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Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.122.059038Circulation. 2022;146:289–298

Abstract

Background:

Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear.

Methods:

In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide).

Results:

Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6–27.7]; P=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P=0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (−1861 versus −727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83–0.95]; P<0.001). There were no differences in the incidence of safety events between groups.

Conclusions:

Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04049045.

Clinical Perspective

What Is New?

  • The addition of synthetic natriuretic peptides, vasopressin antagonism, or ultrafiltration to standard diuretic regimens has failed to improve outcomes in chronic or acute decompensated heart failure.

  • No new therapies for acute decompensated heart failure, including diuretic drugs, have been introduced in decades.

  • The EMPAG-HF study (Empagliflozin in Acute Decompensated Heart Failure) was designed to test the hypothesis that early sodium-glucose cotransporter-2 inhibition with empagliflozin added to standard medical therapy enhances diuresis without furthering kidney injury in patients with acute decompensated heart failure.

What Are the Clinical Implications?

  • Our study shows that in patients with acute decompensated heart failure, early initiation of the sodium-glucose cotransporter-2 inhibitor empagliflozin within 12 hours of hospital presentation in addition to standard treatment is safe and increases urine output without affecting kidney function or injury patterns.

  • EMPAG-HF is the first randomized study to show primary clinical benefits of a drug regimen added to diuretic regimens in patients with acute decompensated heart failure.

  • These observations suggest that addition of sodium-glucose cotransporter-2 inhibition to standard diuretic therapy is a promising strategy to assist with conventional decongestive treatment in patients with acute decompensated heart failure.

Editorial, see p 299

Heart failure (HF) has increased in incidence and prevalence worldwide and has high morbidity and mortality.1,2 Acute decompensated HF (ADHF) is a severe presentation of HF characterized by volume retention and congestion, often accompanied by impaired kidney function and diuretic resistance.3 The only pharmacologic treatments available to augment diuresis are various combinations of diuretics added to loop diuretics or the addition of inotropes or vasodilators when decompensation is severe.2–4 The inability to achieve decongestion is associated with a worse prognosis and a higher rate of rehospitalization for ADHF.2,3

Several randomized controlled trials testing novel pharmacotherapies in patients with ADHF failed to show benefit of these agents on outcomes after discharge, highlighting a critical unmet need.5–8 The addition of natriuretic peptides (nesiritide or ularitide),6,8 vasopressin antagonism,7,9 or ultrafiltration10,11to standard diuretic regimens have not shown consistent clinical benefit in patients with chronic HF or ADHF. Therefore, novel strategies with the potential to improve diuresis in ADHF represent a major therapeutic need.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization in ambulatory patients with stable chronic HF regardless of ejection fraction.12–15 However, the clinical effects of an early start of SGLT2 inhibition within the first 12 hours after clinical presentation in addition to standard loop diuretic–based decongestion strategies have not been studied in patients with ADHF. The EMPAG-HF study (Empagliflozin in Acute Decompensated Heart Failure) was designed to test the hypothesis that early SGLT2 inhibition using empagliflozin plus standard medical therapy enhances diuresis without furthering kidney injury in patients with ADHF.

Methods

Study Design and Oversight

The EMPAG-HF study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT04049045) randomly assigned patients with ADHF to receive empagliflozin or placebo in a double-blind, placebo-controlled trial. The SGLT2 inhibitor empagliflozin at a dose of 25 mg daily was administered within 12 hours of hospitalization for 5 days compared with placebo added to standard decongestive treatment.

The local ethics committee of the University of Jena approved the protocol. All patients gave written informed consent. All authors had full access to the trial data and take responsibility for its integrity and the data analysis. The data that support the findings of the current study are available from the corresponding author on reasonable request.

Patient Cohort

Patients with ADHF (18 to 85 years of age) with BNP (brain natriuretic peptide) >100 pg/mL or NT-proBNP (N-terminal pro-BNP) >300 pg/mL were included. Patients with or without type 2 diabetes or impaired glucose tolerance were included. Patients did not have cognitive impairment. For women of childbearing potential, a negative pregnancy test or documentation of the correct use of a highly effective contraceptive method was required.

Patients were excluded for the following: type 1 diabetes, chronic kidney disease with estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m² or end-stage kidney failure with the need for chronic dialysis treatment, acute kidney injury (Acute Kidney Injury Network stage ≥2 or requiring dialysis treatment), current medication with SGLT2 inhibitors, known intolerance or hypersensitivity to the active substance empagliflozin or a contraindication or intolerance to furosemide, acute HF without signs of congestion (“dry” case), indication for urgent coronary angiography or any planned administration of an iodine-based contrast agent within the next 6 days, need for hemofiltration or any other form of extracorporeal therapy, planned surgery, or recent participation in another clinical trial (within the 3 months before inclusion). Any cause of HF leading to decompensation that needed urgent management (eg, acute coronary syndrome, unstable arrhythmias, mechanical causes, acute pulmonary embolism), inability to understand or provide written informed consent, or documented alcohol abuse (daily alcohol intake of >12 g in women or >24 g in men) also led to exclusion from the study.

Primary and Secondary Outcomes

The primary outcome of EMPAG-HF was the total urine output measured and summed over 5 days. Secondary end points included markers of kidney function under treatment (increase in creatinine of >0.3 mg/dL, doubling of serum creatinine, need for renal replacement therapy) and the trajectory of eGFR, cystatin-C, and changes in baseline kidney function. Net urine output was assessed daily and urine output was also controlled for diuretic dosage according to Clark et al.16 and Oh and Han.4 Additional end points included worsening or persistent HF defined by New York Heart Association class; patient-reported outcomes assessed by a visual analog scale for health status and a quality of life questionnaire (EQ-5D index)17; intermediate care, intensive care unit, and hospital length of stay; markers of liver function (bilirubin, serum aminotransferases, and relevant change in coagulation status); NT-proBNP; oxygen saturation without oxygen therapy or need for oxygen, in liters per minute; presence of rales; changes in chest X-ray; and number of patients alive at discharge and out of hospital after 30 days.

Safety End Points

Prespecified safety end points included serious adverse events (SAEs), events related to study drug discontinuation, and adverse events (AEs) related to deteriorating kidney function.

Other outcome measures included the number of AEs and SAEs including MedDRA SAE preferred terms and system and organization controls in both groups within 30 days. All AEs and SAEs including laboratory measures were documented except for efficacy measures.

The clinical event adjudication committee consisted of 3 independent clinicians blinded to study arm assignment (Supplemental Material). The committee reviewed abstracted clinical data to determine whether major events occurred.

Monitoring and Follow-Up

Blood and spot urine samples were taken daily from day 1 to 5, at hospital discharge, and at day 30 after hospital discharge (safety end point). All laboratory values were measured at the central laboratory of the institution. eGFR was on the basis of serum creatinine and calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Statistical Analysis

All treated patients were included in the full analysis set and were analyzed as randomized with regard to demographic characteristics, protocol deviations, baseline characteristics, drug exposure, and safety, laboratory, and efficacy measures according to the intention-to-treat principle.

Patients without major protocol deviations were included in the per-protocol analysis. A sensitivity analysis was performed for selected demographic and baseline characteristics (ie, age, sex), primary efficacy, and selected secondary efficacy measures (ie, daily urine volume and the diuretics-corrected urine volume).

A per-protocol analysis of the primary variable was performed for patients without major protocol deviations as a sensitivity analysis. Results of this analysis were in line with the analysis on the basis of the intention-to-treat population. To keep the definition of the per-protocol analysis as unaffected as possible, predictable protocol deviations (eg, time window deviations) were classified a priori as minor or major.

The safety analysis set included all patients included in the full analysis. For safety purposes, patients were analyzed as treated.

For all data assessed, descriptive statistics including mean, SD, minimum, quartiles with median and maximum for metric data, and frequency analysis for nonmetric data were evaluated. For selected end points, change from baseline was evaluated. Volume assessments sum values over the complete day 1 (ie, reflect effect of first treatment). Therefore, for these values, no baseline is available. Comparison of treatment groups is on the basis of time point values. Analysis was performed by treatment group and in total.

