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

Study Overview
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Brief Summary
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In an earlier study, eplerenone was shown to improve survival in patients who had heart failure immediately following a heart attack. However, it is not known how patients with established mild-to-moderate heart failure (NYHA Class II), who have the additional risk of sudden death, will respond if treated with eplerenone. In this trial, eplerenone plus standard heart failure medicines is being compared to placebo plus standard heart failure medicines in terms of an additional ability to prolong life and prevent re-hospitalizations for worsening heart failure in these patients. The Data Safety Monitoring Committee (DSMC) observed during its conduct of the protocol-specified second interim analysis on the 6th of May, 2010 that the efficacy of eplerenone had met the pre-specified stopping rules in the protocol. As a result of the discussion between the DSMC and the Executive Steering Committee (ESC), the ESC recommended that EMPHASIS-HF should be terminated, Based on the convincing efficacy and the consideration that it would be unethical not to offer this treatment to patients, the ESC recommended that all the patients in the trial should be transferred to open-label eplerenone. The Open Label Extension eplerenone arm will last for 12 months. Eplerenone is not currently approved for the indication studied in this patient population. On May 26, 2010, further enrollment into EMPHASIS-HF was stopped. The amendment is considered to be the most appropriate way to ensure that all the subjects who participated in the double-blind phase of the EMPHASIS-HF trial can be offered treatment with eplerenone

Official Title
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The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Subjects With NYHA Class II Chronic Systolic Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Eplerenone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History (Hx) of chronic systolic heart failure of ischemic or non-ischemic etiology of at least 4 weeks duration; Currently, New York Heart Association (NYHA) functional Class II and on optimal dose, or maximally tolerated dose of standard heart failure medicines (advisable to include ACE-I/ARBs; beta-blockers) and diuretics if indicated for fluid overload. Should have participated in the double-blind phase of the EMPHASIS-HF trial Exclusion Criteria: Severe chronic systolic heart failure symptomatic at rest despite optimal medical therapy; estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2.

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eplerenone arm<br>Eplerenone administered on top of background standard heart failure therapy | Drug: Eplerenone<br>* Eplerenone administered on top of background standard heart failure therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010) | 
| Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated) | 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. | Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated) | Death due to any cause. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated) | 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). | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated) | 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). | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated) | 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). | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated) |  | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated) |  | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated) | 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). | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With New Onset Atrial Fibrillation or Flutter | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 
| Number of Participants With New Onset Diabetes Mellitus (DM) | 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. | Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-label, single arm mortality/morbidity trial eplerenone chronic systolic heart failure