Nature Medicine FEBRUARY 28, 2022

EMPULSE: Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized

Voors AA, Angermann CE, Teerlink JR, et al.

Bottom Line

The EMPULSE trial demonstrated that early in-hospital initiation of empagliflozin in stabilized patients with acute heart failure provides significant clinical benefit over 90 days, regardless of ejection fraction or diabetes status.

Key Findings

1. Patients treated with empagliflozin were 36% more likely to experience a clinical benefit at 90 days compared with placebo (win ratio 1.36; 95% CI, 1.09–1.68; P = 0.0054).

2. Clinical benefit occurred at a rate of 53.9% in the empagliflozin arm versus 39.7% in the placebo arm.

3. Secondary outcomes indicated all-cause mortality was 4.2% in the empagliflozin group compared to 8.3% in the placebo group.

4. Empagliflozin treatment resulted in a 4.5-point greater improvement in KCCQ-Total Symptom Score (TSS) at 90 days compared to placebo (P = 0.035).

5. Treatment was well-tolerated with serious adverse events reported in 32.3% of the empagliflozin group versus 43.6% in the placebo group.

Study Design

Design

RCT

Double-Blind

Sample

530

Patients

Duration

90 days

Median

Setting

Multinational, multicenter

Population Patients hospitalized with acute de novo or decompensated chronic heart failure, regardless of ejection fraction or diabetes status, who were clinically stable (24 hours to 5 days after admission).

Intervention Empagliflozin 10 mg once daily for 90 days.

Comparator Placebo once daily for 90 days.

Outcome Clinical benefit at 90 days, defined as a hierarchical composite of all-cause death, number of heart failure events, time to first heart failure event, and a ≥5 point difference in change from baseline in KCCQ-TSS.

Study Limitations

• The primary analysis relied on a hierarchical win ratio approach, which can be challenging to interpret compared to traditional time-to-event analyses.

• The study was limited by a relatively small sample size of 530 patients and a short follow-up period of 90 days.

• As an in-hospital study initiated after patient stabilization, the results may not be generalizable to patients with more severe or unstable hemodynamics.

• Some analyses, such as those regarding baseline KCCQ tertiles, were performed post-hoc.

Clinical Significance

The EMPULSE trial suggests that the early in-hospital initiation of SGLT2 inhibitors like empagliflozin is safe and efficacious for patients hospitalized with acute heart failure, offering a window to improve symptoms, reduce rehospitalizations, and potentially lower mortality in a high-risk transition period.

Historical Context

Prior to EMPULSE, SGLT2 inhibitors had demonstrated clear mortality and morbidity benefits in chronic heart failure (e.g., EMPEROR-Reduced, DAPA-HF). EMPULSE filled a critical evidence gap by testing the safety and efficacy of initiating this drug class specifically during the vulnerable acute hospitalization phase, regardless of the patient's ejection fraction or diabetic status.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological mechanism by which SGLT2 inhibitors like empagliflozin promote decongestion in acute heart failure, and why was there historical hesitation to start these medications during the acute phase?

Key Response

SGLT2 inhibitors promote osmotic diuresis and natriuresis by inhibiting glucose and sodium reabsorption in the proximal tubule. This 'smart diuresis' reduces interstitial edema with less sympathetic activation compared to loop diuretics. Historical hesitation stemmed from concerns about acute kidney injury (the 'creatinine bump'), hypotension, and the risk of euglycemic ketoacidosis in the setting of metabolic stress during acute illness.

Resident

In the context of the EMPULSE trial, what specific clinical criteria define a 'stabilized' patient ready for the initiation of empagliflozin, and how does this affect your discharge planning?

Key Response

Stabilization was defined as having a systolic BP ≥100 mmHg, no dose increase in IV diuretics or use of IV vasodilators in the prior 6 hours, and no IV inotropes in the prior 24 hours. Identifying these patients early allows for the initiation of a key pillar of GDMT (SGLT2i) before discharge, which is proven to be a stronger predictor of long-term adherence and early event reduction than starting it in the outpatient setting.

Fellow

The EMPULSE trial utilized a 'win ratio' as its primary hierarchical composite endpoint. How does this statistical approach differ from a traditional time-to-first-event endpoint, and why is it particularly suited for acute heart failure trials?

