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Mineralocorticoid Receptor Antagonists (MRA) in Heart Failure (HF) and Loop Diuretic Resistance

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ClinicalTrials.gov Identifier: NCT02585843
Recruitment Status : Completed
First Posted : October 23, 2015
Results First Posted : July 23, 2019
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
Arthur R. Garan, Columbia University

Brief Summary:
This is a prospective, single-center, double-blind and randomized placebo controlled trial for evaluation of a 7-day 100mg daily dose of spironolactone on weight loss and resolution of signs and symptoms of congestion in outpatients with acute decompensated heart failure (ADHF). Patients who are not responding to their current loop diuretics will be considered for this study. Mineralocorticoid receptor antagonists (MRAs) are recommended as standard of care in management of heart failure (HF) patients. However, recommended doses of MRAs (spironolactone 25mg/daily or eplerenone 50mg/daily) will not have any impact on signs and symptoms of volume overload. Therefore, the proposed study will aim to show the impact of this outpatient regimen to improve diuresis and possible reduction in hospitalization for further diuretic management in HF patients with signs and symptoms of congestion.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Spironolactone 100mg Drug: Spironolactone 25mg Phase 2 Phase 3

Detailed Description:
The incidence and prevalence of heart failure (HF) is rising with more than 5 million Americans suffering from this syndrome. Hospitalization rates for acute decompensated heart failure (ADHF) are also remarkably high, exceeding more than 1 million admissions per year. Congestion is the main cause of hospitalization for ADHF. Loop diuretics as the main therapy for decongestion, often are not adequate since many patients with ADHF develop "loop diuretic resistance". These patients will require hospitalization for intravenous diuretic or other advanced decongestion therapies. Thus, novel decongestion therapies are needed to decrease hospital admission rates and subsequent complications of multiple hospitalizations. Hyperaldosteronism, not only is a pivotal pathogenic factor in HF, but also contributes to loop diuretic resistance. Attempts for normalization of circulatory aldosterone with mineralocorticoid receptor antagonists (MRAs), mainly spironolactone, have shown to decrease mortality in HF patients with reduced left ventricular ejection fraction (LVEF). Moreover, MRAs significantly decrease the rate of rehospitalization in both HF with preserved and reduced LVEF. The dose of spironolactone in these trials is 25mg daily. However, this dose does not increase natriuresis (urinary sodium excretion). Natriuresis is achieved with higher doses of MRAs. Therefore, the primary aim of this study is to examine the efficacy of 7-day 100mg daily of spironolactone on weight loss and resolution of signs and symptoms of congestion in patients aged 60 years with ADHF and loop diuretic resistance.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in Heart Failure and Loop Diuretic Resistance in Outpatients
Actual Study Start Date : November 2015
Actual Primary Completion Date : March 31, 2017
Actual Study Completion Date : March 31, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: High-dose
Spironolactone 100mg: 100mg/day of spironolactone (2 capsules), PO (oral) for 7 days
Drug: Spironolactone 100mg
2 capsules of study medication consist of 100mg, PO (oral) for 7 days
Other Name: Aldactone

Active Comparator: Standard of Care
Spironolactone 25mg: 25mg/day of spironolactone, PO (oral)
Drug: Spironolactone 25mg
25mg/day of spironolactone
Other Name: Aldactone




Primary Outcome Measures :
  1. Change in Body Weight [ Time Frame: 7 days ]
    change in body weight measured in kilograms between weight at baseline and weight at 7 days


Secondary Outcome Measures :
  1. Change in Estimated Jugular Venous Pressure (cmH2O) [ Time Frame: 7 days ]
    Change in estimated jugular venous pressure by physical exam in cmH2O between baseline and 7 days

  2. Change in 6-minute Walk Test Distance (6MWT) [ Time Frame: 7 days ]
    At baseline and final visit. The 6MWT will be conducted per American Thoracic Society guidelines.

  3. Change in Score on the Visual Analogue Scale (VAS) [ Time Frame: 7 days ]
    Dyspnea will be assessed at baseline and at 7 days with the score on the visual analogue scale (VAS). The scores range from 0 (minimum) to 100 (maximum) with higher numbers representing improvements in dyspnea (i.e. better) and lower numbers representing worsening of dyspnea (i.e. worse).

  4. Change From Baseline to Day 7 on the Seven-Level Likert Scale [ Time Frame: 7 days ]
    Dyspnea will be assessed using a Seven-Level Likert Scale at baseline and the day 7 visit. The outcome measure will be reported as a difference between these two assessments (value at 7 days minus the value at baseline). The values on this scale range from 1 to 7 with higher numbers indicating overall better subjective assessment related to the symptom of dyspnea. Therefore, positive numbers represent an overall improvement in dyspnea during the study intervention and the higher (more positive) this difference is, the better the subject's relief of dyspnea at the conclusion of the study intervention.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • History of heart failure with either reduced or preserved ejection fraction for 3 months
  • Patients with New York Heart Association (NYHA) class II- IV heart failure symptoms, with at least one worsening symptom (Dyspnea on exertion, shortness of breath, orthopnea, early satiety) and one sign of congestion (pulmonary rales, elevated jugular venous pressure10cmHg, peripheral edema and ascites)
  • Decision by primary cardiologist or heart failure (HF) specialist to increase the home diuretic dose
  • Stable treatment with beta-blockers for 1 month unless contraindicated (i.e. intolerance, bradycardia) as specified by primary cardiologist/HF provider
  • Stable treatment with angiotensin converting enzyme-1 (ACE-1) or angiotensin receptor blocker (ARB) for 1 month
  • Spironolactone dose 25mg or eplerenone 50mg per day
  • Daily furosemide or furosemide equivalent dose of 80mg or greater
  • Serum potassium concentration 4.5 mmol/L or 5.0 mmol/L if on potassium supplements
  • Estimated Glomerular Filtration Rate (eGFR) by Modification of Diet in Renal Disease (MDRD) equation 40 ml/min/1.73

Exclusion Criteria:

  • Inability to complete informed consent form
  • Allergy or intolerance to spironolactone
  • Systolic blood pressure <100 mmHg
  • Patient in need of hospitalization per cardiologist decision
  • Current inotrope dependency
  • Current mechanical circulatory support
  • Acute coronary syndromes or unstable angina within the past 4 weeks
  • History of cardiac transplant
  • Obstructive cardiac valvular disease
  • Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy
  • Significant ventricular arrhythmia necessitating defibrillator therapy within the past 14 days
  • Atrioventricular conduction abnormality greater than first-degree block
  • Primary liver disease resulted in cirrhosis or abnormal liver function tests (transaminases and alkaline phosphatase levels 3 times the upper limit of normal
  • Acute malignancy
  • Active infection requiring antimicrobial treatment (Suppression antimicrobial for chronic infections are exempt)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02585843


Locations
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United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Investigators
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Principal Investigator: Arthur R Garan, MD Columbia University
  Study Documents (Full-Text)

Documents provided by Arthur R. Garan, Columbia University:
Study Protocol  [PDF] August 30, 2015
Statistical Analysis Plan  [PDF] August 30, 2015

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Responsible Party: Arthur R. Garan, Assistant Professor of Medicine at the Columbia University Medic, Dept of Medicine Cardiology, Columbia University
ClinicalTrials.gov Identifier: NCT02585843    
Other Study ID Numbers: AAAO9102
First Posted: October 23, 2015    Key Record Dates
Results First Posted: July 23, 2019
Last Update Posted: August 8, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Arthur R. Garan, Columbia University:
Heart Failure
Mineralocorticoid receptor antagonists
Loop diuretic resistance
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents