Google Scholar 

  35. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.

    Article  CAS  PubMed  Google Scholar 

  36. Yusuf S, Pfeffer MA, Swedberg K, CHARM Investigators and Committees, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777–81.

    Article  CAS  PubMed  Google Scholar 

  37. Massie BM, Carson PE, McMurray JJ, I-PRESERVE Investigators, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.

    Article  CAS  PubMed  Google Scholar 

  38. Lund LH, Benson L, Dahlström U, Edner M. Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA. 2012;308(20):2108–17. doi:10.1001/jama.2012.14785.

    Article  CAS  PubMed  Google Scholar 

  39. Edelmann F, Wachter R, Schmidt AG, Aldo-DHF Investigators, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF Randomized Controlled Trial. JAMA. 2013;309:781–91.

    Article  CAS  PubMed  Google Scholar 

  40. Nguyen G. The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology. Curr Opin Nephrol Hypertens. 2007;16(2):129–33.

    Article  CAS  PubMed  Google Scholar 

  41. Nguyen G. Renin, (pro)renin and receptor: an update. Clin Sci (Lond). 2011;120(5):169–78.

    Article  CAS  Google Scholar 

  42. Moilanen AM, Rysa J, Serpi R, et al. (Pro)renin Receptor Triggers Distinct Angiotensin II-Independent Extracellular Matrix Remodeling and Deterioration of Cardiac Function. PLoS One. 2012;7(7):e41404.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515–31.

    Article  CAS  PubMed  Google Scholar 

  44. Seed A, Gardner R, McMurray J, et al. Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail. 2007;9(11):1120–7.

    Article  CAS  PubMed  Google Scholar 

  45. van Esch JH, Moltzer E, van Veghel R, et al. Beneficial cardiac effects of the renin inhibitor aliskiren in spontaneously hypertensive rats. J Hypertens. 2010;28(10):2145–55.

    Article  PubMed  Google Scholar 

  46. Gradman AH, Kad R. Renin inhibition in hypertension. J Am Coll Cardiol. 2008;51(5):519–28. doi:10.1016/j.jacc.2007.10.027.

    Article  CAS  PubMed  Google Scholar 

  47. • Pitt B, Latini R, Maggioni AP, et al. Neurohumoral effects of aliskiren in patients with symptomatic heart failure receiving a mineralocorticoid receptor antagonist: the Aliskiren Observation of Heart Failure Treatment study. Eur J Heart Fail. 2011;13(7):755–64. In patients with HF, the addition of Aliskiren to an ACE inhibitor and beta blocker improved plasma BNP and echocardiographic parameters of left-ventricular remodeling.

    Article  CAS  PubMed  Google Scholar 

  48. • Solomon SD, Shin SH, Shah A, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J. 2011;32(10):1227–34. In patients with LV dysfunction post-MI, the addition of aliskiren to a beta blocker and an ACE inhibitor or ARB did not produce any improvement.

    Article  CAS  PubMed  Google Scholar 

  49. Altitude Trial http://www.novartis.com/newsroom/media-releases/en/2011/1572562.shtml. Accessed June 2013.

  50. • Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;12(23):2204–13. The trial was stopped prematurely after the second interim efficacy analysis on the recommendation of its Data Monitoring Committee after it found an increased occurrence of adverse effects and continuation of the study was deemed “futile.”.

    Article  Google Scholar 

  51. • Gheorghiade M, Böhm M, Greene SJ, et al. Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure: The ASTRONAUT Randomized Trial. JAMA. 2013;309(11):1125–35. Addition of aliskiren to standard therapy did not reduce cardiovascular death or HF rehospitalization after an episode of acute decompensated HF.

    Article  CAS  PubMed  Google Scholar 

  52. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013;12:f360. doi:10.1136/bmj.f360.

    Article  Google Scholar 

  53. EMA. Review started of combined use of renin-angiotensin system (RAS)-acting agents. 2013. May 16; Available at URL: http://www.emea.europa.eu/docs/en_GB/document_library/Referrals_document/Renin-angiotensin_system_(RAS)-acting_agents/Procedure_started/WC500143500.pdf. Accessed 4th September 2013.