Sample Size and Power Considerations

A sample size of 52 participants (26 per treatment arm) was estimated to provide a power of 80% at a 2-sided α level of 0.05 to detect a difference in urine volume between the 2 groups if the effect size is 0.8 assuming normal distribution of means. To account for an attrition rate of ≈10% to 15%, 4 participants per group were added, resulting in a total sample size of 60 patients (30 per treatment arm).

Calculation of sample size and 80% power analysis was performed with nQuery Advisor 7.0.

Analysis of the Primary End Point

V5 denotes the total urine volume over the study days 1 to 5: V5E for the empagliflozin treatment group and V5P for the placebo treatment group.

The null hypothesis H0: V5E=V5P was tested against the alternative H0: V5E≠V5P by means of a nonparametric Mann-Whitney U test, α=0.05, 2-sided. The data distribution was checked by graphical means.

Results of 2 patients with missing information on urine volume at day 5 were regarded as missing data.

Analysis of Secondary End Points

The diuretics-corrected daily urine volume (V1D) was evaluated for every patient and day according to the following formula, where V1 denotes the daily urine volume, Vnorm the standard output of urine in the given patient population, D the daily body weight–adopted dose of furosemide, and Dmin the minimal daily body weight–adopted dose of furosemide:

V1D=(V−Vnorm)/D at the respective day

We assumed Vnorm=1.8 L according to Clark et al.16 and Dmin=10 mg/70 kg body weight according to Oh and Han.4 In a case when no diuretics were administered, Dmin/2 was used as denominator.

The daily urine volume V1 and the diuretics-corrected urine volume V1D as well as weight, NT-proBNP (after logarithmic transformation), and eGFR were analyzed by means of a mixed model with the treatment, time, and treatment–time interaction as fixed effects and the patient as random effect.

All tests of secondary measures are regarded as sensitivity analyses and are exploratory. For this reason, the significance level was set to α=0.05 and no α correction for multiple testing was done.

Results

Baseline Demographics

A total of 87 patients were screened between June 2019 and May 2021 at the University Hospital Jena, Germany, of whom 30 were randomized to empagliflozin and 30 to placebo (Figure 1). One patient had to be excluded after randomization before the first dose of trial medication was administered because of acute ECG changes and need for urgent cardiac catheterization. Thus, only 29 patients were included in the placebo group for analysis.

Figure 1.

Figure 1. Consolidated Standards of Reporting Trials diagram.

Baseline demographic characteristics of randomized study participants are described in Table 1. Mean age was 74.7±9.9 years and 38% were female. A total of 53.3% of patients had de novo HF and 68.3% of all patients had ischemic cardiomyopathy. Median NT-proBNP concentrations were 3386 (interquartile range, 2122–5344) pg/mL and mean systolic blood pressure was 135±23 mm Hg. The mean eGFR at baseline was 60.2±18.7 mL/min per 1.73 m2. A total of 21.1% had a left ventricular ejection fraction <30%.

