Clinical trial NCT02235077: Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure
Official title: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Heart Diseases
Cardiovascular Diseases
Spironolactone
Aldactone
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-09-09
Enrollment: 360
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 96 Hour Change in NT-proBNP
timeFrame: Randomization to 96 hours
Secondary outcomes:
measure: 96 Hour Change in Clinical Congestion Score
timeFrame: Randomization through 96 hours
measure: 96 Hour Change in Dyspnea Likert Score
timeFrame: Randomization through 96 hours
measure: 96 Hour Change in Serum Creatinine
timeFrame: Randomization through 96 hours
measure: 96 Hour Net Fluid Output
timeFrame: Randomization through 96 hours
measure: 96 Hour Change in Body Weight
timeFrame: Randomization through 96 hours or earlier discharge
measure: 96 Hour Change in Serum Potassium Levels
timeFrame: Baseline, 96 hours
measure: Change in Loop Diuretics Requirements From Baseline to 30 Days
timeFrame: Randomization through Day 30
measure: Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30
timeFrame: Hospital discharge through Day 30
measure: 96 Hour Change in Dyspnea Visual Analog Scale
timeFrame: Randomization to 96 hours
Other outcomes:
measure: Day 60 Mortality
timeFrame: 60 days post randomization
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: West Roxbury
country: United States
facility: Boston VA Healtcare System
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Lumberton
country: United States
facility: Southeastern Regional Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals - Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Metro Health System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson Medical College
state: Pennsylvania
city: Houston
country: United States
facility: Michael Debakey VA Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
city: Salt Lake City
country: United States
facility: Utah VA Medical Center
state: Utah
city: Burlington
country: United States
facility: The University of Vermont- Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Duke University Health Systems
name: Adrian Hernandez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Braunwald, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.