Circulation

ORIGINAL RESEARCH ARTICLE

Effects of Empagliflozin on Symptoms, Physical

Limitations, and Quality of Life in Patients
Hospitalized for Acute Heart Failure: Results
From the EMPULSE Trial
Mikhail N. Kosiborod , MD*; Christiane E. Angermann , MD*; Sean P. Collins, MD, MSc; John R. Teerlink , MD;
Piotr Ponikowski , MD, PhD; Jan Biegus , MD, PhD; Josep Comin-Colet , MD, PhD; João Pedro Ferreira , MD, PhD;
Robert J. Mentz , MD; Michael E. Nassif, MD; Mitchell A. Psotka, MD, PhD; Jasper Tromp, MD, PhD;
Martina Brueckmann , MD; Jonathan P. Blatchford , CStat; Afshin Salsali, MD; Adriaan A. Voors , MD, PhD

BACKGROUND: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and
physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart
failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2
inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire
(KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized).
METHODS: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days.
The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of
clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ
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Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-
TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations,
quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model.
RESULTS: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8
[24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no
treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01–2.20], 1.37 [0.94–1.99], and
1.48 [1.00–2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed
as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater
improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean
differences [95% CI]: 4.45 [95% CI, 0.32–8.59], P=0.03; 4.80 [95% CI, 0.00–9.61], P=0.05; 4.66 [95% CI, 0.32–9.01],
P=0.04; 4.85 [95% CI, 0.77–8.92], P=0.02; and 4.40 points [95% CI, 0.33–8.48], P=0.03, respectively).
CONCLUSIONS: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless
of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with
benefits seen as early as 15 days and maintained through 90 days.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0415775.

Key Words:  acute heart failure ◼ quality of life ◼ SGLT2 inhibitor

Editorial, see p 299

Correspondence to: Mikhail N. Kosiborod, MD, Saint Luke’s Mid America Heart Institute, University of Missouri-Kansas City, 4330 Wornall Road, Suite 2000, Kansas City,
MO 64111. Email [email protected]
*M.N. Kosiborod and C.E. Angermann contributed equally.
Supplemental Material, the podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.059725.
For Sources of Funding and Disclosures, see page 287.
© 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Circulation is available at www.ahajournals.org/journal/circ

Circulation. 2022;146:279–288. DOI: 10.1161/CIRCULATIONAHA.122.059725 July 26, 2022 279

 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

P
atients hospitalized for acute heart failure (AHF)
Clinical Perspective are at high risk for cardiovascular death and read-
ORIGINAL RESEARCH

mission, and also experience an especially high bur-

What Is New? den of heart failure (HF)–related symptoms and physical
ARTICLE

• Patients hospitalized for acute heart failure experi- limitations (PLS).1–3 Accordingly, improving health status
ence a high burden of symptoms and physical limi- (symptoms, functional status, and quality of life [QoL]) is
tations and poor quality of life. In the post hoc and a key goal of HF management in this vulnerable group.
prespecified analyses of EMPULSE trial (Empa- To date, there has been a lack of therapies with a com-
gliflozin in Patients Hospitalized With Acute Heart pelling benefit on these outcomes in individuals with
Failure Who Have Been Stabilized), we investigated AHF, highlighting a critical unmet need.
the effects of the SGLT2 (sodium-glucose cotrans-
SGLT2 (sodium-glucose cotransporter 2) inhibitors
porter 2) inhibitor empagliflozin on total clinical ben-
have emerged as a therapeutic option for patients with
efit across the range of symptomatic impairment at
baseline and its effect on symptoms, physical limita- HF. Several clinical trials have demonstrated that these
tions, and quality of life, using the Kansas City Car- agents significantly improve symptoms and PLS in ambu-
diomyopathy Questionnaire. latory patients with HF, regardless of ejection fraction.4–8
• We found that initiation of empagliflozin in patients However, whether these effects are also observed in
hospitalized for acute heart failure produced clini- individuals with AHF—the group with greatest symptom-
cal benefit regardless of the degree of symptomatic atic and functional limitations—remains largely unknown.
impairment at baseline and improved symptoms, In the EMPULSE trial (Empagliflozin in Patients Hos-
physical limitations, and quality of life, with benefits pitalized With Acute Heart Failure Who Have Been Sta-
seen as early as 15 days and maintained through bilized), we previously demonstrated that empagliflozin
90 days.
10 mg daily, compared with placebo, resulted in a signifi-
cant clinical benefit (composite of death, HF events, or
What Are the Clinical Implications? change in symptom burden) among individuals hospital-
• These observations are of clinical relevance
ized with AHF, regardless of ejection fraction, HF status
because few therapies have been shown to improve
symptoms and functional status in the early post- (de novo versus decompensated chronic HF), or diabetes
discharge period in patients hospitalized with acute status.9,10 In this report, we sought to address the follow-
heart failure. ing 2 key objectives: (1) to evaluate, in post hoc analyses,
whether the effects of empagliflozin on the primary end
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• The findings were consistent across multiple sub-