Table 1. Baseline Characteristics

CharacteristicsEmpagliflozin (n=30)Placebo (n=29)
Age, y72.9±11.2 (68.8–77.1)76.5±8.3 (73.4–79.7)
Female sex11/30 (36.7)12/29 (41.4)
Type 2 diabetes13/30 (43.3)10/29 (34.5)
NYHA functional class
 II3 (10)5 (17.2)
 III20 (66.7)13 (44.8)
 IV7 (23.3)11 (37.9)
Body mass index, kg/m231.1±9.6 (27.5–34.7)29.9±6.5 (27.1–32.6)
Heart rate, bpm80±17 (73–87)79±23 (70–88)
Systolic blood pressure, mm Hg139±25 (129–148)132±21 (124–140)
Atrial fibrillation13/27 (48.1)14/27 (51.9)
Hypertension27/30 (90)25/29 (86.2)
Left ventricular ejection fraction, %45±16 (39–51)44±14 (30–50)
 ≤30%6/29 (20.7)6/28 (21.4)
Pathogenesis of heart failure
 Ischemic8/30 (27)10/29 (34)
 Nonischemic22/30 (73)19/29 (66)
De novo heart failure18/30 (60)14/29 (48)
Heart failure medication
 Renin–angiotensin inhibitor23/30 (76.7)20/29 (69)
 Sacubitril/valsartan5/30 (16.7)5/29 (17.2)
 Mineralocorticoid receptor antagonist7/30 (23.3)4/29 (13.8)
 β-blocker22/30 (73.3)25/29 (86.2)
 Previous treatment with loop diuretics19/30 (63)17/29 (59)
Laboratory values
 Sodium, mmol/L139±4 (138–141)138±5 (136–140)
 Potassium, mmol/L4.1±0.5 (3.9–4.3)3.9±0.6 (3.7–4.2)
 Creatinine, µmol/L107±29 (96–118)98±28 (87–109)
 eGFR, mL/min per 1.73 m258.2±19.3 (51–66)62.2±18.2 (55–69)
 Hemoglobin A1c, %6.6±1.5 (6.0–7.2)6.4±0.9 (6.0–6.7)
 Fasting glucose, mmol/L8±1.5 (6.7–9.3)7.8±2.3 (6.0–9.5)
 Uric acid, µmol/L458±111 (411–505)488±151 (421–555)
 Urea, mmol/L7.9±3.7 (6.5–9.3)7.7±3.7 (6.3–9.2)
 Bilirubin, µmol/L13.3±9.4 (9.8–16.8)16.8±9.6 (13–20.6)
 Alanine aminotransferase, µmol/L×s0.83±1.8 (0.15–1.51)0.45±0.43 (0.28–0.61)
 Aspartate aminotransferase, µmol/L×s0.92±1.6 (0.3–1.54)0.50±0.2 (0.41–0.58)
 MELD-XI score12.3±2.5 (11.4–13.3)11.9±2.5 (11.0–12.9)
 Lactate dehydrogenase, µmol/L×s4.6±0.9 (4.3–5)5.7±4.2 (3.8–7.3)
 Creatine kinase, µmol/L×s1.9±2.2 (1.1–2.8)1.6±1.0 (1.2–2.0)
 Lactate, mmol/L1.7±0.7 (1.4–2)1.7±0.7 (1.4–2)
 Leukocytes, Gpt/L8.6±2 (7.8–9.3)8.8±3.9 (7.3–10.3)
 Hemoglobin, mmol/L7.7±1.4 (7.2–8.2)7.8±1.5 (7.2–8.3)
 Hematocrit, %37.7±5.9 (35.5–39.9)38.1±6.8 (35.4–40.7)
 Platelets, Gpt/L218±61 (195–240)226±66 (200–252)
 NT-proBNP, pg/mL4726±4516 (2939–6513)4823±4995 (2923–6724)

Values are mean±SD (95% CI) or n/total N (%). eGFR indicates estimated glomerular filtration rate; MELD-XI, Model for End-Stage Liver Disease Excluding International Normalized Ratio; NT-proBNP, N-terminal probrain natriuretic peptide; and NYHA, New York Heart Association.

A total of 63% of patients in the empagliflozin group and 59% of patients in the placebo group had previous treatment with loop diuretic medication (Table 1). No significant differences in baseline characteristics were noted between the 2 groups.

Primary Outcome

Cumulative urine output over 5 days was higher in the empagliflozin group compared with the placebo group (median, 10 775 versus 8650 mL in placebo; group difference, 2125 mL [95% CI 840–3550]; Figure 2). Thus, patients in the empagliflozin group showed a 25% increase in urine output over 5 days compared with patients in the placebo group (P=0.003).

Figure 2.

Figure 2. Primary and secondary outcomes. A, Cumulative urine output over 5 days (primary outcome). B, Dynamics in NT-proBNP levels in relation to baseline (mean and SEM values evaluated under logarithmic transformation). C, Diuretic efficiency over 5 days. Error bars represent SEM.

