Advertisement

Combination Therapy of Renin Angiotensin System Inhibitors and β-Blockers in Patients with Heart Failure

  • Kotaro Nochioka
  • Yasuhiko Sakata
  • Hiroaki Shimokawa
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1067)

Abstract

Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and β-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to β-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and β-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.

Keywords

Angiotensin receptor blocker Angiotensin receptor-neprilysin inhibitor Angiotensin-converting enzyme Direct renin inhibitor Ejection fraction Heart failure Mineralocorticoid receptor antagonist Prognosis Renin-angiotensin-aldosterone system β-blocker 

References

  1. Andrew P (2002) Renin-angiotensin-aldosterone activation in heart failure, aldosterone escape. Chest 122(2):755CrossRefGoogle Scholar
  2. Borghi C, Boschi S, Ambrosioni E, Melandri G, Branzi A, Magnani B (1993) Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol 33(1):40–45CrossRefGoogle Scholar
  3. Carson P, Massie BM, McKelvie R, McMurray J, Komajda M, Zile M et al (2005) The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail 11(8):576–585CrossRefGoogle Scholar
  4. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J et al (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27(19):2338–2345CrossRefGoogle Scholar
  5. Cohn JN, Tognoni G (2001) Valsartan heart failure trial I. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345(23):1667–1675CrossRefGoogle Scholar
  6. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J et al (2012) Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail 14(2):219–225CrossRefGoogle Scholar
  7. Danser AH, van den Meiracker AH (2015) Heart failure: new data do not SUPPORT triple RAAS blockade. Nat Rev Nephrol 11(5):260–262CrossRefGoogle Scholar
  8. Desai AS, Jhund PS (2016) After TOPCAT: what to do now in heart failure with preserved ejection fraction. Eur Heart J 37(41):3135–3140CrossRefGoogle Scholar
  9. Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R et al (2011) Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J 162(6):966–972.e10CrossRefGoogle Scholar
  10. Eichhorn EJ, McGhie AL, Bedotto JB, Corbett JR, Malloy CR, Hatfield BA et al (1991) Effects of bucindolol on neurohormonal activation in congestive heart failure. Am J Cardiol 67(1):67–73CrossRefGoogle Scholar
  11. Filippatos G, Farmakis D, Parissis J, Lekakis J (2015) Drug therapy for patients with systolic heart failure after the PARADIGM-HF trial: in need of a new paradigm of LCZ696 implementation in clinical practice. BMC Med 13:35CrossRefGoogle Scholar
  12. Foody JM, Farrell MH, Krumholz HM (2002) Beta-blocker therapy in heart failure: scientific review. JAMA 287(7):883–889CrossRefGoogle Scholar
  13. Garg R, Yusuf S (1995) Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative group on ACE inhibitor trials. JAMA 273(18):1450–1456CrossRefGoogle Scholar
  14. Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F et al (2013) Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 309(11):1125–1135CrossRefGoogle Scholar
  15. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B et al (2003) 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 362(9386):772–776CrossRefGoogle Scholar
  16. Group CTS (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316(23):1429–1435CrossRefGoogle Scholar
  17. Holmer SR, Hense HW, Danser AH, Mayer B, Riegger GA, Schunkert H (1998) Beta adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics. Heart 80(1):45–48CrossRefGoogle Scholar
  18. Jessup M, Marwick TH, Ponikowski P, Voors AA, Yancy CW (2016) 2016 ESC and ACC/AHA/HFSA heart failure guideline update – what is new and why is it important? Nat Rev Cardiol 13(10):623–628CrossRefGoogle Scholar
  19. Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59(3):251–287CrossRefGoogle Scholar
  20. Krum H, McMurray JJ, Abraham WT, Dickstein K, Kober L, Desai AS et al (2015) The Aliskiren trial to minimize OutcomeS in patients with HEart failure trial (ATMOSPHERE): revised statistical analysis plan and baseline characteristics. Eur J Heart Fail 17(10):1075–1083CrossRefGoogle Scholar
  21. Liu F, Chen Y, Feng X, Teng Z, Yuan Y, Bin J (2014) Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis. PLoS One 9(3):e90555CrossRefGoogle Scholar
  22. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR et al (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359(23):2456–2467CrossRefGoogle Scholar
  23. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL et al (2003) 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 362(9386):767–771CrossRefGoogle Scholar
  24. McMurray JJ, Pitt B, Latini R, Maggioni AP, Solomon SD, Keefe DL et al (2008) Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 1(1):17–24CrossRefGoogle Scholar
  25. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al (2013) 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 15(9):1062–1073CrossRefGoogle Scholar
  26. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004CrossRefGoogle Scholar
  27. McMurray JJ, Krum H, Abraham WT, Dickstein K, Kober LV, Desai AS et al (2016) Aliskiren, Enalapril, or Aliskiren and Enalapril in heart failure. N Engl J Med 374(16):1521–1532CrossRefGoogle Scholar
  28. Miura M, Sakata Y, Miyata S, Shiba N, Takahashi J, Nochioka K et al (2016) Influence of left ventricular ejection fraction on the effects of supplemental use of angiotensin receptor blocker Olmesartan in hypertensive patients with heart failure. Circ J 80(10):2155–2164CrossRefGoogle Scholar
  29. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355(3):251–259CrossRefGoogle Scholar
  30. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM et al (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol heart failure study group. N Engl J Med 334(21):1349–1355CrossRefGoogle Scholar
  31. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P et al (1999a) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353(9146):9–13CrossRefGoogle Scholar
