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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Investigators will determine whether N-of-1 trials, as a pragmatic, participant-centered approach to medication optimization that can overcome key barriers of deprescribing, can lead to increased participant confidence regarding their preference to continue or discontinue beta-blockers in older adults with Heart Failure with Preserved Ejection Fraction (HFpEF).

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 evidence supports the effectiveness of beta-blocker drugs for heart failure?

Research shows that beta-blocker drugs like carvedilol, metoprolol, and bisoprolol improve survival and reduce symptoms in patients with heart failure. These drugs help patients feel better and reduce hospital visits, making them effective for managing heart failure. ^{1 2 3 4 5}

Is it safe to use beta blockers for heart failure?

Beta blockers like metoprolol, bisoprolol, and carvedilol are generally safe with a low risk of serious side effects when used properly, although they can sometimes cause issues like slow heart rate or breathing problems. Large studies have shown they improve survival and symptoms in heart failure patients. ^{1 6 7 8 9}

What makes beta blockers unique for treating heart failure?

Beta blockers like carvedilol, metoprolol, bisoprolol, and nebivolol are unique because they improve survival and symptoms in heart failure by blocking certain receptors in the heart, which helps it pump more efficiently. Carvedilol also blocks additional receptors, offering broader benefits compared to some other beta blockers. ^{1 10 11 12 13}

Research Team

Parag Goyal, MD, MSc

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

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 had episodes of very fast heartbeats.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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 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 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]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

Replacement of carvedilol for propranolol in patients with heart failure. [2019]

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

Are all beta-blockers the same for chronic heart failure? [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Bisoprolol in the treatment of chronic heart failure: from pathophysiology to clinical pharmacology and trial results. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Beta-blockade in heart failure: selective versus nonselective agents. [2018]

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

Beta-blockers in heart failure: are pharmacological differences clinically important? [2018]

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

Role of Metoprolol Succinate in the Treatment of Heart Failure and Atrial Fibrillation: A Systematic Review. [2021]

7. France pubmed.ncbi.nlm.nih.gov

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

8. Germany pubmed.ncbi.nlm.nih.gov

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

9. England 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. [2022]

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

Using beta-blockers to treat heart failure. [2016]

11. New Zealand 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. [2018]

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

Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET. [2018]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. [2022]