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

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Heart Failure: From Research to Clinical Practice

Part of the book series: Advances in Experimental Medicine and Biology ((AIM,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.

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References

  • Andrew P (2002) Renin-angiotensin-aldosterone activation in heart failure, aldosterone escape. Chest 122(2):755

    Article  PubMed  Google Scholar 

  • 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):40–45

    Article  CAS  PubMed  Google Scholar 

  • 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):576–585

    Article  CAS  PubMed  Google Scholar 

  • 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):2338–2345

    Article  CAS  PubMed  Google Scholar 

  • 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):1667–1675

    Article  CAS  PubMed  Google Scholar 

  • 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):219–225

    Article  CAS  PubMed  Google Scholar 

  • Danser AH, van den Meiracker AH (2015) Heart failure: new data do not SUPPORT triple RAAS blockade. Nat Rev Nephrol 11(5):260–262

    Article  CAS  PubMed  Google Scholar 

  • Desai AS, Jhund PS (2016) After TOPCAT: what to do now in heart failure with preserved ejection fraction. Eur Heart J 37(41):3135–3140

    Article  PubMed  Google Scholar 

  • 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.e10

    Article  CAS  PubMed  Google Scholar 

  • 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):67–73

    Article  CAS  PubMed  Google Scholar 

  • 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 13:35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foody JM, Farrell MH, Krumholz HM (2002) Beta-blocker therapy in heart failure: scientific review. JAMA 287(7):883–889

    Article  CAS  PubMed  Google Scholar 

  • 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):1450–1456

    Article  CAS  PubMed  Google Scholar 

  • 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):1125–1135

    Article  CAS  PubMed  Google Scholar 

  • 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):772–776

    Article  CAS  PubMed  Google Scholar 

  • 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):1429–1435

    Article  Google Scholar 

  • 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):45–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):623–628

    Article  PubMed  Google Scholar 

  • 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):251–287

    Article  CAS  PubMed  Google Scholar 

  • 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):1075–1083

    Article  CAS  PubMed  Google Scholar 

  • 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):e90555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2456–2467

    Article  CAS  Google Scholar 

  • 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):767–771

    Article  CAS  PubMed  Google Scholar 

  • 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):17–24

    Article  CAS  PubMed  Google Scholar 

  • 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):1062–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):993–1004

    Article  CAS  PubMed  Google Scholar 

  • 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):1521–1532

    Article  CAS  PubMed  Google Scholar 

  • 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):2155–2164

    Article  CAS  PubMed  Google Scholar 

  • 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):251–259

    Article  CAS  PubMed  Google Scholar 

  • 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):1349–1355

    Article  CAS  PubMed  Google Scholar 

  • 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):9–13

    Article  Google Scholar 

  • 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):2001–2007

    Article  Google Scholar 

  • 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):1651–1658

    Article  CAS  PubMed  Google Scholar 

  • Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86(3):747–803

    Article  CAS  PubMed  Google Scholar 

  • 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):34–42

    Article  CAS  PubMed  Google Scholar 

  • 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):709–717

    Article  CAS  PubMed  Google Scholar 

  • 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):1582–1587

    Article  CAS  PubMed  Google Scholar 

  • 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):1383–1392

    Article  CAS  Google Scholar 

  • 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):2129–2200

    Article  Google Scholar 

  • 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):891–975

    Article  PubMed  Google Scholar 

  • 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):493–504

    Article  CAS  PubMed  Google Scholar 

  • 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):31–36

    Article  PubMed  Google Scholar 

  • 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):915–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1387–1395

    Article  CAS  PubMed  Google Scholar 

  • 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):471–482

    Article  PubMed  Google Scholar 

  • 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):293–302

    Article  Google Scholar 

  • 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):457–465

    Article  CAS  PubMed  Google Scholar 

  • Struthers AD (2004) The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 6(5):539–545

    Article  CAS  PubMed  Google Scholar 

  • 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–66A

    Article  CAS  PubMed  Google Scholar 

  • 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):276–282

    Article  CAS  PubMed  Google Scholar 

  • 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):315–322

    Google Scholar 

  • 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):2150–2158

    Article  CAS  Google Scholar 

  • Waagstein F, Hjalmarson AC (1976) Effect of cardioselective beta-blockade on heart function and chest pain in acute myocardial infarction. Acta Med Scand Suppl 587:193–200

    PubMed  CAS  Google Scholar 

  • 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):889–893

    Article  PubMed  Google Scholar 

  • 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):1109–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I (1975) Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 37(10):1022–1036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weber KT (1999) Aldosterone and spironolactone in heart failure. N Engl J Med 341(10):753–755

    Article  CAS  PubMed  Google Scholar 

  • Willenheimer R (2000) Angiotensin receptor blockers in heart failure after the ELITE II trial. Curr Control Trials Cardiovasc Med 1(2):79–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2426–2435

    Article  CAS  PubMed  Google Scholar 

  • 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):698–705

    Article  CAS  PubMed  Google Scholar 

  • 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–e327

    Article  Google Scholar 

  • 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):110–118

    Article  CAS  PubMed  Google Scholar 

  • 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–ee61

    Article  PubMed  Google Scholar 

  • 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 13:369–382

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):8–16

    Article  CAS  PubMed  Google Scholar 

  • 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):777–781

    Article  CAS  Google Scholar 

  • 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):11–21

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Cardiovascular Medicine and Department of Evidence-based Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

    Kotaro Nochioka, Yasuhiko Sakata & Hiroaki Shimokawa

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  1. Kotaro Nochioka
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  2. Yasuhiko Sakata
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  3. Hiroaki Shimokawa
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Correspondence to Hiroaki Shimokawa .

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  1. Department of Clinical Sciences and Education, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

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Nochioka, K., Sakata, Y., Shimokawa, H. (2018). Combination Therapy of Renin Angiotensin System Inhibitors and β-Blockers in Patients with Heart Failure. In: Islam, M. (eds) Heart Failure: From Research to Clinical Practice. Advances in Experimental Medicine and Biology(), vol 1067. Springer, Cham. https://doi.org/10.1007/5584_2018_179

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  • DOI: https://doi.org/10.1007/5584_2018_179

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