  54. Krum H, Massie B, Abraham WT, et al. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study. Eur J Heart Fail. 2011;13(1):107–14.

    Article  CAS  PubMed  Google Scholar 

  55. McMurray JJ, Abraham WT, Dickstein K, Kober L, Massie BM, Krum H. Aliskiren, ALTITUDE, and the implications for ATMOSPHERE. Eur J Heart Fail. 2012;14(4):341–3.

    Article  PubMed  Google Scholar 

  56. Bevan EG, Connell JMC, Doyle J, et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens. 1992;10(7):607–14.

    Article  CAS  PubMed  Google Scholar 

  57. Lang CC, Motwani J, Coutie WJ, Struthers AD. Influence of candoxatril on plasma brain natriuretic peptide in heart failure. Lancet. 1991;338(8761):255.

    Article  CAS  PubMed  Google Scholar 

  58. McDowell G, Coutie W, Shaw C, Buchanan KD, Struthers AD, Nicholls DP. The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides. Br J Clin Pharmacol. 1997;43(3):329–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Kentsch M, Otter W, Drummer C, Notges A, Gerzer R, Muller-Esch G. Neutral endopeptidase 24.11 inhibition may not exhibit beneficial haemodynamic effects in patients with congestive heart failure. Eur J Clin Pharmacol. 1996;51(3–4):269–72.

    Article  CAS  PubMed  Google Scholar 

  60. Corti R, Burnett Jr JC, Rouleau JL, Ruschitzka F, Luscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104(15):1856–62.

    Article  CAS  PubMed  Google Scholar 

  61. Rouleau JL, Pfeffer MA, Stewart DJ, et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet. 2000;356(9230):615–20.

    Article  CAS  PubMed  Google Scholar 

  62. 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 

  63. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11.

    Article  CAS  PubMed  Google Scholar 

  64. 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  CAS  PubMed  Google Scholar 

  65. 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 

  66. Ruilope LM, Dukat A, Böhm M, Lacourcière 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(9722):1255–66.

    Article  CAS  PubMed  Google Scholar 

  67. Kobalava Z, Pavlikova E, Averkov O, et al. First Experience with Concomitant AT1 and Neprilysin (NEP 24.11) Inhibition with LCZ696 in Patients with Chronic Heart Failure. Circulation. 2010;122, A19378.

    Google Scholar 

  68. Paradigm HF Trial http://clinicaltrials.gov/ct2/show/NCT01035255. Accessed June 2013.

  69. 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(9851):1387–95.

    Article  CAS  PubMed  Google Scholar 

  70. • Mearns BM. Heart failure: Phase II PARAMOUNT trial of LCZ696. Nat Rev Cardiol. 2012. In patients with HFpEF, those receiving LCZ696 over Valsartan had reduced plasma NT-proBNP at 12 weeks and NYHA class at 36 weeks.

  71. Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007;157(5):545–59.

    Article  CAS  PubMed  Google Scholar 

  72. Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant. 2013;28(1):36–43.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

Archyut Valluri declares that he has no conflict of interest.

Allan D. Struthers has received compensation from Roche, Pfizer, and Merck for service as a consultant and has received payment for lectures including service on speakers bureaus from Menarini and Pfizer.

Chim C. Lang has received compensation from Novartis for service as a consultant and has received financial support through grants from Novartis and Pfizer.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Division of Cardiovascular & Diabetes Medicine, Mailbox 2, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

    Archyut Valluri, Allan D. Struthers & Chim C. Lang

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  1. Archyut Valluri
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  2. Allan D. Struthers
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Correspondence to Chim C. Lang.

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Valluri, A., Struthers, A.D. & Lang, C.C. Novel Blockers of the Renin-Angiotensin-Aldosterone System in Chronic Heart Failure. Curr Heart Fail Rep 11, 31–39 (2014). https://doi.org/10.1007/s11897-013-0173-5

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