Canadian Journal of Cardiology
Review| Volume 31, ISSUE 10, P1282-1292, October 2015

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Pharmacologic Options for the Management of Systolic Heart Failure: Examining Underlying Mechanisms

Published:February 19, 2015DOI:


      The optimal management of systolic heart failure includes combination therapy to influence myocardial remodelling favourably by affecting neurohormonal activation and underlying maladaptive pathophysiological pathways. These medications include modulators of the renin-angiotensin-aldosterone system (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists) and β-adrenergic receptor blockers. In addition, an agent with a distinct and complementary mechanism of bradycardic action, the selective pacemaker-current (If) inhibitor ivabradine, provides further reduction of heart rate. Also, a new drug that incorporates neprilysin inhibition combined with angiotensin receptor blockade shows incremental effectiveness. The primary goal of this review is to provide a mechanistic explanation of the complementary role of therapeutic interventions in modulating pathways leading to progressive systolic heart failure. A secondary goal is to summarize the key findings of the pivotal clinical trials that have demonstrated the efficacy of these agents in this population.


      La prise en charge optimale de l’insuffisance cardiaque systolique comprend le traitement combiné pour influencer favorablement le remodelage myocardique en affectant l’activation neurohormonale et les voies physiopathologiques maladaptatives sous-jacentes. Ces médicaments comprennent les modulateurs du système rénine-angiotensine-aldostérone (p. ex. les inhibiteurs de l’enzyme de conversion de l’angiotensine, les antagonistes des récepteurs de l’angiotensine, les antagonistes du récepteur minéralocorticoïde) et les inhibiteurs des récepteurs β-adrénergiques. De plus, un agent ayant un mécanisme d’action bradycardique distinct et complémentaire, l’ivabradine, un inhibiteur sélectif du courant If, réduit davantage la fréquence cardiaque. Également, un nouveau médicament qui combine l’inhibition de la néprilysine au blocage des récepteurs de l’angiotensine montre une efficacité supplémentaire. Le principal objectif de la présente revue est de fournir une explication mécaniste du rôle complémentaire des interventions thérapeutiques dans la modulation des voies menant à l’insuffisance cardiaque systolique. Un objectif secondaire est de résumer les principaux résultats des essais cliniques charnières qui ont démontré l’efficacité de ces agents dans cette population.
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        • Blais C.
        • Dai S.
        • Waters C.
        • et al.
        Assessing the burden of hospitalized and community-care heart failure in Canada.
        Can J Cardiol. 2014; 30: 352-358
        • Chatterjee K.
        • Massie B.
        Systolic and diastolic heart failure: differences and similarities.
        J Card Fail. 2007; 13: 569-576
        • Yeung D.F.
        • Boom N.K.
        • Guo H.
        • et al.
        Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007.
        CMAJ. 2012; 184: 765-773
        • Ezekowitz J.A.
        • Kaul P.
        • Bakal J.A.
        • Quan H.
        • McAlister F.A.
        Trends in heart failure care: has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics?.
        Eur J Heart Fail. 2011; 13: 142-147
        • Go A.S.
        • Mozaffarian D.
        • Roger V.L.
        • et al.
        Heart disease and stroke statistics–2014 update: a report from the American Heart Association.
        Circulation. 2014; 129: e28-e292
        • Heidenreich P.A.
        • Albert N.M.
        • Allen L.A.
        • et al.
        Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association.
        Circ Heart Fail. 2013; 6: 606-619
        • McKelvie R.S.
        • Moe G.W.
        • Ezekowitz J.A.
        • et al.
        The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure.
        Can J Cardiol. 2013; 29: 168-181
        • Swedberg K.
        • Komajda M.
        • Bohm M.
        • et al.
        Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
        • McMurray J.J.
        • Packer M.
        • Desai A.S.
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
      1. McKelvie RS, Moe GW, Ezekowitz JA, et al. Supplemental material for The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Available at: Accessed February 2, 2015.

