Beta Blockers for Kidney Failure

(BRAVO Trial)

Recruiting at 3 trial locations

Overseen By Areef Ishani, MD MS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must be taking: Beta blockers

Disqualifiers: Impaired decision-making, Asthma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 years

2540 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines which beta blocker medication better supports heart health in individuals undergoing hemodialysis, a treatment for kidney failure. It tests two drugs: metoprolol succinate, a beta blocker removable during dialysis, and carvedilol, which remains in the body. Researchers aim to determine which drug leads to better heart outcomes and is easier for patients to adhere to. Individuals on hemodialysis who have been taking a beta blocker like metoprolol or carvedilol might be suitable for this study. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to research that could enhance heart health for dialysis patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it seems you need to be on a beta blocker like metoprolol or carvedilol to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that carvedilol is usually well tolerated by patients. Some studies observed a small increase in serum creatinine levels (a waste product in the blood), but these changes were often temporary and didn't require additional treatment. In patients with chronic kidney disease (CKD), carvedilol has lowered the risk of heart-related problems and helped people live longer.

Metoprolol succinate is also considered safe. Studies have found it can reduce the risk of death in people with heart issues. Its safety is well understood, as it is already approved for other uses.

Both carvedilol and metoprolol succinate are beta blockers, which help the heart function better and lower blood pressure. While generally safe, both medicines can have side effects, so discussing these with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Carvedilol and Metoprolol Succinate for kidney failure because these beta blockers might offer more precise heart rate control, which is crucial for patients with compromised kidney function. Unlike some standard treatments that can affect blood pressure unpredictably, Carvedilol provides the additional benefit of antioxidant properties, potentially offering kidney protection. On the other hand, Metoprolol Succinate is unique due to its once-daily dosing, which could improve patient compliance. Both medications are well-known for their cardiovascular benefits, but the focus here is on their potential to improve outcomes specifically for kidney failure patients.

What evidence suggests that this trial's treatments could be effective for kidney failure?

This trial will compare the effects of Carvedilol and Metoprolol Succinate on patients with kidney failure. Research has shown that Carvedilol can extend the lives of dialysis patients with heart problems, increasing their survival chances over two years, and it also helps lower blood pressure in those with kidney issues. Meanwhile, one study found that Metoprolol Succinate reduces the risk of death by 34% over one year and improves sodium management, which is crucial for patients with heart failure. Both treatments have demonstrated benefits in previous studies, suggesting they may be effective for patients with kidney failure. ^{1 2 3 4 6}

Who Is on the Research Team?

Areef Ishani, MD MS

Principal Investigator

Minneapolis VA Health Care System, Minneapolis, MN

James S Kaufman, MD

Principal Investigator

VA NY Harbor Healthcare System, New York, NY

Are You a Good Fit for This Trial?

This trial is for hemodialysis patients with kidney disease who are already taking certain beta blockers (like metoprolol or carvedilol) prescribed by a VA provider. It's open to men, women, and minorities. Those not eligible include patients whose providers won't consent to medication changes, those without decision-making capacity, asthma patients not on carvedilol, or anyone allergic to the drugs being tested.

Inclusion Criteria

I am currently on hemodialysis.

I am taking a beta blocker prescribed by the VA.

Exclusion Criteria

I have difficulty making decisions due to my health condition.

I have asthma and am not taking carvedilol.

My doctor is not willing to sign for a new medication if I am selected.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either metoprolol succinate or carvedilol, with doses adjusted based on baseline type and dose of beta blocker

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary and secondary outcomes measured

3 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Carvedilol
• Metoprolol Succinate

Trial Overview The study compares two heart medications in dialysis patients: Metoprolol Succinate (which can be removed during dialysis) versus Carvedilol (which cannot). The goal is to see which drug leads to better heart health outcomes. Patients will be randomly assigned one of these drugs in this controlled trial.

How Is the Trial Designed?

