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Heart Failure: A Major Management Challenge With Encouraging Recent Progress

Published:September 23, 2015DOI:https://doi.org/10.1016/j.clinthera.2015.08.020
      Heart failure is a major health problem, affecting an estimated 38 million persons worldwide, accounting for more than a million hospital admissions per year in the United States and Europe, and carrying a prognosis worse than many cancers.
      • Braunwald E.
      The war against heart failure: the Lancet lecture.
      Although it has been commonly assumed that most patients with cardiac failure have reduced left ventricular function (referred to as heart failure with reduced ejection fraction [HFrEF]), there is increasing evidence that many patients can have symptoms and signs of cardiac failure with normal left ventricular function (heart failure with preserved ejection fraction [HFpEF]).
      • Roger V.L.
      Epidemiology of heart failure.
      With increasing understanding of the important role of the adverse effect of neurohumoral factors in heart failure, the focus of pharmacologic attention has moved away from the seemingly logical task of stimulating the heart with inotropic agents
      • Francis G.S.
      • Bartos J.A.
      • Adatya S.
      Inotropes.
      to blocking the neurohumoral mediators of the syndrome. Although recent development of innovative approaches to inotropic therapy with inodilation with calcium-sensitizing therapy in with levosimendan
      • Lim J.Y.
      • Deo S.V.
      • Rababa’h A.
      • et al.
      Levosimendan Reduces Mortality in Adults with Left Ventricular Dysfunction Undergoing Cardiac Surgery: A Systematic Review and Meta-analysis.
      and omecantiv mecarbil
      • Cleland J.G.
      • Teerlink J.R.
      • Senior R.
      • et al.
      The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.
      may yet have the potential to improve systolic performance without increasing the heart’s demand for energy, advances in other areas of drug, device, and transplant currently occupy prominence in heart failure management. This Special Issue reviews these exciting recent advances in the treatment of heart failure.

      Beyond Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

      The role of the renin-angiotensin-aldosterone system (RAAS) inhibitors is also widely accepted, with an extensive evidence base justifying cornerstone status in the treatment of HFrEF.
      • McMurray J.J.
      Consensus to emphasis: The overwhelming evidence which makes blockade of the renin-angiotensin-aldosterone system the cornerstone of therapy for systolic heart failure.
      In the most recent meta-analysis of 54,621 patients with heart failure in randomized clinical trials, RAAS inhibition reduced the risks of hospitalization for heart failure by 20%, cardiovascular mortality by 14%, and all-cause mortality by 11%. The effect was less definite in patients whose ejection fractions were not markedly depressed or normal.
      • Emdin C.A.
      • Callender T.
      • Cao J.
      • et al.
      Meta-Analysis of Large-Scale Randomized Trials to Determine the Effectiveness of Inhibition of the Renin-Angiotensin Aldosterone System in Heart Failure.
      Whether angiotensin receptor blockers (ARBs) should be favored over angiotensin-converting enzyme inhibitors (ACEis) in the treatment of heart failure because of their better side effects profile remains unclear. The most recent Cochrane review
      • Heran B.S.
      • Musini V.M.
      • Bassett K.
      • et al.
      Angiotensin receptor blockers for heart failure.
      on this topic concluded that ARBs do not reduce total mortality or morbidity compared with ACEis, and recent guidelines recommend that the primary choice of RAAS inhibitor in heart failure remains an ACEi, limiting the use of ARBs to patients who are intolerant of ACEis.
      • Hunt S.A.
      • Abraham W.T.
      • Chin M.H.
      • et al.
      2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.
      • McMurray J.J.
      • Adamopoulos S.
      • Anker S.D.
      • et al.
      Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 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.
      Inhibition of aldosterone in heart failure is an increasingly discussed target, not only because it can overcome fluid retention but also because the prospect of inhibiting direct adverse effects of aldosterone on the failing myocardium is alluring. Of the 2 aldosterone antagonists, spironolactone is universally available, and use of eplerenone is restricted in some countries. A concern with hyperkalemia with these drugs is well recognized.
      • Juurlink D.N.
      • Mamdani M.M.
      • Lee D.S.
      • et al.
      Rates of hyperkalemia after publication of the randomized aldactone evaluation study.
      However, in recent trials of eplerenone, hyperkalemia was infrequent and not associated with any mortality.
      • Pitt B.
      • Remme W.
      • Zannad F.
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      EMPHASIS-HF Study Group
      Eplerenone in patients with systolic heart failure and mild symptoms.
      Direct renin inhibitors have been used in an attempt to modulate the damaging effects of renin; however, a large trial of aliskrein added to standard therapy in heart failure was disappointing.
      • Gheorghiade M.
      • Böhm M.
      • Greene S.J.
      • et al.
      ASTRONAUT Investigators and Coordinators
      Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial.
      A new study of aliskrein in combination with enalapril and direct comparison of aliskrein and enalapril is currently under way.
      • Krum H.
      • Massie B.
      • Abraham W.T.
      • et al.
      ATMOSPHERE Investigators
      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.