        • Uehara Y.
        • Miura S.
        • Yahiro E.
        • Saku K.
        Non-ACE pathway-induced angiotensin II production.
        Curr Pharm Des. 2013; 19: 3054-3059
      2. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
        N Engl J Med. 1987; 316: 1429-1435
      3. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
        N Engl J Med. 1991; 325: 293-302
        • Konstam M.A.
        • Rousseau M.F.
        • Kronenberg M.W.
        • 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: 431-438
        • Pfeffer M.A.
        • Braunwald E.
        • Moye L.A.
        • et al.
        Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
        N Engl J Med. 1992; 327: 669-677
      4. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
        Lancet. 1993; 342: 821-828
        • Kober L.
        • Torp-Pedersen C.
        • Carlsen J.E.
        • et al.
        A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
        N Engl J Med. 1995; 333: 1670-1676
        • Flather M.D.
        • Yusuf S.
        • Kober L.
        • et al.
        Long-term ACE inhibitor therapy in patients with heart failure or left ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.
        Lancet. 2000; 355: 1575-1581
        • Gibbs C.R.
        • Blann A.D.
        • Watson R.D.
        • Lip G.Y.
        Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.
        Circulation. 2001; 103: 1746-1751
        • McMurray J.
        The role of angiotensin II receptor blockers in the management of heart failure.
        Eur Heart J Suppl. 2005; 7: J10-J14
        • Su J.B.
        • Barbe F.
        • Houel R.
        • et al.
        Preserved vasodilator effect of bradykinin in dogs with heart failure.
        Circulation. 1998; 98: 2911-2918
        • Dzau V.J.
        Tissue renin-angiotensin system in myocardial hypertrophy and failure.
        Arch Intern Med. 1993; 153: 937-942
        • Grassi G.
        • Cattaneo B.M.
        • Seravalle G.
        • et al.
        Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure.
        Circulation. 1997; 96: 1173-1179
        • Dibner-Dunlap M.E.
        • Smith M.L.
        • Kinugawa T.
        • Thames M.D.
        Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure.
        J Am Coll Cardiol. 1996; 27: 358-364
        • Hornig B.
        • Arakawa N.
        • Haussmann D.
        • Drexler H.
        Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure.
        Circulation. 1998; 98: 2842-2848
        • Varin R.
        • Mulder P.
        • Tamion F.
        • et al.
        Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure: role of nitric oxide, prostanoids, oxidant stress, and bradykinin.
        Circulation. 2000; 102: 351-356
        • Gullestad L.
        • Aukrust P.
        • Ueland T.
        • et al.
        Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.
        J Am Coll Cardiol. 1999; 34: 2061-2067
        • Vaughan D.E.
        • Rouleau J.L.
        • Ridker P.M.
        • et al.
        Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators.
        Circulation. 1997; 96: 442-447
        • Goodfield N.E.
        • Newby D.E.
        • Ludlam C.A.
        • Flapan A.D.
        Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure.
        Circulation. 1999; 99: 2983-2985
        • Guazzi M.
        • Marenzi G.
        • Alimento M.
        • Contini M.
        • Agostoni P.
        Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin.
        Circulation. 1997; 95: 1930-1936
        • Abdulla J.
        • Abildstrom S.Z.
        • Christensen E.
        • Kober L.
        • Torp-Pedersen C.
        A meta-analysis of the effect of angiotensin-converting enzyme inhibitors on functional capacity in patients with symptomatic left ventricular systolic dysfunction.
        Eur J Heart Fail. 2004; 6: 927-935
        • Zannad F.
        • Gattis Stough W.
        • Rossignol P.
        • et al.
        Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.
        Eur Heart J. 2012; 33: 2782-2795
        • Giannattasio C.
        • Achilli F.
        • Failla M.
        • et al.
        Radial, carotid and aortic distensibility in congestive heart failure: effects of high-dose angiotensin-converting enzyme inhibitor or low-dose association with angiotensin type 1 receptor blockade.
        J Am Coll Cardiol. 2002; 39: 1275-1282
        • Udelson J.E.
        • Konstam M.A.
        Relation between left ventricular remodeling and clinical outcomes in heart failure patients with left ventricular systolic dysfunction.
        J Card Fail. 2002; 8: S465-S471
        • Pfeffer M.A.
        • McMurray J.J.V.
        • Velazquez E.J.
        • et al.
        Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
        N Engl J Med. 2003; 349: 1893-1906
        • Pfeffer M.A.
        • Swedberg K.
        • Granger C.B.
        • et al.
        Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
        Lancet. 2003; 362: 759-766
        • Granger C.B.
        • McMurray J.J.
        • 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: 772-776
        • McMurray J.J.
        • 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: 767-771
        • Yusuf S.
        • Pfeffer M.A.
        • Swedberg K.
        • et al.
        Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
        Lancet. 2003; 362: 777-781
        • Arnold J.M.
        • Parker J.
        • Howlett J.
        • et al.
        Current treatment in hospital based outpatient heart failure clinics: the Canadian CHF Clinics Network initial experience.
        Eur J Heart Fail. 2000; 2: 23
        • Cohn J.N.
        • Tognoni G.
        A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
        N Engl J Med. 2001; 345: 1667-1675
        • Heran B.S.
        • Musini V.M.
        • Bassett K.
        • Taylor R.S.
        • Wright J.M.
        Angiotensin receptor blockers for heart failure.
        Cochrane Database Syst Rev. 2012; 4: Cd003040
        • Hunt S.A.
        • Baker D.W.
        • Chin M.H.
        • et al.
        ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure).
        J Am Coll Cardiol. 2001; 38: 2101-2113
        • McKelvie R.S.
        • Rouleau J.L.
        • White M.
        • et al.
        Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure.
        Eur Heart J. 2003; 24: 1727-1734
