Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects
Information source: University of Calgary
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Vasovagal Syncope
Intervention: Metoprolol (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: University of Calgary Official(s) and/or principal investigator(s): Robert S Sheldon, MD, Principal Investigator, Affiliation: University of Calgary
Overall contact: Robert S Sheldon, MD, Phone: (403)220-8191, Email: sheldon@ucalgary.ca
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.
Clinical Details
Official title: Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: The primary outcome measure will be the proportion of patients having at least one syncope recurrence.
Secondary outcome: A secondary outcome will be the time between the first and second syncope recurrences.A secondary outcome will be the frequency of syncopal spells. A secondary outcome is the number, duration, and severity of presyncopal spells (as measured with the Calgary Presyncope Scale) A secondary outcomes will be quality of life as measured by the EQ-5D and the ISQL.
Eligibility
Minimum age: 40 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. ≥1 syncopal spells in the year preceding enrollment,
2. ≥-2 points on the Calgary Syncope Symptom Score for Structurally Normal Hearts, and
(C) Age ≥ 40 years.
Exclusion Criteria:
1. resting heart rate <50 bpm or supine systolic blood pressure <90 mm Hg in the absence
of beta blockers or antihypertensive medications,
2. other causes of syncope, such as sick sinus syndrome, ventricular tachycardia,
complete heart block, postural hypotension or hypersensitive carotid sinus syndrome,
3. an inability to give informed consent,
4. important valvular, coronary, myocardial or conduction abnormality,
5. hypertrophic cardiomyopathy or known or probable genetic arrhythmia
6. a contraindication to beta blockers such as asthma, insulin-dependent diabetes,
severe depression, peripheral vascular disease, chronic obstructive pulmonary
disease, or previous intolerance of beta blockers,
7. another clinical need for beta blockers which can not be met with other drugs,
8. a seizure disorder,
9. major chronic non-cardiovascular disease,
10. an implanted defibrillator,
11. Known hypersensitivity to metoprolol and derivatives.
Locations and Contacts
Robert S Sheldon, MD, Phone: (403)220-8191, Email: sheldon@ucalgary.ca
St. Boniface General, Winnipeg, Manitoba R2H 2A6, Canada; Recruiting Colette Seifer, MD, Phone: (204)237-2380, Email: rmeideiros@sbgh.mb.ca
Hopital du Sacre-Coeur de Montreal, Montreal, Quebec H4J 1C5, Canada; Recruiting Teresa Kus, MD, Phone: (514)338-2222, Email: a-langois@crhsc.rtss.qc.ca
Additional Information
Starting date: October 2014
Last updated: December 1, 2014
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