      Combined Angiotensin Receptor-Neprilyisin Inhibition

      Undoubtedly, the hottest news in the treatment of HFrEF in the past decade has been the September 2014 publication of the PARADIGM (Prospective Comparison of ARNI with ACEi) trial.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      PARADIGM-HF Investigators and Committees
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      In this study, a combined angiotensin receptor–neprilysin inhbitor (ARNi) (LCZ696, the first of a new class of drug) was compared with an ACEi (enalapril).
      The strongly positive results have generated positive commentary on this trial. The accompanying New England Journal of Medicine editorial suggested that the PARADIGM trial “may well represent a new threshold of hope for patients with heart failure.”
      • Jessup M.
      Neprilysin inhibition--a novel therapy for heart failure.
      The development of the research leading to this trial has been lucidly described recently
      • Braunwald E.
      The path to an Angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure.
      and analyzed in detail by Peter MacDonald in this Special Issue.
      • MacDonald P.S.
      Combined Angiotensin Receptor and Neprilysin Antagonists (ARNI): a new paradigm in the management of chronic heart failure.
      The combination of ARNis used in PARADIGM no doubt presages the development of other ARNis for the treatment of cardiac failure.

      New Data on β-Blockers and Heart Rate Slowing

      Although the role of β-blockers in the treatment of HFrEF is now well established,
      • Chatterjee S.
      • Biondi-Zoccai G.
      • Abbate A.
      Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis.
      the choice of β-blocker in individual patients can be a challenging decision for the clinician. With the extensive evidence base for the use of β-blockers in heart failure,
      • Chatterjee S.
      • Biondi-Zoccai G.
      • Abbate A.
      • et al.
      Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis.
      it came as a surprise when an analysis of the treatment of cardiac failure revealed that β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm but not in patients with atrial fibrillation.
      • Kotecha D.
      • Holmes J.
      • Krum H.
      Beta-Blockers in Heart Failure Collaborative Group
      Efficacy of β-blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis.
      The reasons for apparent lack of benefit of β-blockers in atrial fibrillation is still being analyzed, but the data are discussed in detail by Yura Mareev and John Cleland in this Special Issue of Clinical Therapeutics.

      Device Therapy

      The role of device therapy in the treatment of cardiac failure is evolving rapidly and becoming an essential part of the mainstream of therapy for cardiac failure. James Marangou and Vince Paul review the evidence for the use of device therapies in heart failure and the challenges in the choice of device for individual patients.
      • Paul V.
      Review of device therapy in heart failure.
      They review the strengthening evidence for the value of implantable cardioverter defibrillator therapy in patients with reduced left ventricular function and heart failure and clarify the role of cardiac resynchronization therapy in patients with heart failure and a wide QRS complex. The exciting developments in miniaturization of implantable cardioverter defibrillator and the prospect of remote monitoring of the patient’s hemodynamic status indicate an even more important role for devices in the future management of patients with heart failure.

      Cardiac Transplant

      Despite the major advances in drug therapy and devices, cardiac transplant remains an essential resource in the modern management of advanced heart failure. However, there are many limitations to its wide application, including a limited supply of donor organs. Recent advances are reviewed by Andrew Jabbour and Peter MacDonald.
      • MacDonald P.
      Review of Cardiac Transplantation.
      The significant advances in donor organ preservation, limitation of ischemia and reperfusion injury, patient selection, and immunosuppression, which they review, are likely to increase the number of heart transplants and improve outcomes for recipients.

      Progress in HFPEF

      Shane Nanayakkara and David Kaye
      • Kaye D.
      Review of HFpEF.
      review the recent evidence on the causes and treatment of HFpEF. The striking feature of this condition is that it is so common, with 50% of patients diagnosed as having heart failure having a normal or near normal ejection fraction.
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • et al.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      Despite intensive research, clinically available treatments remain limited to control of fluid retention and blood pressure. Of the many approaches being explored, antifibrotic agents carry much hope, although the results of initial trials were limited in their success.
      • Teerlink J.R.
      • Cotter G.
      • Davison B.A.
      • et al.
      Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.

      The Role of The Multidisciplinary Team

      Trish Davidson and colleagues review the evidence for how a multidisciplinary management approach to the management of heart failure can provide patient benefits additional to drug and device therapy. Although there have been many clinical trials to assess multidisciplinary care, the overall consensus is of clear benefit, although the heterogeneity of the studies makes it difficult to quantify the benefit.
      • Savard L.A.
      • Thompson D.R.
      • Clark A.M.
      A meta-review of evidence on heart failure disease management programs: the challenges of describing and synthesizing evidence on complex interventions.
      Applying the trial results outside academic health centers in the most effective way to enhance management of congestive heart failure to enhance outcomes is a system-wide challenge that requires efficient integration of cardiology and primary care.
      • Davidson P.
      Multidisciplinary teams in HF management.

      Conclusion

      Although heart failure still has a dire prognosis, recent advances in drug and device therapy have improved the outcome for many patients. It is likely that ARNIs will take their place alongside β-blockers, ACEis, and ARBs in drug therapy. There is more convincing evidence of progress in HFrEF than HFpEF. Modern device therapy is now an integral part of therapy. Heart transplant retains a crucial place in the treatment of advanced heart failure while its role is changing with the development of newer circulatory assist devices. Evolving approaches to multidisciplinary management enhance outcomes of drug and device therapy.

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