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

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01176968
• Collaborator: (none)
• Enrollment: 1,012
• Locations: 75
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 13.5
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Administration of eplerenone within 24 hours of onset of symptoms of myocardial infarction, in patients without heart failure, reduces cardiovascular mortality / morbidity.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Infarction	Drug: Eplerenone; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 1012 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Double-blind, Randomized, Placebo-controlled Trial Evaluating The Safety And Efficacy Of Early Treatment With Eplerenone In Patients With Acute Myocardial Infarction
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eplerenone plus standard of care	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 Names: Inspra
Placebo Comparator: Placebo plus standard of care Matching placebo for eplerenone 25mg film coated tablets.	Drug: Placebo; Matching placebo tablets

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
2	Walter C Mackenzie Health Sciences Centre (WCM)	Edmonton	Alberta	Canada	T6G 2B7
3	Diamond Health Care Centre (DHCC)	Vancouver	British Columbia	Canada	V5Z 1M9
4	Vancouver General Hospital - Centennial Pavilion	Vancouver	British Columbia	Canada	V5Z 1M9
5	Vancouver General Hospital, Vancouver Coastal Health Authority	Vancouver	British Columbia	Canada	V5Z 1M9
6	Health Sciences Center, Eastern Health	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
7	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
8	St. Michael's Hospital	Toronto	Ontario	Canada	M5B1W8
9	Centre de Sante et de Services Sociaux de Chicoutimi (CSSSC) (Complexe Hospitalier de la Sagamie)	Chicoutimi	Quebec	Canada	G7H 5H6
10	ECOGENE-21 / Centre de sante et de services sociaux de Chicoutimi	Chicoutimi	Quebec	Canada	G7H 7P2
11	Centre Hospitalier Universitaire de Sherbrooke, Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
12	Fakultni nemocnice Brno	Brno		Czechia	62500
13	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
14	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	50005
15	I.Interni klinika-kardiologie FN Olomouc	Olomouc		Czechia	775 20
16	I. Interni klinika - kardiologie FN Olomouc	Olomouc		Czechia	77520
17	Klinika kardiologie IKEM	Praha 4		Czechia	140 21
18	Nemocnice Na Homolce - kardiologicke oddeleni	Praha 5		Czechia	150 30
19	Chu Rangueil Service de Cardiologie, A - Bat H1	Toulouse	Cedex 4	France	31403
20	Chu du Bocage - Centre de Cardiologie	Dijon	Cedex	France	21034
21	Hopital De La Pitie Salpetriere	Paris	Cedex	France	75013
22	Service Cardiologie, Centre Hospitalier de Cannes	Cannes		France	06401
23	Hôpital Henri Mondor - Pysiologie explorations fonctionnelles	Creteil		France	94010
24	Hôpital Henri Mondor	Creteil		France	94010
25	Centre de Cardiologie d'Evecquemont	Evecquemont		France	78740
26	Service Cardiologie Hopital Robert Boulin	Libourne		France	33500
27	Cardiologie Interventionnelle	Pessac Cedex		France	33604
28	Universitaets-Herzzentrum Freiburg Bad Krozingen	Bad Krozingen		Germany	79189
29	Charite - Universitaetsmedizin Berlin	Berlin		Germany	12200
30	Universitätsklinikum Bonn	Bonn		Germany	53127
31	Klinikum Links der Weser gGmbH	Bremen		Germany	28277