groups, extending the health status benefits of point of total clinical benefit in the EMPULSE trial varied
SGLT2 inhibitors to patients hospitalized with acute according to the degree of symptomatic impairment at
heart failure regardless of ejection fraction, de novo baseline; and (2) to examine, in prespecified analyses,
versus chronic decompensated heart failure status, the effect of empagliflozin on the broader range of health
and degree of symptomatic impairment at baseline. status outcomes, as measured by the various domains
of the Kansas City Cardiomyopathy Questionnaire
(KCCQ)—a validated, self-administered instrument that
quantifies HF-related symptoms, function, and QoL,11 as
Nonstandard Abbreviations and Acronyms well as the time course of these effects.
AHF acute heart failure
BNP B-type natriuretic peptide
METHODS
CSS clinical summary score
EMPULSE (URL: https://www.clinicaltrials.gov; Unique iden-
EMPULSE Empagliflozin in Patients Hospitalized tifier: NCT0415775) was a randomized, double-blind, pla-
With Acute Heart Failure Who Have cebo-controlled trial in patients with AHF (both de novo and
Been Stabilized decompensated chronic HF, with reduced or preserved ejection
HF heart failure fraction, and with or without type 2 diabetes) that evaluated the
KCCQ Kansas City Cardiomyopathy efficacy and safety of empagliflozin 10 mg once daily, com-
Questionnaire pared with placebo, when added to standard care. The design,
NT-proBNP N-terminal pro-B-type natriuretic baseline characteristics, and primary results of the trial have
peptide been published.9 The Ethics Committee of each of the 118
OSS overall summary score participating institutions (in 15 countries) approved the proto-
col, and all patients gave written informed consent. Boehringer
PLS physical limitations Ingelheim was responsible for data collection and storage. The
QoL quality of life academic members of the executive committee provided an
SGLT2 sodium-glucose cotransporter 2 independent interpretation of the results. The authors made the
TSS Total Symptom Score decision to submit the article for publication, and assume full
responsibility for the accuracy and completeness of the data.

280 July 26, 2022 Circulation. 2022;146:279–288. DOI: 10.1161/CIRCULATIONAHA.122.059725

 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

Study Patients quantifies the symptom frequency and severity. Additional

domains included in this analysis were KCCQ PLS and QoL

ORIGINAL RESEARCH
Men and women aged ≥18 years (or above the age of legal
consent according to local legislation) were eligible if they were scores, as well as clinical summary score (CSS), which incor-
porates the physical function and symptoms domains, and

