Calcium Channel Blocker + Beta Blocker for Heart Failure

(BLOCK HFpEF Trial)

Overseen By Julio Chirinos, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Pennsylvania

Must be taking: Antihypertensives

Must not be taking: Oral steroids

Disqualifiers: Pregnancy, Coronary artery disease, 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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two common blood pressure medications, a calcium channel blocker and a beta-blocker, affect heart failure with preserved ejection fraction (HFpEF). HFpEF is a form of heart failure where the heart pumps normally but struggles to fill with blood. Participants will receive either amlodipine besylate (a calcium channel blocker) or metoprolol succinate (a beta-blocker) to determine which better addresses issues related to HFpEF. The trial seeks individuals who have been living with both heart failure and high blood pressure for a while and have had stable treatment for at least a month. As a Phase 4 trial, this research focuses on understanding how these FDA-approved treatments can benefit more patients with HFpEF.

Do I need to stop taking my current medications for this trial?

The trial requires a 'washout' period for certain medications. If you are taking a calcium channel blocker (CCB) or a beta-blocker, you may need to stop these medications before the trial, unless it is clinically contraindicated. Please consult with the trial investigator for specific guidance based on your current medications.

What is the safety track record for these treatments?

Previous studies have safely used amlodipine in patients with various heart conditions, including heart failure. Common side effects include swelling, dizziness, flushing, and a pounding heart, but these effects are usually mild. Research has shown that amlodipine does not significantly increase the risk of major heart problems.

Research indicates that metoprolol can reduce the risk of hospital visits due to worsening heart failure by 19% and lower the risk of death from heart issues by 34%. Patients generally tolerate metoprolol well, often experiencing improved symptoms and quality of life.

Both amlodipine and metoprolol are well-tolerated and have been used safely in patients with heart problems. While both have some side effects, studies show their benefits in treating heart-related conditions. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using a combination of Amlodipine Besylate and Metoprolol Succinate for heart failure because these medications offer a dual approach that may enhance treatment outcomes. Amlodipine Besylate is a calcium channel blocker that helps relax blood vessels, lowering blood pressure and reducing heart workload. Meanwhile, Metoprolol Succinate is a beta-blocker that slows heart rate and decreases blood pressure, further supporting heart function. Together, they target both blood vessel relaxation and heart rate reduction, potentially offering a more comprehensive treatment than current options that typically focus on one mechanism at a time.

What evidence suggests that this trial's treatments could be effective for heart failure with preserved ejection fraction?

Research has shown that amlodipine, a calcium channel blocker, effectively lowers blood pressure, reducing the risk of heart problems like strokes and heart attacks. Studies have found that amlodipine can decrease heart-related issues by about 10% and improve recovery after heart failure. In this trial, some participants will receive amlodipine besylate.

Metoprolol, a beta blocker, has been shown to lower the risk of hospital visits due to worsening heart failure by 19% and improve symptoms and quality of life. Additionally, research indicates that metoprolol can reduce the overall death rate in heart failure patients by 34%. Other participants in this trial will receive metoprolol succinate. Both medications aim to manage high blood pressure, a major risk factor in heart failure with preserved ejection fraction (HFpEF). ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-90 with stable high blood pressure treatment, diagnosed heart failure, specific elevated heart pressures, and a history of hypertension. They must have a normal left ventricular ejection fraction (>50%). Excluded are those with certain blood pressure levels, severe lung disease or coronary artery disease, allergies to the drugs tested, kidney issues (eGFR <30), or conditions affecting study participation.

Inclusion Criteria

I have been diagnosed with heart failure.

Your heart has high pressure, as determined by specific measurements.

I have been diagnosed with high blood pressure.

Exclusion Criteria

You have had a bad reaction to amlodipine besylate or metoprolol succinate in the past.