32	Sankt Johannes Hospital Medizinische Klinik I	Dortmund		Germany	44137
33	Sankt Johannes Hospital	Dortmund		Germany	44137
34	Medizinische Fakultaet Carl Gustav Carus Technische Universitaet Dresden	Dresden		Germany	01309
35	Georg-August-Universitaet Goettingen, Zentrum f. Innere Medizin / Kardiologie u. Pneumologie	Goettingen		Germany	37075
36	Universitaeres Herzzentrum Hamburg	Hamburg		Germany	20246
37	Medizinische Hochschule Hannover	Hannover		Germany	30625
38	St. Vincenz Krankenhaus	Limburg		Germany	65549
39	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz		Germany	55131
40	Staedtisches Klinikum Muenchen GmbH Klinikum Neuperlach	Munich		Germany	81737
41	General Hospital of Athens "Georgios Gennimatas"	Athens		Greece	11527
42	General Hospital of Attiki KAT	Athens		Greece	14561
43	University General Hospital of Patra	Rio Patra		Greece	26500
44	Budai Irgalmasrendi Korhaz, Kardiologia	Budapest		Hungary	1027
45	Petz Aladar Megyei Oktato Korhaz, Kardiologiai Osztaly	Gyor		Hungary	9024
46	Josa Andras Oktato Korhaz Egeszsegugyi Szolgaltato Nonprofit Kft., Kardiologia	Nyiregyhaza		Hungary	4400
47	Zala Megyei Korhaz, Kardiologia	Zalaegerszeg		Hungary	8900
48	Onze Lieve Vrouwe Gasthuis, Locatie Oosterpark	Amsterdam		Netherlands	1091 AC
49	St. Antonius Ziekenhuis	Nieuwegein		Netherlands	3435 CM
50	Katedra i Klinika Kardiologii i Chorob Wewnetrznych	Bydgoszcz		Poland	85-094
51	Oddzial Kardiologiczny Wojewodzki Szpital Specjalistyczny w Olsztynie	Olsztyn		Poland	10-561
52	Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii NZOZ w Oswiecimiu G.V.M CARINT Sp. zo.o.	Oswiecim		Poland	32-600
53	Oddzial Kardiologiczny Wojewodzki Szpital Specjalistyczny We Wroclawiu	Wroclaw		Poland	51-124
54	Stredoslovensky ustav srdcovych a cievnych chorob, a.s.	Banska Bystrica		Slovakia	974 01
55	Narodny ustav srdcovych a cievnych chorob, a.s.	Bratislava		Slovakia	833 48
56	Univerzitna nemocnica Martin	Martin		Slovakia	036 59
57	Kardiocentrum Nitra, s.r.o.	Nitra		Slovakia	949 01
58	Vseobecna nemocnica Rimavska Sobota	Rimavska Sobota		Slovakia	979 12
59	Hospital Del Sas de Jerez de La Frontera	Jerez de la Frontera	Cadiz	Spain	11407
60	"Hospital Clinic i Provincial de Barcelona,Instituto Clinic del Torax	Barcelona		Spain	08036
61	Hospital del Mar.	Barcelona		Spain	8003
62	HOSPITAL CLINICO SAN CARLOS- Universidad Complutense de Madrid	Madrid		Spain	28040
63	Hospital Universitario de La Paz	Madrid		Spain	28046
64	Hospital Universitari Son Espases	Palma de Mallorca		Spain	07010
65	Hospital General Universitario de Valencia	Valencia		Spain	46014
66	Blackpool Victoria Hospital NHS Trust , Cardiac Research ,Lancashire Cardiac Centre	Blackpool	Lancashire	United Kingdom	FY3 8NR
67	Edinburgh Royal Infirmary	Edinburgh	Lothian	United Kingdom	EH16 4SA
68	Clinical Trials Unit Morriston Hospital	Swansea	Wales	United Kingdom	SA6 6NL
69	City Hospital	Birmingham		United Kingdom	B18 7QH
70	Academic cardiology Unit	Cottingham Hull		United Kingdom	HU16 5JQ
71	University Hospitals Coventry and Warwickshire NHS Trust	Coventry		United Kingdom	CV2 2DX
72	Ninewells Hospital and Medical School	Dundee		United Kingdom	DD1 9SY
73	The Queens Medical Research Institute- University of Edinburgh	Edinburgh		United Kingdom	EH16 4TJ
74	University Hospital of Leicester (UHL) NHS Trust	Leicester		United Kingdom	LE3 GQP
75	Clinical Trials Unit, Morriston Hospital	Swansea		United Kingdom	SA6 6NL