        • Pitt B.
        • Zannad F.
        • Remme W.J.
        • 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: 709-717
        • 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: 1309-1321
        • Zannad F.
        • McMurray J.J.V.
        • Krum H.
        • et al.
        Eplerenone in patients with systolic heart failure and mild symptoms.
        N Engl J Med. 2011; 364: 11-21
        • Bunda S.
        • Wang Y.
        • Mitts T.F.
        • et al.
        Aldosterone stimulates elastogenesis in cardiac fibroblasts via mineralocorticoid receptor-independent action involving the consecutive activation of G alpha13, c-Src, the insulin-like growth factor-I receptor, and phosphatidylinositol 3-kinase/Akt.
        J Biol Chem. 2009; 284: 16633-16647
        • Zannad F.
        • Alla F.
        • Dousset B.
        • Perez A.
        • Pitt B.
        Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.
        Circulation. 2000; 102: 2700-2706
        • Macdonald J.E.
        • Kennedy N.
        • Struthers A.D.
        Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment.
        Heart. 2004; 90: 765-770
        • Shah N.C.
        • Pringle S.D.
        • Donnan P.T.
        • Struthers A.D.
        Spironolactone has antiarrhythmic activity in ischaemic cardiac patients without cardiac failure.
        J Hypertens. 2007; 25: 2345-2351
        • Yee K.M.
        • Pringle S.D.
        • Struthers A.D.
        Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure.
        J Am Coll Cardiol. 2001; 37: 1800-1807
        • Hayashi M.
        • Tsutamoto T.
        • Wada A.
        • et al.
        Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction.
        Circulation. 2003; 107: 2559-2565
        • Li X.
        • Qi Y.
        • Li Y.
        • et al.
        Impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction: a meta-analysis of randomized controlled trials.
        Circ Heart Fail. 2013; 6: 156-165
        • Packer M.
        • Bristow M.R.
        • Cohn J.N.
        • et al.
        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. 1996; 334: 1349-1355
      5. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
        Lancet. 1999; 353: 9-13
        • Hjalmarson A.
        • Goldstein S.
        • Fagerberg B.
        • et al.
        Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.
        JAMA. 2000; 283: 1295-1302
        • Packer M.
        • Fowler M.B.
        • Roecker E.B.
        • et al.
        Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
        Circulation. 2002; 106: 2194-2199
        • Cullington D.
        • Goode K.M.
        • Clark A.L.
        • Cleland J.G.
        Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target?.
        Eur J Heart Fail. 2012; 14: 737-747
        • Bristow M.R.
        Treatment of chronic heart failure with β-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology.
        Circ Res. 2011; 109: 1176-1194
        • Flannery G.
        • Gehrig-Mills R.
        • Billah B.
        • Krum H.
        Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers.
        Am J Cardiol. 2008; 101: 865-869
        • McAlister F.A.
        • Wiebe N.
        • Ezekowitz J.A.
        • Leung A.A.
        • Armstrong P.W.
        Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure.
        Ann Intern Med. 2009; 150: 784-794
        • Swedberg K.
        • Komajda M.
        The beat goes on: on the importance of heart rate in chronic heart failure.
        Eur Heart J. 2012; 33: 1044-1045
        • Reil J.C.
        • Custodis F.
        • Swedberg K.
        • et al.
        Heart rate reduction in cardiovascular disease and therapy.
        Clin Res Cardiol. 2011; 100: 11-19
        • Katz A.M.
        Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure.
        N Engl J Med. 1990; 322: 100-110
        • Habal M.V.
        • Liu P.P.
        • Austin P.C.
        • et al.
        Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure.
        Circ Heart Fail. 2014; 7: 12-20
        • Logeart D.
        • Seronde M.F.
        • Degroote P.
        • et al.
        Raised heart rate at discharge after acute heart failure is an independent predictor of one-year mortality.
        Eur Heart J. 2012; 33 ([abstract P2775]): 485
        • Greene S.J.
        • Vaduganathan M.
        • Wilcox J.E.
        • et al.
        The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial.
        JACC Heart Fail. 2013; 1: 488-496
        • Castagno D.
        • Skali H.
        • Takeuchi M.
        • et al.
        Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program.
        J Am Coll Cardiol. 2012; 59: 1785-1795
        • Bohm M.
        • Swedberg K.
        • Komajda M.
        • et al.
        Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.
        Lancet. 2010; 376: 886-894
        • McMurray J.J.
        • Adamopoulos S.
        • Anker S.D.
        • 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: 803-869
      6. National Heart Foundation of Australia. Guidelines for the prevention, detection, and management of chronic heart failure in Australia. Available at: Accessed February 2, 2015.

        • Borer J.S.
        • Bohm M.
        • Ford I.
        • et al.
        Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study.
        Eur Heart J. 2012; 33: 2813-2820
        • Ekman I.
        • Chassany O.
        • Komajda M.
        • et al.
        Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study.
        Eur Heart J. 2011; 32: 2395-2404
        • DiFrancesco D.
        • Camm J.A.
        Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease.
        Drugs. 2004; 64: 1757-1765
        • Ferrari R.
        Ivabradine: heart rate and left ventricular function.
        Cardiology. 2014; 128: 226-230
        • Tardif J.C.
        • O'Meara E.
        • Komajda M.
        • et al.
        Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy.
        Eur Heart J. 2011; 32: 2507-2515
        • Fang Y.
        • Debunne M.
        • Vercauteren M.
        • et al.
        Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.
        J Cardiovasc Pharmacol. 2012; 59: 260-267
        • Langenickel T.H.
        • Dole W.P.
        Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure.
        Drug Discov Today. 2012; 9: e131-e139