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

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02235077
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 360
• Locations: 22
• Arms: 2
• Actual Duration (Months): 17.2
• Patients Per Site: 16.4
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Spironolactone; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)
• Actual Study Start Date: Dec 30, 2014
• Actual Primary Completion Date: Apr 12, 2016
• Actual Study Completion Date: Jun 6, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Spironolactone Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours	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 Names: aldactone
Placebo Comparator: Placebo Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours	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.

Outcome Measures

Primary Outcome Measures

1. 96 Hour Change in NT-proBNP [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.

Secondary Outcome Measures

1. 96 Hour Change in Clinical Congestion Score [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.

2. 96 Hour Change in Dyspnea Likert Score [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.

3. 96 Hour Change in Serum Creatinine [Randomization through 96 hours]

   Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours

4. 96 Hour Net Fluid Output [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.

5. 96 Hour Change in Body Weight [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

6. 96 Hour Change in Serum Potassium Levels [Baseline, 96 hours]

   Change in serum potassium levels at 96 hours as compared to baseline.

7. Change in Loop Diuretics Requirements From Baseline to 30 Days [Randomization through Day 30]

   Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization

8. Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30 [Hospital discharge through Day 30]

   Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30

9. 96 Hour Change in Dyspnea Visual Analog Scale [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.

Other Outcome Measures

1. Day 60 Mortality [60 days post randomization]

   All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University School of Medicine	Atlanta	Georgia	United States	30322
2	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
3	Tufts Medical Center	Boston	Massachusetts	United States	02111
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
6	Boston VA Healtcare System	West Roxbury	Massachusetts	United States	02132
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Washington University	Saint Louis	Missouri	United States	63110
9	Saint Louis University Hospital	Saint Louis	Missouri	United States	63117
10	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
11	Duke University	Durham	North Carolina	United States	27705
12	Southeastern Regional Medical Center	Lumberton	North Carolina	United States	28358
13	University Hospitals - Case Medical Center	Cleveland	Ohio	United States	44106
14	Metro Health System	Cleveland	Ohio	United States	44109
15	Cleveland Clinic	Cleveland	Ohio	United States	44195
16	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17603
17	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
18	Jefferson Medical College	Philadelphia	Pennsylvania	United States	19107
19	Michael Debakey VA Medical Center	Houston	Texas	United States	77030
20	University of Utah School of Medicine	Salt Lake City	Utah	United States	84132
21	Utah VA Medical Center	Salt Lake City	Utah	United States	84132
22	The University of Vermont- Fletcher Allen Health Care	Burlington	Vermont	United States	05401

Sponsors and Collaborators

• Duke University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Adrian Hernandez, MD, Duke University Health Systems
• Study Chair: Eugene Braunwald, MD, Harvard University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02235077
• Other Study ID Numbers: Pro00057090; 5U01HL084904
• First Posted: Sep 9, 2014
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Duke University: Heart Failure; Heart Diseases; Cardiovascular Diseases; Spironolactone; Aldactone
• Additional relevant MeSH terms: Heart Failure; Spironolactone

Study Results

Participant Flow

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Period Title: Overall Study
STARTED	182	178
COMPLETED	164	159
NOT COMPLETED	18	19

Baseline Characteristics

Arm/Group Title	Spironolactone	Placebo	Total
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Total of all reporting groups
Overall Participants	182	178	360
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.9 (13.7)	63.5 (14.4)	64.7 (14.1)
Sex: Female, Male (Count of Participants)
Female	65 35.7%	64 36%	129 35.8%
Male	117 64.3%	114 64%	231 64.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.1%	6 3.4%	8 2.2%
Not Hispanic or Latino	180 98.9%	172 96.6%	352 97.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.6%	1 0.6%	4 1.1%
Asian	3 1.6%	1 0.6%	4 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	74 40.7%	77 43.3%	151 41.9%
White	101 55.5%	99 55.6%	200 55.6%
More than one race	1 0.5%	0 0%	1 0.3%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	96 Hour Change in NT-proBNP
Description	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.
Time Frame	Randomization to 96 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	182	178
Mean (Standard Deviation) [log pg/ml]	-0.58 (0.69)	-0.61 (0.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5688
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	96 Hour Change in Clinical Congestion Score
Description	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.
Time Frame	Randomization through 96 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	182	178
Mean (Standard Deviation) [units on a scale]	-5.59 (3.34)	-5.82 (3.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4155
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	96 Hour Change in Dyspnea Likert Score
Description	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.
Time Frame	Randomization through 96 hours

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	166	163
Markedly improved	64 35.2%	79 44.4%
Moderately improved	56 30.8%	39 21.9%
Minimally improved	24 13.2%	18 10.1%
No change	17 9.3%	21 11.8%
Minimally worse	4 2.2%	5 2.8%
Moderately worse	0 0%	0 0%
Markedly worse	1 0.5%	1 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3039
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	96 Hour Change in Serum Creatinine
Description	Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours
Time Frame	Randomization through 96 hours

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	100	101
Mean (Standard Deviation) [mg/dl]	0.15 (0.30)	0.16 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7673
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	96 Hour Net Fluid Output
Description	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.
Time Frame	Randomization through 96 hours

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	87	96
Mean (Standard Deviation) [ml]	5824 (4007)	5507 (3633)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5734
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	319.2
	Confidence Interval	(2-Sided) 95%; -797.4 to 1435.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	96 Hour Change in Body Weight
Description	Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge
Time Frame	Randomization through 96 hours or earlier discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	182	178
Mean (Standard Deviation) [pounds]	-8.1 (10.7)	-7.5 (9.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3528
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -3.05 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	96 Hour Change in Serum Potassium Levels
Description	Change in serum potassium levels at 96 hours as compared to baseline.
Time Frame	Baseline, 96 hours

