A Comparison Of Outcomes In Patients In New York Heart Association (NYHA) Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines (EMPHASIS-HF)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Pfizer

ClinicalTrials.gov Identifier:

NCT00232180

First received: September 30, 2005

Last updated: March 28, 2013

Last verified: March 2013

History of Changes

Results First Received: May 20, 2011

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Heart Failure
Intervention:	Drug: Eplerenone

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 1597 participants who completed the double-blind phase, 1246 entered into the open-label phase and 351 participants were ineligible to participate the open-label phase.

Reporting Groups

	Description
Eplerenone: Double-blind Phase	Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo: Double-blind Phase	Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Eplerenone: Open Label Phase	Participants from double blind phase received eplerenone 25 mg tablet orally once daily on top of standard heart failure therapy for 12 months. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an eGFR between 30 to 49 ml/min/1.73m^2 in the double blind phase, initial dose was 25 mg orally once every other day; at Week 4, dose might had been increased to a maximum of 25 mg once daily based on serum potassium level.

Participant Flow for 2 periods

Period 1: Double-blind (DB) Phase

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
STARTED	1367 ^[1]	1376 ^[1]
Treated	1364	1372
COMPLETED	826	771
NOT COMPLETED	541	605
Death	186	222
Lost to Follow-up	34	28
Withdrawal by Subject	131	148
Protocol Violation	28	21
Adverse Event	83	100
Unspecified	70	75
Randomized but not treated	3	4
Laboratory abnormality	6	7

[1]	Three participants in each arm were enrolled after data cut-off.

Period 2: Open Label Phase

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase	Eplerenone: Open Label Phase
STARTED	0	0	1246
Treated	0	0	1245
COMPLETED	0	0	1098
NOT COMPLETED	0	0	148
Death	0	0	48
Lost to Follow-up	0	0	5
Protocol Violation	0	0	3
Study terminated by sponsor	0	0	3
Withdrawal by Subject	0	0	37
Unspecified	0	0	16
Adverse Event	0	0	25
Laboratory abnormality	0	0	10
Randomized but not treated	0	0	1

Baseline Characteristics

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Reporting Groups

	Description
Eplerenone	Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo	Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Total	Total of all reporting groups

Baseline Measures

	Eplerenone	Placebo	Total
Number of Participants [units: participants]	1367	1376	2743
Age, Customized [units: participants]
Less than (<) 65 years	443	441	884
65 to 74 years	594	607	1201
75 to 84 years	302	299	601
Greater than or equal to (>=) 85 years	28	29	57
Gender [units: participants]
Female	309	302	611
Male	1058	1074	2132

Outcome Measures

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1. Primary:

Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010) ]

Measure Type	Primary
Measure Title	Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date
Measure Description	CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (FAS) using intent-to-treat (ITT) principle: All randomized participants, followed for mortality, other major endpoints for duration of double blind treatment period, regardless of compliance with study drug and protocol. Here 'N' (Number of Participants Analyzed) signifies those participants who were evaluable for this measure.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1364	1373
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date [units: participants]	249	356

Statistical Analysis 1 for Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.630
95% Confidence Interval	( 0.535 to 0.741 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, time from electrocardiogram Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Using an adaptation of Haybittle-Peto stopping criterion adjusting for two interim analyses, p-value for final primary analysis will be compared to alpha=0.049. No adjustment in alpha will be made on parameters/endpoints other than primary endpoint.
[4]	Other relevant estimation information:
	No text entered.

2. Primary:

Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Primary
Measure Title	Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated)
Measure Description	CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated) [units: participants]	288	392

No statistical analysis provided for Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated)

3. Secondary:

Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Measure Description	Death due to any cause or first of occurrence HF hospitalization. HF hospitalization is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	270	376
Up to 59.5 months (complete DB) (n= 1367, 1376)	311	418

Statistical Analysis 1 for Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.647
95% Confidence Interval	( 0.552 to 0.757 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

4. Secondary:

Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated)
Measure Description	Death due to any cause.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	171	213
Up to 59.5 months (complete DB) (n= 1367, 1376)	205	253

Statistical Analysis 1 for Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.0081
Hazard Ratio (HR) ^[4]	0.761
95% Confidence Interval	( 0.622 to 0.932 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

