Prevention of Syncope Trial 6 - Atomoxetine in Vasovagal Syncope
Prevention of Syncope Trial 6 - Atomoxetine in Vasovagal Syncope
Objective: To determine if atomoxetine 40 mg bid (bis in die) in patients ≥18 years old with
 recurrent vasovagal syncope will better prevent syncope during tilt testing than placebo.
Background: Syncope affects about 50% of Canadians, is the cause of 1-2% of emergency room
 visits, and probably is responsible for C$250 million (Canadian dollars) 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.

 There is no known medical treatment for frequent fainting. The investigators performed the
 pivotal Canadian Institutes of Health Research (CIHR)-funded randomized trials that showed
 that neither permanent pacing, beta blockers, nor fludrocortisone help the majority of
 patients. However 2 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, a proof of principle study is needed first.

 Objective: To determine if atomoxetine 40 mg bid (bis in die) in patients ≥18 years old with
 recurrent vasovagal syncope will better prevent syncope during tilt testing than placebo.

 Methods: The investigators will conduct a prospective, randomized, parallel, double-blind,
 proof-of-concept study to test the hypothesis that norepinephrine transporter inhibition with
 Atomoxetine prevents tilt-induced vasovagal syncope (VVS)/pre-syncope in patients with
 clinical vasovagal syncope. Subjects will have had ≥1 faint in the previous year, and a
 diagnosis of vasovagal syncope based on the Calgary Syncope Symptom Score. The primary
 outcome measure will be the time to syncope or presyncope with a trough rate-pressure product
 <7000 mm Hg/min. The primary analysis will be performed on an intention-to-treat basis.
 Secondary analyses will include modelled estimations of systemic vascular resistance and
 stroke volume, based on arterial waveform and blood pressure. This will permit us to address
 whether NET inhibition prevents the vasovagal reflex by maintenance of cardiac preload or
 maintenance of systemic vascular resistance. The investigators will randomize 64 patients in
 a double blind acute phase 2 study to either Atomoxetine 40mg PO bid x 2 doses or matching
 placebo.

 A sample size of 56 syncope patients would 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 we will inflate the sample by 15% to 64
 subjects. A formal, blinded mid-way safety and efficacy analysis will be performed with a
 p<0.01 stopping rule for efficacy. The sample size will be inflated to 74 to account for
 spending power on the interim analysis. This will provide 85% power to detect an 80% relative
 risk reduction.

 Relevance: This will be the first adequately powered study of the ability of atomoxetine to
 prevent the vasovagal reflex. It will also provide insight as to whether norepinephrine
 transport inhibition functions here to maintain venous return or increase systemic vascular
 resistance. If positive, the study will provide a strong biomedical rationale and preliminary
 clinical results leading to a randomized clinical trial of atomoxetine for the prevention of
 vasovagal syncope.
Inclusion Criteria:

 -  1 or more syncopal spells in the year preceding enrolment

 -  More than -2 points on the Calgary Syncope Symptom Score

 -  Age ≥18 years with informed consent

 Exclusion Criteria:

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

 -  Inability to give informed consent

 -  important valvular, coronary, myocardial or conduction abnormality or significant
 arrhythmia.

 -  hypertrophic cardiomyopathy

 -  a permanent pacemaker

 -  a seizure disorder

 -  hypertension defined as >150/90 mm Hg

 -  pregnancy

 -  glaucoma

 -  medications with known effects on blood pressure

 -  Known hypersensitivity to atomoxetine and derivatives