Aldosterone bloCkade for Health Improvement EValuation in End-stage Renal Disease

Overview

Individuals receiving dialysis are at risk of heart failure and heart related death. There is an urgent need for treatments that reduce the risk of these problems in patients that require dialysis. Spironolactone is a pill used to prevent heart failure and related deaths in patients that do not require dialysis. It works by blocking a hormone (aldosterone) in your body that causes high blood pressure and can damage the heart. Although spironolactone is very effective in patients that do not require dialysis, we do not know if spironolactone is effective in dialysis patients. Our research will help determine if spironolactone reduces heart failure and heart related deaths in dialysis patients. The purpose of this study is to determine if spironolactone reduces death or hospitalization for heart failure and is well tolerated in patients that require dialysis.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: April 2023

Detailed Description

Globally, over 2 million people receive dialysis for end-stage renal disease (ESRD) and 650,000 new patients start dialysis each year. Furthermore, the number of patients receiving dialysis is increasing as access to dialysis in the developing world improves and the prevalence of diabetes and vascular disease rises. Despite technical advances in dialysis, the outcomes for patients with ESRD are poor. Patients have frequent hospitalizations, poor health related quality of life and strikingly, high mortality rates. The most common cause of death in patients receiving dialysis is cardiovascular disease, accounting for >40% of all deaths. Observational studies suggest a causal pathway to cardiovascular death that includes progressive ventricular hypertrophy and dilatation as well as accelerated atherosclerosis. These changes result in myocardial ischemia and cardiac fibrosis that, in turn, lead to heart failure, arrhythmias and cardiac arrest. Strongly implicated in this pathophysiology is aldosterone. Mineralocorticoid receptor antagonists (MRAs) in non-ESRD patients, prevent cardiovascular deaths and small randomized controlled trials of MRAs in ESRD suggests they may reduce death and may be safe. Spironolactone is the most commonly used MRA worldwide. We will conduct a multicentre randomized controlled trial (RCT) to determine if spironolactone reduces cardiac mortality and hospitalizations for heart failure in patients treated with dialysis. This trial is called the Aldosterone bloCkade for Health Improvement EValuation in End-stage renal disease (ACHIEVE).

Interventions

  • Drug: Spironolactone 25Mg Tablet
    • Randomized participants will receive a study supply of spironolactone 25 mg tablets. They will be instructed to take 1 tablet daily.
  • Drug: Placebo Oral Tablet
    • Randomized participants will receive a study supply of placebo tablets with no active medical ingredients. They will be instructed to take 1 tablet daily.

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo Oral Tablet
    • A tablet with no active medication that will be an exact match of the active spironolactone in taste and appearance
  • Active Comparator: Spironolactone 25 MG Tablet
    • 25 mg of active spironolactone in tablet form

Clinical Trial Outcome Measures

Primary Measures

  • CV Death or Hospitalization for Heart Failure
    • Time Frame: up to 5 years

Secondary Measures

  • Cause specific death
    • Time Frame: up to 5 years
  • Hospitalization for Heart Failure
    • Time Frame: up to 5 years
  • All-cause death
    • Time Frame: up to 5 years
  • All-cause Hospitalization
    • Time Frame: up to 5 years
  • Hospitalization for hyperkalemia
    • Time Frame: up to 5 years

Participating in This Clinical Trial

Inclusion Criteria

1. Age 1. ≥45 years or 2. ≥18 with a history of diabetes 2. On dialysis ≥ 90 days 3. On either 1. Hemodialysis prescribed at least 2 treatments per week or 2. Peritoneal dialysis prescribed with at least 1 exchange daily 4. Provides informed consent Exclusion Criteria:

1. Hyperkalemia 1. Serum potassium >5.8 mmol/L in the 6 weeks prior to enrollment or 2. Serum potassium >6.0 mmol/L during active run-in 2. Currently taking and unable to withdraw a mineralocorticoid receptor antagonist (i.e. spironolactone or eplerenone). 3. Known sensitivity or allergy to spironolactone 4. Current or planned pregnancy or breastfeeding 5. Scheduled living related donor renal transplant 6. Life expectancy < 6 months in the opinion of a treating nephrologist. 7. Enrolled in another interventional trial testing a mineralocorticoid receptor antagonist or drug that has a known or likely interaction with spironolactone. 8. Treating physician believes either spironolactone is either absolutely indicated or absolutely contra-indicated

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Population Health Research Institute
  • Collaborator
    • Canadian Institutes of Health Research (CIHR)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Michael Walsh, MD, PhD, Principal Investigator, McMaster University
    • PJ Devereaux, MD, PhD, Study Chair, McMaster University
  • Overall Contact(s)
    • Jessica Tyrwhitt, B.A., 9055274322, jessica.tyrwhitt@phri.ca

References

Quach K, Lvtvyn L, Baigent C, Bueti J, Garg AX, Hawley C, Haynes R, Manns B, Perkovic V, Rabbat CG, Wald R, Walsh M. The Safety and Efficacy of Mineralocorticoid Receptor Antagonists in Patients Who Require Dialysis: A Systematic Review and Meta-analysis. Am J Kidney Dis. 2016 Oct;68(4):591-598. doi: 10.1053/j.ajkd.2016.04.011. Epub 2016 Jun 3. Review.

Walsh M, Manns B, Garg AX, Bueti J, Rabbat C, Smyth A, Tyrwhitt J, Bosch J, Gao P, Devereaux PJ, Wald R. The Safety of Eplerenone in Hemodialysis Patients: A Noninferiority Randomized Controlled Trial. Clin J Am Soc Nephrol. 2015 Sep 4;10(9):1602-8. doi: 10.2215/CJN.12371214. Epub 2015 Jul 2.

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