  32. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P et al (1999b) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353(9169):2001–2007CrossRefGoogle Scholar
  33. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P et al (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344(22):1651–1658CrossRefGoogle Scholar
  34. Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86(3):747–803CrossRefGoogle Scholar
  35. Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N et al (2015) Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation 131(1):34–42CrossRefGoogle Scholar
  36. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators. N Engl J Med 341(10):709–717CrossRefGoogle Scholar
  37. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ et al (2000) 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 355(9215):1582–1587CrossRefGoogle Scholar
  38. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370(15):1383–1392CrossRefGoogle Scholar
  39. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ et al (2016a) 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 37(27):2129–2200CrossRefGoogle Scholar
  40. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ et al (2016b) 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 J Heart Fail 18(8):891–975CrossRefGoogle Scholar
  41. Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC et al (2000) Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol 7(7):493–504CrossRefGoogle Scholar
  42. Sakata Y, Nochioka K, Miura M, Takada T, Tadaki S, Miyata S et al (2013) Supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial--rationale and design. J Cardiol 62(1):31–36CrossRefGoogle Scholar
  43. Sakata Y, Shiba N, Takahashi J, Miyata S, Nochioka K, Miura M et al (2015) Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial. Eur Heart J 36(15):915–923CrossRefGoogle Scholar
  44. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E et al (2012) The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 380(9851):1387–1395CrossRefGoogle Scholar
  45. Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J et al (2017) Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial. JACC Heart Fail 5(7):471–482CrossRefGoogle Scholar
  46. SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325(5):293–302CrossRefGoogle Scholar
  47. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A (1981) Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 91(3):457–465CrossRefGoogle Scholar
  48. Struthers AD (2004) The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 6(5):539–545CrossRefGoogle Scholar
  49. Swedberg K, Kjekshus J (1988) Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 62(2):60A–66ACrossRefGoogle Scholar
  50. Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, Ohlin G et al (1999) Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-programme investigators. J Card Fail 5(3):276–282CrossRefGoogle Scholar
  51. The SOLVD Investigators (1990) Studies of left ventricular dysfunction (SOLVD)--rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol 66(3):315–322Google Scholar
  52. van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Babalis D, Roughton M et al (2009) Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure). J Am Coll Cardiol 53(23):2150–2158CrossRefGoogle Scholar
  53. Waagstein F, Hjalmarson AC (1976) Effect of cardioselective beta-blockade on heart function and chest pain in acute myocardial infarction. Acta Med Scand Suppl 587:193–200PubMedGoogle Scholar
  54. Waagstein F, Rutherford JD (2017) The evolution of the use of beta-blockers to treat heart failure: a conversation with Finn Waagstein, MD. Circulation 136(10):889–893CrossRefGoogle Scholar
  55. Waagstein F, Hjalmarson AC, Wasir HS (1974) Apex cardiogram and systolic time intervals in acute myocardial infarction and effects of practolol. Br Heart J 36(11):1109–1121CrossRefGoogle Scholar
  56. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I (1975) Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 37(10):1022–1036CrossRefGoogle Scholar
  57. Weber KT (1999) Aldosterone and spironolactone in heart failure. N Engl J Med 341(10):753–755CrossRefGoogle Scholar
  58. Willenheimer R (2000) Angiotensin receptor blockers in heart failure after the ELITE II trial. Curr Control Trials Cardiovasc Med 1(2):79–82CrossRefGoogle Scholar
  59. Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E, Follath F, Krum H et al (2005) Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 112(16):2426–2435CrossRefGoogle Scholar
  60. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V et al (2003) Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 308(4):698–705CrossRefGoogle Scholar
  61. Writing Committee M, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr et al (2013) 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 128(16):e240–e327CrossRefGoogle Scholar
  62. Yamamoto K, Origasa H, Hori M, Investigators JD (2013) Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail 15(1):110–118CrossRefGoogle Scholar
  63. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM et al (2017) 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 136(6):e137–ee61CrossRefGoogle Scholar
  64. Yandrapalli S, Andries G, Biswas M, Khera S (2017) Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives. Vasc Health Risk Manag 13:369–382CrossRefGoogle Scholar
  65. Yoshikawa T, Port JD, Asano K, Chidiak P, Bouvier M, Dutcher D et al (1996) Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 17(Suppl B):8–16CrossRefGoogle Scholar
  66. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 362(9386):777–781CrossRefGoogle Scholar
  67. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H et al (2011) Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364(1):11–21CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kotaro Nochioka
    • 1
  • Yasuhiko Sakata
    • 1
  • Hiroaki Shimokawa
    • 1
  1. 1.Department of Cardiovascular Medicine and Department of Evidence-based Cardiovascular MedicineTohoku University Graduate School of MedicineSendaiJapan

Personalised recommendations