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NCT03057977

EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)

Completed Phase 3 Results posted Last updated 18 May 2021
What this trial tests

Phase 3 trial testing Empagliflozin in Heart Failure in 3,730 participants. Completed in 28 May 2020.

Timeline
6 March 2017
Primary endpoint
1 May 2020
28 May 2020

Quick facts

Lead sponsorBoehringer Ingelheim
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingdouble
Primary purposetreatment
Enrollment3,730
Start date6 March 2017
Primary completion1 May 2020
Estimated completion28 May 2020
Sites520 locations across Italy, Japan, Poland, South Korea, Netherlands, Belgium, Mexico, Czechia

Drugs / interventions tested

Conditions studied

Sponsor

Boehringer Ingelheim — full company profile →

Who can join

18 and older, any sex, with Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) Primary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to the first event of adjudicated cardiovascular (CV) death or adjudicated hospitalisation for heart failure (HHF). The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 pat

GroupValue95% CI
Placebo21.0019.13 – 22.96
10 mg Empagliflozin15.7714.19 – 17.44
Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent) Secondary · From randomisation until completion of the planned treatment phase, up to 1040 days.

Reported is the total number of HHF events (first and recurrent) which occurred. All data up to the end of the planned treatment period (including the data after the end of treatment for patients not completing the treatment period as planned) from all randomised patients was used.

GroupValue95% CI
Placebo553
10 mg Empagliflozin388
eGFR (CKD-EPI) cr Slope of Change From Baseline Secondary · Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.

Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) \[mL/min/1.73m2\] slope of change from baseline. Available on-treatment change-from-baseline data were to be used. Patients without on-treatment data after randomisation were not to be included in this analysis. Slope represents the long term effect on eGFR. Timepoints after baseline were included in calculation of slope of change from baseline. Descriptive statistic (mean(standard error)) is reported.

GroupValue95% CI
Placebo-2.278± 0.229
10 mg Empagliflozin-0.546± 0.227
Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr Secondary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to the first event in the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), renal transplant, or sustained reduction in Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr). The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a

GroupValue95% CI
Placebo3.072.33 – 3.91
10 mg Empagliflozin1.561.06 – 2.17
Time to First Adjudicated Hospitalisation for Heart Failure (HHF) Secondary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to first adjudicated Hospitalisation for Heart Failure (HHF). The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

GroupValue95% CI
Placebo15.5513.94 – 17.24
10 mg Empagliflozin10.759.45 – 12.13
Time to Adjudicated Cardiovascular (CV) Death Secondary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to adjudicated CV (Cardiovascular) death. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events

GroupValue95% CI
Placebo8.137.05 – 9.29
10 mg Empagliflozin7.556.51 – 8.67
Time to All-cause Mortality Secondary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to all-cause mortality. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-ye

GroupValue95% CI
Placebo10.719.46 – 12.04
10 mg Empagliflozin10.068.85 – 11.34
Time to Onset of Diabetes Mellitus (DM) Secondary · From randomisation until completion of the planned treatment period, up to 1040 days.

Time to onset of DM (Glycated haemoglobin (HbA1c) ≥6.5% or as diagnosed by the investigator) in patients with pre-DM (no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of 5.7 to \<6.5%). The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 \* number of patients with event /time at risk \[years\]) is presented. With time at risk \[year\] calculated as: Sum of time at risk \[days\] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censo

GroupValue95% CI
Placebo10.628.42 – 13.07
10 mg Empagliflozin9.317.27 – 11.60
Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52 Secondary · Assessed at baseline, week 12, week 32 and week 52.

Change from baseline in KCCQ (Kansas City cardiomyopathy questionnaire) clinical summary score at Week 52. The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, selfefficacy, and quality of life in patients with Heart Failure. The KCCQ-clinical summary score comprises the following domains: Symptom frequency, symptom burden and physical limitation. The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicatin

GroupValue95% CI
Placebo-3.36± 0.69
10 mg Empagliflozin-1.30± 0.69
Number of All-cause Hospitalizations (First and Recurrent) Secondary · From randomisation until completion of the planned treatment phase, up to 1040 days.

Number of all-cause hospitalizations (first and recurrent).

GroupValue95% CI
Placebo1570
10 mg Empagliflozin1364

Adverse events — posted to ClinicalTrials.gov

Time frame: From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 896/1863 (48%)
Deaths: 266/1867
10 mg Empagliflozin
Serious: 772/1863 (41%)
Deaths: 249/1863

Serious adverse events (581 terms)

ReactionSystemPlacebo10 mg Empagliflozin
Cardiac failureCardiac disorders
PneumoniaInfections and infestations
Ventricular tachycardiaCardiac disorders
Acute kidney injuryRenal and urinary disorders
Atrial fibrillationCardiac disorders
Cardiac failure congestiveCardiac disorders
Cardiac failure chronicCardiac disorders
Cardiac failure acuteCardiac disorders
DeathGeneral disorders
Renal impairmentRenal and urinary disorders
Acute myocardial infarctionCardiac disorders
Ischaemic strokeNervous system disorders
Cerebrovascular accidentNervous system disorders
SyncopeNervous system disorders
Coronary artery diseaseCardiac disorders
Myocardial infarctionCardiac disorders
FallInjury, poisoning and procedural complications
Urinary tract infectionInfections and infestations
Renal failureRenal and urinary disorders
HypotensionVascular disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
Angina unstableCardiac disorders
Atrial flutterCardiac disorders
Cardiogenic shockCardiac disorders
AnaemiaBlood and lymphatic system disorders
Other adverse events (4 terms — click to expand)

ReactionSystemPlacebo10 mg Empagliflozin
HypotensionVascular disorders
HyperuricaemiaMetabolism and nutrition disorders
HyperkalaemiaMetabolism and nutrition disorders
NasopharyngitisInfections and infestations

Most-reported serious reactions: Cardiac failure, Pneumonia, Ventricular tachycardia, Acute kidney injury, Atrial fibrillation, Cardiac failure congestive, Cardiac failure chronic, Cardiac failure acute.

Data from ClinicalTrials.gov NCT03057977 adverse events section.

Sponsor's own description

The aim of the study is to investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.
    Packer M, Anker SD, Butler J, Filippatos G, et al · · 2020 · cited 3605× · PMID 32865377 · DOI 10.1056/nejmoa2022190
  2. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials.
    Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, et al · · 2017 · cited 330× · PMID 29061576 · DOI 10.1161/circulationaha.117.030012
  3. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.
    Packer M, Anker SD, Butler J, Filippatos G, et al · · 2021 · cited 281× · PMID 33081531 · DOI 10.1161/circulationaha.120.051783
  4. Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.
    Packer M, Butler J, Zannad F, Filippatos G, et al · · 2021 · cited 268× · PMID 34459213 · DOI 10.1161/circulationaha.121.056824
  5. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.
    Anker SD, Butler J, Filippatos G, Khan MS, et al · · 2021 · cited 248× · PMID 33175585 · DOI 10.1161/circulationaha.120.051824
  6. Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity.
    Pereira MJ, Eriksson JW. · · 2019 · cited 231× · PMID 30701480 · DOI 10.1007/s40265-019-1057-0
  7. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.
    Das SR, Everett BM, Birtcher KK, Brown JM, et al · · 2018 · cited 222× · PMID 30497881 · DOI 10.1016/j.jacc.2018.09.020
  8. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced.
    Zannad F, Ferreira JP, Pocock SJ, Zeller C, et al · · 2021 · cited 210× · PMID 33095032 · DOI 10.1161/circulationaha.120.051685

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Trials by the same sponsor.

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