Trial Outcomes & Findings for EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) (NCT NCT03057977)

Last Updated: 2021-05-18

Results Overview

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 patient-years (pt-yrs) at risk.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3730 participants

Primary outcome timeframe

From randomisation until completion of the planned treatment period, up to 1040 days.

Results posted on

2021-05-18

Participant Flow

A randomised, double-blind trial to demonstrate superiority of empagliflozin versus placebo, in patients with chronic Heart Failure with reduced Ejection Fraction (HFrEF).

Patients were included in the trial after they had signed the informed consent form (ICF). All patients who met the all inclusion and none of the exclusion criteria during screening and at the randomisation approximately 1 to 4 weeks later were randomised to empagliflozin or placebo in a 1:1 ratio.

Participant milestones

Participant milestones
Measure	Placebo 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Discontinuation From Treatment STARTED	1867	1863
Discontinuation From Treatment Treated	1863	1863
Discontinuation From Treatment COMPLETED	1352	1381
Discontinuation From Treatment NOT COMPLETED	515	482
Discontinuation From Trial STARTED	1867	1863
Discontinuation From Trial Treated	1863	1863
Discontinuation From Trial COMPLETED	1847	1841
Discontinuation From Trial NOT COMPLETED	20	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Discontinuation From Treatment Withdrawal by Subject	124	92
Discontinuation From Treatment Lost to Follow-up	11	17
Discontinuation From Treatment Protocol Violation	6	5
Discontinuation From Treatment Not treated	4	0
Discontinuation From Treatment Adverse Event	343	337
Discontinuation From Treatment Reason Unknown	0	1
Discontinuation From Treatment Personal Reasons	1	1
Discontinuation From Treatment Unblinded medication	1	0
Discontinuation From Treatment Patient received Empagliflozin for Diabetes	1	1
Discontinuation From Treatment Principle Investigator Decision	2	0
Discontinuation From Treatment Other medical condition (no Adverse Event)	2	4
Discontinuation From Treatment Patient moved away/being abroad	4	3
Discontinuation From Treatment Unable to continue treatment	4	1
Discontinuation From Treatment Not attending study visit	3	10
Discontinuation From Treatment Due to Covid-19 Pandemic	1	4
Discontinuation From Treatment Patient decision to stop/interrupt medication	8	6
Discontinuation From Trial Lost to follow-up to primary endpoint	9	9
Discontinuation From Trial Limited follow-up agreed	2	2
Discontinuation From Trial Withdrawal by Subject	9	11

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.	Total n=3730 Participants Total of all reporting groups
Age, Continuous	66.5 Years STANDARD_DEVIATION 11.2 • n=93 Participants	67.2 Years STANDARD_DEVIATION 10.8 • n=4 Participants	66.8 Years STANDARD_DEVIATION 11.0 • n=27 Participants
Sex: Female, Male Female	456 Participants n=93 Participants	437 Participants n=4 Participants	893 Participants n=27 Participants
Sex: Female, Male Male	1411 Participants n=93 Participants	1426 Participants n=4 Participants	2837 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	613 Participants n=93 Participants	616 Participants n=4 Participants	1229 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1178 Participants n=93 Participants	1164 Participants n=4 Participants	2342 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	76 Participants n=93 Participants	83 Participants n=4 Participants	159 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	24 Participants n=93 Participants	15 Participants n=4 Participants	39 Participants n=27 Participants
Race (NIH/OMB) Asian	335 Participants n=93 Participants	337 Participants n=4 Participants	672 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	6 Participants n=93 Participants	8 Participants n=4 Participants	14 Participants n=27 Participants
Race (NIH/OMB) Black or African American	134 Participants n=93 Participants	123 Participants n=4 Participants	257 Participants n=27 Participants
Race (NIH/OMB) White	1304 Participants n=93 Participants	1325 Participants n=4 Participants	2629 Participants n=27 Participants
Race (NIH/OMB) More than one race	33 Participants n=93 Participants	28 Participants n=4 Participants	61 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	31 Participants n=93 Participants	27 Participants n=4 Participants	58 Participants n=27 Participants

PRIMARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Randomised Set: All randomised patients.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF)	21.00 Patients with events/ 100 pt-yrs at risk Interval 19.13 to 22.96	15.77 Patients with events/ 100 pt-yrs at risk Interval 14.19 to 17.44

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment phase, up to 1040 days.