Secondary Outcomes

Patients in the empagliflozin group showed no significant difference in body weight reduction compared with patients in the placebo group over 5 days (mean −4.2 versus −3.0 kg; difference, −1.2 kg [95% CI −2.99 to 0.63]; P=0.198), which persisted until hospital discharge with a trend toward lower levels at follow-up on day 30 (difference in slope, −0.07 kg/d [95% CI, −0.131 to 0.001]; P=0.054; Figure 3A). This was accompanied by a greater reduction in mean NT-proBNP from baseline in the empagliflozin group compared with placebo (−1861 versus −727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI 0.83–0.95]; P<0.001; Figure 2B). The treatment effect on NT-proBNP remains similar when the mixed model analysis is adjusted for de novo HF and previous use of loop diuretics (P=0.0006).

Figure 3.

Figure 3. Secondary outcomes with extended 30-day follow-up. A, Change in body weight from baseline in both groups. B, Dynamics in estimated glomerular filtration rate (eGFR) as change from baseline in both groups. Error bars represent SEM.

Both total and net urine output over 5 days were higher in the empagliflozin group compared with the placebo group (Table 2). Daily furosemide equivalent dose and the cumulative dose of loop diuretics were lower and diuretic efficiency expressed as milliliters urine production per milligram furosemide equivalent was higher in the empagliflozin group compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6–27.7]; P<0.041; Table 2, Figure 2C, and Tables S2 and S3; Hodges-Lehmann estimate of group difference 43.7 mL urine per milligram furosemide equivalent [95% CI, 0.1–93]). Urine output and diuretic efficiency are independent of de novo HF or previous loop diuretic use (Tables S2 and S3).

Table 2. Primary and Secondary End Points

OutcomesEmpagliflozinPlaceboEstimation of group difference* (95% CI)
Total urine output over 5 days, mL10 775 (9100 to 12 925)8650 (6450 to 10 350)2125 (840 to 3550)
Secondary outcomes
 Net urine output over 5 days, mL3725 (2622 to 5830)1480 (650 to 3826)1950 (674 to 3250)
 Net fluid output over 5 days, mL3925 (2825 to 6505)1680 (850 to 4026)2005 (700 to 3300)
 Change in body weight, kg (day 5)– 4.19±3.5–3.02±2.9–1.18 (–2.99 to 0.63)
 Cumulative dose of diuretics (in milligrams furosemide equivalent)313±194.6351.4±220.7–38.4 (–176.7 to 70.0)
 Diuretic efficiency (mL/mg furosemide equivalent)8.3 (–32.9 to 58.8)–25.9 (–80.3 to 16.8)43.7 (0.1 to 93)
Renal function measures under treatment (day 5)
 Increase in serum creatinine of ≥26.5 µmol/L (0.3 mg/dL)3/26 (11.5)9/28 (32.1)
 Doubling of serum creatinine0 of 260 of 28
 Need for renal replacement therapy0 of 290 of 29
 Total urinary sodium excretion, mmol/L (day 5)93±36.899.4±30.6–6.4 (–27.6 to 14.8)
 Fractional excretion of sodium (day 5)3170±2802.22439.1±2134.6731 (–939 to 2400)

Values are mean±SD (95% CI), median (interquartile range), or n/total N (%).

* Hodges-Lehman estimation for median.

† Wilcoxon 2-sample test; P=0.003.

No differences in changes in eGFR during the treatment period were observed between the 2 groups (eGFR, 51±19 versus 54±17 mL/min per 1.73 m²; P=598). Previous use of loop diuretics or de novo HF had no effect on eGFR levels (Table S3). At the 30-day follow-up visit, patients in the placebo group had lower eGFR compared with patients in the empagliflozin group (Figure 3B). Additional serum markers of kidney function and injury including creatinine, urea, and cystatin-C as well as urine markers of kidney injury including urinary total protein, albumin, and α1-microglobulin (corrected for urine creatinine) were not different between the 2 groups (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; both P=0.066; Table 3). Patients in the empagliflozin group had lower levels of serum uric acid during the 5-day study period.

