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

Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Spironolactone; Drug: Placebo

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: Interventional
• Enrollment (Actual): 360
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • West Roxbury, Massachusetts, United States, 02132
      • Boston VA Healtcare System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63117
      • Saint Louis University Hospital
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
    • Lumberton, North Carolina, United States, 28358
      • Southeastern Regional Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44109
      • Metro Health System
    • Cleveland, Ohio, United States, 44106
      • University Hospitals - Case Medical Center
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17603
      • Lancaster General Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Medical College
  • Texas
    • Houston, Texas, United States, 77030
      • Michael Debakey VA Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah School of Medicine
    • Salt Lake City, Utah, United States, 84132
      • Utah VA Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont- Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
96 Hour Change in Clinical Congestion Score	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.	Randomization through 96 hours
96 Hour Change in Dyspnea Likert Score	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.	Randomization through 96 hours
96 Hour Change in Serum Creatinine	Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours	Randomization through 96 hours
96 Hour Net Fluid Output	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.	Randomization through 96 hours
96 Hour Change in Body Weight	Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge	Randomization through 96 hours or earlier discharge
96 Hour Change in Serum Potassium Levels	Change in serum potassium levels at 96 hours as compared to baseline.	Baseline, 96 hours
Change in Loop Diuretics Requirements From Baseline to 30 Days	Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization	Randomization through Day 30
Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30	Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30	Hospital discharge through Day 30
96 Hour Change in Dyspnea Visual Analog Scale	Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.	Randomization to 96 hours

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Adrian Hernandez, MD, Duke University Health Systems

Publications and helpful links

General Publications

• 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.
• Greene SJ, Felker GM, Giczewska A, Kalogeropoulos AP, Ambrosy AP, Chakraborty H, DeVore AD, Fudim M, McNulty SE, Mentz RJ, Vaduganathan M, Hernandez AF, Butler J. Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial. Can J Cardiol. 2019 Sep;35(9):1097-1105. doi: 10.1016/j.cjca.2019.01.022. Epub 2019 Feb 7.
• Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, Mann DL, Margulies KB, McNulty SE, Mentz RJ, Redfield MM, Tang WHW, Whellan DJ, Shah M, Desvigne-Nickens P, Hernandez AF, Braunwald E; National Heart Lung and Blood Institute Heart Failure Clinical Research Network. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol. 2017 Sep 1;2(9):950-958. doi: 10.1001/jamacardio.2017.2198.
• Butler J, Hernandez AF, Anstrom KJ, Kalogeropoulos A, Redfield MM, Konstam MA, Tang WH, Felker GM, Shah MR, Braunwald E. Rationale and Design of the ATHENA-HF Trial: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure. JACC Heart Fail. 2016 Sep;4(9):726-35. doi: 10.1016/j.jchf.2016.06.003. Epub 2016 Aug 10.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2014
• Primary Completion (Actual): April 12, 2016
• Study Completion (Actual): June 6, 2016

Study Registration Dates

• First Submitted: September 3, 2014
• First Submitted That Met QC Criteria: September 5, 2014
• First Posted (Estimate): September 9, 2014

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 22, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Heart Failure; Cardiovascular Diseases; Heart Diseases; Spironolactone; Aldactone
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: Pro00057090; 5U01HL084904 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No