Diuretic and Natriuretic Effect of High-dose Spironolactone in Patients With Acute Heart Failure (DANAUS-AHF)

This is a prospective, single-center, open-label and randomized trial for evaluation of the effect of a 5-day administration of high doses of spironolactone (≥100mg daily) on diuresis, natriuresis, weight loss and levels of NT-proBNP in hospitalized patients with acute decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) are recommended as standard of care (SOC) in management of heart failure (HF) patients. However, recommended doses of MRAs (up to 50mg daily) have any impact on signs and symptoms of volume overload. Therefore, the proposed study will aim to show the impact of high doses of spironolactone to improve diuresis, natriuresis, weight loss and levels of NT-proBNP in hospitalized patients with ADHF.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; With Decompensation; Heart Failure Acute
• Intervention / Treatment: Drug: Spironolactone

Detailed Description

Congestion represents a hallmark feature of ADHF, which is present in more than 90% of patients hospitalized for this diagnosis. Intravenous loop diuretics are the mainstay of treatment. Nonetheless, nearly half of the patients who are hospitalized for AdHF continue to have residual symptoms and sign of congestion at time of discharge. Various pharmacological and non-pharmacological interventions have been proposed over the past years as potential means for relieving congestion in hospitalized ADHF patients. However, their efficacy has not been shown.

Given that hyperaldosteronism is a key feature in HF, the hypothesis that administration of high doses of spironolactone can potentiate the natriuretic effects of loop diuretics and relieve congestion in the setting of ADHF has been raised.

According to the most recent guidelines spironolactone can be considered in combination with loop diuretic in patients with resistant edema or insufficient symptomatic response. However, spironolactone at a dose of 100 mg daily has failed to increase diuresis in patients with ADHF.

The present study will assess the effect of high per os doses of spironolactone (≥100mg) on top of SOC treatment compared with SOC treatment alone on diuresis, natriuresis, weight loss and levels of NT-proBNP in hospitalized patients with ADHF.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• Greece
  • Attiki
    • Athens, Attiki, Greece, 11527
      • Laiko General Hospital

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:

• Diagnosis of acute heart failure within the past 8 hours
• Two of the following: 1. edema, 2. ascites, 3. jugular vein distention, 4. pulmonary congestion
• NT-proBNP >1,000 pg/ml or >3,000 pg/ml (in the presence of atrial fibrillation)
• Per os mean daily loop diuretic dose equivalent to 80 mg of furosemide for at least 1 month prior to presentation and at least one of the following: 1. serum urea/serum creatinine > 50 at presentation, 2. serum creatinine increased >0.3 mg/dl compared with previous value (within the last year), 3. serum creatinine > 1.8 mg/dl.

Exclusion Criteria:

• pregnancy or breast feeding
• current acute coronary syndrome
• significant valvular disease
• pulmonary embolism
• allergy or intolerance to spironolactone
• current mechanical circulatory support
• primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy
• mean arterial pressure <65mmHg or systolic arterial pressure <90 mmHg at presentation
• anticipated use of inotropes or vasodilators (other than renal doses of dopamine, i.e. <2.5 μg/kg/min)
• anticipated need of ultrafiltration
• exposure to nephrotoxic agents within 3 days of presentation
• serum potassium> 5 mmol/L
• per os receipt of spironolactone or eplerenone in a dose > 50 mg daily prior to presentation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: High-dose spironolactone; Participants in this arm will receive high doses of per os spironolactone, defined as doses ≥100 mg daily, on top of standard of care treatment for acute heart failure	Drug: Spironolactone; Patients randomized to the high-dose spironolactone group will receive oral spironolactone (≥100 mg) on top of standard of care treatment for acute heart failure immediately after randomization and in the afternoon of each subsequent day unless the serum potassium level is >5 mmol/L. The exact dose will be determined based on a pre-specified algorithm provided.; Other Names: Aldactone
NO_INTERVENTION: Standard of care; Participants in this arm will standard of care treatment for acute heart failure, which may include per os spironolactone at a maximum dose of 50 mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily urine output	Urine output in liters per 24 hours will be tracked from enrollment to day 5.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total urine output	Urine output in total liters from enrollment to day 5 will be measured.	5 days
Total weight change	Patient weight in kilos will be tracked from enrollment to day 5.	5 days
Daily weight change	Patient weight in kilos will be tracked from enrollment to day 5.	5 days
Natriuresis on days 1, 3 and 5	Urine sodium will be measured on days 1, 3 and 5	5 days
Changes in natriuresis between days 1, 3 and 5	Urine sodium will be measured on days 1, 3 and 5	5 days
Changes in NT-proBNP between days 1 and 5	NT-proBNP will be measured on days 1, 3 and 5	5 days

Collaborators and Investigators

• Sponsor: Laikο General Hospital, Athens
• Investigators: Study Chair: John Barbetseas, MD, Laikon General Hospital

Publications and helpful links

General Publications

• Kapelios CJ, Bonou M, Vogiatzi P, Tzanis G, Mantzouratou P, Lund LH, Barbetseas J. Association Between High-Dose Spironolactone and Decongestion in Patients with Acute Heart Failure: An Observational Retrospective Study. Am J Cardiovasc Drugs. 2018 Oct;18(5):415-422. doi: 10.1007/s40256-018-0290-3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 20, 2020
• Primary Completion (ANTICIPATED): December 20, 2021
• Study Completion (ANTICIPATED): March 1, 2022

Study Registration Dates

• First Submitted: November 1, 2020
• First Submitted That Met QC Criteria: November 1, 2020
• First Posted (ACTUAL): November 6, 2020

Study Record Updates

• Last Update Posted (ACTUAL): November 10, 2020
• Last Update Submitted That Met QC Criteria: November 6, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: heart failure; spironolactone; diuretics; natriuresis; diuretic resistance; cardio-renal syndrome
• 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: 15606

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The individual participant data of the study will be shared on reasonable request to the principle investigator

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No