Impact Of Eplerenone On Cardiovascular Outcomes In Patients Post Myocardial Infarction (REMINDER)

• Cardiovascular Mortality [ Time Frame: 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.
• Diagnosis of Heart Failure [ Time Frame: 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. [ Time Frame: 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). [ Time Frame: 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). [ Time Frame: 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). [ Time Frame: 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). [ Time Frame: 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.
• Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization. [ Time Frame: 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.
• Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted). [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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.

• Time to cardiovascular mortality [ Time Frame: 0-18 months ]
• Time to diagnosis of heart failure [ Time Frame: 0-18 months ]
• Time to first and each subsequent episode (after an event free interval of ≥ 48 hours) of sustained ventricular tachycardia or ventricular fibrillation. [ Time Frame: 0-18 months ]
• Time to first recorded ejection fraction of ≤ 40% (recorded 1 month or later post-randomization). [ Time Frame: 0-18 months ]
• Time to 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). [ Time Frame: 0-18 months ]
• Time to decision to provide an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT). [ Time Frame: 0-18 months ]
• Time to second or subsequent non-fatal myocardial infarction. [ Time Frame: 0-`18 months ]
• QRS duration at 6 months post-randomization. [ Time Frame: 6 months ]
• Left atrial diameter (recorded on each occasion an echocardiogram is conducted). [ Time Frame: 0-18 months ]
• Change in serum levels of biomarkers at 6 months post-randomization. Blood samples for biomarkers will be stored and analyzed post completion of the study. [ Time Frame: 6 months ]

• Drug: Eplerenone
  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.
  Other Name: Inspra
• Drug: Placebo
  Matching placebo tablets

• Experimental: Eplerenone plus standard of care
  Intervention: Drug: Eplerenone
• Placebo Comparator: Placebo plus standard of care
  Matching placebo for eplerenone 25mg film coated tablets.
  Intervention: Drug: Placebo

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.