CSP #2026 - Beta Blocker Dialyzability on Cardiovascular Outcomes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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End-Stage Kidney Disease, End-Stage Renal Disease

Intervention / Treatment
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* Drug: Metoprolol Succinate
* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study design is a multicenter clinically integrated prospective randomized open-label blinded-endpoint (PROBE) trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metoprolol Succinate<br>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<br>* a dialyzable, beta-1 selective beta blocker<br>|
| Active Comparator: Carvedilol<br>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<br>* a non-dialyzable, non-selective beta blocker with alpha-1 antagonist properties<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dialysis, beta-Blockers, Adrenergic, Cardiovascular Diseases, Point of Care Research, Comparative Effectiveness Research, Metoprolol Succinate, Carvedilol, Hemodialysis