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT01176968
• Other Study ID Numbers: A6141116; 2010-019844-38; REMINDER
• First Posted: Aug 6, 2010
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: Eplerenone; myocardial infarction; mortality; morbidity
• Additional relevant MeSH terms: Myocardial Infarction; Infarction; Eplerenone

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Period Title: Overall Study
STARTED	506	506
Treated	505	505
COMPLETED	422	424
NOT COMPLETED	84	82

Baseline Characteristics

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care	Total
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.	Total of all reporting groups
Overall Participants	506	506	1012
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.5 (10.8)	57.8 (11.0)	58.2 (10.9)
Sex: Female, Male (Count of Participants)
Female	86 17%	103 20.4%	189 18.7%
Male	420 83%	403 79.6%	823 81.3%

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	92	149

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	All analyses for primary endpoint were tested at two-sided, α-level of 0.05, without adjusting for multiplicity.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.581
	Confidence Interval	(2-Sided) 95%; 0.446 to 0.756
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Cardiovascular Mortality
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	2	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6406
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.562
	Confidence Interval	(2-Sided) 95%; 0.050 to 6.308
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Diagnosis of Heart Failure
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	7	11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5338
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.726
	Confidence Interval	(2-Sided) 95%; 0.265 to 1.990
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	First and Each Subsequent Episode (After an Event Free Interval of ≥ 48 Hours) of Sustained Ventricular Tachycardia or Ventricular Fibrillation.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	0	0

5. Secondary Outcome

Title	First Recorded Ejection Fraction (EF) of ≤40% (Recorded 1 Month or Later Post-randomization).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	20	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8042
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.083
	Confidence Interval	(2-Sided) 95%; 0.575 to 2.040
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	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).
Description	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

Outcome Measure Data

Analysis Population Description

The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	81	131

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.598
	Confidence Interval	(2-Sided) 95%; 0.452 to 0.791
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Decision to Provide an Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT).
Description	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

Outcome Measure Data

Analysis Population Description

The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9353
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.069
	Confidence Interval	(2-Sided) 95%; 0.213 to 5.371
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Second or Subsequent Non-fatal Myocardial Infarction (MI).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Number [Events]	10	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3757
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.600
	Confidence Interval	(2-Sided) 95%; 0.566 to 4.525
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Electrocardiogram Q Wave to the End of the S Wave Corresponding to Ventricle Depolarization (QRS) Duration at 6 Months Post-randomization.
Description	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

Outcome Measure Data

Analysis Population Description

The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	347	343
Mean (Standard Deviation) [Milliseconds (msec)]	93.31 (15.04)	94.62 (16.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1744
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.45
	Confidence Interval	(2-Sided) 95%; -3.55 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Left Atrial Diameter (LAD) (Recorded on Each Occasion an Echocardiogram is Conducted).
Description	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

Outcome Measure Data

Analysis Population Description

The FAS using the ITT principle, regardless of compliance with the study drug and the protocol was used.

Arm/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	506	506
Month 6 (N = 268, 243)	3.92 (0.654)	3.90 (0.703)
Final Visit (N = 393, 378)	3.91 (0.641)	3.87 (0.658)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7123
	Comments	ANCOVA was used for between-treatment comparisons of the LSMeans, 95% CI of LSMEANS, LSMeans difference, 95% CI of LSMeans difference, and p-value with observed value at the given time point as variable.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4105
	Comments	ANCOVA was used for between-treatment comparisons of the LSMeans, 95% CI of LSMEANS, LSMeans difference, 95% CI of LSMeans difference, and p-value with observed value at the given time point as variable.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change in Serum Levels of Biomarkers (Aldosterone and Cortisol) at 6 Months Post-randomization.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	266	260
Aldosterone	0.355	0.210
Serum Cortisol	379.0	366.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- Aldosterone, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- Aldosterone, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.5552
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- Aldosterone, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- Serum Cortisol, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- Serum Cortisol, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- Serum Cortisol, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3347
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