Group I: Carvedilol Active Control 1 Intervention

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)

Group II: Metoprolol Succinate Active Control 1 Intervention

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

Carvedilol is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Coreg for:

• Hypertension
• Heart failure
• Left ventricular dysfunction following myocardial infarction

Approved in European Union as Dilatrend for:

• Hypertension
• Heart failure
• Left ventricular dysfunction following myocardial infarction

Approved in Canada as Eucardic for:

• Hypertension
• Heart failure
• Left ventricular dysfunction following myocardial infarction

Approved in Japan as Carloc for:

• Hypertension
• Heart failure
• Left ventricular dysfunction following myocardial infarction

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a study of 974 patients with heart failure and reduced left ventricular function, atenolol showed a lower unadjusted mortality rate (3.2%) compared to metoprolol tartrate (7.5%) and was comparable to carvedilol (4.2%).

After adjusting for patient characteristics, atenolol was associated with a significantly lower risk of death compared to metoprolol tartrate, suggesting it may be an effective treatment option for heart failure, warranting further randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival among patients with left ventricular systolic dysfunction treated with atenolol. Kapoor, JR., Heidenreich, PA.[2016]

Carvedilol, unlike metoprolol, antagonizes multiple adrenoreceptors involved in heart failure and also reduces oxidative stress, suggesting it may offer superior benefits for patients with heart failure.

Despite the potential advantages of carvedilol, the actual use of beta-blockers like carvedilol and metoprolol in heart failure patients remains low, partly due to a lack of clinical trials directly comparing their efficacy at optimal doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical differences among beta-adrenoreceptor antagonists in myocardial failure: debating the MERIT of COMET. McBride, BF., White, CM.[2018]

The COMET trial, involving 3029 patients across 15 European countries, aims to compare the effects of carvedilol and metoprolol on morbidity and mortality in chronic heart failure, highlighting the importance of their differing pharmacological profiles.

Carvedilol, which blocks multiple adrenergic receptors and has additional metabolic and antioxidant benefits, is being compared to metoprolol, a selective beta(1)-adrenergic antagonist, to determine if these differences impact patient outcomes in heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Poole-Wilson, PA., Cleland, JG., Di Lenarda, A., et al.[2019]

Switching from metoprolol to carvedilol in patients with chronic heart failure (CHF) is associated with a significantly lower rate of serious adverse events and hospitalizations (3.1%) compared to switching from carvedilol to metoprolol (12.3%).

The transition to carvedilol is safe and well-tolerated, especially when starting with a reduced dose, making it a beneficial strategy for optimizing CHF treatment, particularly in patients with more severe heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exchange of beta-blockers in heart failure patients. Experiences from the poststudy phase of COMET (the Carvedilol or Metoprolol European Trial). Di Lenarda, A., Remme, WJ., Charlesworth, A., et al.[2018]

Activation of the sympathetic nervous system in chronic kidney disease patients contributes to hypertension and worsens kidney function, making effective blood pressure management crucial.

Carvedilol, a newer vasodilating beta-blocker, not only lowers blood pressure but also improves kidney function by reducing renal vascular resistance and may help slow the progression of kidney damage and albuminuria in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should beta-blockers be used to control hypertension in people with chronic kidney disease? Hart, PD., Bakris, GL.[2007]

In a study of 4,016 patients with chronic heart failure, there was no significant difference in all-cause mortality between those treated with carvedilol and those treated with metoprolol succinate after adjusting for various factors.

While initial analyses suggested that metoprolol was associated with higher mortality compared to carvedilol, this difference disappeared after adjusting for dose equivalents and propensity scores, indicating that both medications may have similar safety and efficacy profiles in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol Compared With Metoprolol Succinate in the Treatment and Prognosis of Patients With Stable Chronic Heart Failure: Carvedilol or Metoprolol Evaluation Study. Fröhlich, H., Zhao, J., Täger, T., et al.[2018]

Bisoprolol has been proven to significantly reduce all-cause mortality and sudden death in patients with chronic heart failure, as shown in the CIBIS-II trial, where mortality rates were 11.8% for bisoprolol compared to 17.3% for placebo.

Recent studies, including CIBIS-III, confirm that bisoprolol is as effective and safe as enalapril for initiating heart failure treatment, with a potential survival advantage, solidifying its role alongside other beta-blockers in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisoprolol in the treatment of chronic heart failure: from pathophysiology to clinical pharmacology and trial results. Metra, M., Nodari, S., Bordonali, T., et al.[2021]

In a study of 3029 patients with chronic heart failure, carvedilol significantly reduced total mortality compared to metoprolol tartrate, with a hazard ratio of 0.83, indicating a 17% lower risk of death.

