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
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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) ]

Show Outcome Measure 1

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) ]

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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

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]	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) ]

Show Outcome Measure 3

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) ]

Show Outcome Measure 4

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) ]

Show Outcome Measure 5

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) ]

Show Outcome Measure 6

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) ]

Show Outcome Measure 7

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) ]

Show Outcome Measure 8

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) ]

Show Outcome Measure 9

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) ]

Show Outcome Measure 10

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) ]

Show Outcome Measure 11

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) ]

Show Outcome Measure 12

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) ]

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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) ]

Show Outcome Measure 14

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) ]

Show Outcome Measure 15

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) ]

Show Outcome Measure 16

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) ]

Show Outcome Measure 17

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) ]

Show Outcome Measure 18

Serious Adverse Events

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Other Adverse Events

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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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