Any medical condition that, under the investigator's discretion, will interfere with safe completion of the study or validity of the endpoint assessments

I have a serious lung condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive either Metoprolol succinate or Amlodipine besylate for hypertension management

4 weeks

End of phase visit for outcome measures

Treatment Phase 2

Participants switch to the alternate medication for hypertension management

4 weeks

End of phase visit for outcome measures

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amlodipine Besylate
• Metoprolol Succinate

Trial Overview

The trial investigates how two common blood pressure medications—Amlodipine Besylate (a calcium channel blocker) and Metoprolol Succinate (a beta-blocker)—impact heart function in patients with HFpEF. It aims to understand which medication better targets the physiological abnormalities associated with this type of heart failure.

How Is the Trial Designed?

Group I: Metoprolol succinate Active Control 1 Intervention

Initial dose 100mg (1 capsule) daily, titrated up to 200mg (2 capsules) daily for a home systolic BP ≥135 mmHg and heart rate ≥50 bpm after the first week of use

Group II: Amlodipine besylate Active Control 1 Intervention

Initial dose 5mg (1 capsule) daily, titrated up to 10mg (2 capsules) daily for a home systolic BP ≥135 mmHg and heart rate ≥50 bpm after the first week of use

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

Approved in United States as Norvasc for:

• Hypertension
• Angina pectoris
• Coronary artery disease

Approved in European Union as Amlodipine Besylate for:

• Hypertension
• Angina pectoris
• Coronary artery disease

Approved in Canada as Amlodipine Besylate for:

• Hypertension
• Angina pectoris

Approved in Japan as Amlodipine Besylate for:

• Hypertension
• Angina pectoris

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Julio Chirinos, MD, PhD

Collaborator

Trials

1

Recruited

50+

Raymond Townsend, MD

Collaborator

Trials

1

Recruited

50+

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]

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]

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]

Carvedilol, metoprolol succinate, and bisoprolol are equally effective in reducing mortality by approximately 30% over one year in patients with Class III or IV systolic heart failure.

There is not enough evidence from head-to-head studies to recommend one beta-blocker over the others at equipotent doses, indicating that all three options are viable for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical inquiry: what is the best beta-blocker for systolic heart failure? Hulkower, S., Aiken, BA., Stigleman, S.[2015]

Among 15,205 Medicare beneficiaries hospitalized for heart failure with reduced ejection fraction (HFrEF), only 38% received a prescription for a beta-blocker within 30 days of discharge, indicating low adherence to recommended post-hospitalization treatment.

Common contraindications like hypotension and COPD were present in many patients, but they only partially explained the low rates of beta-blocker prescriptions, suggesting other factors may also contribute to underutilization of these effective medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Utilization of Beta-Blockers Among Medicare Beneficiaries Hospitalized for Heart Failure With Reduced Ejection Fraction. Loop, MS., van Dyke, MK., Chen, L., et al.[2020]

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 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 meta-analysis of 30,943 patients treated with carvedilol and 69,925 patients treated with metoprolol, carvedilol was found to reduce all-cause mortality compared to metoprolol tartrate, suggesting a potential advantage for carvedilol in this specific comparison.

However, when comparing carvedilol to metoprolol succinate, there were no significant differences in all-cause mortality or hospitalizations, indicating that both medications may be equally effective for patients with heart failure with reduced ejection fraction (HFrEF).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. Briasoulis, A., Palla, M., Afonso, L.[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]

Metoprolol CR/XL has been shown to improve survival rates and reduce hospitalizations in patients with heart failure classified as New York Heart Association class II-IV, indicating its efficacy in this population.

The drug's unique pharmacokinetic and pharmacodynamic properties compared to conventional metoprolol tartrate highlight the importance of individualized patient evaluation for optimal dosing and to avoid potential drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metoprolol CR/XL in the treatment of chronic heart failure. Gattis, WA.[2019]

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The FDA label indicates that the most common adverse effects of amlodipine include edema, dizziness, flushing, and palpitations. Recent years ...