Current Controversies and Implications for Clinical Trials

The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with regard to the understanding of heart failure with preserved ejection fraction. Our analysis is based on an expert panel discussion “Think Tank” meeting that included representatives from academia, the National Institutes of Health, the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, and industry. (J Am Coll Cardiol HF 2018;6:619–32) © 2018 by the American College of Cardiology Foundation. A pproximately 6.5 million American adults are estimated to have heart failure (HF), and the number of persons is projected to increase 46% by 2030 (1); approximately one-half of these patients have heart failure with preserved ejection fraction (HFpEF) (2). Perhaps the most agreed-upon characteristic of HFpEF is that a better understanding is needed. Critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in HFpEF. In particular, it remains unknown whether the term HFpEF applies to a single disease state or multiple diseases that are characterized by unique underlying pathophysiologic mechanisms. In this expert panel report, we identify gaps in evidence with regard to the understanding of HFpEF in 3 pivotal areas: 1) definition of the disease; 2) subtypes of HFpEF; and 3) endpoints in HFpEF clinical trials. Our analysis is based on an expert panel discussion “Think Tank” meeting that was hosted by the Duke Clinical Research Institute in Washington, DC, in June 2017, which included representatives from academia, the National Institutes of Health, the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, and industry. In the following discussion, we approach critical HFpEF issues from a variety of perspectives in hopes of elucidating common themes and offering a potential future roadmap for improved HFpEF care (Central Illustration). To focus our discussion and avoid overlap with different disease processes, we do not address the HF patient populations with mid-range ejection fraction (EF) (i.e., 40% to 49%) or recovered EF while considering these issues. IS HFpEF A SINGLE ENTITY? Challenges associated with HFpEF begin with its definition. HFpEF is usually diagnosed after excluding noncardiac causes of dyspnea that can mimic HF, and alternate established diseases with left ventricular EF >50% causing HF symptoms (e.g., constrictive pericarditis, infiltrative cardiomyopathies, isolated right-sided HF, valvular heart disease, non–group 2 pulmonary hypertension [PH]) (3). Early studies of HFpEF focused on 1 or 2 predominant mechanistic pathways, such as diastolic dysfunction (4,5); however, subsequent key studies demonstrated that not only was diastolic dysfunction not ubiquitously present on resting echocardiography in HFpEF, but several other mechanisms were likely implicated, including atrial dysfunction, systolic impairment, ventricular-vascular stiffening, and chronotropic incompetence (6–8). As a result, the definition of HFpEF has evolved over the last 2 decades, moving away from a primary focus on echocardiographic ABBR EV I A T I ON S