CSP #2026 - Beta Blocker Dialyzability on Cardiovascular Outcomes (BRAVO)

CSP #2026 - Beta Blocker Dialyzability on Cardiovascular Outcomes (BRAVO)

The investigators aim to determine, using a point-of-care randomized controlled trial design, if hemodialysis patients, who are randomized to metoprolol succinate (a dialyzable, beta-1 selective beta blocker), have an improved cardiovascular outcome compared to those randomized to carvedilol (a non-dialyzable, non-selective beta blocker with alpha-1 antagonist properties). The investigators will also examine intervention practices to identify components that best support engagement and sustainability.

Study Overview

• Status: Recruiting
• Conditions: End-Stage Renal Disease; End-Stage Kidney Disease
• Intervention / Treatment: Drug: Metoprolol Succinate; Drug: Carvedilol

Detailed Description

Approximately 35,000 Veterans have end stage kidney disease (ESKD) with an incidence of 13,000 annually. These numbers are increasing because of the epidemic of diabetes, the most common cause of ESKD, among the Veteran population. Patients with ESKD on hemodialysis have substantial cardiovascular morbidity. Veterans annual mortality is in excess of 15% and more than half the deaths are due to cardiovascular disease. Beta blockers have been shown to prevent cardiovascular events in randomized clinical trials in patients without chronic kidney disease, particularly those with heart failure and after myocardial infarction. Beta blockers are a mainstay of therapy in dialysis patients, with two-thirds of Veterans on dialysis receiving a beta blocker. There are no head-to-head randomized studies comparing the two most commonly used beta blockers in ESKD patients in the United States, metoprolol and carvedilol, but observational studies suggest superior outcomes for patients treated with metoprolol. The identification of the superior beta blocker may significantly improve the morbidity and mortality of the VA dialysis population.

The investigators aim to compare two beta blockers with similar indications, usage and availability within the VA but with major differences in patients dialysis clearance and adrenergic effects. The investigators aim to determine if patients undergoing dialysis have improved survival when using metoprolol succinate, a beta blocker that is removed by dialysis and is beta-1 selective, compared to carvedilol, a beta blocker that is not removed by dialysis and is not beta-selective and is also an alpha-blocker.

• Study Type: Interventional
• Enrollment (Estimated): 2540
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jade Fiotto; Phone Number: (617) 232-9500; Email: Jade.Fiotto@va.gov
• Study Contact Backup: Name: Christopher M Donnelly; Email: Christopher.Donnelly2@va.gov

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90822
      • Recruiting
      • VA Long Beach Healthcare System, Long Beach, CA
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov
  • Florida
    • Gainesville, Florida, United States, 32608-1135
      • Recruiting
      • North Florida/South Georgia Veterans Health System, Gainesville, FL
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov
  • Georgia
    • Decatur, Georgia, United States, 30033-4004
      • Recruiting
      • Atlanta VA Medical and Rehab Center, Decatur, GA
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov
  • Iowa
    • Iowa City, Iowa, United States, 52246-2292
      • Recruiting
      • Iowa City VA Health Care System, Iowa City, IA
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov
  • Massachusetts
    • Boston, Massachusetts, United States, 02130-4817
      • Not yet recruiting
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
      • Contact: Jade Fiotto, MPH; Phone Number: 617-232-9500; Email: jade.fiotto@va.gov
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417-2309
      • Recruiting
      • Minneapolis VA Health Care System, Minneapolis, MN
      • Contact: Areef Ishani, MD MS; Phone Number: 314431 612-467-4431; Email: areef.ishani@va.gov
      • Study Chair: Areef Ishani, MD MS
  • Nebraska
    • Omaha, Nebraska, United States, 68105-1850
      • Recruiting
      • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108-5153
      • Recruiting
      • New Mexico VA Health Care System, Albuquerque, NM
      • Contact: Srihari Raju, MD; Email: Srihari.Raju@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• On hemodialysis
• Received one of the following beta blockers through the VA pharmacy: metoprolol (succinate or tartrate), atenolol, labetalol, carvedilol, bisoprolol

Exclusion Criteria:

• Impaired decision-making capacity
• Patients not receiving carvedilol who have a history of asthma
• known hypersensitivity to any component of either drug
• Provider unwilling to sign a new medication order for a randomized patient
• No surrogate consent will be allowed

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metoprolol Succinate; Depending on baseline type and dose of beta blocker: 25 mg once daily (12.5 mg once daily if > NYHA class II); 50 mg (or 25 mg) once daily; 100 mg (or 50 mg) once daily; 200 mg (or 100 mg titrated to 200 mg) once daily	Drug: Metoprolol Succinate; a dialyzable, beta-1 selective beta blocker
Active Comparator: Carvedilol; Depending on baseline type and dose of beta blocker: 3.125 mg twice daily; 6.25 mg twice daily; 12.5 mg twice daily; 25 mg twice daily (may titrate to 5 0mg twice daily if > 85 kg)	Drug: Carvedilol; a non-dialyzable, non-selective beta blocker with alpha-1 antagonist properties

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to major cardiovascular event	The Primary outcome measure will be time to a non-fatal adverse cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: myocardial infarction, stroke, or hospitalization for heart failure, and all-cause mortality	Randomization to time to event; average follow-up 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-fatal myocardial infarction	Non-fatal myocardial infarction	Randomization to time to event; average follow-up 3 years
Non-fatal stroke	Non-fatal stroke	Randomization to time to event; average follow-up 3 years
Hospitalization for heart failure	Hospitalization for heart failure	Randomization to time to event; average follow-up 3 years
All-cause mortality	All-cause mortality	Randomization to time to event; average follow-up 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause hospitalization	All-cause hospitalization	Randomization to time to event; average follow-up 3 years
ED visit or hospitalization possibly related to low BP including falls, fractures, hypotension, or serious injury	Number of emergency department visits or hospitalization for events that may be a consequence of low blood pressure or beta blocker excess or withdrawal including falls, fractures, hypotension, or serious injury	Number of events; average follow-up 3 years
Use of BP raising medications	Use and dose of midodrine	Use of drug; average follow-up 3 years
ED or hospital visits for atrial fibrillation and uncontrolled rate	Emergency department visit or hospitalization for atrial fibrillation with uncontrolled rate (to capture poor control with beta blocker withdrawal)	Randomization to time to event; average follow-up 3 yars

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Study Chair: Areef Ishani, MD MS, Minneapolis VA Health Care System, Minneapolis, MN

Publications and helpful links

General Publications

• Leatherman SM, Ishani A. Point-of-Care Clinical Trials in Nephrology. J Am Soc Nephrol. 2024 Jun 1;35(6):812-814. doi: 10.1681/ASN.0000000000000340. Epub 2024 Feb 29. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: June 26, 2023
• First Posted (Actual): July 5, 2023

Study Record Updates

• Last Update Posted (Actual): January 9, 2026
• Last Update Submitted That Met QC Criteria: January 7, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Carvedilol; Dialysis; Hemodialysis; Comparative Effectiveness Research; Point of Care Research; beta-Blockers, Adrenergic; Metoprolol Succinate
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Renal Insufficiency, Chronic; Pathological Conditions, Signs and Symptoms; Cardiovascular Diseases; Kidney Failure, Chronic; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Alcohols; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Heterocyclic Compounds, 3-Ring; Carbazoles; Carvedilol; Metoprolol
• Other Study ID Numbers: 2026 (Capital Health Development Research Special Project); CSP2026 (Other Identifier: VA Cooperative Studies Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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