Official Title: “Bumetanide Has a More Favourable Effect on Insulin Resistance Than Furosemide in Patients With Heart Failure - A Pilot Study”

Patients with NYHA FC II-III heart failure will be randomized in a cross-over fashion to 8 weeks of bumetanide vs. furosemide therapy (equipotent dose), to test whether bumetanide therapy has a superior effect on insulin resistance compared to furosemide. Patients will be subject to a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model (MINMOD) analysis to assess insulin resistance and to a 6-minute walk test (6MWT) to assess functional capacity; patient recruitment and retention success, as well as medication adherence, will also be assessed.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: June 2010

Insulin resistance is common in patients with heart failure (HF) and is associated with a worse functional capacity and more severe symptoms of heart failure. The majority of HF patients take furosemide on at least a daily basis for symptom relief. Bumetanide is a loop diuretic with a similar therapeutic diuretic effect to furosemide. There is evidence from observational and small comparative trials that bumetanide has a significantly less deleterious effect on indirect measures of insulin resistance compared with furosemide.

However, a formal comparison between the 2 drugs using rigorous measures of insulin resistance has never been conducted in patients with HF. If bumetanide can be demonstrated to have a similar diuretic and a superior (less deleterious) effect on insulin resistance in patients with HF, the potential exists for bumetanide to have a significantly reduced morbidity in patients with heart failure compared to furosemide. In order to prepare for such a study, the variance of the MINMOD-derived insulin resistance from the FSIGT (26), in this group of patient needs to be determined along with the feasibility of conducting such a study. Functional capacity will be determined by duplicate 6-minute walk tests.

Intervention(s) in this Clinical Trial

• Drug: Furosemide
  • Current dose of furosemide will be maintained and equivalent dose bumetanide will be used following crossover
• Drug: Bumetanide
  • Equivalent dose to pre-existing furosemide will be used
• Drug: furosemide
  • 20mg to 80mg orally once or twice daily
• Drug: bumetanide
  • 0.5mg to 2mg orally once or twice daily

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: A
  • Arm A patients will take 20mg to 80mg furosemide orally once or twice daily for an 8-week period.
• Active Comparator: B
  • Eight-week bumetanide therapy at an equipotent dose to furosemide therapy (1mg bumetanide is equivalent to 40mg furosemide).

Primary Measures

• Insulin resistance, as determined by frequently sampled intravenous glucose tolerance test with minimal model analysis (FSIGT MINMOD)
  • Time Frame: 3 months
    Safety Issue?: No

Secondary Measures

• Fasting blood glucose
  • Time Frame: 3 months
    Safety Issue?: No
• Glycosylated hemoglobin (HbA1c)
  • Time Frame: 3 months
    Safety Issue?: No
• Serum creatinine, sodium, potassium, and chloride
  • Time Frame: 3 months
    Safety Issue?: Yes
• Submaximal exercise capacity as determined by the 6-minute walk test
  • Time Frame: 3 months
    Safety Issue?: No
• New York Heart Association Function Class heart failure (NYHA FC)
  • Time Frame: 3 months
    Safety Issue?: No

Inclusion Criteria:

• 1. Men and women ≥18 years of age
• 2. NHYA FC II or III HF AND documented LVEF ≤40% within 6 months prior to study entry
• 3. Taking 20 mg to 80 mg furosemide orally once or twice per day
• 4. No changes to cardiac medications for 3 months prior to study entry and no anticipated changes of medications for the duration of the study
• 5. No changes to oral anti-diabetic medications (if applicable) for 3 months prior to study entry, and no anticipated changes for the duration of the study (metformin, sulphonylurea type, glitazone type)
• 6. Ability to provide written consent

Exclusion Criteria:

• 1. Known sensitivity to bumetanide
• 2. Myocardial infarction, coronary angioplasty, coronary artery bypass surgery, admission for HF or unstable angina within a 3 month period prior to study recruitment
• 3. Planned coronary intervention within 6 months
• 4. Patients who are taking insulin
• 5. Patients with chronic renal (serum creatinine ≥ 200 μmol/L) or hepatic impairment (known cirrhosis or AST or ALT > 1.5 x upper limit of normal)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Lawson Health Research Institute

Overall Clinical Trial Officials and Contacts

Neville Suskin, MBChB, etc Principal Investigator LHSC, University of Western Ontario  

Overall Contact: Neville Suskin, MBChB, etc (519) 685-8300 neville.suskin@lhsc.on.ca

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00372762

Study ID Number: R-06-415

ClinicalTrials.gov Identifier: NCT00372762

Health Authority: Canada: Health Canada