ARTICLE
hospitalized with a primary diagnosis of AHF with dyspnea on
exertion or at rest, and had at least 2 of the following: con- KCCQ overall summary score (OSS), which is derived from all
gestion on chest radiograph, rales on chest auscultation, clini- domains (TSS, physical function, QoL, and social function). For
cally relevant edema, or an elevated jugular venous pressure. each domain, the validity, reproducibility, responsiveness, and
Participants were randomized after at least 24 hours and no interpretability have been independently established.11 Scores
later than 5 days after admission, as early as possible after are transformed to a range of 0 to 100, in which higher scores
stabilization, and while still in the hospital. Stabilization crite- reflect better health status.
ria were a systolic blood pressure of at least 100 mm Hg; no
inotropic support for at least 24 hours; no symptoms of hypo- Statistical Analysis
tension; no increase in the intravenous diuretic dose and no In a post hoc analysis, patients were divided into 3 subgroups,
intravenous vasodilators in the 6 hours before randomization. on the basis of the tertiles of baseline KCCQ-TSS (which was
Patients were required to have an NT-proBNP (N-terminal pro- the KCCQ domain prespecified as a component of the pri-
B-type natriuretic peptide) concentration of at least 1600 pg/ mary, as well as a secondary end point): (1) <27.1, (2) ≥27.1
mL or a BNP (B-type natriuretic peptide) concentration of at to <52.1, and (3) ≥52.1 points. Baseline characteristics were
least 400 pg/mL (NT-proBNP or BNP of at least 2400 pg/mL summarized as means and SDs, medians, and interquartile
or 600 pg/mL, respectively, if atrial fibrillation was present) and ranges, or percentages. Ordinal regression likelihood ratio
have received at least 40 mg (20 mg for Japanese patients) tests were used to compare trends across tertile categories
of intravenous furosemide or equivalent. Key exclusion criteria of KCCQ-TSS at baseline.
included cardiogenic shock; pulmonary embolism, cerebrovas- To evaluate the effects of empagliflozin versus placebo on
cular accident, or acute myocardial infarction as the primary the primary hierarchical composite end point of clinical benefit
trigger for the current hospitalization or in the preceding 90 across the KCCQ-TSS tertiles, we conducted a post hoc analy-
days; current or expected cardiac transplantation, left ventricu- sis comparing patients randomized to empagliflozin with those
lar assist device, or inotropic support; an estimated glomerular randomized to placebo, within tertiles of baseline KCCQ-TSS.
filtration rate <20 mL/min/1.73m2 or requiring dialysis; and Each comparison of 2 patients followed the hierarchy of com-
previous ketoacidosis. A full list of exclusion criteria is provided paring time to death, number of HF events, time to HF event,
in the design article.10 or a 5-point or greater difference in change from baseline in
the KCCQ-TSS at day 90, until conclusion of a win or loss or
Downloaded from http://ahajournals.org by on September 13, 2022

Study Procedures otherwise concluding by a tie, as previously described.9 We cal-

culated the win ratio as the number of wins in the empagliflozin
After the provision of informed consent, patients were
group divided by the number of losses. The treatment effect
screened, and if eligible, randomized to empagliflozin 10 mg
by baseline KCCQ-TSS tertile interaction was tested using
daily or matching placebo. Efficacy and safety parameters
Cochran’s Q statistic (inverse variance-weighting approach).
were assessed during follow-up visits at 3, 5, 15, 30, and 90
A multiple imputation approach, according to whether patients
days after randomization. During the onsite visits at 15, 30,
were on treatment or off treatment, was used to impute missing
and 90 days, patients’ health status was assessed using the
data for the KCCQ-TSS, as previously described.9
KCCQ. Because of the ongoing COVID-19 pandemic, phone
We analyzed the differences between treatment groups in
or home visits were allowed if patients were unable to attend
mean KCCQ-TSS, PLS, QoL, CSS, and OSS at days 15, 30,
the study visit in person.
and 90 using a mixed effects model for repeated measures
adjusted for HF status and baseline score by visit interaction;
Primary Outcome KCCQ-TSS at 90 days was a prespecified secondary end
The primary outcome was clinical benefit at 90 days, defined as point, and the rest were prespecified exploratory end points. In
a hierarchical composite end point of time to all-cause death, addition, we performed a post hoc analysis evaluating whether
the number of HF events (defined as HF hospitalizations, the effects of empagliflozin versus placebo on change in
urgent HF visits, and unplanned outpatient HF visits), time to KCCQ-TSS from baseline to 90 days differed across multiple
first HF event, and a 5-point or greater difference in change subgroups on the basis of patients’ demographic and clinical
from baseline in KCCQ Total Symptom Score (TSS) after 90 characteristics at baseline.
days of treatment. We conducted responder analyses examining proportions of
patients with a deterioration (≥5 point worsening), and clinically
important improvements in KCCQ-TSS at 90 days, using estab-
Kansas City Cardiomyopathy Questionnaire lished, clinically meaningful thresholds for KCCQ (≥5 point
The KCCQ was completed electronically by patients, without [at least small], ≥10 point [moderate], and ≥20 point [large]
assistance by site study staff (as validated), and evaluated at change) for all responder analyses. Among these outcomes, the
randomization, 15, 30, and 90 days. The KCCQ is a 23-item, proportion of patients with a ≥10 point improvement in KCCQ-
self-administered disease-specific instrument that quantifies TSS was a prespecified secondary, whereas ≥5 point and ≥20
symptoms (frequency, severity, and recent change), physical point improvements were prespecified exploratory end points,
function, QoL, and social function over the previous 2 weeks. and ≥5 point worsening end point was analyzed post hoc. The
KCCQ-TSS, which was a prespecified secondary outcome, proportion of responders was compared between those treated

Circulation. 2022;146:279–288. DOI: 10.1161/CIRCULATIONAHA.122.059725 July 26, 2022 281

 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

with empagliflozin versus placebo using multiple imputation to effect heterogeneity (win ratio [95% CI] from lowest to
account for missing KCCQ values. Odds ratios to estimate dif- highest tertile: 1.49 [95% CI, 1.01–2.20], 1.37 [95% CI,
ORIGINAL RESEARCH

ferences between treatment groups, and their corresponding 0.94–1.99], and 1.48 [95% CI, 1.00–2.20], respectively;
95% CIs and 2-sided P values, were estimated from logistic P for interaction=0.94; Figure 1).
ARTICLE

regression models (which included treatment group, stratifica-

tion variable [de novo versus decompensated chronic HF], and
baseline KCCQ-TSS values). All analyses were performed with Health Status Outcomes
SAS software, version 9.3 or higher (SAS Institute). P values
of 0.05 were considered statistically significant, and were not Baseline KCCQ-TSS was low overall (mean [SD], 40.8
adjusted for multiple comparisons. [24.0] points), and improved substantially by 90 days
(mean [95% CI] change in empagliflozin group, +36.2
[95% CI, 33.3–39.1]; placebo group, +31.7 [95%
Data Sharing Statement CI, 28.8–34.7]). The mean changes in KCCQ-TSS,
The data that support the findings of this study are available
PLS, QoL, CSS, and OSS over time are presented in
on reasonable request. To ensure independent interpretation
Figure 2A, 2B, 2C, 2D, and 2E, respectively. Empa-
of clinical study results and enable authors to fulfill their role
and obligations under the International Committee of Medical gliflozin-treated patients had a greater improvement in
Journal Editors criteria, Boehringer Ingelheim grants all exter- KCCQ-TSS, PLS, QoL, CSS, and OSS at day 90 (pla-
nal authors access to relevant clinical study data. In adher- cebo-adjusted mean differences [95% CI]: 4.45 [95%
ence with the Boehringer Ingelheim Policy on Transparency CI, 0.32–8.59], P=0.03; 4.80 [95% CI, 0.00–9.61],
and Publication of Clinical Study Data, scientific and medical P=0.05; 4.66 [95% CI, 0.32–9.01], P=0.04; 4.85 [95%
researchers can request access to clinical study data after CI, 0.77–8.92], P=0.02; and 4.40 [95% CI, 0.33–8.48],
publication of the primary article in a peer-reviewed journal, P=0.03, respectively), with significant benefits already
regulatory activities are complete, and other criteria are met. present as early as 15 days (eg, for KCCQ-TSS, place-
Researchers should use the https://vivli.org/ link to request bo-adjusted mean difference, 5.35 [95% CI, 1.51–9.19]
access to study data and visit https://www.mystudywindow.
points; P<0.01) and maintained through 90 days. The
com/msw/datasharing for further information.
results in terms of KCCQ-TSS at 90 days for empa-
gliflozin versus placebo-treated patients were generally
consistent across the prespecified demographic and
RESULTS clinical subgroups, including ejection fraction of ≤40
Overall, 530 patients were randomized (265 each arm); versus >40%, de novo versus chronic decompensated
Downloaded from http://ahajournals.org by on September 13, 2022

526 patients (99.2% of the overall trial population) had AHF, and degree of symptomatic impairment (measured
KCCQ data available at baseline. Of these, 473 patients by tertiles of KCCQ-TSS) at baseline (Figure 3).
(89.2% of the overall trial population) had KCCQ evalu- The results of the responder analysis at 90 days
ated at 15 days; 471 (88.9% of the overall trial popula- are shown in Figure S1, and include the proportion
tion) had KCCQ evaluated at 30 days; and 451 (85.1% of patients treated with empagliflozin versus placebo
of the overall trial population) had KCCQ evaluated at 90 that had a clinically significant deterioration (≥5 point
days. The proportions of patients with missing KCCQ val- decline in KCCQ-TSS [8.0% versus 11.7%; odds ratio,
ues were similar in the empagliflozin and placebo groups 0.67 [95% CI, 0.35–1.30; P=0.24); and at least small
at 15, 30, and 90 days (12.1% versus 9.4%, 10.6% ver- (87.5% versus 82.4%), moderate (83.1% versus 76.3%),
sus 11.7%, and 13.2% versus 16.6%, respectively). The or large (70.4% versus 65.5%) improvements in KCCQ-
number and proportion of patients in the KCCQ-TSS ter- TSS (corresponding odds ratio [95% CI]: 1.49 [95% CI,
tiles are shown in the Table. 0.84–2.64], P=0.17; 1.52 [95% CI, 0.93–2.50], P=0.10;
Compared with participants with higher KCCQ-TSS 1.22 [95% CI, 0.78–1.89], P=0.38); these results did not
scores at baseline, those with lower scores were younger; reach statistical significance.
more often women, Black or African American, enrolled in
North America, with a history of hypertension and type 2
diabetes; had higher New York Heart Association class, DISCUSSION
body mass index, and NT-proBNP; and were more likely to In this secondary analysis of the EMPULSE trial, we ob-
have chronic decompensated versus de novo AHF (Table). served that treatment with empagliflozin improved the
end point of total clinical benefit among patients hos-
pitalized with AHF to a similar extent across the entire
Clinical Outcomes range of KCCQ, indicating that the beneficial effects of
The effects of empagliflozin on the primary hierarchical empagliflozin on HF outcomes in this patient group are
end point of clinical benefit stratified by KCCQ-TSS ter- independent of the health status impairment at base-
tiles are summarized in Figure 1. Patients treated with line. Moreover, empagliflozin significantly improved all
empagliflozin experienced greater clinical benefit across key KCCQ domains, including TSS, PLS, QoL, CSS, and
the range of KCCQ-TSS, with no evidence of treatment OSS (which collectively encompass symptoms, physical

282 July 26, 2022 Circulation. 2022;146:279–288. DOI: 10.1161/CIRCULATIONAHA.122.059725

 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

Table.  Baseline Characteristics of the EMPULSE Study Population by Tertiles of KCCQ

ORIGINAL RESEARCH
KCCQ-TSS at baseline
P value for
Tertile 1 (n=166) Tertile 2 (n=184) Tertile 3 (n=176) Total (n=526) trend

ARTICLE
Demographic characteristics
  Age, y, mean (SD) 66.5 (13.4) 69.5 (12.9) 69.4 (13.3) 68.5 (13.3) 0.045
  Sex, n (%) 0.014
 Male 98 (59.0) 125 (67.9) 126 (71.6) 349 (66.3)
 Female 68 (41.0) 59 (32.1) 50 (28.4) 177 (33.7)
  Race/ethnicity, n (%) <0.001
 White 130 (78.3) 150 (81.5) 129 (73.3) 409 (77.8)
  Black/African American 22 (13.3) 19 (10.3) 13 (7.4) 54 (10.3)
 Asian 11 (6.6) 12 (6.5) 34 (19.3) 57 (10.8)
 Other 2 (1.2) 3 (1.6) 0 5 (1.0)
 Missing 1 (0.6) 0 0 1 (0.2)
  Geographic region, n (%) <0.001
 Asia 10 (6.0) 12 (6.5) 34 (19.3) 56 (10.6)
 Europe 96 (57.8) 129 (70.1) 112 (63.6) 337 (64.1)
  North America 60 (36.1) 43 (23.4) 30 (17.0) 133 (25.3)
Medical history, n (%)
  Cause of HF 0.733
  Ischemic 47 (28.3) 54 (29.3) 47 (26.7) 148 (28.1)
  Nonischemic 119 (71.7) 130 (70.7) 129 (73.3) 378 (71.9)
  Previous MI 36 (21.7) 44 (23.9) 47 (26.7) 127 (24.1) 0.277
  Previous CABG or PCI 45 (27.1) 53 (28.8) 55 (31.3) 153 (29.1) 0.398
 Hypertension 143 (86.1) 151 (82.1) 130 (73.9) 424 (80.6) 0.004
Downloaded from http://ahajournals.org by on September 13, 2022

