Myocardial Infarction
Conditions
Keywords
Eplerenone, myocardial infarction, mortality, morbidity
Brief summary
Administration of eplerenone within 24 hours of onset of symptoms of myocardial infarction, in patients without heart failure, reduces cardiovascular mortality / morbidity.
Interventions
DRUGEplerenone
Maximum dose of 2x25 mg film coated tablets per day for the duration of the study (approximately 18 months maximum). Lower doses may be administered determined by blood biochemistry data.
DRUGPlacebo
Matching placebo tablets
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have experienced a myocardial infarction (STEMI) within the previous 24 hours confirmed by symptoms and ECG.
Exclusion criteria
* Subjects with a known low ejection fraction of less than 40% or any previous history of heart failure. * Subjects treated with eplerenone or other aldosterone antagonists within the past 1 month. * The subject has uncontrolled hypotension (SBP\<90mmHg). * Subjects with eGFR ≤30ml/min (based on admission serum creatinine and the MDRD formula) or serum creatinine ≥220µmol/L.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Event of Cardiovascular Mortality, Re-hospitalization or Extended Initial Hospital Stay Due to Diagnosis of Heart Failure, Sustained Ventricular Tachycardia or Fibrillation, Ejection Fraction ≤40% or BNP Above Age Adjusted Cut Off | 0-24 months | Cardiovascular mortality is defined as any mortality adjudicated as death due to sudden cardiac death, myocardial infarction (MI), worsening heart failure, cardiac arrhythmia, other cause (such as pulmonary embolism, peripheral arterial disease \[PAD\], etc.). Hospitalization due to congestive heart failure (CHF) and requires extended hospital stay or frequent visits to emergency room, observation unit or in-patient care, due to CHF as the primary or secondary diagnosis supported by a discharge report or clinical summary for hospitalization as determined by the endpoint adjudication committee (EAC). A composite of time to first event of cardiovascular mortality (CV), re-hospitalization or extended initial hospital stay due to diagnosis of heart failure, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40% after 1 month or BNP \>200 pg/mL or NT-proBNP \>450 pg/mL (age \<50 years); \>900 pg/mL (age 50 to 75 years) or \>1800 pg/mL (age \>75 years) after 1 month. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diagnosis of Heart Failure | 0-24 months | The occurrence of first diagnosis of heart failure from the date of randomization. Time-to-event analyses were measured from the date of randomization, and a subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation. | 0-24 months | The occurrence of first and each subsequent episode (after an event-free interval of ≥ 48 hours) of sustained ventricular tachycardia or ventricular fibrillation. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization). | 0-24 months | The occurrence of first recorded EF ≤40% (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| Brain (B-type) Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP >450, >900 or >1800 pg/mL for Ages <50 Years, 50-75 Years and >75 Years, Respectively (Recorded 1 Month or Later Post-randomization). | 0-24 months | The occurrence of first occurrence of BNP \>200 pg/mL or NT-proBNP \>450, \>900 or \>1800 pg/mL for ages \<50 years, 50 to 75 years and \>75 years, respectively (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT). | 0-24 months | The decision to provide an ICD or CRT. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| Second or Subsequent Non-fatal Myocardial Infarction (MI). | 0-24 months | The occurrence of second or subsequent nonfatal MI. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| Cardiovascular Mortality | 0-24 months | The occurrence of cardiovascular mortality from randomization. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence. |
| Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). | 0-24 months | LAD recorded each time an echocardiogram is conducted. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study. |
| Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. | 6 months | Change in serum levels of aldosterone and cortisol at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study. |
| Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | 6 months | Change in serum levels of PIIINP, Galectin 3, and PINP at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study. |
| Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization. | 6 months | Change in serum level of ICTP at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study. |
| Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization. | 6 months | Change in serum level of Interleukin-6 at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study. |
| Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization. | 6 months | Electrocardiogram Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) duration at 6 months post-randomization. The continuous endpoints were assessed using analysis of covariance (ANCOVA) model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on last observation carried forward (LOCF) and also using all available data up to end of study. |
Countries
Canada, Czechia, France, Germany, Greece, Hungary, Netherlands, Poland, Slovakia, Spain, United Kingdom
Participant flow
Pre-assignment details