Table 3. Dynamics in Renal Function

Renal function measureEmpagliflozinPlacebo
Day 1Day 3Day 5Day 30Day 1Day 3Day 5Day 30
Daily urine output, mL1688±9722241±6292555±11921580±15241963±8711929±889
Daily net urine output, mL737±971784±6361060±1027616±1521601±924466±746
Diuretics-controlled urine output, mL/mg furosemide−28.4±60.916.8±45.120.9±69−48.4±87.00.5±26.67.5±34.5
Serum markers of renal function
 Creatinine, µmol/L107±28.8115±34.8119±33.9120±42.197.8±28.2107±24.7111±29.4118.4±29.4
 eGFR, mL/min per 1.73 m²58.2±19.3253.2±19.851.1±19.152.9±23.762.2±18.255.0±16.753.7±17.447.5±11.7
 Urea, mmol/L7.9 C3.79.0±3.59.7±3.58.0±3.37.7±3.78.8±3.18.9±3.09.7±4.5
 Cystatin-C, mg/L2±1.52.1±1.52.0±0.82.3±1.31.5±0.31.7±0.41.6±0.41.7±0.3
 Uric acid, µmol/L458±111436±117423±121482±146488±151512±138509±152501±147
Urine markers
 Urine total protein, mg/g creatinine343±333583±742492±845664±930273±168418±469503±847309±214
 Urine albumin, mg/g creatinine112±153250±543233±682309±81280.6±93.1127±177164±40886.7±82.2
 Urine α1- microglobulin, mg/g creatinine95.1±91105±15955.4±38.676.7±75.8141±258141±49631.3±33.620.6±15.7
 Urine creatinine, mmol/L5.8±5.34.48±3.114.6±3.56.3±3.06.78±4.326.45±4.666.5±7.37.92±6.77
 Urine uric acid, µmol/L1460±10451852±17671635±12431820±16951460±14441635±17821595±11641537±1346
 Urine glucose, mmol/L7.4±15.684.7±76.370.1±82.313.7±44.50.3±0.35.5±18.87.7±29.415.5±30.2

All data are expressed as mean±SD. eGFR indicates estimated glomerular filtration rate.

Quality of Life Questionnaires

Patients in the empagliflozin group had a greater absolute change in New York Heart Association class from baseline to day 5 and until hospital discharge (Figure S1). The absolute improvement in EQ-5D index and visual analogue scale health status was numerically higher in the empagliflozin group compared with placebo but not statistically significant (Figure 4).17

Figure 4.

Figure 4. Clinical outcomes. A, Change in EQ-5D. B, Change in health status visual analogue scale. Error bars represent SEM.

Safety and Adverse Events

No statistically significant differences in the occurrence of safety events were observed between the 2 groups during the study period or during follow-up of 30 days after randomization (Table 4). No early discontinuation of trial drug was registered. No patient was lost to follow-up. Two patients died in the placebo group and 1 patient died in the empagliflozin arm.

Table 4. Safety Events

EventEmpagliflozinPlacebo
Worsening heart failure1 (3.3)4 (13.8)
Worsening renal function (increase in serum creatinine ≥26.5 µmol/L [0.3 mg/dL])3/26 (11.5)9/28 (32.1)
Worsening liver function00
Change in coagulation status at day 51/23 (4.3)2/25 (8)
Urinary tract infection1 (3.3)4 (13.8)
Stroke or transient ischemic attack1 (11.1)0
30-day mortality1 (3.3)2 (6.9)

All data are expressed as n/total N (%).

Discussion

In patients with ADHF, early initiation of empagliflozin added to standard decongestive treatments led to a 25% increase in cumulative urine output over 5 days of treatment. Empagliflozin also led to an increase in diuretic efficiency as well as greater reduction in NT-proBNP and a trend toward lower body weight (Figures 2 and 3). These effects were not accompanied by increased kidney dysfunction compared with placebo (Figure 3B and Tables 2 and 3).

