Beta Blockers for Heart Failure

(PRE-INFORMED Trial)

Overseen By Parag Goyal, MD, MSc

Age: 65+

Sex: Any

Trial Phase: Phase 4

Sponsor: Weill Medical College of Cornell University

Must be taking: Beta-blockers

Disqualifiers: Severe aortic stenosis, Angina, others

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

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 12-36 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how older adults with heart failure, where the heart pumps normally but symptoms persist, feel about staying on or stopping beta blockers, a common heart medication. Participants will alternate between taking their usual dose and gradually reducing it to determine their preference. It is ideal for those aged 65 and older who can walk independently and are already taking beta blockers for heart issues.

As a Phase 4 trial, this research aims to understand how an FDA-approved and effective treatment benefits more patients, offering valuable insights for those involved.

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 focuses on whether to continue or stop beta-blockers. It seems you will need to be on a beta-blocker to participate.

What is the safety track record for beta blockers?

Research shows that beta blockers are generally safe and effective for people. They have long been used to treat various heart problems. Studies indicate that beta blockers can help those with heart failure by slowing the heart and reducing its workload, easing stress on the heart.

The FDA has approved some beta blockers, such as carvedilol and metoprolol, specifically for heart failure. In one study with heart failure patients, carvedilol lowered the risk of death, demonstrating its safety and effectiveness.

However, like all medicines, beta blockers can cause side effects. Common ones include fatigue, cold hands or feet, and dizziness. It's important to discuss any concerns with a healthcare provider, who can help determine if beta blockers are suitable. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores a personalized approach to beta-blocker treatment for heart failure, which is different from the typical one-size-fits-all method. Standard treatments for heart failure often involve a fixed regimen of beta-blockers, but this trial allows participants to experiment with alternating periods of being on and off beta-blockers. This flexible approach helps participants determine their personal preference and tolerance, potentially leading to more tailored and effective management of their condition. By understanding individual responses to beta-blocker cycles, the trial aims to enhance patient outcomes and quality of life.

What is the effectiveness track record for beta blockers in treating heart failure?

Research has shown that beta blockers effectively treat heart failure by reducing the heart's workload and lowering blood pressure. Studies have found that beta blockers can extend the lives of people with heart failure. In this trial, participants will alternate between taking and not taking beta blockers to determine their personal preference for continuing or discontinuing the medication. For those with heart failure with preserved ejection fraction (HFpEF), beta blockers might help manage symptoms by controlling heart rate and blood pressure, although the benefits for this type are less clear. Overall, beta blockers are widely used and have a strong history of improving heart health. ^{1 2 3 4 5}

Who Is on the Research Team?

Parag Goyal, MD, MSc

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for adults aged 65 or older with Heart Failure with Preserved Ejection Fraction (HFpEF), who are currently taking beta-blockers and meet specific heart function criteria. People can't join if they have other heart conditions, recent severe cardiac events, certain arrhythmias, uncontrolled blood pressure, or any instability that could affect the study.

Inclusion Criteria

I am 65 or older with heart failure but my heart still pumps well.

I am currently taking a beta-blocker medication.

Exclusion Criteria

I have had a heart attack or heart surgery in the last 3 years.

My heart condition is not caused by severe valve issues, constrictive pericarditis, high output failure, or infiltrative cardiomyopathy.

I have been diagnosed with thickened heart muscles.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a two-arm crossover withdrawal/reversal design with up to 6 periods, each lasting up to 6 weeks, involving titration of beta-blockers

12-36 weeks

Multiple visits as per participant's choice of 2-6 periods

Follow-up

Participants are monitored for safety and effectiveness after treatment, with qualitative interviews conducted to assess confidence and decision-making

up to 52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Beta blocker

Trial Overview

The study aims to see if N-of-1 trials help patients decide whether to continue or stop using beta-blockers for HFpEF by increasing their confidence in the decision-making process.

How Is the Trial Designed?

Group I: Beta-Blocker ABAB Sequence Active Control 1 Intervention

This arm will follow an ABAB sequence: ON beta-blockers (A) and OFF beta-blockers (B). Participants start with their home beta-blocker dose in Period 1 (A), and then switch to Period 2 (B), where the dose is slowly reduced until they are off their beta-blocker (or the lowest tolerable dose). Participants are then asked if they have enough information to clarify their preference about continuing or discontinuing their beta-blocker. Participants can choose to engage in 2-6 periods based on whether they need more information to make a preference. These extra phases follow the same ON-OFF pattern (ABABAB), meaning if the participant chooses to continue into Period 3 (A), the study team will restart the participant's beta-blocker, and slowly up-titrate until they reach their home dose, or their highest tolerable dose. This continues until the participant has enough information to clarify their preference about their beta-blocker, with a limit of 6 periods.

Group II: Beta-Blocker BABA Sequence Active Control 1 Intervention

This arm will follow a BABA sequence: OFF beta-blockers (B) and ON beta-blockers (A). Participants start Period 1 (B) by slowly reducing the participant's beta-blocker home dose by 50% each week until they are off (or the lowest tolerable dose), then switch to Period 2 (A), where they restart their beta-blocker and slowly up-titrate until they reach their home dose (or the highest tolerable dose). Participants are then asked if they have enough information to clarify their preference about continuing or discontinuing their beta-blocker. Participants can choose to engage in 2-6 periods based on whether they need more information. The extra phases follow the same OFF-ON pattern (BABABA), meaning if they choose to continue into Period 3 (B), the participant will slowly reduce their beta-blocker until they are off (or the lowest tolerable dose). This continues until the participant has enough information to clarify their preference about their beta-blocker, with a max of 6 periods.