5. Secondary:

Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated)
Measure Description	CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism).
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	147	185
Up to 59.5 months (complete DB) (n= 1367, 1376)	178	215

Statistical Analysis 1 for Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.0120
Hazard Ratio (HR) ^[4]	0.757
95% Confidence Interval	( 0.609 to 0.941 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

6. Secondary:

Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated)
Measure Description	Hospitalization due to any cause is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility).
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	408	491
Up to 59.5 months (complete DB) (n= 1367, 1376)	463	552

Statistical Analysis 1 for Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.768
95% Confidence Interval	( 0.673 to 0.876 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

7. Secondary:

Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated)
Measure Description	First occurrence of HF hospitalization. Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	164	253
Up to 59.5 months (complete DB) (n= 1367, 1376)	186	277

Statistical Analysis 1 for Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.576
95% Confidence Interval	( 0.473 to 0.702 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

8. Secondary:

Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated)
Measure Description	Death due to any cause or hospitalization due to any cause. Hospitalization due to any cause is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility).
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	462	569
Up to 59.5 months (complete DB) (n= 1367, 1376)	530	636

Statistical Analysis 1 for Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.751
95% Confidence Interval	( 0.664 to 0.849 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

9. Secondary:

Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Measure Description	Death due to HF or first occurrence of HF hospitalization. Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	170	262
Up to 59.5 months (complete DB) (n= 1367, 1376)	194	287

Statistical Analysis 1 for Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.577
95% Confidence Interval	( 0.475 to 0.701 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

10. Secondary:

Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated)
Measure Description	First occurrence of CV hospitalization. CV hospitalization is defined as hospitalization due to HF (first or subsequent), acute myocardial infarction, angina pectoris (unstable), cardiac arrhythmia (atrial fibrillation [AF], atrial flutter, supraventricular arrhythmias, or ventricular arrhythmias), stroke/CVA, other CV reasons (such as hypotension or peripheral vascular disease), implantation of a cardioverter defibrillator (ICD), or cardiac resynchronization therapy (CRT) with CV event as the primary reason for hospitalization as determined by endpoint committee adjudicator.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	304	399
Up to 59.5 months (complete DB) (n= 1367, 1376)	346	439

Statistical Analysis 1 for Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	<0.0001
Hazard Ratio (HR) ^[4]	0.694
95% Confidence Interval	( 0.598 to 0.806 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

11. Secondary:

Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated)
Measure Description	No text entered.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	45	33
Up to 59.5 months (complete DB) (n= 1367, 1376)	49	40

Statistical Analysis 1 for Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.2321
Hazard Ratio (HR) ^[4]	1.316
95% Confidence Interval	( 0.839 to 2.064 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

12. Secondary:

Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated)
Measure Description	No text entered.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	21	26
Up to 59.5 months (complete DB) (n= 1367, 1376)	24	31

Statistical Analysis 1 for Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.4213
Hazard Ratio (HR) ^[4]	0.789
95% Confidence Interval	( 0.443 to 1.406 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

13. Secondary:

Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated)
Measure Description	First occurrence of implantation of cardiac defibrillator (ICD). ICD is an electronic device capable of monitoring the heart rhythm. When the heart is beating normally, the device remains inactive. If the heart develops a life-threatening tachycardia, the ICD delivers electrical shocks to the heart to terminate the abnormal rhythm and return the heart rhythm to normal.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	61	59
Up to 59.5 months (complete DB) (n= 1367, 1376)	76	78

Statistical Analysis 1 for Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.9754
Hazard Ratio (HR) ^[4]	0.994
95% Confidence Interval	( 0.694 to 1.424 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

14. Secondary:

Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated)
Measure Description	First occurrence of implantation of resynchronization device. CRT is use of a specialized pacemaker to re-coordinate the action of the right and left ventricles in heart failure.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	33	41
Up to 59.5 months (complete DB) (n= 1367, 1376)	45	53

Statistical Analysis 1 for Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.2652
Hazard Ratio (HR) ^[4]	0.770
95% Confidence Interval	( 0.485 to 1.220 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