 T2DM 93 (56.0) 78 (42.4) 66 (37.5) 237 (45.1) <0.001

  Atrial fibrillation 84 (50.6) 92 (50.0) 84 (47.7) 260 (49.4) 0.592
HF characteristics
  HF status, n (%) 0.025
  De novo 43 (25.9) 65 (35.3) 66 (37.5) 174 (33.1)
  Decompensated chronic 123 (74.1) 119 (64.7) 110 (62.5) 352 (66.9)
  NYHA class, n (%) <0.001
  II 26 (15.7) 76 (41.3) 84 (47.7) 186 (35.4)
  III 105 (63.3) 96 (52.2) 76 (43.2) 277 (52.7)
  IV 33 (19.9) 10 (5.4) 6 (3.4) 49 (9.3)
  KCCQ-TSS (points), mean (SD) 14.4 (7.8) 37.9 (7.3) 68.8 (12.6) 40.8 (24.0) <0.001
  KCCQ-TSS (points), median (IQR) 14.6 (8.3–20.8) 37.5 (31.3–44.8) 66.7 (58.3–77.1) 37.5 (21.9–58.3)
Vital signs, mean (SD)
  Systolic BP, mm Hg 124.6 (18.0) 123.0 (18.0) 124.6 (18.2) 124.0 (18.1) 0.997
  Diastolic BP, mm Hg 72.4 (13.4) 72.9 (11.1) 74.2 (12.3) 73.2 (12.3) 0.166
  Heart rate, bpm 77.8 (14.8) 76.5 (14.3) 74.9 (12.9) 76.4 (14.0) 0.056
  Body mass index, kg/m 2
32.6 (9.1) 30.0 (7.7) 27.4 (5.9) 29.9 (7.9) <0.001
Laboratory values
  eGFR, mL/min/1.73 m2, mean (SD) 52.8 (20.9) 55.1 (20.6) 54.2 (19.5) 54.1 (20.3) 0.566
  NT-proBNP, pg/mL, median (IQR) 3687.3 3188.7 2520.2 3245.8 0.004
(2143.9–6446.8) (1725.2–5936.8) (1463.1–6012.9) (1735.4–6104.3)
Heart failure treatments, n (%)
 ACEI/ARB/ARNI 107 (64.5) 136 (73.9 125 (71.0) 368 (70.0) 0.194

(Continued )

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 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

Table. Continued
ORIGINAL RESEARCH

KCCQ-TSS at baseline
P value for
Tertile 1 (n=166) Tertile 2 (n=184) Tertile 3 (n=176) Total (n=526) trend
ARTICLE

  β-Blocker 136 (81.9) 137 (74.5) 145 (82.4) 418 (79.5) 0.877

  MRA 83 (50.0) 89 (48.4) 102 (58.0) 274 (52.1) 0.133

  Diuretics other than MRA 144 (86.7) 154 (83.7) 143 (81.3) 441 (83.8) 0.169
Implanted devices, n (%)
  Pacemaker 2 (1.2) 6 (3.3) 2 (1.1) 10 (1.9) 0.935
  ICD 19 (11.4) 21 (11.4) 21 (11.9) 61 (11.6) 0.886

ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BP, blood pressure;
CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; EMPULSE, Empagliflozin in Patients Hospitalized With Acute Heart Failure Who
Have Been Stabilized; HF, heart failure; ICD, implantable cardioverter defibrillator; IQR, interquartile range; KCCQ, Kansas City Cardiomyopathy Questionnaire; MI,
myocardial infarction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PCI,
percutaneous coronary intervention; T2DM, type 2 diabetes; and TSS, total symptom score.