Beta blocker is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Approved in United States as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Approved in Canada as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Approved in Japan as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Approved in China as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Approved in Switzerland as Beta blockers for:

• Hypertension
• Heart failure
• Angina
• Arrhythmias
• Migraine
• Glaucoma
• Anxiety disorders

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In a study of 29 heart failure patients, replacing carvedilol with propranolol did not worsen heart function, as measured by ejection fraction, after 6 months, indicating that propranolol can be a safe alternative.

The study found that propranolol led to a significant increase in ejection fraction, suggesting it may be effective in improving heart function in patients previously stabilized on carvedilol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Replacement of carvedilol for propranolol in patients with heart failure. Marques, F., Castro, RB., Nobre, F., et al.[2019]

Modern beta blockers, including metoprolol, bisoprolol, atenolol, and carvedilol, are generally safe with a low incidence of serious side effects when used appropriately, making them suitable for a variety of medical conditions.

These medications have shown significant prognostic benefits in large clinical trials, particularly for patients recovering from heart attacks and those with heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Differential therapy with beta blockers. What is their value, what are the risks?]. Bäumer, AT., Erdmann, E.[2017]

Beta-adrenergic receptor blockers, such as bisoprolol, metoprolol, and carvedilol, have been proven to significantly improve survival rates and reduce hospitalization in heart failure patients, leading to better overall patient well-being.

While investigational beta-blocker bucindolol showed only mild improvements in survival, the differences in properties among beta-blockers, such as selectivity and vasodilation effects, remain to be fully understood in terms of their impact on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are all beta-blockers the same for chronic heart failure? Gottlieb, SS.[2019]

Beta-blockers like bisoprolol, carvedilol, metoprolol, and nebivolol are effective in improving survival rates for patients with systolic heart failure, highlighting their importance in heart failure management.

The article provides guidance on how healthcare practitioners can properly start and adjust the dosages of these beta-blockers to ensure patients receive the maximum therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using beta-blockers to treat heart failure. Nguyen, T., Shaheed, A., Venigalla, S., et al.[2016]

In a study of 70 patients with chronic heart failure, both nebivolol and carvedilol improved left ventricular function, with increases in ejection fraction and decreases in end-systolic volume after 6 months of treatment, although the differences between the two drugs were not statistically significant.

Both medications resulted in a significant reduction in heart rate and blood pressure, and there were no significant differences in adverse events, indicating that nebivolol is as safe and effective as carvedilol for treating patients with reduced left ventricular systolic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of nebivolol versus carvedilol on left ventricular function in patients with chronic heart failure and reduced left ventricular systolic function. Lombardo, RM., Reina, C., Abrignani, MG., et al.[2018]

In a study of 61 moderate heart failure patients, Nebivolol and Bisoprolol showed better lung diffusion and exercise performance compared to Carvedilol, likely due to less interference with β2-mediated alveolar fluid clearance.

Carvedilol demonstrated improved ventilation efficiency during exercise, suggesting it may modulate chemoreceptor responses differently than the other β-blockers, which could help tailor treatment for individual heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. Contini, M., Apostolo, A., Cattadori, G., et al.[2022]

A systematic review of 18 studies indicates that metoprolol succinate effectively reduces the incidence of atrial fibrillation (AF) in high-risk patients and provides significant mortality and morbidity benefits in heart failure (HF) treatment.

Despite the emergence of newer beta-blockers, metoprolol succinate continues to be a valuable treatment option for both HF and AF, supported by extensive clinical experience since the 1970s.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Metoprolol Succinate in the Treatment of Heart Failure and Atrial Fibrillation: A Systematic Review. Vinereanu, D., Spinar, J., Pathak, A., et al.[2021]

Beta-blockers with vasodilating properties, such as nebivolol, are more effective in reducing left ventricular workload and improving arterial health compared to non-vasodilator beta-blockers like propranolol and atenolol, which do not positively affect arterial thickness or rigidity.

Third-generation beta-blockers, including celiprolol, carvedilol, and nebivolol, possess antioxidant properties that may protect endothelial function and minimize harmful metabolic effects, making them potentially safer options for long-term treatment in hypertensive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Endothelial dysfunction: role of vasodilating betablockers in hypertension and chronic heart failure]. Thuillez, C.[2010]

Long-term beta-blocker therapy has shown beneficial effects in over 13,000 patients with chronic heart failure, with metoprolol, bisoprolol, and carvedilol demonstrating positive impacts on prognosis, although they differ in their pharmacologic characteristics.

Carvedilol may offer a more comprehensive blockade of adrenergic receptors compared to selective beta-blockers like metoprolol and bisoprolol, potentially leading to better left ventricular function, but the long-term effects on patient outcomes are still being evaluated in the ongoing COMET trial with over 3,000 participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-blockade in heart failure: selective versus nonselective agents. Metra, M., Nodari, S., Dei Cas, L.[2018]

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]

In a comparison of beta-blockers for heart failure, bisoprolol, carvedilol, and metoprolol CR/XL showed similar efficacy in reducing mortality and hospitalization rates among patients with systolic heart failure, regardless of their NYHA class or ejection fraction.

Nebivolol was found to be less effective and not better tolerated than the other beta-blockers, indicating that it may not be the best choice for patients with heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. Wikstrand, J., Wedel, H., Castagno, D., et al.[2022]

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]

Only three beta-blockers—carvedilol, bisoprolol, and metoprolol succinate—have shown positive effects on prognosis in chronic heart failure patients, highlighting their importance in treatment.

Carvedilol not only blocks beta(1)-adrenergic receptors but also beta(2)- and alpha(1)-adrenergic receptors, and has additional properties that may contribute to its superior mortality reduction compared to metoprolol, as demonstrated in the COMET trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-blockers in heart failure: are pharmacological differences clinically important? Metra, M., Cas, LD., di Lenarda, A., et al.[2018]

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