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Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure (ATHENA-HF)

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ClinicalTrials.gov Identifier: NCT02235077
Recruitment Status : Completed
First Posted : September 9, 2014
Results First Posted : May 17, 2017
Last Update Posted : June 14, 2017
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Duke University

Tracking Information
First Submitted Date  ICMJE September 3, 2014
First Posted Date  ICMJE September 9, 2014
Results First Submitted Date  ICMJE April 7, 2017
Results First Posted Date  ICMJE May 17, 2017
Last Update Posted Date June 14, 2017
Actual Study Start Date  ICMJE December 30, 2014
Actual Primary Completion Date April 12, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
96 Hour Change in NT-proBNP [ Time Frame: Randomization to 96 hours ]
The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively. NT-proBNP was converted to log scale.
Original Primary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
Change in NT-proBNP [ Time Frame: Randomization to 96 hours ]
The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2017)
  • 96 Hour Change in Clinical Congestion Score [ Time Frame: Randomization through 96 hours ]
    Clinical congestion score will be assessed at randomization, 96 hours, and at discharge. Scale consisted of sum of six signs and symptoms of congestion, each scored 0-3. Zero indicates no sign/symptom and 3 indicates worst case of sign/symptom. Score range 0-18 with 18 being worst score.
  • 96 Hour Change in Dyspnea Likert Score [ Time Frame: Randomization through 96 hours ]
    Dyspnea relief via 7-point Likert scale will be assessed at randomization, 96 hours, and at discharge. The Likert score was defined as 1=markedly improved, 2=moderately improved, 3=minimally improved; 4=no change, 5=minimally worse, 6=moderately worse, and 7=markedly worse as compared with the degree of dyspnea present at randomization.
  • 96 Hour Change in Serum Creatinine [ Time Frame: Randomization through 96 hours ]
    Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours
  • 96 Hour Net Fluid Output [ Time Frame: Randomization through 96 hours ]
    Fluid intake and urine output will be assessed daily while in hospital through 96 hours. Net fluid output (output minus input) through 96 hours is reported.
  • 96 Hour Change in Body Weight [ Time Frame: Randomization through 96 hours or earlier discharge ]
    Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge
  • 96 Hour Change in Serum Potassium Levels [ Time Frame: Baseline, 96 hours ]
    Change in serum potassium levels at 96 hours as compared to baseline.
  • Change in Loop Diuretics Requirements From Baseline to 30 Days [ Time Frame: Randomization through Day 30 ]
    Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization
  • Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30 [ Time Frame: Hospital discharge through Day 30 ]
    Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30
  • 96 Hour Change in Dyspnea Visual Analog Scale [ Time Frame: Randomization to 96 hours ]
    Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
  • Change in clinical congestion score [ Time Frame: Randomization through discharge, an expected average of 5 days ]
    Clinical congestion score will be assessed at randomization, 96 hours, and at discharge
  • Change in dyspnea [ Time Frame: Randomization through discharge, an expected average of 5 days ]
    Dyspnea relief via 7-point Likert and Visual Analog Scale will be assessed at randomization, 96 hours, and at discharge
  • Change in renal function [ Time Frame: Randomization through discharge, an expected average of 5 days ]
    Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours
  • Effect on fluid status [ Time Frame: 24 hours through 96 hours ]
    Fluid intake and urine output will be assessed daily while in hospital through 96 hours
  • Change in body weight [ Time Frame: Randomization through discharge, an expected average of 5 days ]
    Baseline body weight assessment will be completed, and changes in weight documented daily through discharge
  • Effect on serum potassium levels [ Time Frame: Randomization through discharge, an expected average of 5 days ]
    Potassium levels will be monitored at randomization, daily from 24 hours through 96 hours, and at discharge to identify hyperkalemia.
  • Need for loop diuretics [ Time Frame: Randomization through Day 30 ]
    Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization
  • Change in acute heart failure symptoms [ Time Frame: Randomization through Day 30 ]
    In-hospital worsening heart failure symptoms will be assessed daily through 96 hours, at discharge, and at Day 30
Current Other Pre-specified Outcome Measures
 (submitted: April 7, 2017)
Day 60 Mortality [ Time Frame: 60 days post randomization ]
All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).
Original Other Pre-specified Outcome Measures
 (submitted: September 5, 2014)
Vital Statistics [ Time Frame: At 6 months post randomization ]
All participants will be contacted by telephone at 6 months, +/- 14 days post randomization to assess vital status (death).
 
