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

Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in Heart Failure and Loop Diuretic Resistance in Outpatients

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Spironolactone 100mg; Drug: Spironolactone 25mg

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 Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight	change in body weight measured in kilograms between weight at baseline and weight at 7 days	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Estimated Jugular Venous Pressure (cmH2O)	Change in estimated jugular venous pressure by physical exam in cmH2O between baseline and 7 days	7 days
Change in 6-minute Walk Test Distance (6MWT)	At baseline and final visit. The 6MWT will be conducted per American Thoracic Society guidelines.	7 days
Change in Score on the Visual Analogue Scale (VAS)	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).	7 days
Change From Baseline to Day 7 on the Seven-Level Likert Scale	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.	7 days

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Arthur R Garan, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: August 30, 2015
• First Submitted That Met QC Criteria: October 22, 2015
• First Posted (Estimate): October 23, 2015

Study Record Updates

• Last Update Posted (Actual): August 8, 2019
• Last Update Submitted That Met QC Criteria: July 24, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Heart Failure; Mineralocorticoid receptor antagonists; Loop diuretic resistance
• 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: AAAO9102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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