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	99	101
Mean (Standard Deviation) [mEq/L]	0.31 (0.54)	0.15 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0846
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in Loop Diuretics Requirements From Baseline to 30 Days
Description	Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	164	158
Mean (Standard Deviation) [mg]	19.66 (69.95)	30.70 (68.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0842
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.17
	Confidence Interval	(2-Sided) 95%; -25.98 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30
Description	Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30
Time Frame	Hospital discharge through Day 30

Outcome Measure Data

Analysis Population Description

All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	166	163
Count of Participants [Participants]	19 10.4%	17 9.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7628
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.56 to 2.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	96 Hour Change in Dyspnea Visual Analog Scale
Description	Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.
Time Frame	Randomization to 96 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	182	178
Mean (Standard Deviation) [units on a scale]	17.2 (25.0)	17.9 (24.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6102
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) 95%; -5.02 to 2.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Other Pre-specified Outcome

Title	Day 60 Mortality
Description	All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).
Time Frame	60 days post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.	Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
Measure Participants	182	178
Count of Participants [Participants]	8 4.4%	10 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Spironolactone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5818
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data was collected by the sites from randomization through 30 days, but was not collected on the case report form. Only Serious Adverse Events were collected on the data forms.
Adverse Event Reporting Description	Adverse event data was collected by the sites from randomization through 30 days, but was not collected on the case report form.
Arm/Group Title	Spironolactone		Placebo
Arm/Group Description	Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.		Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours. Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.
All Cause Mortality
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/182 (2.7%)		7/178 (3.9%)
Serious Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/182 (11.5%)		13/178 (7.3%)
Blood and lymphatic system disorders
Anaemia	1/182 (0.5%)	1	0/178 (0%)	0
Cardiac disorders
Aortic valve stenosis	1/182 (0.5%)	1	0/178 (0%)	0
Cardiogenic shock	1/182 (0.5%)	1	0/178 (0%)	0
Gastrointestinal disorders
Gastrointestinal Haemmorhage	1/182 (0.5%)	1	0/178 (0%)	0
Protalgia	1/182 (0.5%)	1	0/178 (0%)	0
General disorders
Multi-organ failure	1/182 (0.5%)	1	0/178 (0%)	0
Non-cardiac chest pain	1/182 (0.5%)	1	0/178 (0%)	0
Systemic inflammatory response syndrome	1/182 (0.5%)	1	0/178 (0%)	0
Infections and infestations
H1N1 Influenza	1/182 (0.5%)	1	0/178 (0%)	0
Oesophageal Candidiasis	0/182 (0%)	0	1/178 (0.6%)	1
Pneumonia	3/182 (1.6%)	3	1/178 (0.6%)	1
Tooth abscess	0/182 (0%)	0	1/178 (0.6%)	1
Urinary tract infection	1/182 (0.5%)	1	0/178 (0%)	0
Injury, poisoning and procedural complications
Fall	1/182 (0.5%)	1	1/178 (0.6%)	1
Post-procedural haemotoma	0/182 (0%)	0	1/178 (0.6%)	1
Traumatic haemotoma	1/182 (0.5%)	1	0/178 (0%)	0
Vascular pseudoaneurysm	0/182 (0%)	0	1/178 (0.6%)	1
Investigations
International Normalised Ratio Increased	1/182 (0.5%)	1	0/178 (0%)	0
Metabolism and nutrition disorders
Gout	0/182 (0%)	0	1/178 (0.6%)	1
Hyperglycaemia	1/182 (0.5%)	1	0/178 (0%)	0
Hypokalaemia	1/182 (0.5%)	1	0/178 (0%)	0
Lactic acidosis	1/182 (0.5%)	1	0/178 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	0/182 (0%)	0	1/178 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/182 (0.5%)	1	0/178 (0%)	0
Basal cell carcinoma	0/182 (0%)	0	1/178 (0.6%)	1
Nervous system disorders
Hepatic encephalopathy	0/182 (0%)	0	1/178 (0.6%)	1
Partial seizures with secondary generalisation	0/182 (0%)	0	1/178 (0.6%)	1
Psychiatric disorders
Delerium	1/182 (0.5%)	1	0/178 (0%)	0
Psychogenic seizure	0/182 (0%)	0	1/178 (0.6%)	1
Suicidal ideation	0/182 (0%)	0	1/178 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	4/182 (2.2%)	4	0/178 (0%)	0
Bronchial haemmorhage	0/182 (0%)	0	1/178 (0.6%)	1
Chronic obstructive pulmonary disease	1/182 (0.5%)	1	1/178 (0.6%)	1
Pneumonia aspiration	1/182 (0.5%)	1	0/178 (0%)	0
Vascular disorders
Aortic dissection	1/182 (0.5%)	1	0/178 (0%)	0
Distributive shock	1/182 (0.5%)	1	0/178 (0%)	0
Hypertension	0/182 (0%)	0	1/178 (0.6%)	1
Hypertensive crisis	1/182 (0.5%)	1	0/178 (0%)	0
Hypertensive emergency	2/182 (1.1%)	2	0/178 (0%)	0
Hypotension	1/182 (0.5%)	1	0/178 (0%)	0
Hypovolaemic shock	1/182 (0.5%)	1	0/178 (0%)	0
Other (Not Including Serious) Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

To minimize the probability of inaccurate data in published materials, it is the policy of the Heart Failure Network that all data and text considered for all papers, and all abstracts for presentation at scientific meetings be submitted to the Publication and Presentation Subcommittee, the NHLBI Project Officer, and the Coordinating Center for review and approval prior to presentation or publication.