A Proof of Principal Study of Atomoxetine for the Prevention of Vasovagal Syncope
A Proof of Principal Study of Atomoxetine for the Prevention of Vasovagal Syncope
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.There is no
 known medical treatment for frequent fainting. Two randomized studies suggest that inhibition
 of norepinephrine transport (NET) reuptake with sibutramine and reboxetine (NET inhibitors)
 prevents syncope on tilt testing by about 80%, and the investigators reported that
 sibutramine markedly reduced the frequency of vasovagal syncope in 7 of our most symptomatic
 patients. Sibutramine and reboxetine, for different reasons, are not available in Canada.
 However atomoxetine is available and is used to help patients with attention deficit
 disorder. There are no data pertaining to its hemodynamic effects in patients with vasovagal
 syncope. Although a randomized clinical trial of atomoxetine for the prevention of vasovagal
 syncope would be needed before clinical use, the investigators first need a proof of
 principle study. The objective is to determine in a prospective, randomized, parallel,
 double-blind study if atomoxetine 40 mg bid in patients at least 18 years old with recurrent
 vasovagal syncope will better prevent syncope during tilt testing than placebo.
Study Design: This will be a randomized, double-blind, parallel-arm study in which the
 subjects will undergo a tilt table test following 2 doses of atomoxetine 40mg PO (evening
 before and morning of study) or after 2 doses of matching placebo (on separate days). On the
 morning of the study, the fasting subject (except for medications) will be instrumented, on
 an empty bladder. ECG electrodes will be applied to monitor continuous heart rhythm. Blood
 pressure will be monitored continuously using a finger volume clamp method using one or more
 of several extant devices, and calibrated with intermittent brachial cuff measurements. One
 intravenous cannula will be placed in the contralateral arm (to the blood pressure cuff) for
 blood sampling.

 Tilt Table Protocol: Following the insertion of the venous cannulae, a period of at least 20
 minutes will be allowed to elapse before a 10-minute basal control (baseline) period.
 Baseline data will be digitally recorded in this time. In the last 5 minutes of this period,
 blood will be drawn for fractionated plasma catecholamines. The table will be rapidly raised
 to 80 degrees for up to 60 minutes. The investigators are deliberately avoiding tilt test
 methods with provocative medications to avoid the issue of multiple causal factors. At 10
 minutes and 30 minutes following onset of tilt (or at the onset of severe presyncope or
 hypotension [systolic blood pressure <70 mmHg]), venous fractionated catecholamines will be
 sampled. The study will be terminated if the subject develops hypotension with severe
 presyncopal symptoms associated with a systolic blood pressure ≤70 mmHg or at the completion
 of the protocol.

 A sample size of 56 syncope patients will have 85% power to detect a 60% relative risk
 reduction from a placebo outcome rate of 65%, using an unmatched 2-tailed test with
 alpha=0.05. To compensate for the report dropout rate the investigators will inflate the
 sample by 15% to 64 subjects. A formal, blinded mid-way safety and efficacy analysis will be
 performed with a p<0.05 stopping rule for efficacy. This also will provide 85% power to
 detect an 80% relative risk reduction.

 Randomization will be carried out using a computerized algorithm. Patients will be randomized
 in a double blind fashion to receive atomoxetine 40mg PO x2 or matching placebo with a 1:1
 randomization ratio. Medication containers will be centrally filled and labeled with the
 randomization code number.
Inclusion Criteria:

 -  ≥1 syncopal spells in the year preceding enrolment

 -  ≥-2 points on the Calgary Syncope Symptom Score

 -  Age ≥18 years with informed consent

 -  The Calgary Syncope Symptom Score is used to diagnose VVS in patients with
 structurally normal hearts

 Exclusion Criteria:

 -  Other causes of syncope, such as ventricular tachycardia, complete heart block,
 orthostatic hypotension or hypersensitive carotid sinus syndrome

 -  An inability to give informed consent

 -  Important valvular, coronary, myocardial or conduction abnormality or significant
 arrhythmia

 -  Hypertrophic cardiomyopathy

 -  Permanent pacemaker

 -  Seizure disorder

 -  Hypertension defined as >150/90 mm Hg

 -  Pregnancy

 -  Glaucoma

 -  Medications with known effects on blood pressure

 -  Known hypersensitivity to atomoxetine and derivatives

 -  Other factors which, in the investigator's opinion, would prevent the subject from
 completing the protocol.