Carvedilol also showed a notable reduction in cardiovascular deaths and incidents of fatal or nonfatal myocardial infarctions, highlighting its superior efficacy in managing heart failure-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET. Torp-Pedersen, C., Poole-Wilson, PA., Swedberg, K., et al.[2018]

Recent clinical trials have shown that beta-blockers like carvedilol and metoprolol succinate significantly reduce morbidity and mortality in heart failure, while other beta-blockers lack supporting evidence for their use.

Differences in the pharmacokinetic and pharmacodynamic properties of beta-blockers mean that not all beta-blockers are equally effective in heart failure, highlighting the need for further studies to compare carvedilol directly with metoprolol succinate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of beta blockers in heart failure. Talbert, RL.[2018]

In a study of 4217 patients with systolic heart failure, carvedilol therapy significantly reduced all-cause mortality and cardiovascular-related outcomes in those with non-dialysis-dependent chronic kidney disease (CKD), indicating its efficacy in this population.

Carvedilol was generally well tolerated, although there was a noted increase in serum creatinine levels in CKD patients; however, its effectiveness was not significantly different from placebo in patients with more advanced CKD (eGFR <45 mL/min/1.73 m²).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of carvedilol in treatment of heart failure with chronic kidney disease: a meta-analysis of randomized trials. Wali, RK., Iyengar, M., Beck, GJ., et al.[2018]

Sympathetic overactivity in chronic kidney disease (CKD) increases cardiovascular risks and renal disease progression, yet beta-blockers, which can help manage these issues, are underutilized in CKD patients due to tolerability concerns.

Newer vasodilating beta-blockers like carvedilol show promise in reducing cardiovascular events and albuminuria in CKD patients, suggesting that increasing their use could significantly lower the risk of heart failure, a leading cause of death in dialysis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta blockers in the management of chronic kidney disease. Bakris, GL., Hart, P., Ritz, E.[2006]

The COMET trial demonstrated that carvedilol, a nonselective beta-blocker, significantly reduces all-cause and cardiovascular mortality compared to metoprolol tartrate in patients with chronic heart failure.

This evidence suggests that switching patients from metoprolol tartrate to carvedilol could provide better cardiovascular outcomes, highlighting that not all beta-blockers are interchangeable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary on the Carvedilol or Metoprolol European Trial (COMET). Poole-Wilson, PA.[2018]

In a study of 27,064 hemodialysis patients, initiating carvedilol was linked to higher all-cause mortality (8% increase) and cardiovascular mortality (18% increase) compared to metoprolol over a 1-year follow-up period.

Patients starting carvedilol also experienced a greater incidence of intradialytic hypotension, which may explain the increased mortality risk associated with this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparative Study of Carvedilol Versus Metoprolol Initiation and 1-Year Mortality Among Individuals Receiving Maintenance Hemodialysis. Assimon, MM., Brookhart, MA., Fine, JP., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21036889/

Efficacy and safety of carvedilol in treatment of heart failure ... Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need ...

2. ahajournals.org ahajournals.org/doi/10.1161/circheartfailure.109.932558

Efficacy and Safety of Carvedilol in Treatment ... In individuals without CKD, prolonged use of carvedilol has been shown to improve symptoms of HF, increase LVEF, mitigate neurohormonal ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0735109703002419

Carvedilol increases two-year survivalin dialysis patients ... The results of the current study provide the first demonstration that carvedilol can prolong survival in dialysis patients with dilated cardiomyopathy.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/1378134/

Pharmacokinetics and efficacy of carvedilol in hypertensive ... In hypertensive renal failure patients, treatment with carvedilol (5 mg/day) for 1 week produced a significant decrease in blood pressure (from 172/101 to 146/ ...

5. jacc.org jacc.org/doi/10.1016/j.jacc.2019.09.059

Impact of Renal Impairment on Beta-Blocker Efficacy in ... In patients with sinus rhythm and moderate or moderately severe renal impairment, 77% managed to reach one-half of the target dose of beta- ...

6. kidney-international.org kidney-international.org/article/S0085-2538(15)51873-5/fulltext

Beta blockers in the management of chronic kidney disease Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This ...