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Unmet Needs and Prioritization in Heart Failure
Journal of Cardiac Failure Vol. 22 No. 8 2016
Editor’s Page
Unmet Needs and Prioritization in Heart Failure LARS H. LUND, MD PHD,1,2 AND PAUL J. HAUPTMAN, MD3 Stockholm, Sweden; and Saint Louis, Missouri
Mortality in Patients With Chronic Heart Failure and Reduced Ejection Fraction (PARADIGM-HF) trial shift focus toward better utilization of generic interventions such as mineralocorticoid receptor antagonists, which are used in minority of patients with HFrEF in both Sweden2 and the United States?5 Should we focus on better monitoring of renal function and potassium, or will novel approaches include “enabling” mineralocorticoid receptor antagonist use by concomitant potassium binding? In contrast, in HF with preserved ejection fraction (HFpEF), and in the emerging concept of a distinct HF with midrange ejection fraction phenotype, innovation is desperately needed, with HFpEF being identified as “the greatest unmet need in cardiovascular medicine.”6 Trials have not produced any convincing evidence supporting the use of conventional neurohormonal antagonist drugs in this syndrome. Did trials study the wrong intervention and wrong pathophysiological target, in which case novel approaches need to be developed? Did trials enroll the wrong patients and study the wrong endpoints, in which case better designed, pragmatic, efficient, and inexpensive trials of existing generic drugs are warranted? Or can we not escape that HFpEF is dominated by age, frailty, and comorbidity and is not amenable to clinically meaningful treatment effects? Finally, acute decompensated HF and, more importantly, the early postdischarge period, are emerging as dominant drivers of poor quality of life, frequent readmissions, and of increasing costs to society. HF is now the most common cause of hospitalization.7 HFpEF, which is not treatable, will soon be the dominant form of HF, and direct costs for HF care are expected to increase 3-fold between 2010 and 2030.8 Novel vasoactive and inotropic agents with pleiotropic and potentially long-term effects are the center of investigation for acute decompensated HF. But is it possible that organizational factors such as early access to specialized hospital care, along the lines of the “time is muscle” concept in acute coronary syndromes, as well as early and structured postdischarge care, potentially with an active treatment component, are more promising approaches to acute HF? Further, it is reasonable to ask if our fragmented health care system is losing track of patient preferences in end-stage HF and end-of-life care? With an aging population, undertreatment of HF risk factors,9 and concerns about increased HF prevalence, we are
At a recent symposium on cardiac resynchronization therapy, one of us (L.H.L.) was introduced to quadripolar pacing leads, considered an important advance and an area of growing educational and promotional effort from industry. As heart failure (HF) clinicians, we could not help but reflect that ensuring access to existing and now inexpensive cardiac resynchronization therapy technology for more patients is just as important as the introduction of novel leads. For example, in Sweden, only about 20% with an indication have a cardiac resynchronization therapy device implanted,1 and less than 10% have an implantable cardioverter-defibrillator.2 Compounding the problem, underutilization of guideline-directed medical therapy for HF before implantable cardioverter-defibrillator implantation has been observed.3,4 In HF with reduced ejection fraction (HFrEF), perhaps implementation science is now becoming more important than innovation science. Indeed, as cardiology in general and HF in particular are becoming increasingly specialized, now with US and European sub-sub-specialty certification in HF, it is useful to step back to consider what the major contemporary unmet needs are in HF. In HFrEF, we have understood that, regardless of underlying etiology, the HF syndrome spontaneously progresses because of compensatory but maladaptive neurohormonal activation, and the era of neurohormonal blockade represents remarkable progress in evidence-based medicine and HF therapy. The introduction of sacubitril/valsartan represents a conceptual shift, instead leveraging endogenous compensatory systems. Will sacubitril/valsartan be broadly implemented, or will concerns over high costs or limited generalizability of the A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and From the 1Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden; 2Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden and 3Saint Louis University School of Medicine, Saint Louis, Missouri. Reprint requests: Lars H. Lund, MD, PhD, Department of Cardiology, Karolinska Institutet, N305, Solna, 171 76 Stockholm, Sweden. Tel: +46 8 51770000; Fax: +46 8 311044. E-mail: [email protected]. See page 588 for disclosure information. 1071-9164/$ - see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2016.06.011
587
588 Journal of Cardiac Failure Vol. 22 No. 8 August 2016 facing more complex challenges, in which better health care integration and resource utilization will be required to move the HF discipline forward. There are, of course, no easy solutions but the time is nigh for us to reassess where we are and where we should be today and in the years to follow. Disclosures No conflicts of interest to declare. References 1. Lund LH, Benson L, Stahlberg M, Braunschweig F, Edner M, Dahlstrom U, et al. Age, prognostic impact of QRS prolongation and left bundle branch block, and utilization of cardiac resynchronization therapy: findings from 14 713 patients in the Swedish Heart Failure Registry. Eur J Heart Fail 2014;16:1073–81. 2. Thorvaldsen T, Benson L, Dahlstrom U, Edner M, Lund LH. Use of evidence-based therapy and survival in heart failure in Sweden 2003–2012. Eur J Heart Fail 2016;18:503–11.
3. Hauptman PJ, Swindle J, Burroughs T. Underutilization of beta blockers in patients undergoing implantable cardioverter defibrillator and cardiac resynchronization procedures. Circ Cardiovasc Qual Outcomes 2010;3:204–11. 4. Roth GA, Poole JE, Zaha R, Zhou W, Skinner J, Morden NE. Use of guideline-directed medications for heart failure before cardioverterdefibrillator implantation. J Am Coll Cardiol 2016;67:1062–9. 5. Hernandez AF, Mi X, Hammill BG, Hammill SC, Heidenreich PA, Masoudi FA, et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction. JAMA 2012;308:2097–107. 6. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, et al. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2014;2:97–112. 7. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33. 8. Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. 9. Cohn J. Trials and tribulations. J Card Fail 2016;22:180–1.
Editor’s Page
Unmet Needs and Prioritization in Heart Failure LARS H. LUND, MD PHD,1,2 AND PAUL J. HAUPTMAN, MD3 Stockholm, Sweden; and Saint Louis, Missouri
Mortality in Patients With Chronic Heart Failure and Reduced Ejection Fraction (PARADIGM-HF) trial shift focus toward better utilization of generic interventions such as mineralocorticoid receptor antagonists, which are used in minority of patients with HFrEF in both Sweden2 and the United States?5 Should we focus on better monitoring of renal function and potassium, or will novel approaches include “enabling” mineralocorticoid receptor antagonist use by concomitant potassium binding? In contrast, in HF with preserved ejection fraction (HFpEF), and in the emerging concept of a distinct HF with midrange ejection fraction phenotype, innovation is desperately needed, with HFpEF being identified as “the greatest unmet need in cardiovascular medicine.”6 Trials have not produced any convincing evidence supporting the use of conventional neurohormonal antagonist drugs in this syndrome. Did trials study the wrong intervention and wrong pathophysiological target, in which case novel approaches need to be developed? Did trials enroll the wrong patients and study the wrong endpoints, in which case better designed, pragmatic, efficient, and inexpensive trials of existing generic drugs are warranted? Or can we not escape that HFpEF is dominated by age, frailty, and comorbidity and is not amenable to clinically meaningful treatment effects? Finally, acute decompensated HF and, more importantly, the early postdischarge period, are emerging as dominant drivers of poor quality of life, frequent readmissions, and of increasing costs to society. HF is now the most common cause of hospitalization.7 HFpEF, which is not treatable, will soon be the dominant form of HF, and direct costs for HF care are expected to increase 3-fold between 2010 and 2030.8 Novel vasoactive and inotropic agents with pleiotropic and potentially long-term effects are the center of investigation for acute decompensated HF. But is it possible that organizational factors such as early access to specialized hospital care, along the lines of the “time is muscle” concept in acute coronary syndromes, as well as early and structured postdischarge care, potentially with an active treatment component, are more promising approaches to acute HF? Further, it is reasonable to ask if our fragmented health care system is losing track of patient preferences in end-stage HF and end-of-life care? With an aging population, undertreatment of HF risk factors,9 and concerns about increased HF prevalence, we are
At a recent symposium on cardiac resynchronization therapy, one of us (L.H.L.) was introduced to quadripolar pacing leads, considered an important advance and an area of growing educational and promotional effort from industry. As heart failure (HF) clinicians, we could not help but reflect that ensuring access to existing and now inexpensive cardiac resynchronization therapy technology for more patients is just as important as the introduction of novel leads. For example, in Sweden, only about 20% with an indication have a cardiac resynchronization therapy device implanted,1 and less than 10% have an implantable cardioverter-defibrillator.2 Compounding the problem, underutilization of guideline-directed medical therapy for HF before implantable cardioverter-defibrillator implantation has been observed.3,4 In HF with reduced ejection fraction (HFrEF), perhaps implementation science is now becoming more important than innovation science. Indeed, as cardiology in general and HF in particular are becoming increasingly specialized, now with US and European sub-sub-specialty certification in HF, it is useful to step back to consider what the major contemporary unmet needs are in HF. In HFrEF, we have understood that, regardless of underlying etiology, the HF syndrome spontaneously progresses because of compensatory but maladaptive neurohormonal activation, and the era of neurohormonal blockade represents remarkable progress in evidence-based medicine and HF therapy. The introduction of sacubitril/valsartan represents a conceptual shift, instead leveraging endogenous compensatory systems. Will sacubitril/valsartan be broadly implemented, or will concerns over high costs or limited generalizability of the A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and From the 1Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden; 2Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden and 3Saint Louis University School of Medicine, Saint Louis, Missouri. Reprint requests: Lars H. Lund, MD, PhD, Department of Cardiology, Karolinska Institutet, N305, Solna, 171 76 Stockholm, Sweden. Tel: +46 8 51770000; Fax: +46 8 311044. E-mail: [email protected]. See page 588 for disclosure information. 1071-9164/$ - see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2016.06.011
587
588 Journal of Cardiac Failure Vol. 22 No. 8 August 2016 facing more complex challenges, in which better health care integration and resource utilization will be required to move the HF discipline forward. There are, of course, no easy solutions but the time is nigh for us to reassess where we are and where we should be today and in the years to follow. Disclosures No conflicts of interest to declare. References 1. Lund LH, Benson L, Stahlberg M, Braunschweig F, Edner M, Dahlstrom U, et al. Age, prognostic impact of QRS prolongation and left bundle branch block, and utilization of cardiac resynchronization therapy: findings from 14 713 patients in the Swedish Heart Failure Registry. Eur J Heart Fail 2014;16:1073–81. 2. Thorvaldsen T, Benson L, Dahlstrom U, Edner M, Lund LH. Use of evidence-based therapy and survival in heart failure in Sweden 2003–2012. Eur J Heart Fail 2016;18:503–11.
3. Hauptman PJ, Swindle J, Burroughs T. Underutilization of beta blockers in patients undergoing implantable cardioverter defibrillator and cardiac resynchronization procedures. Circ Cardiovasc Qual Outcomes 2010;3:204–11. 4. Roth GA, Poole JE, Zaha R, Zhou W, Skinner J, Morden NE. Use of guideline-directed medications for heart failure before cardioverterdefibrillator implantation. J Am Coll Cardiol 2016;67:1062–9. 5. Hernandez AF, Mi X, Hammill BG, Hammill SC, Heidenreich PA, Masoudi FA, et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction. JAMA 2012;308:2097–107. 6. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, et al. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2014;2:97–112. 7. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33. 8. Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. 9. Cohn J. Trials and tribulations. J Card Fail 2016;22:180–1.