Population: Randomised Set (RS): All randomised patients.

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.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent)	553 HHF events	388 HHF events

SECONDARY outcome

Timeframe: Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.

Population: Treated Set (TS): All patients treated with at least one dose of the study medication and at least one on-treatment measurement of eGFR.

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.

Outcome measures

Outcome measures
Measure	Placebo n=1792 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1799 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
eGFR (CKD-EPI) cr Slope of Change From Baseline	-2.278 Milliliter/minute/1.73 meters squared Standard Error 0.229	-0.546 Milliliter/minute/1.73 meters squared Standard Error 0.227

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Randomised Set: All randomised patients.

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 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.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr	3.07 Patients with events/ 100 pt-yrs at risk Interval 2.33 to 3.91	1.56 Patients with events/ 100 pt-yrs at risk Interval 1.06 to 2.17

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Randomised Set (RS): All randomised patients.

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.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to First Adjudicated Hospitalisation for Heart Failure (HHF)	15.55 Patients with events/ 100 pt-yrs at risk Interval 13.94 to 17.24	10.75 Patients with events/ 100 pt-yrs at risk Interval 9.45 to 12.13

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Randomised Set: All randomised patients.

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 per 100 patient-years (pt-yrs) at risk.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to Adjudicated Cardiovascular (CV) Death	8.13 Patients with events/ 100 pt-yrs at risk Interval 7.05 to 9.29	7.55 Patients with events/ 100 pt-yrs at risk Interval 6.51 to 8.67

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Randomised Set: All randomised patients.

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-years (pt-yrs) at risk.

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to All-cause Mortality	10.71 Patients with events/ 100 pt-yrs at risk Interval 9.46 to 12.04	10.06 Patients with events/ 100 pt-yrs at risk Interval 8.85 to 11.34

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment period, up to 1040 days.

Population: Patients in the randomised set with pre-DM.

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 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.

Outcome measures

Outcome measures
Measure	Placebo n=636 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=632 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Time to Onset of Diabetes Mellitus (DM)	10.62 Patients with events/ 100 pt-yrs at risk Interval 8.42 to 13.07	9.31 Patients with events/ 100 pt-yrs at risk Interval 7.27 to 11.6

SECONDARY outcome

Timeframe: Assessed at baseline, week 12, week 32 and week 52.

Population: Patients in the randomized set (RS) with available data for this endpoint, including values obtained on treatment or post-treatment.

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 indicating better health status. For patients who died, a worst score (score of 0) is imputed at all subsequent scheduled visits after the date of death. Standard error is adjusted standard error. Change from baseline in KCCQ-score at week 52 was modeled using a MMRM with visit (week 12, 32 and 52) as repeated measures, adjusted mean (standard error) at week 52 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=1395 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1401 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52	-3.36 Score on a scale Standard Error 0.69	-1.30 Score on a scale Standard Error 0.69

SECONDARY outcome

Timeframe: From randomisation until completion of the planned treatment phase, up to 1040 days.

Population: Randomised Set: All randomised patients.

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

Outcome measures

Outcome measures
Measure	Placebo n=1867 Participants 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 Participants Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Number of All-cause Hospitalizations (First and Recurrent)	1570 Hospitalizations for any cause	1364 Hospitalizations for any cause

Adverse Events

Placebo

Serious events: 896 serious events

Other events: 369 other events

Deaths: 266 deaths

10 mg Empagliflozin

Serious events: 772 serious events

Other events: 328 other events

Deaths: 249 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=1863 participants at risk 1 film-coated tablet of matching placebo was administered orally once daily.	10 mg Empagliflozin n=1863 participants at risk Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
Infections and infestations Nasopharyngitis	5.0% 94/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.	4.8% 89/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.
Metabolism and nutrition disorders Hyperkalaemia	5.9% 109/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.	5.3% 99/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.
Metabolism and nutrition disorders Hyperuricaemia	6.2% 115/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.	3.4% 63/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.
Vascular disorders Hypotension	5.9% 109/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.	6.4% 120/1863 • From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days. \[All-Cause Mortality\]: Randomised Set: All randomised patients. \[Serious Adverse Events and Other Adverse Events\]: Treated Set: All patients treated with at least one dose of study drug.

Additional Information

Boehringer Ingelheim, Call Centre

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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