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

• 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: Columbia University
• Information provided by (Responsible Party): Arthur R. Garan, Columbia University

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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)

Contacts and Locations

Locations

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

Sponsors and Collaborators

Columbia University

Investigators

• 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

More Information

• 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
• 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

• 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:

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