By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: Among patients presenting to the ED with acute heart failure, those who received the first dose of intravenous furosemide within 60 minutes of arrival demonstrated lower in-hospital mortality compared to those receiving the first dose after 60 minutes.

SOURCE: Matsue Y, Damman K, Voors AA, et al. Time-to-furosemide treatment and mortality in patients hospitalized with acute heart failure. J Am Coll Cardiol 2017;69:3042-3051.

Acute heart failure (AHF) is a common reason for ED visits and hospitalizations. Clinical practice guidelines emphasize the importance of early diagnosis and treatment of patients presenting with AHF. However, no prospective study has demonstrated that prompt treatment is associated with improved patient outcomes.

To evaluate the relationship between time to treatment and outcome in AHF, the authors of the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure (REALITY-AHF) trial enrolled patients presenting to one of 20 EDs in Japan for AHF who received IV furosemide within 24 hours of arrival. The primary metric of early care, the door-to-furosemide (D2F) time, was defined as the time from patient arrival to the ED to the first administration of IV furosemide. Patients who received the first dose of IV furosemide within 60 minutes were defined as the early treatment group, and those receiving the first dose after 60 minutes of arrival were defined as the non-early treatment group. The primary outcome was in-hospital mortality. The final cohort included 1,291 AHF patients. Median D2F was 90 minutes (interquartile range, 36-186 minutes), and 37.3% of patients met criteria for early treatment. Patients in the early treatment group were more congested, more likely to arrive by ambulance, and less likely to have a prior diagnosis of heart failure. Patients in the early treatment group had significantly lower in-hospital mortality compared to the non-early group (2.3% vs. 6.0%; P = 0.00). In multivariate analyses, early treatment was associated strongly with lower in-hospital mortality (odds ratio, 0.39; P = 0.006). Patients were stratified per baseline risk for adverse outcomes according to a risk prediction model. The association between D2F and mortality was observed regardless of the patient’s baseline risk. The relationship between D2F and mortality was non-linear. Delaying D2F was associated with a steep increase in the risk of mortality over the first 100 minutes, but after that, the effect leveled off. The authors concluded that early treatment with IV loop diuretics is associated with lower in-hospital mortality among patients presenting to the ED with AHF.

COMMENTARY

Despite great efforts over the past decades, no novel treatment has been proved to meaningfully improve outcomes in patients with AHF. Therefore, providers must do the best they can using the available treatments, with IV loop diuretics as the primary therapy. Several retrospective studies have suggested a benefit associated with prompt initiation of treatment (vasodilators or diuretics), but none have prospectively studied the association between early administration of IV diuretics and outcomes.

Matsue et al demonstrated a clear association between early administration of IV furosemide and reduced in-hospital mortality in patients with AHF. This finding is not entirely surprising. Recent studies have shown that myocardial and end-organ damage begins early in AHF and progresses over time. Treating congestion earlier may minimize the damage, and recent studies have shown that AHF patients with decreased markers of congestion, myocardial injury, and end-organ damage demonstrate decreased mortality compared to those with ongoing evidence of organ dysfunction. Interestingly, the observed relationship between D2F and mortality was non-linear. Beyond 100 minutes, further increases in D2F did not increase mortality. If the benefits of early diuretic administration are primarily because of halting the process of ongoing myocardial and end-organ dysfunction, then it is difficult to explain why the benefits of early D2F end at 100 minutes. Alternatively, it is possible that patients who were treated quickly were those in whom the diagnosis was obvious at the time of ED arrival. This fits with the finding that patients with early D2F were more likely to exhibit classic symptoms of congestion, including jugular venous distention and orthopnea. Diagnosing AHF in a patient presenting with dyspnea can be challenging when classic findings are absent. Multiple studies have shown that diagnostic delays are associated with longer time to medication administration, prolonged hospitalization, and even increased mortality.

Will D2F become a quality of care measure similar to the door-to-balloon time for ST-segment elevation myocardial infarction? Not based on the results of this study alone. The findings will need to be replicated in larger, more diverse cohorts, and the optimal D2F needs to be identified. It also will be important to further clarify whether it is in fact D2F, and not the delay in diagnosis, that leads to worse outcomes. For now, it seems reasonable for clinicians treating AHF patients to strive for both earlier diagnosis and initiation of IV diuretic therapy in patients presenting to the ED with possible AHF. This may include increased use of serum B-type natriuretic peptide measurement or other tests to promptly diagnose AHF and prompt initiation of IV diuretics once AHF is determined to be the most likely diagnosis. Until new therapies are identified to improve outcomes in AHF, we must use the tools we have as effectively as possible.