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

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Heart failure with preserved ejection fraction (HFpEF) is a critical public health problem. Heart failure (HF) affects over 5 million adults in the United States (US), and is a major source of morbidity, mortality, and impaired quality of life. Approximately half of individuals with HF have a preserved left ventricular (LV) ejection fraction (EF), termed HF with preserved EF (HFpEF). While there are several effective pharmacologic therapies for HF with reduced ejection fraction (HFrEF), none have been identified for HFpEF. Hypertension, which is present in approximately 80% of individuals with HFpEF, is the foremost modifiable risk factor for the development and progression of HFpEF. Despite the clinical importance of hypertension in HFpEF, there is limited information on how common antihypertensive agents, particularly calcium channel blockers (CCBs) and β-blockers, effect pathophysiologic mechanisms of HFpEF. This is a mechanistic investigation of the role of dihydropyridine CCBs compared to β-blockers (commonly used antihypertensive agents in clinical practice) in targeting key physiologic abnormalities in 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 data supports the idea that Calcium Channel Blocker + Beta Blocker for Heart Failure is an effective drug?

The available research shows that metoprolol succinate, a type of beta blocker, is effective in treating heart failure. It has been shown to improve survival and reduce hospital visits for patients with heart failure. Studies have also shown that metoprolol succinate is better than metoprolol tartrate, another form of the drug, because it lasts longer in the body. Additionally, carvedilol, another beta blocker, has been found to reduce the risk of death more than metoprolol tartrate. However, more studies are needed to directly compare carvedilol and metoprolol succinate. Overall, metoprolol succinate and carvedilol are both supported by evidence for treating heart failure. ^{1 2 3 4 5}

What safety data exists for using calcium channel blockers and beta blockers in heart failure treatment?

The safety data for beta blockers in heart failure treatment primarily involves metoprolol succinate, which is approved for use in heart failure, along with carvedilol and bisoprolol. Metoprolol tartrate has been found to be inferior in some studies. The COMET trial showed carvedilol reduced all-cause mortality compared to metoprolol tartrate, but no direct comparison with metoprolol succinate was made. Meta-analyses suggest similar effects on mortality between carvedilol and metoprolol succinate. No specific safety data for calcium channel blockers like amlodipine in heart failure is provided in the research. ^{1 2 5 6 7}

Is the drug Amlodipine Besylate, Metoprolol Succinate a promising treatment for heart failure?

Yes, Metoprolol Succinate is a promising drug for heart failure. It is one of the few beta-blockers approved in the U.S. for heart failure and has been shown to reduce mortality and hospitalizations in patients with heart failure. Amlodipine Besylate is not specifically mentioned in the studies, but Metoprolol Succinate has strong evidence supporting its use. ^{1 2 8 9 10}

Eligibility Criteria

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 am between 18 and 90 years old.

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.

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

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

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

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

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

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

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

Commentary on the Carvedilol or Metoprolol European Trial (COMET). [2018]

6. England pubmed.ncbi.nlm.nih.gov

Critical differences among beta-adrenoreceptor antagonists in myocardial failure: debating the MERIT of COMET. [2018]

7. United States 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. [2018]

8. Brazil pubmed.ncbi.nlm.nih.gov

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

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

Clinical inquiry: what is the best beta-blocker for systolic heart failure? [2015]

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

Low Utilization of Beta-Blockers Among Medicare Beneficiaries Hospitalized for Heart Failure With Reduced Ejection Fraction. [2020]