Metoprolol for Fainting

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Calgary

Must not be taking: Beta blockers

Disqualifiers: Asthma, Diabetes, COPD, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 50 weeks

52 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on beta blockers or antihypertensive medications, you might need to discuss this with the trial team, as certain conditions related to these medications are part of the exclusion criteria.

What data supports the effectiveness of the drug metoprolol for preventing fainting?

Research shows that metoprolol, a type of beta-blocker, can help prevent fainting in some people with vasovagal syncope, although results are mixed. In one study, patients taking metoprolol had fewer fainting episodes compared to those who did not receive any medication. ^{1 2 3 4 5}

Is metoprolol generally safe for humans?

Metoprolol is generally well tolerated and has been used safely for many years to treat conditions like high blood pressure and heart disease. Common side effects include temporary fatigue, dizziness, and headache, but it is considered safe for most people, including those with asthma and diabetes, due to its selective action on the heart. ^{6 7 8 9 10}

How does the drug metoprolol differ from other treatments for fainting?

Metoprolol is unique because it is a selective beta1-receptor blocker, which means it specifically targets the heart to reduce heart rate and blood pressure, potentially helping with fainting by stabilizing cardiovascular function. Unlike some other treatments, metoprolol is available in various forms, including immediate and controlled release, allowing for flexible dosing options. ^{6 8 11 12 13}

What is the purpose of this trial?

Syncope affects about 50% of Canadians, is the cause of 1-2% of emergency room visits, and probably is responsible for CDN $250 million in health care spending each year. It is associated with decreased quality of life, trauma, loss of employment, and limitations in daily activities. The most common cause is vasovagal syncope. This occurs in people of all ages, and is a lifelong predilection. While the median number of faints in the population is 2, those who come to the investigators care have a median 10-15 lifetime spells, and have an increased frequency in the year before presentation. Vasovagal syncope is due to abrupt hypotension and transient bradycardia, which cause cerebral hypoperfusion. The pathophysiology may be either failure of venous return or progressive vasodilation, both due to inappropriately low sympathetic outflow. Sympathetic stimulation might be involved early in the reflex cascade. There is no known medical treatment for frequent fainting. The investigators performed the pivotal CIHR-funded randomized trials that showed that neither permanent pacing, beta blockers, nor fludrocortisone help the majority of patients. However 3 observational studies suggested that beta blockers prevent syncope in older subjects, and the Prevention of Syncope Trial (POST1) showed in a prespecified, -stratified analysis that patients ≥42 years tended to benefit. The investigators recent meta-analysis showed a benefit from metoprolol in these patients, with a hazard ratio of 0.52 (CI 0.27 to 1.01), and an age-specific response to beta blockers (p = 0.007). These results suggest the need for a randomized clinical trial of metoprolol for the prevention of vasovagal syncope in older subjects. Accordingly,the investigators conducted a poll of 48 cardiologists and neurologists in Canada and abroad: 98% stated that a randomized trial was necessary, and 92% agreed to participate in such a trial. Separately, this study emerged as the first choice for syncope randomized trials after consultation with Canadian and international experts. Objective: To determine if treatment with metoprolol in patients ≥40 years old with moderate to severely frequent vasovagal syncope will better suppress syncope recurrences than placebo. Methods: This will be a longitudinal, prospective, parallel design, placebo-controlled, randomized clinical trial. Patients will be enrolled during a recruitment period of 4 years and followed for a fixed period of 1 year. Subjects will have had ≥1 faint in the previous year, and a diagnosis of vasovagal syncope based on a quantitative diagnostic score. They will be randomized to receive either metoprolol or placebo at an initial dose of 50 mg bid. Dose adjustments will be made according to treating physician discretion to optimize tolerance and compliance while maximizing dose. The primary outcome measure will be the time to the first recurrence of syncope (after a 2 week dose titration wash-in period) over the 1-year observation period. The primary analysis will be performed on an intention-to-treat basis. Secondary analyses will include an on-treatment analysis, as well as analyses comparing syncope and presyncope frequency, number needed to treat, quality of life, impact of syncope on daily living, and cost from the perspective of the publicly funded health care system. The investigators will enroll 248 patients to have an 85% power to detect a reduction (p\<0.05) in the primary outcome from 50% (placebo group) to 30% (midodrine group), a 40% relative risk reduction. This sample size also allows for a 11% rate of subject dropout with loss to follow-up before a syncopal event. The University of Calgary Syncope Clinic has a well-functioning clinical trial apparatus that successfully completed the randomized, multicenter Prevention of Syncope Trials (POST1: metoprolol for vasovagal syncope; POST2: fludrocortisone for vasovagal syncope) and SIRCAT (Statin-Induced Reduction of Cardiomyopathy Trial). Enrolment is underway in the CIHR-funded POST3 (pacing versus loop recorders in syncope patients with bifascicular block) and POST4 (midodrine for vasovagal syncope). Study centres that were highly productive in POST1-4 have agreed to participate. The investigators therefore will have ample syncope enrolling centres. Relevance: This study will provide evidence to inform the use of metoprolol in the treatment of moderate to severely frequent syncope in older patients with vasovagal syncope. Given the lack of any other conventional medical therapy the investigators expect it to have rapid impact on care.

Research Team

Robert S Sheldon, MD, PhD

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for people aged 40 or older who have had at least one fainting episode in the past year and score above a certain threshold on a syncope symptom score. It's not suitable for those with structural heart abnormalities.