12. Secondary Outcome

Title	Change in Serum Levels of Biomarkers (PIIINP, Galectin 3, and PINP) at 6 Months Post-randomization.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	266	260
PIIINP	4.20	4.30
Galectin 3	11.20	10.60
PINP	30.0	32.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- PIIINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- PIIINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- PIIINP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1558
	Comments
	Method	Wilcoxon-Rank Sum test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- Galecting 3, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- Galecting 3, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- Galecting 3, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0293
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- PINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1723
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- PINP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0295
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- PINP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0865
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

13. Secondary Outcome

Title	Change in Serum Level of Biomarker (ICTP) at 6 Months Post-randomization.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	266	260
Median (Inter-Quartile Range) [μg/L]	3.70	3.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- ICTP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0944
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- ICTP, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0360
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- ICTP, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6459
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

14. Secondary Outcome

Title	Change in Serum Level of Biomarker (Interleukin-6) at 6 Months Post-randomization.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Eplerenone Plus Standard of Care	Placebo Plus Standard of Care
Arm/Group Description	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.	Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
Measure Participants	266	260
Median (Inter-Quartile Range) [pg/mL]	1.845	1.755

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care
	Comments	For Biomarker- Interleukin-6, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Standard of Care
	Comments	For Biomarker- Interleukin-6, signed rank test for change from baseline at Month 6 within treatment difference was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Signed Rank Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone Plus Standard of Care, Placebo Plus Standard of Care
	Comments	For Biomarker- Interleukin-6, Wilconxon rank-sum test for between treatment difference at Month 6 was used to derive p-value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0801
	Comments
	Method	Wilcoxon Rank-Sum test
	Comments