A total of 1012 subjects were enrolled for participation in this study. A total of 505 subjects were randomized to treatment with eplerenone and 505 subjects were randomized to the placebo group; a total of 422 and 424 subjects in the eplerenone and placebo groups, respectively, completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Eplerenone Plus Standard of Care Eplerenone group received eplerenone 25 milligram (mg) once daily (OD), and on day 2, the dose of study drug increased to 50 mg OD (2 tablets) if serum potassium \<5.0 mmol/L and with normal renal function. | 506 |
| Placebo Plus Standard of Care Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets. | 506 |
| Total | 1,012 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 11 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Did Not Meet Entrance Criteria | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 16 | 14 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Reason not defined | 5 | 3 |
| Overall Study | Study terminated by sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 48 | 48 |
Baseline characteristics
| Characteristic | Eplerenone Plus Standard of Care | Placebo Plus Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 58.5 Years STANDARD_DEVIATION 10.8 | 57.8 Years STANDARD_DEVIATION 11 | 58.2 Years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 86 Participants | 103 Participants | 189 Participants |
| Sex: Female, Male Male | 420 Participants | 403 Participants | 823 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 151 / 506 | 153 / 506 |
| serious Total, serious adverse events | 100 / 505 | 101 / 505 |
Outcome results
Primary
First Event of Cardiovascular Mortality, Re-hospitalization or Extended Initial Hospital Stay Due to Diagnosis of Heart Failure, Sustained Ventricular Tachycardia or Fibrillation, Ejection Fraction ≤40% or BNP Above Age Adjusted Cut Off
Cardiovascular mortality is defined as any mortality adjudicated as death due to sudden cardiac death, myocardial infarction (MI), worsening heart failure, cardiac arrhythmia, other cause (such as pulmonary embolism, peripheral arterial disease \[PAD\], etc.). Hospitalization due to congestive heart failure (CHF) and requires extended hospital stay or frequent visits to emergency room, observation unit or in-patient care, due to CHF as the primary or secondary diagnosis supported by a discharge report or clinical summary for hospitalization as determined by the endpoint adjudication committee (EAC). A composite of time to first event of cardiovascular mortality (CV), re-hospitalization or extended initial hospital stay due to diagnosis of heart failure, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40% after 1 month or BNP \>200 pg/mL or NT-proBNP \>450 pg/mL (age \<50 years); \>900 pg/mL (age 50 to 75 years) or \>1800 pg/mL (age \>75 years) after 1 month.
Time frame: 0-24 months
Population: The Full Analysis Set (FAS) using the intent-to-treat (ITT) principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | First Event of Cardiovascular Mortality, Re-hospitalization or Extended Initial Hospital Stay Due to Diagnosis of Heart Failure, Sustained Ventricular Tachycardia or Fibrillation, Ejection Fraction ≤40% or BNP Above Age Adjusted Cut Off | 92 Events |
| Placebo Plus Standard of Care | First Event of Cardiovascular Mortality, Re-hospitalization or Extended Initial Hospital Stay Due to Diagnosis of Heart Failure, Sustained Ventricular Tachycardia or Fibrillation, Ejection Fraction ≤40% or BNP Above Age Adjusted Cut Off | 149 Events |
Comparison: Hazard ratio, 95% confidence interval (CI) of hazard ratio, and p-value for the Primary Analysis based on a Cox proportional hazard model with treatment as the major factor, adjusted for baseline estimated glomerular filtration rate (eGFR), with/without previous MI, time of first dose administered post onset of index symptom, and location of index MI anterior or non-anterior.p-value: <0.000195% CI: [0.446, 0.756]Regression, Cox
Secondary
Brain (B-type) Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP >450, >900 or >1800 pg/mL for Ages <50 Years, 50-75 Years and >75 Years, Respectively (Recorded 1 Month or Later Post-randomization).
The occurrence of first occurrence of BNP \>200 pg/mL or NT-proBNP \>450, \>900 or \>1800 pg/mL for ages \<50 years, 50 to 75 years and \>75 years, respectively (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | Brain (B-type) Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP >450, >900 or >1800 pg/mL for Ages <50 Years, 50-75 Years and >75 Years, Respectively (Recorded 1 Month or Later Post-randomization). | 81 Events |
| Placebo Plus Standard of Care | Brain (B-type) Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP >450, >900 or >1800 pg/mL for Ages <50 Years, 50-75 Years and >75 Years, Respectively (Recorded 1 Month or Later Post-randomization). | 131 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as a factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.000395% CI: [0.452, 0.791]Regression, Cox
Secondary
Cardiovascular Mortality
The occurrence of cardiovascular mortality from randomization. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints. Furthermore, only events confirmed by the EAC were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | Cardiovascular Mortality | 2 Events |
| Placebo Plus Standard of Care | Cardiovascular Mortality | 2 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as the major factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.640695% CI: [0.05, 6.308]Regression, Cox
Secondary
Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization.
