High-Dose Aldactone for Treatment of Diuretic Resistant Heart Failure

April 19, 2016 updated by: The University of Texas Health Science Center at San Antonio
Prospective, open-label, randomized cohort study comparing adding high-dose spironolactone to usual heart failure care versus usual care in patients with acute decompensated heart failure. Patients will be randomized in a 1:1 fashion to either usual care or high-dose spironolactone plus usual care. Both arms of the study will continue with treatment of ADHF until euvolemia as defined as the resolution of pulmonary edema, peripheral edema, abdominal bloating and/or jugular venous distention. Assessment of clinical status and serum electrolytes, symptoms and renal function will be performed in accordance to standard of care.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Congestive heart failure (CHF) is common and currently affects an estimated 6.6 million adults in the United States (1). In addition being highly prevalent, CHF is responsible for ~ 1 million hospital discharges per year and approximately 50% of patients with CHF will die within 5 years making it a highly morbid and lethal disease (1).

Manifestations of CHF include symptoms of volume overload such as dyspnea, abdominal bloating and/or fatigue. The genesis of these symptoms begins with loss of the integrity of arterial circulation due to decreased cardiac output (2). Decreased activation of mechanoreceptors in the carotid sinus, left ventricle, aortic arch and renal afferent arterioles due to lower systemic arterial pressure stimulates the sympathetic nervous system (SNS), renal-angiotensin-aldosterone system (RAAS) and non-osmotic release of arginine vasopressin (3). As a result, sodium reabsorption in the proximal tubule followed by water absorption increases causing accumulation of intravascular volume to compensating for arterial underfilling (4). Consequently, activation of neurohumoral reflexes result in increased cardiac afterload and preload, cardiac remodeling, hyponatremia and pulmonary edema (5). Renal vasoconstriction, sodium and water retention leads to a continuous positive feedback loop of further salt and water accumulation accompanied by further renal vasoconstriction (6).

Diuretic therapy is the most common means to relieve congestion in acute decompensated heart failure (ADHF) and approximately 90% of patients are treated with loop diuretics (7). Although loop diuretics are a cornerstone ADHF care and carries the highest level of recommendation by the American Heart Association (Class I); the guideline is supported by the lowest level of evidence (Class C) (8). While effective at natriuresis, loop diuretics are known to stimulate the SNS and RAAS, both of which have adverse consequence in heart failure (9,10). Not only is the RAAS system stimulated due to changes in arterial filling, furosemide blocks sodium chloride transport at the macula densa causing renin release independent of renal sodium loss (11). With increase stimulation of renin release, vasoconstriction of the renal artery ensues causing or further exacerbating renal insufficiency (12). Long-term utilization of loop diuretics results in hypertrophy of the distal nephron and increased expression of a sodium chloride co-transporter (13). These changes along with increased aldosterone levels further enhances distal sodium reabsorption and prevents aldosterone escape (14).

In treating heart failure patients as a population, diuretic resistance is encountered commonly and escalating doses of furosemide may be utilized to achieve fluid loss (15). Clinically, use of high-doses of loop diuretics is associated with greater rates of clinical events such as mechanical ventilation and myocardial infarction compared to low-dose loop diuretics (16). High-dose loop diuretic administration is associated with worsening renal function (17), increased length of hospital stay and greater in-hospital mortality (17-19). There is in fact a linear correlation with diuretic dose and mortality (20).

Given the potential hazards of administering loop diuretics in CHF patients, the remaining options are limited. Changing diuretics strategies from bolus to continuous loop diuretic infusion does not appear to change overall outcomes (21). Alternative strategies for relieving congestion include inhibition of the distal nephron using thiazide diuretics. Thiazide diuretics work synergistically with loop diuretics to induce natriuresis but have an independent association with worsening renal function and death (20,22). Utilizing inotropes to increasing renal perfusion pressure may improve natriuresis, however, it comes with the price of increasing mortality regardless of whether beta-adrenergic agonists (dobutamine) or phosphodiesterase inhibitors are used (23,24). Ultrafiltration and mechanical unloading of the heart is another therapeutic option, however it was found to be ineffective and associated with worsening renal function (25). Even low doses of dopamine or nesiritide were not effective in improving outcomes in patients with cardiorenal syndrome (26). Higher doses of spironolactone were recently shown to be safe in a prospective cohort treated for acute decompensated heart failure (27). Recently a case report was published showing that patients hospitalized with congestive heart failure, worsening renal function and diuretic resistance were able to be diuresed without adverse effect on renal function or hyperkalemia by treating with escalating doses of spironolactone (28)

