Carvedilol for Atrial Fibrillation

Overseen By Jennifer McKeage, R.N.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Calgary

Must not be taking: Beta blockers

Disqualifiers: Persistent AF, CHF, others

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

Compensation: Varies

Number of Visits: 1

Duration: 12 months

300 Participants Needed

Trial Summary

What is the purpose of this trial?

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is associated with significant symptoms and health problems including an increased risk of stroke and death. Current drug therapies are often ineffective and associated with significant side effects. Abnormalities of calcium regulation in cells may lead to triggers for AF. Emerging data suggest that abnormal intracellular calcium regulation mediated through the ryanodine receptor in heart cells may contribute to AF. Recently the investigators have shown that the β-blocker carvedilol which is most commonly used to treat patients with heart failure, modifies calcium regulation mediated through the ryanodine receptor. At present this drug is not frequently used to treat AF. Therefore the investigators will conduct a randomized trial comparing carvedilol to metoprolol for prevention of paroxysmal AF. This may result in improved health and quality of life for people who suffer AF.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Carvedilol for Atrial Fibrillation?

Research shows that Carvedilol, a drug used for heart failure, has been more effective than Metoprolol in reducing mortality in patients with chronic heart failure. This suggests that Carvedilol may have beneficial effects on heart conditions, potentially including atrial fibrillation. ^{1 2 3 4 5}

Is carvedilol safe for humans?

Carvedilol has been shown to reduce mortality and improve outcomes in patients with chronic heart failure, indicating it is generally safe for human use in this context. It is a long-acting beta-blocker with additional properties that may contribute to its safety and effectiveness. ^{1 2 5 6 7}

How does the drug Carvedilol differ from other treatments for atrial fibrillation?

Carvedilol is unique because it blocks multiple types of receptors (beta1, beta2, and alpha1), which may offer broader heart protection compared to other drugs like metoprolol that primarily target beta1 receptors. This broader action could potentially provide better outcomes for patients with heart conditions. ^{1 3 6 8 9}

Research Team

Anne M Gillis, M.D.

Principal Investigator

Professor of Medicine

Eligibility Criteria

This trial is for people with a heart rhythm disorder called paroxysmal atrial fibrillation, who've had symptoms recently. They must be able to consent and not have other serious heart conditions or life-threatening illnesses. It's not for those who can't take beta blockers due to past bad reactions.

Inclusion Criteria

Your heart must be in a normal rhythm when you join the study.

You have had more than two episodes of symptomatic atrial fibrillation that lasted for more than 15 minutes each time, as shown on an ECG test.

Exclusion Criteria

I have heart failure that affects my daily activities.

You live in a place that is far away from other people or services.

You are not expected to live for more than 1 year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Drug Titration

Carvedilol and metoprolol are dose titrated over one month to achieve target doses

4 weeks

1 visit (in-person)

Treatment

Participants are followed for AF occurrence using event recorders after drug titration

12 months

Quarterly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Carvedilol
• Metoprolol

Trial Overview The study compares two drugs, Carvedilol and Metoprolol, to see which one is better at preventing episodes of irregular heartbeat in patients with atrial fibrillation. Participants will be randomly assigned to receive one of the two medications.

Participant Groups

Group I: Metoprolol Active Control 1 Intervention

The metoprolol arm patients are stratified by the arrhythmia management strategy Rate or Rhythm control and metoprolol is dose titrated from 25 mg bid to a maximum of 50 mg bid over one month then patients are followed for 6 months.

Group II: Carvedilol Active Control 1 Intervention

The carvedilol arm patients are stratified by the arrhythmia management strategy Rate or Rhythm control and carvedilol is dose titrated from 3.25 mg bid to maximum dose of 25 mg bid over one month then patients are followed for 6 months.

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?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Libin Cardiovascular Institute of Alberta

Collaborator

Trials

4

Recruited

650+

Heart and Stroke Foundation of Canada

Collaborator

Trials

131

Recruited

72,600+

Findings from Research

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]

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]

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]

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]

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]

A study assessed the pharmaceutical quality of Dilatrend (carvedilol) and 35 generic products, revealing that while all Dilatrend strengths met specifications, nearly 49% of the generics failed to meet key quality standards.

The failure of many generic products in tests for carvedilol content, tablet hardness, dissolution, and purity raises concerns about their efficacy and safety, suggesting that substituting Dilatrend with these generics could lead to unpredictable treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation? Smith, JC., Tarocco, G., Merazzi, F., et al.[2018]

References

1. England 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). [2018]

2. England pubmed.ncbi.nlm.nih.gov

Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. [2019]

3. United States 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. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Do metoprolol and carvedilol have equivalent effects on diurnal heart rate in patients with chronic heart failure? [2018]

5. England pubmed.ncbi.nlm.nih.gov

Has COMET solved the controversy as to whether carvedilol is better than metoprolol in heart failure? [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Survival among patients with left ventricular systolic dysfunction treated with atenolol. [2016]

7. United States pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation? [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Carvedilol or sustained-release metoprolol for congestive heart failure: a comparative effectiveness analysis. [2018]