Inclusion Criteria

I am 40 years old or older.

≥-2 points on the Calgary Syncope Symptom Score for Structurally Normal Hearts

I have fainted at least once in the past year.

Exclusion Criteria

My resting heart rate is below 50 bpm or my blood pressure is below 90/60 without medication.

Major chronic non-cardiovascular disease

I have a thickened heart muscle or a genetic heart rhythm problem.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Titration

Participants receive an initial dose of 50 mg BID of metoprolol or placebo, titrated over 2 weeks to a target of 100 mg BID

2 weeks

Treatment

Participants continue receiving metoprolol or placebo for the remainder of the 1-year observation period

50 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Matching Placebo
• Metoprolol

Trial Overview The study tests if Metoprolol, a beta blocker, can prevent fainting episodes better than a placebo in older adults with frequent vasovagal syncope. Participants will be randomly assigned to receive either Metoprolol or placebo.

Participant Groups

Group I: Metoprolol Active Control 1 Intervention

Metoprolol 50 mg po tablets will be provided for final dosing range (25 mg po BID to 100 mg po BID) for study duration (1 year). Patients will be started at 50 mg po BID and titrated over 2 weeks to target of 100 mg po BID.

Group II: Placebo Placebo Group 1 Intervention

Matching placebo will be identical in appearance to the active treatment pill. Patients will be started at 50 mg po BID and titrated over 2 weeks to target of 100 mg po BID.

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Vanderbilt University

Collaborator

Trials

714

Recruited

6,143,000+

Findings from Research

In a randomized, placebo-controlled trial involving 208 patients with vasovagal syncope, metoprolol did not significantly reduce the risk of recurrent syncope compared to placebo over a 1-year treatment period.

The study found that neither the age of the patients nor their initial tilt-test results predicted any benefit from metoprolol, indicating that this beta-blocker is not effective for preventing vasovagal syncope.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Sheldon, R., Connolly, S., Rose, S., et al.[2022]

The ongoing UNAMET study is evaluating the impact of metoprolol on quality of life and the incidence of adverse drug reactions (ADRs) in outpatients, using standard questionnaires over a 6-week period.

The study aims to determine if genotyping for the CYP2D6 enzyme can help guide initial dosing of metoprolol, particularly for patients who are poor metabolizers and may be at higher risk for ADRs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rationale and methods of the UNAMET study (dose- and CYP2D6-genotype-dependent adverse drug reactions of metoprolol)--a contribution to quality improvement in pharmacotherapy]. Fux, R., Meisner, C., Schwab, M., et al.[2015]

Metoprolol is an effective treatment for mild to moderate hypertension and angina pectoris, showing comparable efficacy to other medications like beta-blockers and diuretics, and can be administered in both twice-daily and once-daily doses.

While metoprolol has shown some benefits in reducing mortality in post-myocardial infarction patients over a longer term, its use during the acute phase of myocardial infarction remains controversial due to mixed results in mortality reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metoprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischaemic heart disease and related cardiovascular disorders. Benfield, P., Clissold, SP., Brogden, RN.[2018]

In a study of 60 patients over 6 months, metoprolol succinate was found to be safe and well tolerated, with no significant differences in quality of life or withdrawal rates compared to placebo.

Patients taking metoprolol succinate experienced a significant increase in left ventricular ejection fraction and a reduction in ventricular ectopic beats, indicating improved heart function and rhythm stability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metoprolol CR/XL in patients with heart failure: A pilot study examining the tolerability, safety, and effect on left ventricular ejection fraction. Goldstein, S., Kennedy, HL., Hall, C., et al.[2019]

Metoprolol, particularly in its controlled release (CR/XL) form, has been shown to significantly lower mortality rates in patients with chronic heart failure compared to other forms, such as immediate release (IR) and sustained release (SR).

While metoprolol SR does not demonstrate superior antihypertensive efficacy compared to IR or CR/XL, the new controlled release formulation (CD/ERT) has been proven bioequivalent to CR/XL, suggesting it may offer similar benefits in managing heart conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evolution of oral drug forms of metoprolol: advantages of long acting modified release forms with modified release]. Leonova, MV., Maneshina, OA., Belousov, IuB.[2017]

References

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

Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. [2022]

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

A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Predictor of Syncopal Recurrence in Children With Vasovagal Syncope Treated With Metoprolol. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Metoprolol in hypertension: an open evaluation. [2013]

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

Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents. [2014]

6. Germany pubmed.ncbi.nlm.nih.gov

[Rationale and methods of the UNAMET study (dose- and CYP2D6-genotype-dependent adverse drug reactions of metoprolol)--a contribution to quality improvement in pharmacotherapy]. [2015]

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

Metoprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischaemic heart disease and related cardiovascular disorders. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. [2019]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Metoprolol CR/XL: advanced formulation of a classical beta-blocker]. [2017]

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

Metoprolol CR/XL in patients with heart failure: A pilot study examining the tolerability, safety, and effect on left ventricular ejection fraction. [2019]

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

Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension. [2019]

12. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Evolution of oral drug forms of metoprolol: advantages of long acting modified release forms with modified release]. [2017]

13. Sweden pubmed.ncbi.nlm.nih.gov

The effect of metoprolol --a new selective adrenergic beta1-receptor blocking agent-- in mild hypertension. [2019]