Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02123056|
Recruitment Status : Recruiting
First Posted : April 25, 2014
Last Update Posted : October 12, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Vasovagal Syncope||Drug: Metoprolol Drug: Matching Placebo||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||248 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects|
|Study Start Date :||October 2014|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
Active Comparator: Metoprolol
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.
the daily dose range is 25mg twice a day to a maximum of 100mg twice a day
Placebo Comparator: Placebo
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.
Drug: Matching Placebo
the daily dose range is 25mg twice a day to a maximum of 100mg twice a day
- The primary outcome measure will be the proportion of patients having at least one syncope recurrence. [ Time Frame: 1 year. ]
- A secondary outcome will be the time between the first and second syncope recurrences. [ Time Frame: 1 year ]
- A secondary outcome will be the frequency of syncopal spells. [ Time Frame: 1 year ]
- A secondary outcome is the number, duration, and severity of presyncopal spells (as measured with the Calgary Presyncope Scale) [ Time Frame: 1 year ]
- A secondary outcomes will be quality of life as measured by the EQ-5D and the ISQL. [ Time Frame: 1 year ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02123056
|Contact: Robert S Sheldon, MD||(403)firstname.lastname@example.org|
|St. Boniface General||Recruiting|
|Winnipeg, Manitoba, Canada, R2H 2A6|
|Contact: Colette Seifer, MD (204)237-2380 email@example.com|
|Hopital du Sacre-Coeur de Montreal||Recruiting|
|Montreal, Quebec, Canada, H4J 1C5|
|Contact: Teresa Kus, MD (514)338-2222 firstname.lastname@example.org|
|Principal Investigator:||Robert S Sheldon, MD||University of Calgary|