Change in serum level of ICTP at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study.
Time frame: 6 months
Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone Plus Standard of Care | Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization. | 3.70 μg/L |
| Placebo Plus Standard of Care | Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization. | 3.70 μg/L |
Comparison: For Biomarker- ICTP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.0944Signed Rank Test
Comparison: For Biomarker- ICTP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.036Signed Rank Test
Comparison: For Biomarker- ICTP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.6459Wilcoxon Rank-Sum test
Secondary
Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization.
Change in serum level of Interleukin-6 at 6 months post-randomization. The continuous endpoint was assessed using ANCOVA model, fitted with corresponding baseline and treatment. It was analyzed at 6 months based on LOCF and also using all available data up to end of study.
Time frame: 6 months
Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone Plus Standard of Care | Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization. | 1.845 pg/mL |
| Placebo Plus Standard of Care | Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization. | 1.755 pg/mL |
Comparison: For Biomarker- Interleukin-6, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Interleukin-6, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Interleukin-6, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.0801Wilcoxon Rank-Sum test
Secondary
Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization.
Change in serum levels of aldosterone and cortisol at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.
Time frame: 6 months
Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (carboxyterminal telopeptide of type I collagen \[ICTP\], procollagen type I N-terminal peptide \[PINP\], procollagen type III N-terminal peptide \[PIIINP\], Interleukin-6, aldosterone, cortisol, and Galactin 3) available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eplerenone Plus Standard of Care | Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. | Aldosterone | 0.355 nmol/L |
| Eplerenone Plus Standard of Care | Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. | Serum Cortisol | 379.0 nmol/L |
| Placebo Plus Standard of Care | Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. | Aldosterone | 0.210 nmol/L |
| Placebo Plus Standard of Care | Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization. | Serum Cortisol | 366.0 nmol/L |
Comparison: For Biomarker- Aldosterone, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Aldosterone, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.5552Signed Rank Test
Comparison: For Biomarker- Aldosterone, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: <0.0001Wilcoxon Rank-Sum test
Comparison: For Biomarker- Serum Cortisol, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Serum Cortisol, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Serum Cortisol, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.3347Wilcoxon Rank-Sum test
Secondary
Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization.
Change in serum levels of PIIINP, Galectin 3, and PINP at 6 months post-randomization. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.
Time frame: 6 months
Population: The Biomarker Analysis Set is a subset of FAS subjects who have the biomarker data (ICTP, PINP, PIIINP, Interleukin-6, aldosterone, cortisol, and Galactin 3) available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eplerenone Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | PIIINP | 4.20 ng/mL |
| Eplerenone Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | Galectin 3 | 11.20 ng/mL |
| Eplerenone Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | PINP | 30.0 ng/mL |
| Placebo Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | PIIINP | 4.30 ng/mL |
| Placebo Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | Galectin 3 | 10.60 ng/mL |
| Placebo Plus Standard of Care | Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization. | PINP | 32.0 ng/mL |
Comparison: For Biomarker- PIIINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.0005Signed Rank Test
Comparison: For Biomarker- PIIINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- PIIINP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.1558Wilcoxon-Rank Sum test
Comparison: For Biomarker- Galecting 3, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.0008Signed Rank Test
Comparison: For Biomarker- Galecting 3, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: <0.0001Signed Rank Test
Comparison: For Biomarker- Galecting 3, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.0293Wilcoxon Rank-Sum test
Comparison: For Biomarker- PINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.1723Signed Rank Test
Comparison: For Biomarker- PINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.p-value: 0.0295Signed Rank Test
Comparison: For Biomarker- PINP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.p-value: 0.0865Wilcoxon Rank-Sum test
Secondary
Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT).
The decision to provide an ICD or CRT. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT). | 3 Events |
| Placebo Plus Standard of Care | Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT). | 3 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as a factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.935395% CI: [0.213, 5.371]Regression, Cox
Secondary
Diagnosis of Heart Failure
The occurrence of first diagnosis of heart failure from the date of randomization. Time-to-event analyses were measured from the date of randomization, and a subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints. Furthermore, only events confirmed by the EAC were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | Diagnosis of Heart Failure | 7 Events |
| Placebo Plus Standard of Care | Diagnosis of Heart Failure | 11 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as a factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.533895% CI: [0.265, 1.99]Regression, Cox
Secondary
Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization.
