Author + information
- Scott D. Solomon, MD∗ ( and )
- Akshay S. Desai, MD, MPH
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Recent updates to clinical guidelines (1,2) underscore the considerable progress that has been made in the development of effective therapy for ambulatory patients with chronic HF (HF) and reduced ejection fraction. The expanding arsenal of therapies proven to reduce morbidity and mortality in chronic HF and reduced ejection fraction has only served to underscore the lack of effective treatments for patients with HF and “preserved” ejection fraction and those with acute decompensated HF.
Irrespective of ejection fraction, hospitalization for acute decompensated HF is recognized as a sentinel event in the life cycle of patients with HF, bringing a high risk for recurrent hospitalization (nearly 50% at 6 months) and a 1-year risk for mortality of nearly 30% (3,4). Heart failure is already the leading cause of hospitalization in the Medicare-eligible population, and the burden of HF admissions is projected to increase over time, with staggering implications for overall health care costs. Recognizing the need to improve management of acute HF syndrome, treatment guidelines have been published (2,5), but few randomized controlled trial data are available to support the recommendations. Most attempts at pharmacological therapy of acute decompensated HF have failed to meaningfully influence rates of death or hospital readmission and, accordingly, management of acute HF syndromes remains largely empiric and consensus-driven.
A central challenge in the design of effective clinical trials for acute HF is that there is no generally agreed taxonomy for HF syndromes requiring hospitalization. Accordingly, patients with diverse pathophysiology and risk for adverse outcomes are typically grouped as a single entity, with the predictable result that any signal of treatment benefit is diluted by the noise of disease heterogeneity. In this issue of the Journal, Greene et al. (6) present a secondary analysis of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial examining differences in the clinical characteristics and outcomes of 2 important subsets of patients with acute decompensated HF: those with a de novo presentation or recent diagnosis of HF and those with acute worsening of chronic HF of longer duration. Of the 7,141 patients across the spectrum of ejection fraction hospitalized with acute decompensated HF and randomized to treatment with nesiritide or placebo in ASCEND-HF, the duration of HF before randomization was reported by investigators in 5,741 (80.4%) patients. The 1,536 enrolled subjects for whom HF was reported as recently diagnosed (within 30 days of the index HF admission) were more likely to be women with nonischemic heart disease, higher ejection fraction, higher baseline blood pressure, better renal function, and fewer comorbidities than those with HF of longer duration. Despite adjustment for these lower risk features, patients with recently diagnosed HF had better prognosis than those with longer duration HF, with less dyspnea reported at 24 h and lower rates of mortality at 180 days. Differences between recent-onset HF and worsening of chronic HF were consistent in subgroups defined according to age, race, HF etiology, and ejection fraction. There was a nominal statistical interaction according to sex, suggesting a more pronounced association between HF duration and 180-day mortality in women than in men.
A few caveats are important to note. First, data regarding the duration of HF were derived from unvalidated investigator reports and were unavailable for nearly 20% of patients (6). Although the patients with missing data did not systematically differ from those included in the study, it is difficult to exclude residual confounding by selection bias. Second, hospitalization outcomes were adjudicated only to 30 days’ post-discharge, limiting the power to infer differences in readmission rates according to HF duration. Finally, it remains unclear whether a different threshold for “recent” onset might have altered the results. Among those with HF duration >30 days, there was no clear, graded relationship between HF duration and clinical outcomes; thus, it would seem that the most relevant distinction may be between hospitalization for onset of truly “new” HF (a de novo diagnosis) and worsening of established HF.
Despite these limitations, the data of Greene et al. (6) highlight that the subset of patients who are newly or recently diagnosed is a potentially distinct and lower risk phenotype of acute HF from the balance of patients with acute exacerbations of chronic or established disease. Intuitively, this theory makes sense, because those hospitalized with worsening HF represent patients with disease progression despite application of effective therapy, whereas those with new-onset disease may be treatment naive and might be stabilized with appropriate medical therapy. The implication is that HF hospitalization is a more efficient discriminator of risk in patients with an established HF diagnosis than in those with newly identified disease and that the response to therapy might similarly vary in these populations. As the authors note, these data complement evolving evidence that worsening of chronic HF may have similar prognostic implications when it is documented in the ambulatory setting as in situations when it provokes the need for hospital admission (7). The data argue for more careful segmentation of the acute HF population at the time of trial entry, as well as a more thorough ascertainment of worsening HF endpoints, independent of the treatment context in which they occur.
Importantly, these data represent only one step toward a more granular classification of acute HF syndromes. Current guidelines postulate that there may be value to further subcategorization of patients based on hemodynamic profiles at presentation, admitting blood pressure, precipitating factors (e.g., acute coronary syndrome, arrhythmias, valvular disease, pulmonary embolism), and clinical features (e.g., the presence or absence of pulmonary edema); however, none of these designations has been systematically used in the design of clinical trials of novel therapeutics in practice. Expanding ambulatory alternatives to hospitalization for the management of patients with HF and worsening congestion mean that hospitalization is no longer a sufficient surrogate for identifying patients with worsening HF, whatever the etiology. Real progress in the effective treatment of acute decompensated HF may rely on a taxonomy that is driven by meaningful pathophysiological distinctions and is agnostic to the location in which care happens to be delivered.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Desai has received consulting fees and research grants from Novartis; and consulting fees from AstraZeneca, Abbott, Relypsa, Janssen, and Sanofi. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, Theracos; and is a consultant for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos.
- 2017 American College of Cardiology Foundation
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