The study will be a prospective, open-label, randomized cohort study comparing adding high-dose spironolactone to usual heart failure care versus usual care in patients with acute decompensated heart failure. Patients will be randomized in a 1:1 fashion to either usual care or high-dose spironolactone plus usual care. Both arms of the study will continue with treatment of ADHF until euvolemia as defined as the resolution of pulmonary edema, peripheral edema, abdominal bloating and/or jugular venous distention. Assessment of clinical status, urine and serum electrolytes, symptoms and renal function will be performed in accordance to standard of care.

Study Type

Interventional

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78229
        • University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  1. 18 years or older patients with congestive heart failure
  2. Hypervolemic by at least 2 of the following criteria: 1) Peripheral edema; 2) jugular venous distention greater than 7 cm; 3) radiographic pulmonary edema or pleural effusion; 4) enlarged liver or ascites; 5) pulmonary rales, paroxysmal nocturnal dyspnea or orthopnea
  3. Diuretic resistance as defined by loop diuretic requirements of furosemide greater or equal to 160 mg IV total daily dose or equivalent dose of torsemide or bumetanide. ( 1 mg bumetanide = 10 mg torsemide = 20 mg furosemide)
  4. Estimated glomerular filtration rate (eGFR) of > 30ml/min. according to the MDRD Study equation at the time of admission.
  5. Female patients of child bearing potential must have a negative urine pregnancy test to be eligible.

Exclusion Criteria:

  1. Acute coronary syndrome
  2. Patients with a baseline eGFR < 30 ml/min according to the MDRD equation.
  3. Baseline potassium serum concentration 5.3 meq/L
  4. Requirement for intravenous pressors
  5. Systemic infection
  6. Patients with concomitant end-stage liver disease
  7. Significant valvular disease
  8. Patients with pulmonary embolism
  9. Patients with high output heart failure
  10. Pregnant patients

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: High dose spironolactone
This arm of the study will include addition of high dose spironolactone upto 100mg twice daily in adjunct to usual care of hospitalized acute decompensated heart failure patients with loop diuretics.
Drug: Spironolactone
Administration of spironolactone 25-50mg orally twice daily for two days and subsequently titrated upto 100mg twice daily with daily serum potassium monitoring. Spironolactone will continue until patient is euvolemic and appropriate for discharge. Titration of loop diuretics in this arm will not be escalated.
Other Names:
  • aldactone
  • potassium-sparing diuretics
No Intervention: Usual Care
This arm of the study will continue the usual care of hospitalized acute decompensated heart failure patients with loop diuretics.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of adjunctive high-dose Spironolactone on weight loss.
Time Frame: 7 days
Weight will be tracked from enrollment to 7 days or when patient reaches euvolemia for all patients, whichever occurs first.
7 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of adjunctive high-dose Spironolactone on dyspnea.
Time Frame: 7 days
Using Likert scale, dyspnea and functional status will be assessed at enrollment and re-evaluate at 7days or at euvolemia for all patients, whichever occurs first.
7 days
Risk of hyperkalemia and renal dysfunction with use of adjunctive high-dose Spironolactone.
Time Frame: 7 days
Assessment of serum potassium and creatinine daily on all patients to assess relative safety of spironolactone use in diuretic resistant heart failure patients.
7 days
Length of hospitalization
Time Frame: 7 days
Comparison of length of hospitalization with use of high dose spironolactone to heart failure therapy compared to usual care.
7 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas Health Science Center at San Antonio

Investigators

  • Principal Investigator: Marvin H Eng, M.D., University of Texas Heatlh Science Center at San Antonio

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2014

Primary Completion (Actual)

October 1, 2015

Study Completion (Actual)

October 1, 2015

Study Registration Dates

First Submitted

September 27, 2014

First Submitted That Met QC Criteria

April 23, 2015

First Posted (Estimate)

April 29, 2015

Study Record Updates

Last Update Posted (Estimate)

April 20, 2016

Last Update Submitted That Met QC Criteria

April 19, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSC20140274H

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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