Electrocardiogram Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) duration at 6 months post-randomization. The continuous endpoints were assessed using analysis of covariance (ANCOVA) model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on last observation carried forward (LOCF) and also using all available data up to end of study.
Time frame: 6 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eplerenone Plus Standard of Care | Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization. | 93.31 Milliseconds (msec) | Standard Deviation 15.04 |
| Placebo Plus Standard of Care | Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization. | 94.62 Milliseconds (msec) | Standard Deviation 16 |
Comparison: ANCOVA model was used with observed value as the dependent variable, treatment as a major factor, and baseline QRS duration, baseline eGFR, with/without previous MI, time (in hours) of first dose administered post onset of index symptom, and location of index MI (anterior versus all other locations) as covariates.p-value: 0.174495% CI: [-3.55, 0.65]ANCOVA
Secondary
First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation.
The occurrence of first and each subsequent episode (after an event-free interval of ≥ 48 hours) of sustained ventricular tachycardia or ventricular fibrillation. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints. Furthermore, only events confirmed by the EAC were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation. | 0 Events |
| Placebo Plus Standard of Care | First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation. | 0 Events |
Secondary
First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization).
The occurrence of first recorded EF ≤40% (recorded 28 days or later post-randomization). Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization). | 20 Events |
| Placebo Plus Standard of Care | First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization). | 19 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as the major factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.804295% CI: [0.575, 2.04]Regression, Cox
Secondary
Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted).
LAD recorded each time an echocardiogram is conducted. The continuous endpoints were assessed using ANCOVA model, fitted with corresponding baseline and treatment. These were analyzed at 6 months based on LOCF and also using all available data up to end of study.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eplerenone Plus Standard of Care | Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). | Month 6 (N = 268, 243) | 3.92 Centimeters (cm) | Standard Deviation 0.654 |
| Eplerenone Plus Standard of Care | Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). | Final Visit (N = 393, 378) | 3.91 Centimeters (cm) | Standard Deviation 0.641 |
| Placebo Plus Standard of Care | Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). | Final Visit (N = 393, 378) | 3.87 Centimeters (cm) | Standard Deviation 0.658 |
| Placebo Plus Standard of Care | Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). | Month 6 (N = 268, 243) | 3.90 Centimeters (cm) | Standard Deviation 0.703 |
Comparison: For the Between-Treatment difference for Eplerenone and Placebo groups of observed value taken at Month 6 visit, ANCOVA model was performed for LAD based on the LOCF method including treatment groups with/without adjustments for baseline eGFR (in mL/min/1.73 m2), previous MI (yes/no), time (in hours) of first dose administered post-onset of symptom, index MI location (anterior versus all others) as covariates.p-value: 0.712395% CI: [-0.1, 0.14]ANCOVA
Comparison: For the Between-Treatment difference for Eplerenone and Placebo groups of observed value taken at Month 6 visit, ANCOVA model was performed for LAD based on the LOCF method including treatment groups with/without adjustments for baseline eGFR (in mL/min/1.73 m2), previous MI (yes/no), time (in hours) of first dose administered post-onset of symptom, index MI location (anterior versus all others) as covariates.p-value: 0.410595% CI: [-0.05, 0.13]ANCOVA
Secondary
Second or Subsequent Non-fatal Myocardial Infarction (MI).
The occurrence of second or subsequent nonfatal MI. Time-to-event analyses were measured from the date of randomization. A subject who did not experience the endpoint(s) of interest was censored on the last day the subject was confirmed by the investigator to be endpoint-free. The time-to-event distributions were summarized by treatment group using Kaplan-Meier estimates of cumulative incidence.
Time frame: 0-24 months
Population: The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used. The efficacy analysis data sets for clinical events included all available study endpoints. Furthermore, only events confirmed by the EAC were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eplerenone Plus Standard of Care | Second or Subsequent Non-fatal Myocardial Infarction (MI). | 10 Events |
| Placebo Plus Standard of Care | Second or Subsequent Non-fatal Myocardial Infarction (MI). | 6 Events |
Comparison: Hazard ratio, 95% CI of hazard ratio, p-value for all secondary endpoints based on Cox proportional hazard model with treatment as the major factor, adjusted for baseline eGFR, with/without previous MI, index MI location, time of first dose administered post onset of index symptom.p-value: 0.375795% CI: [0.566, 4.525]Regression, Cox