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Eplerenone Plus Standard of Care		Placebo Plus Standard of Care
Arm/Group Description	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.		Placebo group received matching placebo for eplerenone 25 milligram (mg) film coated tablets.
All Cause Mortality
	Eplerenone Plus Standard of Care		Placebo Plus Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eplerenone Plus Standard of Care		Placebo Plus Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	100/505 (19.8%)		101/505 (20%)
Blood and lymphatic system disorders
Anaemia	1/505 (0.2%)		1/505 (0.2%)
Leukopenia	0/505 (0%)		1/505 (0.2%)
Spontaneous haematoma	0/505 (0%)		1/505 (0.2%)
Cardiac disorders
Acute coronary syndrome	2/505 (0.4%)		0/505 (0%)
Acute myocardial infarction	5/505 (1%)		4/505 (0.8%)
Angina pectoris	12/505 (2.4%)		10/505 (2%)
Angina unstable	4/505 (0.8%)		9/505 (1.8%)
Arrhythmia	1/505 (0.2%)		0/505 (0%)
Arteriospasm coronary	0/505 (0%)		1/505 (0.2%)
Atrial fibrillation	1/505 (0.2%)		0/505 (0%)
Atrial flutter	1/505 (0.2%)		0/505 (0%)
Atrioventricular block complete	1/505 (0.2%)		0/505 (0%)
Atrioventricular block second degree	1/505 (0.2%)		1/505 (0.2%)
Bradycardia	1/505 (0.2%)		1/505 (0.2%)
Cardiac arrest	0/505 (0%)		1/505 (0.2%)
Cardiac asthma	0/505 (0%)		1/505 (0.2%)
Cardiac failure	3/505 (0.6%)		9/505 (1.8%)
Cardiac failure acute	0/505 (0%)		1/505 (0.2%)
Cardiac failure congestive	2/505 (0.4%)		4/505 (0.8%)
Cardiac perforation	0/505 (0%)		1/505 (0.2%)
Cardiogenic shock	0/505 (0%)		2/505 (0.4%)
Coronary artery disease	1/505 (0.2%)		2/505 (0.4%)
Intracardiac thrombus	0/505 (0%)		1/505 (0.2%)
Coronary artery stenosis	1/505 (0.2%)		2/505 (0.4%)
Left ventricular dysfunction	1/505 (0.2%)		1/505 (0.2%)
Left ventricular failure	1/505 (0.2%)		0/505 (0%)
Long QT syndrome	0/505 (0%)		1/505 (0.2%)
Myocardial infarction	5/505 (1%)		2/505 (0.4%)
Myocardial ischaemia	1/505 (0.2%)		1/505 (0.2%)
Palpitations	2/505 (0.4%)		0/505 (0%)
Pericardial disease	1/505 (0.2%)		0/505 (0%)
Pericardial effusion	0/505 (0%)		1/505 (0.2%)
Pericarditis	3/505 (0.6%)		2/505 (0.4%)
Tachyarrhythmia	1/505 (0.2%)		0/505 (0%)
Tachycardia	1/505 (0.2%)		0/505 (0%)
Ventricular fibrillation	0/505 (0%)		3/505 (0.6%)
Ear and labyrinth disorders
Tinnitus	1/505 (0.2%)		0/505 (0%)
Vertigo	2/505 (0.4%)		1/505 (0.2%)
Vertigo positional	0/505 (0%)		1/505 (0.2%)
Eye disorders
Photophobia	1/505 (0.2%)		0/505 (0%)
Gastrointestinal disorders
Abdominal pain	0/505 (0%)		1/505 (0.2%)
Abdominal pain upper	1/505 (0.2%)		1/505 (0.2%)
Anal fissure	1/505 (0.2%)		0/505 (0%)
Anal haemorrhage	1/505 (0.2%)		0/505 (0%)
Constipation	1/505 (0.2%)		0/505 (0%)
Dieulafoy's vascular malformation	0/505 (0%)		1/505 (0.2%)
Erosive oesophagitis	1/505 (0.2%)		0/505 (0%)
Gastric polyps	1/505 (0.2%)		0/505 (0%)
Gastritis	1/505 (0.2%)		0/505 (0%)
Gastritis erosive	1/505 (0.2%)		0/505 (0%)
Gastrointestinal haemorrhage	0/505 (0%)		1/505 (0.2%)
Gastrooesophageal reflux disease	0/505 (0%)		1/505 (0.2%)
