Project rationale: Vasovagal syncope (VVS) affects up to 50% of people, and recurrent syncope
markedly reduces quality of life. We recently reported that it is frequently associated with
injury and not surprisingly with clinical anxiety. Although conservative measures help many
patients there remain many who require more care. CIHR-funded studies have shown that
fludrocortisone and midodrine are effective but cannot be used in patients with
contraindications such as hypertension and heart failure. Pacemakers are partially effective
in older patients, but this is established only in the small minority with proven asystole.
There remains a need for a simple, once-daily medication with few contraindications that can
be used as first-line therapy for most patients with recurrent vasovagal syncope.
Preliminary Studies: Norepinephrine transport (NET) inhibitors show promise as a novel
treatment. Three (reboxetine, sibutramine, and atomoxetine) all prevent vasovagal syncope in
healthy subjects and vasovagal syncope patients on tilt tests. Atomoxetine, approved to treat
attention deficit disorder, is a highly selective NET inhibitor. We reported a
proof-of-principle, randomized, placebo-controlled trial of the efficacy of atomoxetine to
prevent vasovagal syncope on tilt table tests. Patients underwent tilt testing after
receiving either atomoxetine 40 mg or placebo. Fewer VVS patients fainted with atomoxetine
than placebo (10/29 vs. 19/27; odds ratio 0.22, p < 0.01). Our meta-analysis of the effects
of NET inhibition on the vasovagal reflex induced by tilt tests was highly positive. A
pre-post study showed that sibutramine reduced syncope frequency in highly symptomatic and
drug-refractory patients. A similar pre-post study showed that atomoxetine also reduces
syncope frequency about 85% in patients with frequent and drug-intolerant or drug-resistant
vasovagal syncope. Therefore,NET inhibition by atomoxetine merits assessment based on
positive proof-of-principle studies, an apparent class effect, and two open-label pre-post
studies. These results provide the rationale for a formal randomized, placebo-controlled,
crossover trial of atomoxetine in moderate-to-high risk patients with VVS.
Hypothesis: We will test the hypothesis that oral atomoxetine prevents syncope in patients
with recurrent VVS.
The Study: Patients will be included based on a positive Calgary Syncope Symptom Score and a
history of at least 2 faints in the previous year. Eligible patients will be randomized to
atomoxetine 40 mg po twice daily or matching placebo in a randomized, placebo-controlled,
parallel design, double-blind, crossover trial. Each arm will last 6 months with a 1-week
washout period. The primary outcome measure will be the proportion of patients with at least
1 syncope recurrence. The study will be powered to detect a beneficial odds ratio of 0.5,
selected on the basis of the control outcome rates in 2 similarly designed, previous studies
and international expert requirements for effect size. A sample size of 180 subjects will
provide 85% power of detecting a difference between the arms at p<0.05. We will assess the
effects of atomoxetine on quality of life, anxiety, injury, and the cost-effectiveness of
atomoxetine treatment, and the effects of genetic factors on outcomes.
Substudies : The quality of life scales will be the SF-36 and the Euroqol EQ5D, which will
also be used as the health utility index for the economic studies. The depression and anxiety
scales will be the Hospital and Anxiety Depression Score (HADS) and the General Anxiety
Disorder - 7 Score (GAD-7). Clinical anxiety is highly prevalent in patients with recurrent
syncope. Injury will be self-reported using our published definitions. The health economic
substudy will be from the health system perspective and will use Alberta administrative data.
DNA will be collected from spit acquired in the Oragene saliva self-collection kits, and an
initial candidate gene study might include alleles of CYP2D6, COMT, the serotonin (SLC6A4)
and norepinephrine (SLC6A2) reuptake transporters, and the 5HT1A and 5HT3 receptors.
Summary: Adults who faint recurrently are highly symptomatic. There are no therapies suitable
for most patients have withstood the test of randomized clinical trials. If successful,
atomoxetine will reduce syncope and improve quality of life.