function, QoL, and social function), with benefits gener- on patients earlier in the course of hospitalization, during
ally consistent regardless of demographic and clinical a more acute phase. Second, we included patients with
characteristics, seen as early as 15 days, and maintained de novo AHF, a previously unstudied but important group.
through 90 days. Third, our trial enrolled individuals both with and without
These results expand on the previously reported effects type 2 diabetes. Fourth, we demonstrated the benefits of
of empagliflozin specifically, and SGLT2 inhibitors overall, SGLT2 inhibition in the immediate postdischarge period,
on health status, as measured by KCCQ in patients with starting as early as 15 days. Last, we extended the analy-
HF. Several previous trials demonstrated that empagliflozin ses to the entire spectrum of HF-related health status by
and dapagliflozin improve symptoms and PLS in outpatients evaluating all key KCCQ domains.
with HF and reduced ejection fraction.4–6 More recent trials Our results are of clinical importance, because few
also show that these agents similarly improve health sta- therapies have been previously shown to improve symp-
tus in ambulatory patients with HF and preserved ejection toms and functional status in the early postdischarge
fraction.7,8 However, until now, the data about the effects period in individuals hospitalized with AHF. To our knowl-
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of this class on symptoms, physical function, and QoL in edge, the only other pharmacotherapy shown to have
patients hospitalized for AHF have been limited. The only such benefits (aside from SGLT inhibition) is intravenous
trial that previously evaluated a similar patient population is ferric carboxymaltose, which improved KCCQ-12 OSS by
SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular 3.7 points at 12 weeks in the AFFIRM-AHF trial (Study
Events in Patients With Type 2 Diabetes Post Worsening to Compare Ferric Carboxymaltose With Placebo in
Heart Failure), which enrolled patients with type 2 diabetes Patients With Acute Heart Failure and Iron Deficiency).13
hospitalized with or recently discharged after an episode of However, that study specifically focused on individuals
decompensated HF, and showed favorable effects of sota- with iron deficiency and ejection fraction <50%, and
gliflozin, a mixed SGLT1/2 inhibitor, on the 12-item KCCQ these benefits did not emerge until after the first 2 weeks.
score at 4 months (mean 4.1-point improvement com- Demonstrating health status benefits in this patient
pared with placebo).12 Our findings from EMPULSE add population is especially challenging, because the indi-
to these data in several ways. First, we specifically focused viduals hospitalized for AHF have marked symptomatic

Figure 1. Effects of empagliflozin vs placebo on the primary hierarchical composite end point of clinical benefit across tertiles
of KCCQ-TSS.
KCCQ-TSS indicates Kansas City Cardiomyopathy Questionnaire-Total Symptom Score.

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 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

ORIGINAL RESEARCH
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Figure 2. Effects of empagliflozin vs placebo on change in KCCQ domains over time.

A, TSS. B, OSS. C, CSS. D, PLS. E, QoL. The data are presented as adjusted least-square means ± SE. CSS indicates clinical summary score;
KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, overall summary score; PLS, physical limitations score; QoL, quality of life; and TSS, total
symptom score.
and functional impairments at the time of randomization, These observations may also be of potential rel-
and because the result of aggressive management during evance when considered in the context of the 30-day
hospitalization and the immediate postdischarge period mortality and readmission metric, which, at least in the
tend to experience marked improvements in health sta- United States, is currently used to assess the quality of
tus, regardless of whether they are assigned to active care for patients hospitalized for AHF (and for which
treatment or placebo. This was the case in EMPULSE, poor performance may lead to financial penalties).14 To
as well as in many other previous trials in AHF.2,12,13 Our our knowledge, the early improvement in KCCQ (a well-
findings of significant improvements in every domain of known predictor of cardiovascular death and HF read-
KCCQ, seen just after 2 weeks postdischarge, and per- missions15) that we observed with empagliflozin at 15
sisting to 3 months, are, therefore, especially notable. days is the first such observation, and if corroborated

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 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure
ORIGINAL RESEARCH
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Figure 3. Effects of empagliflozin vs placebo on KCCQ-TSS at day 90 across prespecified subgroups.

