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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00232180




Registration number
NCT00232180
Ethics application status
Date submitted
30/09/2005
Date registered
4/10/2005
Date last updated
22/12/2020

Titles & IDs
Public title
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
Scientific title
The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Subjects With NYHA Class II Chronic Systolic Heart Failure
Secondary ID [1] 0 0
A6141079
Universal Trial Number (UTN)
Trial acronym
EMPHASIS-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Eplerenone

Active comparator: Eplerenone arm - Eplerenone administered on top of background standard heart failure therapy


Treatment: Drugs: Eplerenone
Eplerenone administered on top of background standard heart failure therapy
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date
Timepoint [1] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010)
Primary outcome [2] 0 0
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated)
Timepoint [2] 0 0
Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [1] 0 0
Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Timepoint [1] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [2] 0 0
Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated)
Timepoint [2] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [3] 0 0
Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated)
Timepoint [3] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [4] 0 0
Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated)
Timepoint [4] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [5] 0 0
Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated)
Timepoint [5] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [6] 0 0
Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated)
Timepoint [6] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [7] 0 0
Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Timepoint [7] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [8] 0 0
Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated)
Timepoint [8] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [9] 0 0
Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated)
Timepoint [9] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [10] 0 0
Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated)
Timepoint [10] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [11] 0 0
Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated)
Timepoint [11] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [12] 0 0
Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated)
Timepoint [12] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [13] 0 0
Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated)
Timepoint [13] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [14] 0 0
Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated)
Timepoint [14] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [15] 0 0
Number of Participants With New Onset Atrial Fibrillation or Flutter
Timepoint [15] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Secondary outcome [16] 0 0
Number of Participants With New Onset Diabetes Mellitus (DM)
Timepoint [16] 0 0
Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)

Eligibility
Key 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
Minimum age
55 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Severe chronic systolic heart failure symptomatic at rest despite optimal medical therapy; estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/03/2006
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/01/2012
Sample size
Target
Accrual to date
Final
2743
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS
Recruitment hospital [1] 0 0
Pfizer Investigational Site - Concord
Recruitment hospital [2] 0 0
Pfizer Investigational Site - Brisbane
Recruitment hospital [3] 0 0
Pfizer Investigational Site - Launceston
Recruitment postcode(s) [1] 0 0
2139 - Concord
Recruitment postcode(s) [2] 0 0
4029 - Brisbane
Recruitment postcode(s) [3] 0 0
7250 - Launceston
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
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California
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United States of America
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Colorado
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United States of America
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Connecticut
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Illinois
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Kentucky
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Louisiana
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Maine
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Maryland
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Massachusetts
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Mississippi
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Nebraska
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Hradec Kralove
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Plzen
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Czechia
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Praha 10
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Czechia
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Praha 1
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Czechia
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Praha 2
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Czechia
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Praha 6
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Czechia
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Pribram
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France
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Cedex 4
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Angers Cedex 01
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Brest
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Cergy-Pontoise
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Chateauroux
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Gap CEDEX
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France
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Nantes Cedex 01
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France
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Nice CEDEX 1
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France
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Nîmes
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Paris CEDEX 13
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Hagen
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Halle
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Angelholm
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Sweden
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Vaxjo
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State/province [196] 0 0
Crimea
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Estado Miranda

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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
Trial website
https://clinicaltrials.gov/study/NCT00232180
Trial related presentations / publications
Vaduganathan M, Ferreira JP, Rossignol P, Neuen BL, Claggett BL, Pfeffer MA, McMurray JJV, Pitt B, Zannad F, Solomon SD. Effects of steroidal mineralocorticoid receptor antagonists on acute and chronic estimated glomerular filtration rate slopes in patients with chronic heart failure. Eur J Heart Fail. 2022 Sep;24(9):1586-1590. doi: 10.1002/ejhf.2635. Epub 2022 Aug 31.
Martens P, Ferreira JP, Vincent J, Abreu P, Busselen M, Mullens W, Tang WHW, Bohm M, Pitt B, Zannad F, Rossignol P. Prognostic relevance of magnesium alterations in patients with a myocardial infarction and left ventricular dysfunction: insights from the EPHESUS trial. Eur Heart J Acute Cardiovasc Care. 2022 Feb 8;11(2):148-159. doi: 10.1093/ehjacc/zuab111.
Ferreira JP, Lamiral Z, McMurray JJV, Swedberg K, van Veldhuisen DJ, Vincent J, Rossignol P, Pocock SJ, Pitt B, Zannad F. Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial. Circ Heart Fail. 2021 Jun;14(6):e008075. doi: 10.1161/CIRCHEARTFAILURE.120.008075. Epub 2021 Jun 15.
Martens P, Ferreira JP, Vincent J, Abreu P, Busselen M, Mullens W, Tang WWH, Bohm M, Pitt B, Zannad F, Rossignol P. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial. Clin Res Cardiol. 2022 Apr;111(4):380-392. doi: 10.1007/s00392-021-01853-8. Epub 2021 Apr 23.
Chung EY, Ruospo M, Natale P, Bolignano D, Navaneethan SD, Palmer SC, Strippoli GF. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 27;10(10):CD007004. doi: 10.1002/14651858.CD007004.pub4.
Monzo L, Ferreira JP, Abreu P, Szumski A, Bohm M, McMurray JJV, Pitt B, Swedberg K, van Veldhuisen DJ, Girerd N, Vincent J, Zannad F, Rossignol P. Visit-to-visit blood pressure variation and outcomes in heart failure with reduced ejection fraction: findings from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial. J Hypertens. 2020 Mar;38(3):420-425. doi: 10.1097/HJH.0000000000002275.
Stienen S, Ferreira JP, Vincent J, Busselen M, Li B, McMurray JJV, Pitt B, Girerd N, Rossignol P, Zannad F. Estimated Long-Term Survival With Eplerenone. J Am Coll Cardiol. 2019 May 14;73(18):2357-2359. doi: 10.1016/j.jacc.2019.02.043. No abstract available.
Ferreira JP, Duarte K, McMurray JJV, Pitt B, van Veldhuisen DJ, Vincent J, Ahmad T, Tromp J, Rossignol P, Zannad F. Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns. Circ Heart Fail. 2018 Jul;11(7):e004926. doi: 10.1161/CIRCHEARTFAILURE.118.004926.
Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ, Shi H, Messig M, Vincent J, Girerd N, Bakris G, Pitt B, Zannad F. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014 Jan;7(1):51-8. doi: 10.1161/CIRCHEARTFAILURE.113.000792. Epub 2013 Dec 2.
Eschalier R, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, Shi H, Vincent J, Rossignol P, Zannad F, Pitt B; EMPHASIS-HF Investigators. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol. 2013 Oct 22;62(17):1585-93. doi: 10.1016/j.jacc.2013.04.086. Epub 2013 Jun 27.
Krum H, Shi H, Pitt B, McMurray J, Swedberg K, van Veldhuisen DJ, Vincent J, Pocock S, Zannad F; EMPHASIS-HF Study Group. Clinical benefit of eplerenone in patients with mild symptoms of systolic heart failure already receiving optimal best practice background drug therapy: analysis of the EMPHASIS-HF study. Circ Heart Fail. 2013 Jul;6(4):711-8. doi: 10.1161/CIRCHEARTFAILURE.112.000173. Epub 2013 Apr 26.
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. doi: 10.1056/NEJMoa1009492. 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. doi: 10.1093/eurjhf/hfq049. Epub 2010 Apr 13.
Public notes

Contacts
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Pfizer CT.gov Call Center
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Pfizer
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Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00232180