Myocardial Infarction
Conditions
Brief summary
This is a study in adults who had a heart attack (myocardial infarction). The purpose of this study is to find out whether a medicine called empagliflozin helps to lower the chances of having to go to the hospital for heart failure and whether it lowers the chances of dying from cardiovascular disease. People who are in hospital may join the study soon after being treated for their heart attack. Participants are put into 2 groups by chance. One group takes 1 empagliflozin tablet a day. The other group takes 1 placebo tablet a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. All participants continue their standard treatment. Empagliflozin belongs to a class of medicines known as SGLT-2 inhibitors. Empagliflozin is a medicine that helps people with type 2 diabetes to lower their blood sugar. Researchers think that empagliflozin might also help people after heart attack who are at risk for heart failure, whether or not they have diabetes. Participants are in the study for about 1 to 2 years. During this time, there are about 4 visits inperson, 2 visits are done either by phone or by use of an mobile application. Results between the empagliflozin and placebo groups are compared. The doctors also regularly check the general health of the participants.
Interventions
DRUGEmpagliflozin
Empagliflozin
DRUGPlacebo
Placebo
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinded investigator review of events in place of centralized adjudication.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Of full age of consent (according to local legislation, at least ≥ 18 years) at screening. 2. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. 3. Male or female patients. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. 4. Diagnosis of spontaneous Acute Myocardial Infarction (AMI): ST-Elevation Myocardial Infarction (STEMI) or Non-ST Elevation Myocardial Infarction (NSTEMI) with randomisation to occur no later than 14 calendar days after hospital admission. For patients with an in-hospital Myocardial Infarction (MI) as qualifying event, randomization must still occur within 14 days of hospital admission. 5. High risk of HF, defined as EITHER 1. Symptoms (e.g. dyspnea; decreased exercise tolerance; fatigue), or signs of congestion (e.g. pulmonary rales, crackles or crepitations; elevated jugular venous pressure; congestion on chest X-ray), that require treatment (e.g. augmentation or initiation of oral diuretic therapy; i.v. diuretic therapy; i.v. vasoactive agent; mechanical intervention etc.) at any time during the hospitalization. OR 2. Newly developed Left Ventricular Ejection Fraction (LVEF) \< 45% as measured by echocardiography, ventriculography, cardiac Computer Tomography (CT), Magnetic Resonance Imaging (MRI) or radionuclide imaging during index hospitalisation. 6. In addition at least one of the following risk factors: * Age \> 65 years, * Newly developed LVEF \< 35%, * Prior MI (before index MI) documented in medical records, * Estimated Glomerular Filtration Rate (eGFR) \< 60 ml/min/1.73m2 (using Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) formula based on creatinine from local lab at any time during index hospitalisation), * Atrial fibrillation (persistent or permanent ; if paroxysmal, only valid if associated with index MI), * Type 2 diabetes mellitus (prior or new diagnosis), * N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) \>1,400 pg/mL for patients in sinus rhythm, \>2,800 pg/mL if atrial fibrillation; Brain Natriuretic Peptide (BNP) \>350 pg/mL for patients in sinus rhythm, \>700 pg/mL if atrial fibrillation, measured at any time during hospitalisation, * Uric acid \>7.5 mg/dL (\>446 μmol/L), measured at any time during hospitalisation, * Pulmonary Artery Systolic Pressure \[or right ventricular systolic pressure\] \>40 mmHg (non-invasive \[usually obtained from clinically indicated post-MI echocardiography\] or invasive, at any time during hospitalisation), * Patient not revascularized (and no planned revascularization) for the index MI (Includes e.g. patients where no angiography is performed, unsuccessful revascularization attempts, diffuse atherosclerosis not amenable for intervention; but does NOT include if revascularization was not performed due to nonobstructive coronary arteries), * 3-vessel coronary artery disease at time of index MI, * Diagnosis of peripheral artery disease (extracoronary vascular disease, e.g. lower extremity artery disease or carotid artery disease).