Haematemesis	1/505 (0.2%)		0/505 (0%)
Nausea	1/505 (0.2%)		0/505 (0%)
Peptic ulcer haemorrhage	0/505 (0%)		1/505 (0.2%)
Proctitis ulcerative	0/505 (0%)		1/505 (0.2%)
Upper gastrointestinal haemorrhage	1/505 (0.2%)		0/505 (0%)
General disorders
Chest discomfort	0/505 (0%)		1/505 (0.2%)
Chest pain	4/505 (0.8%)		9/505 (1.8%)
Death	1/505 (0.2%)		0/505 (0%)
Device dislocation	0/505 (0%)		2/505 (0.4%)
Non-cardiac chest pain	2/505 (0.4%)		2/505 (0.4%)
Sudden death	1/505 (0.2%)		0/505 (0%)
Vessel puncture site haemorrhage	0/505 (0%)		1/505 (0.2%)
Hepatobiliary disorders
Biliary colic	1/505 (0.2%)		1/505 (0.2%)
Infections and infestations
Bronchitis	1/505 (0.2%)		0/505 (0%)
Bronchopneumonia	1/505 (0.2%)		0/505 (0%)
Cellulitis	1/505 (0.2%)		0/505 (0%)
Cholecystitis infective	1/505 (0.2%)		0/505 (0%)
Device related infection	2/505 (0.4%)		0/505 (0%)
Gangrene	1/505 (0.2%)		0/505 (0%)
Gastroenteritis	1/505 (0.2%)		1/505 (0.2%)
Peritonitis	0/505 (0%)		1/505 (0.2%)
Pneumonia	1/505 (0.2%)		2/505 (0.4%)
Subcutaneous abscess	0/505 (0%)		1/505 (0.2%)
Urinary tract infection	0/505 (0%)		1/505 (0.2%)
Injury, poisoning and procedural complications
Arteriovenous graft site haemorrhage	0/505 (0%)		1/505 (0.2%)
Coronary artery restenosis	0/505 (0%)		1/505 (0.2%)
Overdose	1/505 (0.2%)		0/505 (0%)
Post procedural haemorrhage	0/505 (0%)		1/505 (0.2%)
Tendon rupture	1/505 (0.2%)		0/505 (0%)
Vascular graft occlusion	1/505 (0.2%)		0/505 (0%)
Investigations
Haemoglobin decreased	0/505 (0%)		1/505 (0.2%)
Metabolism and nutrition disorders
Dehydration	0/505 (0%)		1/505 (0.2%)
Hyperglycaemia	2/505 (0.4%)		0/505 (0%)
Hypovolaemia	1/505 (0.2%)		0/505 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	1/505 (0.2%)		0/505 (0%)
Back pain	2/505 (0.4%)		1/505 (0.2%)
Joint hyperextension	0/505 (0%)		1/505 (0.2%)
Musculoskeletal chest pain	1/505 (0.2%)		0/505 (0%)
Musculoskeletal pain	2/505 (0.4%)		0/505 (0%)
Myalgia	1/505 (0.2%)		0/505 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/505 (0.2%)		0/505 (0%)
Bladder neoplasm	0/505 (0%)		1/505 (0.2%)
Bladder papilloma	0/505 (0%)		1/505 (0.2%)
Bronchial carcinoma	0/505 (0%)		1/505 (0.2%)
Colon cancer	0/505 (0%)		1/505 (0.2%)
Lung squamous cell carcinoma stage unspecified	1/505 (0.2%)		0/505 (0%)
Rectal cancer	1/505 (0.2%)		0/505 (0%)
Malignant melanoma	1/505 (0.2%)		0/505 (0%)
Nervous system disorders
Cerebellar infarction	1/505 (0.2%)		0/505 (0%)
Cerebral artery thrombosis	0/505 (0%)		1/505 (0.2%)
Cerebral haemorrhage	1/505 (0.2%)		0/505 (0%)
Cerebral infarction	0/505 (0%)		1/505 (0.2%)
Cerebrovascular accident	4/505 (0.8%)		2/505 (0.4%)
Dizziness	2/505 (0.4%)		0/505 (0%)
Dysarthria	0/505 (0%)		1/505 (0.2%)
Headache	1/505 (0.2%)		0/505 (0%)
Ischaemic stroke	1/505 (0.2%)		0/505 (0%)
Lethargy	1/505 (0.2%)		0/505 (0%)
Loss of consciousness	1/505 (0.2%)		0/505 (0%)
Multiple system atrophy	1/505 (0.2%)		0/505 (0%)
Subarachnoid haemorrhage	1/505 (0.2%)		1/505 (0.2%)
Syncope	3/505 (0.6%)		4/505 (0.8%)
Thoracic outlet syndrome	1/505 (0.2%)		0/505 (0%)