Key Response

A win ratio ranks outcomes hierarchically (e.g., Death > HF Events > Change in KCCQ score). It allows the analysis to prioritize the most clinically significant events (mortality) while still capturing the benefit of symptomatic improvement (QoL). This is superior in AHF trials where mortality might be low in the short term, but the burden of symptoms and rehospitalization is high, ensuring that the 'quality' of the clinical benefit is accounted for.

Attending

Given that EMPULSE showed benefit across the entire spectrum of LVEF and regardless of diabetes status, how should this study influence the 'wait and see' approach for patients with Heart Failure with Preserved Ejection Fraction (HFpEF) during an index hospitalization?

Key Response

EMPULSE, alongside the DELIVER and EMPEROR-Preserved trials, effectively eliminates the 'wait and see' rationale. Because the benefit in EMPULSE was independent of LVEF, it establishes SGLT2 inhibitors as the first-line therapy to be initiated immediately upon stabilization for HFpEF, a population that previously had limited inpatient therapeutic options to improve post-discharge outcomes.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Evaluate the internal validity of using the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score as a component of a hierarchical win ratio in a 90-day trial. How might the 'unblinding' effect of early diuretic response bias this specific component?

Key Response

The KCCQ is a patient-reported outcome. Because empagliflozin has a noticeable diuretic effect, patients and clinicians might correctly guess the treatment assignment (unblinding). If patients perceive they are on the active drug due to increased urine output, their subjective QoL reporting on the KCCQ may be biased upward, potentially inflating the win ratio if a large number of 'wins' are determined by the KCCQ tier rather than hard clinical events.

Journal Editor

Despite the positive win ratio, the individual components of death and heart failure events did not reach nominal significance in EMPULSE. As a reviewer, would you argue that the trial is underpowered to change mortality guidelines, or does the hierarchical composite provide sufficient evidence for a broad clinical mandate?

Key Response

A critical reviewer would note the small sample size (n=530) and short follow-up (90 days). While the win ratio is statistically efficient, the lack of significant reduction in hard endpoints (mortality) alone suggests the trial is more about 'clinical benefit' (including symptoms) rather than 'survival.' The editorial challenge is balancing the strength of a novel statistical method against the traditional requirement for hard-event reduction in guideline-changing evidence.

Guideline Committee

How do the EMPULSE findings supplement the 2022 AHA/ACC/HFSA Heart Failure guidelines regarding the timing of SGLT2i initiation, specifically concerning the transition from Class IIa to Class I recommendations for inpatient starts?

Key Response

The 2022 guidelines already provide a Class 1 recommendation for SGLT2i in HFrEF and Class 2a for HFpEF/HFmrEF. EMPULSE provides the 'Level B-R' evidence needed to specifically mandate 'in-hospital' initiation for all stabilized AHF patients. It bridges the gap between chronic management trials and the acute setting, supporting a move toward a 'stronger' recommendation for immediate inpatient initiation to prevent the 'inertia' of outpatient follow-up.

Clinical Landscape

Noteworthy Related Trials

2020

EMPEROR-Reduced Trial

n = 3,730 · NEJM

Tested

Empagliflozin 10mg daily

Population

Patients with HFrEF

Comparator

Placebo

Endpoint

Composite of cardiovascular death or hospitalization for heart failure

Key result: Empagliflozin significantly reduced the risk of cardiovascular death or hospitalization for heart failure in patients with HFrEF, regardless of diabetes status.

2021

EMPEROR-Preserved Trial

n = 5,988 · NEJM

Tested

Empagliflozin 10mg daily

Population

Patients with HFpEF

Comparator

Placebo

Endpoint

Composite of cardiovascular death or hospitalization for heart failure

Key result: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with HFpEF.

2021

SOLOIST-WHF Trial

n = 1,222 · NEJM

Tested

Sotagliflozin

Population

Patients with T2DM hospitalized for worsening heart failure

Comparator

Placebo

Endpoint

Total number of deaths from cardiovascular causes, hospitalizations, and urgent visits for heart failure

Key result: Initiation of sotagliflozin before or shortly after hospital discharge resulted in a significantly lower rate of cardiovascular deaths and heart failure-related hospitalizations.

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