15. Secondary:

Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated)
Measure Description	First occurrence of hospitalization due to worsening renal function. Hospitalization due to worsening renal function is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to worsening renal function as the primary reason for hospitalization as determined by endpoint committee adjudicator. Worsening renal function is defined as doubling of serum creatinine level from baseline level.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	9	8
Up to 59.5 months (complete DB) (n= 1367, 1376)	10	10

Statistical Analysis 1 for Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.9537
Hazard Ratio (HR) ^[4]	0.971
95% Confidence Interval	( 0.366 to 2.578 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

16. Secondary:

Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated)
Measure Description	First occurrence of hospitalization due to hyperkalemia. Hospitalization due to hyperkalemia is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to hyperkalemia as the primary reason for hospitalization as determined by endpoint committee adjudicator. Hyperkalemia is defined as serum potassium level greater than (>) 5.5 milliequivalents per liter (mEq/L).
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	1367	1376
Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated) [units: participants]
Up to 50 months (cut-off) (n= 1364, 1373)	4	3
Up to 59.5 months (complete DB) (n= 1367, 1376)	4	3

Statistical Analysis 1 for Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.8539
Hazard Ratio (HR) ^[4]	1.154
95% Confidence Interval	( 0.251 to 5.312 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

17. Secondary:

Number of Participants With New Onset Atrial Fibrillation or Flutter [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With New Onset Atrial Fibrillation or Flutter
Measure Description	New onset of atrial fibrillation or flutter is defined as the diagnosis of atrial fibrillation or flutter in a participant after randomization, where atrial fibrillation was not present before randomization.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: Here 'N' (Number of Participants Analyzed) signifies those who did not report a history of atrial fibrillation at baseline and “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	956	940
Number of Participants With New Onset Atrial Fibrillation or Flutter [units: participants]
Up to 50 months (cut-off) (n= 950, 937)	32	52
Up to 59.5 months (complete DB) (n= 956, 940)	41	59

Statistical Analysis 1 for Number of Participants With New Onset Atrial Fibrillation or Flutter

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.0175
Hazard Ratio (HR) ^[4]	0.585
95% Confidence Interval	( 0.376 to 0.910 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

18. Secondary:

Number of Participants With New Onset Diabetes Mellitus (DM) [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

Measure Type	Secondary
Measure Title	Number of Participants With New Onset Diabetes Mellitus (DM)
Measure Description	The definition of new onset diabetes mellitus is the diagnosis of diabetes mellitus in a participant after randomization, when DM was not present before randomization.
Time Frame	Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: Here 'N' (Number of Participants Analyzed) signifies those who did not report a history of diabetes mellitus at baseline and “n” signifies participants evaluated at that time point.

Reporting Groups

Description

Eplerenone: Double-blind Phase

Placebo: Double-blind Phase

Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values

	Eplerenone: Double-blind Phase	Placebo: Double-blind Phase
Number of Participants Analyzed [units: participants]	907	975
Number of Participants With New Onset Diabetes Mellitus (DM) [units: participants]
Up to 50 months (cut-off) (n= 904, 973)	34	40
Up to 59.5 months (complete DB) (n= 907, 975)	42	47

Statistical Analysis 1 for Number of Participants With New Onset Diabetes Mellitus (DM)

Groups ^[1]	All groups
Method ^[2]	Cox proportional hazard model
P Value ^[3]	0.6009
Hazard Ratio (HR) ^[4]	0.885
95% Confidence Interval	( 0.559 to 1.400 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistically significant if p-value <0.01
[4]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com

No publications provided by Pfizer

Publications automatically indexed to this study:

Rogers JK, McMurray JJ, Pocock SJ, Zannad F, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B. Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. Circulation. 2012 Nov 6;126(19):2317-23. doi: 10.1161/CIRCULATIONAHA.112.110536. Epub 2012 Oct 5.

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. Epub 2010 Nov 14.

Zannad F, McMurray JJ, Drexler H, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B. Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF). Eur J Heart Fail. 2010 Jun;12(6):617-22. Epub 2010 Apr 13.

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT00232180 History of Changes
Other Study ID Numbers:	A6141079
Study First Received:	September 30, 2005
Results First Received:	May 20, 2011
Last Updated:	March 28, 2013
Health Authority:	United States: Food and Drug Administration

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