AF indicates atrial fibrillation; eGFR, estimated glomerular filtration rate; HF, heart failure; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire-
Total Symptom Score; LVEF, left ventricular ejection fraction; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

by future studies would suggest that initiation of SGLT2 missing KCCQ values was similar among those treated
inhibitors during hospitalization for AHF may be a tool with empagliflozin and placebo. Third, the relatively mod-
for improving the quality of hospital-to-home transitions. est sample size of this study did not provide sufficient
The results of this study should be considered in the power for the responder analyses. However, the large
context of several potential limitations. First, although spontaneous improvement in KCCQ observed in both
KCCQ-TSS was a component of the primary composite the empagliflozin and placebo groups during the imme-
end point, and a predefined secondary end point, and pro- diate postdischarge period (and likely associated with
spective assessments of KCCQ domains were prespeci- intensification of HF treatment) makes the traditional
fied, several of the analyses, including the evaluation of KCCQ thresholds for responder analyses more method-
the primary end point by tertiles of baseline KCCQ-TSS, ologically challenging, and less meaningful. Fourth, the
were performed post hoc. Second, as in most trials, some follow-up period of 90 days was relatively short. Last, as
patients had missing health status assessments during in all trials, the inclusion and exclusion criteria may limit
follow-up; however, the proportion of participants with generalizability.

286 July 26, 2022 Circulation. 2022;146:279–288. DOI: 10.1161/CIRCULATIONAHA.122.059725

 Kosiborod et al Empagliflozin and KCCQ in Acute Heart Failure

In conclusion, initiation of empagliflozin in patients Centered Outcomes Research Institute, AstraZeneca, and Beckman Coulter. Dr
Teerlink has received research support and/or has been a consultant for Amgen,
hospitalized for AHF produced clinical benefit regardless

ORIGINAL RESEARCH
AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics,
of the degree of symptomatic impairment at baseline, and Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr Ponikowski re-
improved symptoms, PLS, and QoL, with benefits seen as ports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers

ARTICLE
Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie, and grants and personal
early as 15 days and maintained through 90 days. fees from Vifor Pharma. Dr Comin-Colet has received unrestricted grants from Vifor
and Novartis paid directly to his institute, and consulting fees from AstraZeneca,
Bayer, and Boehringer Ingelheim. Dr Ferreira is a consultant for Boehringer Ingel-
ARTICLE INFORMATION heim and receives research support from AstraZeneca. Dr Mentz reports research
support and personal fees from Boehringer Ingelheim, Abbott, American Regent,
Received February 18, 2022; accepted March 17, 2022. Amgen, AstraZeneca, Bayer, Boston Scientific, Cytokinetics, Fast BioMedical, Gil-
This work was presented as an abstract at ACC Scientific Sessions, April ead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor,
2–4, 2022. Windtree Therapeutics, and Zoll. Dr Nassif has received speaking honoraria from
Abbott and is a consultant for Vifor, Roche, and Amgen. Dr Tromp is supported by the
Affiliations National University of Singapore Start-Up grant; has been a consultant for and holds
Saint Luke’s Mid America Heart Institute, Kansas City, MO (M.N.K., M.E.N.). School minor stocks in Us2.ai; has received personal fees from Roche Diagnostics, Daiichi
of Medicine, University of Missouri-Kansas City (M.N.K., M.E.N.). The George Insti- Sankyo, and Boehringer Ingelheim; and has a patent awarded for an “automatic
tute for Global Health, University of New South Wales, Sydney, Australia (M.N.K.). clinical workflow” that recognizes and analyzes 2-dimensional and Doppler modality
Comprehensive Heart Failure Centre, University and University Hospital of Würz- echocardiogram images for automated cardiac measurements. Dr Brueckmann and
burg, Germany (C.E.A.). Department of Emergency Medicine, Vanderbilt University Dr Salsali are employees of Boehringer Ingelheim. J.P. Blatchford is an employee of
Medical Center, Nashville, TN (S.P.C.). Geriatric Research and Education Clinical Elderbrook Solutions GmbH. Dr Voors has received research support or has been a
Care, Tennessee Valley Healthcare Facility VA Medical Center, Nashville (S.P.C.). consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics,
Section of Cardiology, San Francisco Veterans Affairs Medical Center and School Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Drs Biegus and
of Medicine, University of California San Francisco (J.R.T.). Institute of Heart Dis- Psotka report no conflicts.
eases, Medical University, Wroclaw, Poland (P.P., J.B.). Hospital Universitari de
Bellvitge, The Institute of Biomedical Research of Bellvitge (IDIBELL), Barcelona, Supplemental Material
Spain (J.C.-C.). Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France Figure S1
(J.P.F.). Cardiovascular Research and Development Center, Department of Surgery
and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.).
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