The findings of the current study add to the increasing evidence on effects of SGLT2 inhibition in patients with cardiovascular diseases.12–15,18–21 The effects of empagliflozin in patients with ADHF are consistent with findings of previous studies in patients with kidney dysfunction and HF with preserved and reduced ejection fraction regardless of diabetes status that consistently showed the clinical benefits of SGLT2 inhibition.12–15,19

First introduced as antihyperglycemic drugs, SGLT2 inhibitors have shown benefits in cardiovascular risk prevention and in patients with chronic stable HF.12–15,18,19 SGLT2 inhibitors reduce renal glucose reabsorption and thus increase urinary glucose excretion. In addition to glucosuric effects, empagliflozin is also associated with osmotic diuresis and natriuresis.22 Chronic use decreases body weight and blood pressure without increases in heart rate and has favorable effects on markers of arterial stiffness and vascular resistance.21 In patients with HF with reduced and preserved ejection fraction, SGLT2 inhibition prevented the decline in eGFR over time.14,15,18,21

The current study is distinct from previous clinical trials of SGLT2 inhibition in HF in several aspects. First, no previous trial has recruited patients at such an early time period (<12 hours) after hospital admission without hemodynamic stabilization. Second, this trial was designed to monitor early effects of SGLT2 inhibition including risks and benefits during the acute phase of decongestive treatment in decompensated HF. Third, patients were monitored during the most vulnerable phase of acute HF treatment from admission to clinical stabilization (full study observation time was 5 days).

The dosage of 25 mg empagliflozin in EMPAG-HF was chosen to maximize potential diuretic effects in ADHF. We hypothesized that the higher dose would result in increased urine output compared with 10 mg. We aimed to explore potentially negative effects of empagliflozin in ADHF in combination with high-dose loop diuretics and other HF drugs.

Previous studies on the role of ultrafiltration in decompensated HF, such as UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive HF) and AVOID-HF (Aquapheresis Versus Intravenous Diuretics and Hospitalization for HF), have demonstrated that these therapies may cause incremental weight loss comparable with the effects of SGLT2 inhibition as shown in EMPAG-HF.10,11 Results from AQUAMARINE (Answering the Question of Tolvaptan’s Efficacy for Patients With ADHF and Kidney Failure) demonstrated that tolvaptan was associated with incremental diuresis and no evidence for untoward effects on kidney function in acute HF.9 However, early initiation of tolvaptan in patients with HF and reduced ejection fraction did not improve outcomes in EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan).7

Because of concerns about AEs, recent acute HF trials have focused on initiation of medication (eg, sacubitril-valsartan [PIONEER-HF (Comparison of Sacubitril-Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode)]23 or empagliflozin [EMPULSE (Empagliflozin Compared to Placebo Initiated in Patients Hospitalized for Acute Heart Failure Who Have Been Stabilized)])20 only after clinical stabilization. A previous study using 10 mg of empagliflozin versus placebo initiated within 24 hours of hospitalization for ADHF (EMPA-RESPONSE [Randomized, Double Blind, Placebo Controlled, Multicenter Pilot Study on the Effects of Empagliflozin on Clinical Outcomes in Patients with Acute Decompensated Heart Failure]) failed to show a difference in the primary end point of dyspnea score, diuretic response, length of stay, or change in NT-proBNP.24 Here, we show for the first time in a randomized study the safety and tolerability of an early initiation of the SGLT2 inhibitor empagliflozin on top of diuretic regimens in patients with ADHF without negative effects on kidney function or injury patterns.

Consistent with data from previous trials in ambulatory patients with HF, an initial decrease of eGFR was noted that was lower in the empagliflozin group compared with placebo, followed by higher eGFR in the empagliflozin group at 30 days.18 This suggests the possible absence of a reduction in intraglomerular pressure attributable to enhanced tubulo-glomerular feedback19,21,25 occurring during the very early phase of SGLT-2 inhibition in patients with ADHF. An intermittent reduction of glomerular filtration was typically seen during the first 2 to 4 weeks of treatment with SGLT2 inhibitors and subsequently increased within 2 to 3 months.19,26,27 This finding led to concerns about the very early use of SGLT2 inhibitors in patients with acute HF, especially in those with concurrent renal impairment. Moreover, this so-called eGFR dip caused by SGLT2 inhibition was more pronounced in patients having additional diuretic therapy and more advanced kidney disease.27 Despite this background, our study demonstrated that the early use of empagliflozin in ADHF is safe and well-tolerated without evidence of kidney dysfunction or injury.

