Clinical Trial Summary
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.