Descriptive Information
Brief Title  ICMJE Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure
Official Title  ICMJE Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)
Brief Summary The primary objective of this study is to test the hypothesis that high-dose spironolactone will lead to greater proportional reduction in NT-proBNP levels from randomization to 96 hours over standard of care.
Detailed Description

Mineralocorticoid receptor antagonist (MRA) therapy is recommended in stable chronic systolic heart failure (HF) and post-infarction HF patients for improving morbidity and mortality. MRA therapy in AHF and in high doses is less well studied. The effectiveness and safety of early high dose MRA therapy in AHF is supported by a single-blind study showing lower risk of worsening renal function and need for loop diuretics, and improved congestion. MRA therapy in AHF may improve outcomes by relieving congestion at higher doses through their natriuretic property, in addition to preventing the deleterious effects of exacerbation of neuro-hormonal activation by loop diuretics.

This randomized, double blind, placebo-controlled study of high-dose spironolactone vs. placebo (for patients not receiving MRA at home) or low-dose spironolactone (for patients already receiving low-dose spironolactone) in AHF, will enroll 360 participants at approximately 30 clinical centers. After obtaining informed consent, subjects who fulfill all the inclusion criteria and none of the exclusion criteria will be randomized. Randomization will be performed by using procedures determined by the Coordinating Center (CC).

  • Patients receiving no MRA therapy at baseline will be randomized to receive either spironolactone 100 mg or placebo daily for 96 hours.
  • Patients already receiving low-dose spironolactone at baseline (12.5 mg or 25 mg daily) will be randomized to 100 mg or 25 mg spironolactone daily for 96 hours.

Within 24 hours prior to randomization, all study participants will undergo:

  • Medical History
  • Review of medications including pre-hospital loop diuretics, MRA, and potassium doses
  • Physical examination, vital signs and body weight
  • Measurement of creatinine, blood urea nitrogen (BUN), and electrolytes
  • Dyspnea Relief Assessments (7-point Likert and Visual Analog Scale)
  • Serum pregnancy test for all women of childbearing potential
  • Collection of samples for measurement of NT-proBNP levels (Core Lab)

Study drug will be initiated as follows:

  • Patients receiving no MRA therapy at baseline: 4x25 mg study capsules once daily; starting dose 100 mg spironolactone or placebo; if dose adjustment is required, active capsules will be adjusted by pharmacy to achieve the required dose.
  • Patients already receiving low-dose spironolactone at baseline: 4x25 mg study capsules once daily; one capsule containing 25 mg spironolactone and 3x25 mg study capsules containing spironolactone or placebo; if dose adjustment is required, active capsules will be adjusted by pharmacy to achieve the required dose.

Patients will be followed every 24 hours following randomization through 96 hours. Study drug will be administered daily for 96 hours. Study drug administration time is anchored to time of randomization. Dose adjustments (continue, hold, stop) are permitted according to serum K+ and renal function.

Assessment at 24 hours post randomization includes: Review of medications, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse events.

If the 24 hour assessment is also the day of discharge, include:

  • Physical exam / Vital signs
  • Dyspnea Relief (7-Point Likert and VAS) worksheets
  • Biomarkers (NT-proBNP) (Core Lab)

Assessment at 48 hours post randomization includes: Review of medications, physical exam/vital signs, body weight, fluid intake/urine output, Dyspnea Relief (7-Point Likert and VAS) worksheets, creatinine, blood urea nitrogen (BUN), and electrolytes, biomarker levels (NT-proBNP) by Core Lab.

Assessment at 72 hours post randomization includes: Review of medications, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse events.

If the 72 hour assessment is also the day of discharge, include:

  • Physical exam / Vital signs
  • Dyspnea Relief (7-Point Likert and VAS) worksheets
  • Biomarkers (NT-proBNP) (Core Lab)

Assessment at 96 hours post randomization includes: Review of medications, physical exam/vital signs, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, Dyspnea Relief (7-Point Likert and VAS), and biomarker levels (NT-proBNP) by Core Lab.

If patient is clinically euvolemic in less than 96 hours, the investigator may consider changing loop diuretics to oral dose.

Study drug will be discontinued after 96 hours and further use of MRA will be left to the treating physician's discretion.

Assessment at Discharge: If discharge occurs after the 96 hour assessment but prior to the 30 day follow-up telephone call,the following will be documented: Medication review (prescribed medications at the time of discharge), body weight (if available), creatinine, blood urea nitrogen (BUN), and electrolytes (if available), and adverse events.

Ejection fraction data will be obtained from echocardiogram within 6 months prior to randomization. Those patients who do not have an echocardiogram recorded within this time frame will get an echocardiogram, nuclear perfusion study, MRI, or MUGA performed prior to the 96 hour in-hospital assessment to ascertain ejection fraction.

Follow-up Telephone Call at Day 30: All participants will be contacted by telephone at day 30 (+3 days) following randomization to assess tertiary endpoints, including medication use and adverse events.

Follow-up Telephone Call at Day 60: All participants will be contacted by telephone at day 60 (+/-3 days) following randomization to assess vital status.

During the consent process, patients will be asked if interested in donating samples and data for research purposes via a biorepository and/or genetic study. Based on site and IRB preference, this optional part of the study may be incorporated into the main consent or may be a separate consent and IRB application.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure
Intervention  ICMJE
  • Drug: Spironolactone

    Patients receiving no MRA at home will receive spironolactone 100 mg (4x25 mg capsules) once daily for 96 hours.

    Patients already receiving low-dose MRA at home will be randomized to receive spironolactone 25 mg (1x25 mg capsules) or 100 mg (4x25 mg capsules) in hospital for 96 hours. The patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.

    Other Name: aldactone
  • Drug: Placebo

    Patients receiving no MRA at home will receive 100 mg placebo (4x25 mg capsules) once daily for 96 hours.

    Patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.

Study Arms  ICMJE
  • Active Comparator: Spironolactone
    Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours
    Intervention: Drug: Spironolactone
  • Placebo Comparator: Placebo
    Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 5, 2014)
360
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 6, 2016
Actual Primary Completion Date April 12, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female patient ≥21 years old
  • Admitted to hospital for AHF with at least 1 symptom (dyspnea, orthopnea, or fatigue) and 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography) of congestion
  • Patient must be randomized within 24 hours of first IV diuretic dose administered for the current episode of decompensation (regardless of where the diuretic was given e.g. office, ED, ambulance, hospital etc.)
  • Estimated GFR of ≥30 mL/min/1.73m2 determined by the MDRD equation
  • Serum K+ ≤5.0 mmol/L at enrollment
  • NT-proBNP ≥1000 pg/mL or BNP ≥250 pg/mL, measured within 24h from randomization
  • Not on MRA or on low-dose spironolactone (12.5 mg or 25 mg daily) at baseline

Exclusion Criteria:

  • Taking eplerenone or >25 mg spironolactone at baseline
  • eGFR < 30 ml/min/1.73m2
  • Serum K+ >5.0 mmol/L. If a repeat measurement within the enrollment window is <5.0, the patient can be considered for inclusion.
  • Systolic blood pressure <90 mmHg
  • Hemodynamically significant arrhythmias or defibrillator shock within 1 week
  • Acute coronary syndrome currently suspected or within the past 4 weeks
  • Severe liver disease (ALT or AST >3 x normal, alkaline phosphatase or bilirubin >2x normal)
  • Active infection (current use of oral or IV antimicrobial agents)
  • Active gastrointestinal bleeding
  • Active malignancy other than non-melanoma skin cancers
  • Current or planned mechanical circulatory support within 30 days
  • Post cardiac transplant or listed for transplant and expected to receive one within 30 days
  • Current inotrope use
  • Complex congenital heart disease
  • Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
  • Previous adverse reaction to MRAs
  • Enrollment in another randomized clinical trial during index hospitalization
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02235077
Other Study ID Numbers  ICMJE Pro00057090
5U01HL084904 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Adrian Hernandez, MD Duke University Health Systems
Study Chair: Eugene Braunwald, MD Harvard University
PRS Account Duke University
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP