Beta Blocker vs Calcium Channel Blocker for Stable Angina

(LIVEBETTER Trial)

Recruiting in Palo Alto (17 mi)

+10 other locations

Overseen by Michael Nanna, MD

Age: 65+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Yale University

Must not be taking: Beta-blockers, Calcium channel blockers

Disqualifiers: Hypotension, AV block, Bradycardia, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

To establish the effectiveness and tolerability of standard of care anti-anginal treatment (beta-blocker and calcium channel blocker medications) in older adults with symptomatic Stable Ischemic Heart Disease (SIHD) and multiple chronic conditions (MCC).

Will I have to stop taking my current medications?

If you are currently taking beta-blockers or calcium channel blockers, you cannot participate in this trial. The trial does not specify about other medications, so it's best to discuss with the trial team.

What evidence supports the effectiveness of beta blockers for treating stable angina?

Research shows that beta blockers like carvedilol, metoprolol, and bisoprolol improve survival and symptoms in heart failure patients, suggesting they may also help with stable angina. These drugs have additional benefits like reducing blood pressure and improving heart function, which can be beneficial for angina. ^{1 2 3 4 5}

Are beta blockers and calcium channel blockers generally safe for humans?

Beta blockers like metoprolol, bisoprolol, and carvedilol are generally safe with a low risk of serious side effects if used correctly, though they can cause issues like slow heart rate or breathing problems in some cases. Calcium channel blockers are not specifically mentioned in the provided research, but beta blockers have been shown to be safe in large studies for conditions like heart failure. ^{1 6 7 8 9}

What makes the drug for stable angina unique?

The drug for stable angina is unique because it compares beta blockers, which can have additional benefits like vasodilation and antioxidant properties, with calcium channel blockers. Some beta blockers, like nebivolol, also improve blood vessel function by releasing nitric oxide, which can be beneficial for heart health. ^{3 5 10 11 12}

Research Team

Michael Nanna, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for older adults aged 75 and above with stable angina, heart disease, and at least two other chronic conditions. They must be planning to start medical therapy for their heart condition but can't have severe reactions to beta-blockers or calcium channel blockers, nor plans for immediate complete revascularization.

Inclusion Criteria

I am 75 years old or older.

I am an older adult with stable ischemic heart disease and multiple chronic conditions.

I am 18 years old or older.

Exclusion Criteria

You cannot participate if you have certain heart or lung conditions, are at high risk for heart disease, need certain medications, or have specific medical history or treatment plans.

I am currently taking a beta-blocker or calcium channel blocker.

Professional caregiver (i.e. not a relative or close friend of the participant), Primary language other than English or Spanish, Inability to complete follow-up, Previously enrolled in LIVEBETTER, Refused informed consent

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Beta-Blocker or Calcium Channel Blocker therapy as part of the study medication

12 months

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cognitive assessments

12 months

4 visits (in-person)

Ancillary Neurocognitive Study

Extended follow-up to assess cognitive decline and incidence of mild cognitive impairment and probable dementia

12 months

Treatment Details

Interventions

• Beta blocker (Beta Blocker)
• Calcium channel blocker (Calcium Channel Blocker)

Trial Overview The study tests the effectiveness of standard anti-anginal medications (beta-blockers and calcium channel blockers) in managing symptoms of Stable Ischemic Heart Disease in seniors with multiple health issues. The choice of medication is left to the clinician's discretion.

Participant Groups

Group I: Calcium Channel Blockers (CCB) Therapy Experimental Treatment 2 Interventions

Participants randomized to this arm will be given a calcium channel blocker. Specific and appropriate drug selection from the class of calcium channel blockers (i.e. type of CCB, dosing, and escalation of dose) will be left to the site clinician in accordance with clinical guidelines. All CCB will be administered orally (i.e. pills).

Group II: Beta-Blockers (BB) Therapy Experimental Treatment 2 Interventions

Participants randomized to this arm will be given a beta-blocker. Specific and appropriate drug selection from the class of beta blockers (i.e. type of BB, dosing, and escalation of dose) will be left to the site clinician in accordance with clinical guidelines. All BB will be administered orally (i.e. pills).

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

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

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]

Third generation beta-adrenoceptor antagonists, like nebivolol and carvedilol, not only lower blood pressure but also improve vascular function through mechanisms such as nitric oxide-mediated vasodilation and anti-inflammatory effects.

These drugs have been shown to reduce mortality and morbidity in conditions like heart failure and post-myocardial infarction, highlighting their efficacy in treating cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of newer beta-adrenoceptor antagonists on vascular function in cardiovascular disease. Wehland, M., Grosse, J., Simonsen, U., et al.[2019]

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]

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-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]

Chronic heart failure (CHF) is more common in elderly patients, yet most studies on beta-adrenoceptor antagonists have excluded those over 63 years old, raising concerns about the applicability of these treatments to older populations.

Nebivolol, a third-generation beta-adrenoceptor antagonist, has shown significant efficacy in reducing the risk of death or cardiovascular hospitalization in elderly CHF patients, making it the preferred choice for this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-adrenoceptor antagonists in elderly patients with chronic heart failure: therapeutic potential of third-generation agents. Coats, AJ.[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]

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]

Conventional beta-blockers may lead to poorer clinical outcomes and negatively affect quality of life, lipid, and carbohydrate metabolism compared to other antihypertensive medications, raising concerns about their use in treating hypertension.

Nebivolol, a cardioselective vasodilating beta-blocker, may offer advantages in treating complicated hypertension, especially in patients with diabetes, the elderly, and African Americans, highlighting the importance of considering the mechanism of action when selecting a beta-blocker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of nitric oxide in improving endothelial function and cardiovascular health: focus on nebivolol. Bakris, GL., Basile, JN., Giles, TD., et al.[2015]

Celiprolol is an effective treatment for angina pectoris, showing significant benefits compared to placebo in multiple studies.

Its efficacy in managing angina and ischemia is comparable to traditional beta-blockers like propranolol and atenolol, while also offering unique hemodynamic properties due to its selective adrenergic-blocking and vasodilator effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol in angina pectoris. Soberman, JE., Frishman, WH.[2019]

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. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The effects of newer beta-adrenoceptor antagonists on vascular function in cardiovascular disease. [2019]

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. Germany pubmed.ncbi.nlm.nih.gov

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

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

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

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

Beta-adrenoceptor antagonists in elderly patients with chronic heart failure: therapeutic potential of third-generation agents. [2018]

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

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

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

The role of nitric oxide in improving endothelial function and cardiovascular health: focus on nebivolol. [2015]

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

Celiprolol in angina pectoris. [2019]