No difference in renal or cardiovascular safety end points was detected and no event of ketoacidosis occurred in this study despite reduced eGFR and albuminuria at baseline. Of note, patients in the empagliflozin group had lower levels of uric acid. This observation supports the hypothesis that the use of SGLT2 inhibition in patients with ADHF may affect the incidence of acute gout attacks, a common complication of intensive diuretic regiments.

Our trial has some limitations. The short observation period of only 5 days may not be sufficient to observe AEs that occur after discharge and during longer use. The study was not powered or designed for analysis of clinical end points such as cardiovascular mortality and hospitalization. The focus on early decongestion and inclusion of patients within 12 hours of hospitalization also excluded patients with a more prolonged course of cardiac decompensation. Our study used New York Heart Association classification, the EQ-5D index, and visual analogue scale health status for clinical status and quality of life assessment instead of visual assessment scales for assessment of dyspnea and well-being and other conventional HF symptom assessment instruments such as the Kansas City Cardiomyopathy Questionnaire. Because of the COVID-19 pandemic, we recruited patients at slower enrollment rates and over a relatively long period (2019 through 2021). The use of sacubitril-valsartan was low and patients with previous SGLT2 inhibition were excluded.

In patients with ADHF, early initiation of the SGLT2 inhibitor empagliflozin in addition to standard treatment is safe and increases urine output without affecting kidney function. Thus, addition of SGLT2 inhibition to standard diuretic therapy is a promising strategy to improve early decongestion in patients with ADHF.

Article Information

Supplemental Material

Executive Committee and Data Safety Monitoring Board

Study Protocol and Statistical Analysis Plan

Figure S1

Tables S1–S3

Nonstandard Abbreviations and Acronyms

ADHF

acute decompensated heart failure

AE

adverse event

BNP

brain natriuretic peptide

CKD-EPI

Chronic Kidney Disease Epidemiology Collaboration

eGFR

estimated glomerular filtration rate

EMPAG-HF

Empagliflozin in Acute Decompensated Heart Failure

HF

heart failure

NT-proBNP

N-terminal probrain natriuretic peptide

SAE

serious adverse event

SGLT2

sodium-glucose cotransporter-2

Disclosures Dr Schulze received honoraria and travel support from Bayer, Astra Zeneca, Daiichi Sankyo, Novartis, Actelion, Roche, Sanofi Aventis, Pharmacosmos, Medtronic, Thoratec, Boehringer Ingelheim, HeartWare, Coronus, Abbott, Edwards Inc, Boston Scientific, St Jude Medical, Abiomed, and the German Cardiac Society; research support from the National Institutes of Health, the German Research Foundation, the Else Kröner Fresenius Foundation, the German Heart Foundation, the European Society of Cardiology, Actelion, Medtronic, BMBF, Abiomed, Boehringer Ingelheim, and Boston Scientific; and served on advisory boards for the German Research Council, Eurotransplant, Novartis, Bayer, Pharmacosmos, Astra Zeneca, Boehringer Ingelheim Inc, the German Cardiac Society, and the European Society of Cardiology. Dr Möbius-Winkler received honoraria and travel support from Bayer, Daiichi Sankyo, Novartis, Boston Scientific, Abiomed, and the German Society of Cardiology; and research support from Boston Scientific and Abiomed. Dr von Haehling has been a paid consultant for or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor; and reports research support from Amgen, AstraZeneca, Boehringer Ingelheim, IMI, and the German Center for Cardiovascular Research (DZHK). Dr Busch has been a paid consultant for or received honoraria payments or travel support from Novartis, AstraZeneca, Boehringer Ingelheim, Vifor Pharma, OTSUKA, Bristol Myers Squibb, and Pfizer. The other authors report no conflicts.

Footnotes

Circulation is available at www.ahajournals.org/journal/circ

Supplemental Material, the podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.059038.

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For Sources of Funding and Disclosures, see page 297.

Correspondence to: P. Christian Schulze, MD, PhD, Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, Am Klinikum 1, 07743 Jena, Germany. Email

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