Medical Treatment of Heart Failure with Reduced Ejection Fraction – Prognostic Indication

Giuseppe Rosano


An up-to-date review on guideline directed medical therapies that aim to improve prognosis in HFrEF patients.  Research on medical interventions that may improve prognosis in patients with chronic heart failure has had great success in the past decades. Therefore, there are well- established classes of drugs – ACEi, beta- blockers, MRAs – that should be used as first line treatment in all patients with heart failure. In the past few years newer therapeutic approaches have been shown to improve prognosis in patients with heart failure but, since the evidence generated by these newer classes of drugs is less than that of the first three classes of drugs these therapies should be implemented only after an initial treatment with the first line drugs has been implemented. This article reviews the advances that have achieved in the treatment of heart failure in terms of a prognostic benefit.


Heart Failure; Guidelines; Prognosis; Therapy

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Ponikowski P, Voors A, Anker S et al The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Journal of Heart Failure. Published online 26 May 2016

Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273:1450 – 1456.

Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF, Ryde´ n L, Thygesen K, Uretsky BF, ATLAS Study Group. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312 – 2318.

SOLVD Investigattors. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293 – 302.

Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, ElAllaf D, V´ıtovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Ja´nosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. MERIT-HF Study Group. 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). JAMA 2000;283:1295 – 1302.

Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651 – 1658.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Rando- mised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001 – 2007.

Packer M. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the Carvedilol Prospective Randomized Cumulative Sur- vival (COPERNICUS) Study. Circulation 2002;106:2194 – 2199.

CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9 – 13.

Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E, Follath F, Krum H, Ponikowski P, Skene A, van de Ven L, Verkenne P, Lechat P, CIBIS III Investigators. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite se- quence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112:2426 – 2435.

Flather MD, Shibata MC, Coats AJS, Van Veldhuisen DJ, Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Boehm M, Anker SD, Thompson SG, Poole-Wilson PA, SENIORS Investigators. Randomized trial to determine the ef- fect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215 – 225.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 – 717.

Zannad F, McMurray JJV, Krum H, Van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11 – 21.

Swedberg K, Komajda M, Boehm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875 – 885.

Swedberg K, Komajda M, Boehm M, Borer J, Robertson M, Tavazzi L, Ford I. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol 2012;59:1938 – 1945.

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993 – 1004.

Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K. 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.

Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667 – 1675.

Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, Prettin C, Putnikovic B, Neskovic AN, Krotin M, Sakac D, Lainscak M, Edelmann F, Wachter R, Rau T, Eschenhagen T, Doehner W, Anker SD, Waagstein F, Herrmann-Lingen C, Gelbrich G, Dietz R; CIBIS-ELD investigators and Project Multicentre Trials in the Competence Network Heart Failure. Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011 Jun;13(6):670-80.

Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JGF, Lip GYH, Coats AJS, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD. Efficacy of b blockers in patients with heart fail- ure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384:2235 – 2243.

Boehm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil J-C, Swedberg K, Tavazzi L. Heart rate at baseline influences the effect of ivab- radine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 2013;102:11 – 22.

Fox K, Komajda M, Ford I, Robertson M, Böhm M, Borer JS, Steg PG, Tavazzi L, Tendera M, Ferrari R, Swedberg K. Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur Heart J. 2013 Aug;34(29):2263-70.

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 Jan 28;346:f360.

Grajek S, Michalak M. The effect of trimetazidine added to pharmacological treatment on all-cause mortality in patients with systolic heart failure. Cardiology. 2015;131(1):22-9.

Zhang L, Lu Y, Jiang H, Zhang L, Sun A, Zou Y, Ge J. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol. 2012 Mar 6;59(10):913-22.

Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011 Feb;97(4):278-86.

Lopatin YM, Rosano GM, Fragasso G, Lopaschuk GD, Seferovic PM, Gowdak LH, Vinereanu D, Hamid MA, Jourdain P, Ponikowski P. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol. 2016 Jan 15;203:909-15.

Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L, Calori G, Kang SM, Sahakyan L, Sanosyan A, Vitale C, Marazzi G, Margonato A, Belardinelli R. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol. 2013 Mar 10;163(3):320-5.

Iyengar SS, Rosano GM. Effect of antianginal drugs in stable angina on predicted mortality risk after surviving a myocardial infarction: a preliminary study (METRO). Am J Cardiovasc Drugs. 2009;9(5):293-7.

Marazzi G, Wajngarten M, Vitale C, Patrizi R, Pelliccia F, Gebara O, Pierri H, Ramires JA, Volterrani M, Fini M, Rosano GM. Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease. Int J Cardiol. 2007 Aug 9;120(1):79-84.

Vitale C, Wajngaten M, Sposato B, Gebara O, Rossini P, Fini M, Volterrani M, Rosano GM. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J. 2004 Oct;25(20):1814-21.

Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A. Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol 2002;82:149 – 158.

Shewan LG, Coats AJS, Henein M. Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015;2:2


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