Exclusion criteria
1. Diagnosis of chronic Heart Failure (HF) prior to index MI. 2. Systolic blood pressure \< 90 mmHg at randomisation. 3. Cardiogenic shock or use of i.v. inotropes in last 24 hours before randomisation. 4. Coronary Artery Bypass Grafting planned at time of randomisation. 5. Current diagnosis of Takotsubo cardiomyopathy. 6. Any current severe (stenotic or regurgitant) valvular heart disease. 7. eGFR \< 20 ml/min/1.73m2 (using CKD-EPI formula based on most recent creatinine from local lab during index hospitalisation) or on dialysis. 8. Type I diabetes mellitus. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Time to First Heart Failure Hospitalisation or All-cause Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The composite of time to first heart failure hospitalization or all-cause mortality is reported as the incidence rate of the first occurrence of hospitalization for heart failure (HHF) or death, whichever is earliest. The incidence rate was calculated as: the number of patients with an event for hospitalization for heart failure or death by treatment group during time at risk divided by the total time patients were at risk in that treatment group multiplied by 100 (per 100 Pt-years, Pt as abbreviation of patient). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint - Total Number of Hospitalisations for Heart Failure (HHF) or All-cause Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The total number of hospitalisations for heart failure (HHF) or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable. |
| Key Secondary Endpoint - Total Number of Non-elective Cardiovascular (CV) Hospitalisations or All-cause Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The total number of non-elective cardiovascular (CV) hospitalisations or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable. |
| Key Secondary Endpoint - Total Number of Non-elective All-cause Hospitalisations or All-cause Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The total number of non-elective all-cause hospitalisations or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable. |
| Key Secondary Endpoint - Total Number of Hospitalisations for Myocardial Infarction (MI) or All-cause Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The total number of hospitalisations for myocardial infarction (MI) or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for factors for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable. |
| Time to Cardiovascular (CV) Mortality | From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days. | The time to cardiovascular (CV) mortality is reported as the incidence rate of cardiovascular (CV) mortality, including deaths of unknown cause. The incidence rate was calculated as: the number of patients with a cardiovascular death event by treatment group during time at risk divided by the total time patients were at risk in that treatment group multiplied by 100 (per 100 Pt-years, Pt as abbreviation of patient). |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, China, Denmark, France, Germany, Hungary, India, Israel, Japan, Netherlands, Poland, Romania, Russia, Serbia, South Korea, Spain, Ukraine, United States
Participant flow
Recruitment details
Streamlined, randomised, placebo-controlled, double-blind, parallel-group trial in acute myocardial infarction (MI) hospitalised patients with high-risk for subsequent hospitalization for heart failure (HHF) and mortality. Patients were randomised 1:1 to empagliflozin or placebo within 14 days of hospitalisation. Patients were treated and remained in the trial until approximately a total number of 532 patients had primary endpoint events (i.e. event driven).
Pre-assignment details
All patients were screened for eligibility prior to participation in the trial. Patients attended a specialist site which ensured all inclusion and none of the exclusion criteria were met. Patients were not to be allocated to a treatment group if any of the entry criteria were violated. The randomised set included all randomised patients, whether treated or not. A patient randomised in error after death (i.e. mis-randomization) would be excluded as per statistical analysis plan definition.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients with an acute myocardial infarction event took, on top of standard of care, one placebo matching-empagliflozin 10 milligrams (mg) film-coated tablet, orally, once daily, at the same time every morning, with a glass of water. | 3,262 |
| Empagliflozin 10 mg Patients with an acute myocardial infarction event took, on top of standard of care, one empagliflozin (Jardiance®) 10 milligrams (mg) film-coated tablet, orally, once daily, at the same time every morning, with a glass of water. | 3,260 |
| Total | 6,522 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event, non-fatal event | 107 | 118 |
| Overall Study | Adverse event, serious fatal event | 11 | 4 |
| Overall Study | Lost to Follow-up | 31 | 39 |
| Overall Study | Not treated | 33 | 26 |
| Overall Study | Other reason than listed | 106 | 95 |
| Overall Study | Patient refusal to continue, not due to adverse event | 452 | 418 |
| Overall Study | Protocol Violation | 9 | 10 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin 10 mg | Total |
|---|---|---|---|
| Age, Continuous | 63.7 Years STANDARD_DEVIATION 10.8 | 63.6 Years STANDARD_DEVIATION 11 | 63.6 Years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 331 Participants | 338 Participants | 669 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2859 Participants | 2866 Participants | 5725 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 72 Participants | 56 Participants | 128 Participants |
| Race/Ethnicity, Customized Asian | 413 Participants | 421 Participants | 834 Participants |
| Race/Ethnicity, Customized Black/African-American | 48 Participants | 44 Participants | 92 Participants |
| Race/Ethnicity, Customized Missing | 73 Participants | 56 Participants | 129 Participants |
| Race/Ethnicity, Customized Other, including mixed race | 7 Participants | 9 Participants | 16 Participants |
| Race/Ethnicity, Customized White | 2721 Participants | 2730 Participants | 5451 Participants |
| Sex: Female, Male Female | 813 Participants | 812 Participants | 1625 Participants |
| Sex: Female, Male Male | 2449 Participants | 2448 Participants | 4897 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 178 / 3,262 | 169 / 3,260 |
| other Total, other adverse events | 0 / 3,229 | 0 / 3,234 |
| serious Total, serious adverse events | 798 / 3,229 | 765 / 3,234 |
Outcome results
Primary
Composite of Time to First Heart Failure Hospitalisation or All-cause Mortality
The composite of time to first heart failure hospitalization or all-cause mortality is reported as the incidence rate of the first occurrence of hospitalization for heart failure (HHF) or death, whichever is earliest. The incidence rate was calculated as: the number of patients with an event for hospitalization for heart failure or death by treatment group during time at risk divided by the total time patients were at risk in that treatment group multiplied by 100 (per 100 Pt-years, Pt as abbreviation of patient).
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite of Time to First Heart Failure Hospitalisation or All-cause Mortality | 6.58 Pt with events/100 pt-years at risk |
| Empagliflozin 10 mg | Composite of Time to First Heart Failure Hospitalisation or All-cause Mortality | 5.85 Pt with events/100 pt-years at risk |
Comparison: The primary endpoint was analysed using a Cox proportional hazards model with treatment, type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates.p-value: 0.206195% CI: [0.76, 1.06]Regression, Cox
Secondary
Key Secondary Endpoint - Total Number of Hospitalisations for Heart Failure (HHF) or All-cause Mortality
The total number of hospitalisations for heart failure (HHF) or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable.
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint - Total Number of Hospitalisations for Heart Failure (HHF) or All-cause Mortality | 8.25 Events/100 patient-years at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint - Total Number of Hospitalisations for Heart Failure (HHF) or All-cause Mortality | 7.14 Events/100 patient-years at risk |
p-value: 0.242395% CI: [0.68, 1.1]Negative binomial regression
Secondary
Key Secondary Endpoint - Total Number of Hospitalisations for Myocardial Infarction (MI) or All-cause Mortality
The total number of hospitalisations for myocardial infarction (MI) or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for factors for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable.
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint - Total Number of Hospitalisations for Myocardial Infarction (MI) or All-cause Mortality | 6.27 Events/100 patient-years at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint - Total Number of Hospitalisations for Myocardial Infarction (MI) or All-cause Mortality | 6.66 Events/100 patient-years at risk |
p-value: 0.631195% CI: [0.83, 1.35]Negative binomial regression
Secondary
Key Secondary Endpoint - Total Number of Non-elective All-cause Hospitalisations or All-cause Mortality
The total number of non-elective all-cause hospitalisations or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable.
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint - Total Number of Non-elective All-cause Hospitalisations or All-cause Mortality | 26.28 Events/100 patient-years at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint - Total Number of Non-elective All-cause Hospitalisations or All-cause Mortality | 22.96 Events/100 patient-years at risk |
p-value: 0.046395% CI: [0.7654, 0.9978]Negative binomial regression
Secondary
Key Secondary Endpoint - Total Number of Non-elective Cardiovascular (CV) Hospitalisations or All-cause Mortality
The total number of non-elective cardiovascular (CV) hospitalisations or all-cause mortality is reported using the adjusted event rate. The adjusted event rate is based on a negative binomial model adjusted for treatment and type-2 diabetes at baseline, geographical region, age at baseline, estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, persistent or permanent atrial fibrillation at baseline, prior myocardial infarction at baseline, peripheral artery disease at baseline and smoking at baseline as covariates. The log(observation time) was used as an offset variable.
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Key Secondary Endpoint - Total Number of Non-elective Cardiovascular (CV) Hospitalisations or All-cause Mortality | 16.90 Events/100 patient-years at risk |
| Empagliflozin 10 mg | Key Secondary Endpoint - Total Number of Non-elective Cardiovascular (CV) Hospitalisations or All-cause Mortality | 15.52 Events/100 patient-years at risk |
p-value: 0.286795% CI: [0.78, 1.07]Negative binomial regression
Secondary
Time to Cardiovascular (CV) Mortality
The time to cardiovascular (CV) mortality is reported as the incidence rate of cardiovascular (CV) mortality, including deaths of unknown cause. The incidence rate was calculated as: the number of patients with a cardiovascular death event by treatment group during time at risk divided by the total time patients were at risk in that treatment group multiplied by 100 (per 100 Pt-years, Pt as abbreviation of patient).
Time frame: From randomisation or first study drug administration (if randomisation occurred after first drug administration), until individual day of trial completion. Up to 1004 days.
Population: Randomised set (RS): All randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cardiovascular (CV) Mortality | 2.76 Pt with events/100 pt-years at risk |
| Empagliflozin 10 mg | Time to Cardiovascular (CV) Mortality | 2.78 Pt with events/100 pt-years at risk |
p-value: 0.812495% CI: [0.81, 1.31]Regression, Cox