Author + information
- Published online November 13, 2017.
- Benjamin A. Steinberg, MD, MHS∗ ( and )
- James C. Fang, MD
- Division of Cardiovascular Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah
- ↵∗Address for correspondence:
Dr. Benjamin A. Steinberg, Division of Cardiovascular Medicine, University of Utah Health Sciences Center, 30 North 1900 East, Room 4A100, Salt Lake City, Utah 84132.
The treatment of chronic heart failure (HF) has yielded significant improvements in outcomes for many patients over the last 30 years, although the majority of these advances have been in the therapy for heart failure with reduced ejection (HFrEF) (1,2). This momentum continues; the novel agent sacubitril/valsartan reduced cardiovascular mortality another 16% when compared with traditional optimal medical therapy for HFrEF in the landmark PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (3). However, HF is ultimately fatal; even in that contemporary clinical trial of optimally-managed outpatients, 2-year mortality was 20% (2). The inpatient HF story is worse: in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan) trial of tolvaptan for acute decompensated HF (ADHF), all-cause mortality was just over 25% at a median follow-up of 10 months (4). However, as remarkable as these data are, where do we stand in the world of routine practice across the spectrum of HF?
In this issue of the Journal, Shah et al. (5) explore longer-term outcomes among older patients hospitalized with HF in the GWTG-HF (Get With The Guidelines–Heart Failure) cohort who were linked to Medicare; these patients were stratified by ejection fraction (EF) into HFrEF, heart failure with borderline ejection fraction (HFbEF), or heart failure with preserved ejection fraction (HFpEF). There are 3 important messages in this study of a large, well-characterized HF registry: 1) regardless of EF, there is an alarming 75% mortality at 5 years (with the vast majority of events occurring in the first 2 years after index admission); 2) patients with acute heart failure that results in hospital admission are at particular high risk (in contrast to the “stable” outpatients who are generally the candidates enrolled in a clinical trial); and 3) despite longstanding, robust evidence for many medications in HFrEF to reduce mortality and HF hospitalizations, most rates of guideline-directed medical therapy at discharge were disappointing in this quality-improvement population.
There is surprisingly limited clinical trial data exploring long-term outcomes following acute HF hospitalization—most randomized trials examine 30-, 60-, or 90-day outcomes, in part due to the high early event rates and increased costs associated with longer trial follow-up. These new data are highly relevant, and it is enlightening to compare the outcomes of such trials to the current dataset (Figure 1).
One of the most striking findings is not only the relative risk of HFpEF mortality to HFrEF, but also the sobering 5-year survival among patients with HFpEF: 75% 5-year mortality, and an even higher readmission rate than those with HFrEF. Prior data from GWTG-HF demonstrated the rise in proportion of patients hospitalized with HFpEF relative to HFrEF, but noted that in-hospital mortality had improved over time for patients with HFpEF (6). And, prior data from the CHARM (Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity) trial showed that the presence of HFrEF portended a worse prognosis compared with HFpEF (7). Yet, all historical data have not been consistent on this point, and the present analysis lays bare the significant long-term risk among patients hospitalized with HFpEF. There are likely a few reasons for this. First, despite significant advances in our understanding of the clinical entity of HFpEF, including unique clinical phenotypes and the role of the kidney in HFpEF pathophysiology (8,9), the pace of therapeutic development to effectively reduce morbidity and/or mortality in patients with HFpEF remains disappointing.
Second, we may be seeing the limitations inherent in classification of HF by EF, which is notoriously dynamic: almost one-half of patients with HFpEF will drop their EF <50% over 5 years, and conversely, close to one-half of patients with HFrEF will increase their EF to >50% over a similar period (10). Moreover, EF has long been recognized to be only a marginal predictor of sudden cardiac death and may be at best a modest biomarker (11). As we learn more about the neurohormonal and inflammatory mechanisms of HFrEF and the renocardiac interactions in HFpEF, new paradigms may emerge to classify HF patients using novel biomarkers that improve risk stratification, allow for more personalized treatments, and render EF a relic.
Alternatively, some might interpret this data as showing that outcomes of patients with HF and systolic dysfunction have “caught up” to those with preserved EF, potentially attributable to either the continued development of effective management strategies for HFrEF or at least their wider adoption in clinical practice. Perhaps a more conservative interpretation is that an HF hospitalization is a great “equalizer,” and marks the transition point in the HF syndrome to an inexorable progression of the disease, regardless of EF. Moreover, debate continues on whether HF hospitalizations represent disease markers or disease factors. In light of the high mortality and high readmission rates, independent of EF, a case can be made that HF hospitalization is a sentinel event and represents disease progression of HF and/or the natural history of a compendium of comorbidities. It would appear that the presence of the decompensated HF syndrome conveys significant subsequent mortality risk, not the echocardiogram.
Equally disappointing is the suboptimal use of guideline-directed medical therapy at discharge for patients with HFrEF. Despite numerous guideline statements, educational efforts, and practice metrics, it is hard to understand why only 83% of patients with HFrEF were discharged on beta-blockers, 16%/56% on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 21% on aldosterone antagonists. As these therapies are well-known to reduce morbidity and mortality in HFrEF over the intermediate-term, this represents 1 opportunity to improve the sobering outcomes presented here.
It is important, however, to consider some limitations when interpreting these data. First, although the cohort is large, there are some selection biases, including: selection of hospitals participating in GWTG-HF, a voluntary quality-improvement program; and exclusion of both non-Medicare patients and Medicare patients who could not be could be linked to GWTG-HF. Notably, the 27% of patients who could not be linked were younger and were more likely to have risk factors for ischemic heart failure (diabetes, hypertension, and prior myocardial infarction). Furthermore, these data are primarily applicable to patients ≥65 years of age. Last, although detailed data are available from GWTG-HF at the time of index hospitalization, the use of Medicare for longer-term data limits those elements available over the 5-year follow-up—for example, longitudinal changes in EF are not typically available.
Nevertheless, the analysis by Shah et al. (5) serves as a dramatic reminder that when it comes to the syndrome of acute HF, with or without systolic dysfunction, there remains significant room for improvement in long-term outcomes as the absolute risk is large. The median survival of 2 years following HF hospitalization should be a particularly profound statistic to all who care for these patients. Moreover, EF does not appear to be an accurate biomarker for risk stratification after a patient has crossed the threshold to an HF admission. These data should serve as another wake-up call to all providers to recognize the risk associated with HF, and another call to arms for HF researchers to urgently find new targets and strategies to manage HF. For the time being, we are certainly not there yet, and we have a long way to go.
↵∗ 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. Steinberg has received research support from Boston Scientific, St. Jude Medical (now Abbott Vascular), and Janssen; and has served as a consultant for Janssen and Biosense Webster. Dr. Fang has served as a member of the Steering Committee for GALACTIC-HF, sponsored by Amgen; and has served as a member of the Data Safety and Monitoring Board for EVALUATE-HF, sponsored by Novartis.
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