Atomoxetine for Fainting (Vasovagal Syncope)
(POST7 Trial)
Trial Summary
What is the purpose of this trial?
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.
Will I have to stop taking my current medications?
Yes, you will need to stop taking certain medications before participating in this trial. Specifically, you cannot be on β-blockers, bupropion, α1-adrenergic agonists or antagonists, tricyclic antidepressants, serotonin reuptake inhibitors, scopolamine, theophylline, or fludrocortisone.
Is atomoxetine generally safe for humans?
Atomoxetine, also known as Strattera, is generally used for ADHD and can cause side effects like stomach issues and, less commonly, heart-related problems such as fainting, fast heartbeat, and low blood pressure. Overdose can lead to seizures and mild heart issues, and there are rare reports of heart attacks.12345
How is the drug atomoxetine unique for treating vasovagal syncope?
Atomoxetine is unique for treating vasovagal syncope because it is a selective norepinephrine reuptake inhibitor (NET inhibitor) that increases sympathetic tone, which may help prevent fainting episodes. Unlike other treatments, it is being explored for its potential to reduce syncope in patients without coexisting conditions like hypertension or heart failure.12678
Eligibility Criteria
This trial is for adults who've fainted at least twice in the past year due to vasovagal syncope, as defined by American College of Cardiology Guidelines. Participants must be over 18 and score at least -2 on a specific Syncope Symptom Score. Those with uncontrolled blood pressure or thyroid issues, pacemakers, certain eye conditions, or taking conflicting medications cannot join.Inclusion Criteria
Exclusion Criteria
Timeline
Screening
Participants are screened for eligibility to participate in the trial
Treatment
Participants are randomized to receive either atomoxetine 40 mg twice daily or matching placebo in a double-blind, crossover trial
Follow-up
Participants are monitored for safety and effectiveness after treatment
Extension
Optional open-label extension for continued monitoring and assessment of long-term effects
Treatment Details
Interventions
- Atomoxetine Hydrochloride
Atomoxetine Hydrochloride is already approved in United States, European Union, Canada for the following indications:
- Attention Deficit Hyperactivity Disorder (ADHD)
- Attention Deficit Hyperactivity Disorder (ADHD)
- Attention Deficit Hyperactivity Disorder (ADHD)
Find a Clinic Near You
Who Is Running the Clinical Trial?
University of Calgary
Lead Sponsor