BRAVO: CSP #2026 - Beta Blocker Dialyzability on Cardiovascular Outcomes

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05931276
• Collaborator: (none)
• Enrollment: 2,540
• Locations: 5
• Arms: 2
• Anticipated Duration (Months): 51.9
• Patients Per Site: 508
• Patients Per Site Per Month: 9.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
End-Stage Kidney Disease; End-Stage Renal Disease	Drug: Metoprolol Succinate; Drug: Carvedilol	Phase 3

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 2540 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The study design is a multicenter clinically integrated prospective randomized open-label blinded-endpoint (PROBE) trialThe study design is a multicenter clinically integrated prospective randomized open-label blinded-endpoint (PROBE) trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CSP #2026 - Beta Blocker Dialyzability on Cardiovascular Outcomes (BRAVO)
• Anticipated Study Start Date: Sep 4, 2023
• Anticipated Primary Completion Date: Nov 4, 2024
• Anticipated Study Completion Date: Dec 31, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Time to major cardiovascular event [Randomization to time to event; average follow-up 3 years]

   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

Secondary Outcome Measures

1. Non-fatal myocardial infarction [Randomization to time to event; average follow-up 3 years]

   Non-fatal myocardial infarction

2. Non-fatal stroke [Randomization to time to event; average follow-up 3 years]

   Non-fatal stroke

3. Hospitalization for heart failure [Randomization to time to event; average follow-up 3 years]

   Hospitalization for heart failure

4. All-cause mortality [Randomization to time to event; average follow-up 3 years]

   All-cause mortality

Other Outcome Measures

1. All-cause hospitalization [Randomization to time to event; average follow-up 3 years]

   All-cause hospitalization

2. ED visit or hospitalization possibly related to low BP including falls, fractures, hypotension, or serious injury [Number of events; average follow-up 3 years]

   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

3. Use of BP raising medications [Use of drug; average follow-up 3 years]

   Use and dose of midodrine

4. ED or hospital visits for atrial fibrillation and uncontrolled rate [Randomization to time to event; average follow-up 3 yars]

   Emergency department visit or hospitalization for atrial fibrillation with uncontrolled rate (to capture poor control with beta blocker withdrawal)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Eligible patients are those (including men, women and minorities)

• On hemodialysis

• Received one of the following beta blockers through the VA pharmacy prescribed by a VA provider: metoprolol (succinate or tartrate), atenolol, labetalol, carvedilol, bisoprolol, nadolol, pindolol, nebivolol

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts	United States	02130-4817
2	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts	United States	02130
3	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota	United States	55417-2309
4	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York	United States	10010-5011
5	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York	United States	10010

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Study Chair: Areef Ishani, MD MS, Minneapolis VA Health Care System, Minneapolis, MN
• Study Chair: James S Kaufman, MD, Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT05931276
• Other Study ID Numbers: 2026; CSP2026
• First Posted: Jul 5, 2023
• Last Update Posted: Jul 5, 2023
• Last Verified: Jun 1, 2023

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by VA Office of Research and Development: Dialysis; beta-Blockers, Adrenergic; Cardiovascular Diseases; Point of Care Research; Comparative Effectiveness Research; Metoprolol Succinate; Carvedilol; Hemodialysis
• Additional relevant MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Metoprolol; Carvedilol

Study Results

No Results Posted as of Jul 5, 2023