Transient ischaemic attack	0/505 (0%)		1/505 (0.2%)
Psychiatric disorders
Alcoholism	0/505 (0%)		1/505 (0.2%)
Confusional state	1/505 (0.2%)		0/505 (0%)
Delirium	1/505 (0.2%)		0/505 (0%)
Depression	1/505 (0.2%)		0/505 (0%)
Psychiatric decompensation	0/505 (0%)		1/505 (0.2%)
Psychotic disorder	0/505 (0%)		1/505 (0.2%)
Renal and urinary disorders
Haematuria	1/505 (0.2%)		0/505 (0%)
Renal failure acute	0/505 (0%)		1/505 (0.2%)
Renal impairment	0/505 (0%)		1/505 (0.2%)
Urinary bladder haemorrhage	0/505 (0%)		1/505 (0.2%)
Reproductive system and breast disorders
Menorrhagia	0/505 (0%)		1/505 (0.2%)
Ovarian cyst	0/505 (0%)		1/505 (0.2%)
Prostatitis	1/505 (0.2%)		0/505 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/505 (0.2%)		1/505 (0.2%)
Epistaxis	0/505 (0%)		1/505 (0.2%)
Haemoptysis	1/505 (0.2%)		0/505 (0%)
Hyperventilation	0/505 (0%)		1/505 (0.2%)
Idiopathic pulmonary fibrosis	1/505 (0.2%)		0/505 (0%)
Pulmonary embolism	1/505 (0.2%)		1/505 (0.2%)
Pulmonary oedema	1/505 (0.2%)		0/505 (0%)
Vocal cord polyp	0/505 (0%)		1/505 (0.2%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/505 (0.2%)		0/505 (0%)
Rash	1/505 (0.2%)		0/505 (0%)
Surgical and medical procedures
Implantable defibrillator insertion	1/505 (0.2%)		1/505 (0.2%)
Inguinal hernia repair	1/505 (0.2%)		0/505 (0%)
Percutaneous coronary intervention	1/505 (0.2%)		0/505 (0%)
Vascular disorders
Circulatory collapse	0/505 (0%)		2/505 (0.4%)
Hypertension	1/505 (0.2%)		0/505 (0%)
Hypotension	0/505 (0%)		1/505 (0.2%)
Infarction	0/505 (0%)		1/505 (0.2%)
Ischaemia	1/505 (0.2%)		1/505 (0.2%)
Orthostatic hypotension	1/505 (0.2%)		0/505 (0%)
Peripheral arterial occlusive disease	3/505 (0.6%)		2/505 (0.4%)
Other (Not Including Serious) Adverse Events
	Eplerenone Plus Standard of Care		Placebo Plus Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	151/506 (29.8%)		153/506 (30.2%)
Cardiac disorders
Angina pectoris	16/506 (3.2%)		22/506 (4.3%)
Bradycardia	12/506 (2.4%)		7/506 (1.4%)
Ventricular tachycardia	11/506 (2.2%)		7/506 (1.4%)
Gastrointestinal disorders
Abdominal pain upper	13/506 (2.6%)		3/506 (0.6%)
Constipation	7/506 (1.4%)		13/506 (2.6%)
Diarrhoea	22/506 (4.3%)		14/506 (2.8%)
Nausea	7/506 (1.4%)		11/506 (2.2%)
General disorders
Chest pain	23/506 (4.5%)		24/506 (4.7%)
Fatigue	10/506 (2%)		20/506 (4%)
Non-cardiac chest pain	16/506 (3.2%)		13/506 (2.6%)
Oedema peripheral	8/506 (1.6%)		11/506 (2.2%)
Metabolism and nutrition disorders
Diabetes mellitus	11/506 (2.2%)		6/506 (1.2%)
Musculoskeletal and connective tissue disorders
Back pain	12/506 (2.4%)		13/506 (2.6%)
Nervous system disorders
Dizziness	21/506 (4.2%)		19/506 (3.8%)
Headache	8/506 (1.6%)		16/506 (3.2%)
Psychiatric disorders
Anxiety	11/506 (2.2%)		8/506 (1.6%)
Respiratory, thoracic and mediastinal disorders
Cough	16/506 (3.2%)		17/506 (3.4%)
Dyspnoea	12/506 (2.4%)		17/506 (3.4%)
Vascular disorders
Hypertension	12/506 (2.4%)		18/506 (3.6%)
Hypotension	21/506 (4.2%)		19/506 (3.8%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.