Rationale for the prevention of syncope trial IV: assessment of midodrine

Abstract

Background Vasovagal syncope is a common problem associated with a poor quality of life, which improves when the frequency of syncope is reduced. Effective pharmacological therapies for vasovagal syncope have been elusive. Midodrine is a pro-drug whose primary metabolite is an alpha-1 adrenoreceptor agonist. Small studies have suggested that it may be beneficial in syncope, but all have had significant methodological limitations. A placebo-controlled clinical trial of midodrine for the prevention of vasovagal syncope is needed. Structure of study The Prevention of Syncope Trial IV (POST 4) is a multicenter, international, randomized, placebo-controlled study of midodrine in the prevention of vasovagal syncope. The primary endpoint is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive midodrine 10–30 mg/day or matching placebo, and followed for 1 year. Secondary endpoints include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention to treat approach, with a secondary on-treatment analysis. Power calculations A total sample size of 112, split equally between the two groups achieves 85% power to detect a 50% relative risk reduction when the event rates are 55% and 27.5% in the placebo and midodrine arms. Allowing for 20% dropout, we propose to enroll 140 patients. Registration POST 4 is registered with www.clinicaltrials.gov (NCT01456481). Implications This study will be the first adequately powered trial to determine whether midodrine is effective in preventing vasovagal syncope. If it is effective, then midodrine may become the first line pharmacological therapy for this condition.

Age-Dependent Effect of β-Blockers in Preventing Vasovagal Syncope

“…It is the subject of POST 4, a randomized placebo-controlled study of midodrine in moderately severe vasovagal syncope. 23 Fludrocortisone was recently assessed in POST 2, a randomized placebo-controlled study of fludrocortisone in moderately severe vasovagal syncope, 24 and also should not be used in patients with hypertension. Permanent pacing is effective in highly selected patients with documented asystole during clinical syncope.…”

Syncope in the Older Person

“…Midodrine has been shown to be of benefit in small randomized studies and is the subject of a larger randomized trial. 60 However, our own audit data show that up to 25% of older patients may discontinue midodrine because of its side effect profile (which may include urinary frequency, urgency, piloerection, and worsening of angina).…”

Expanding the Evidence Base in the Pharmacological Management of Vasovagal Syncope – the Next Post

“…Gratifyingly, there are current trials examining the effectiveness of other medications. Prevention of Syncope Trial IV is recruiting symptomatic patients with vasovagal syncope to assess whether midodrine is effective at reducing syncope recurrence 12 and POST V is assessing metoprolol in patients over the age of 42 compared with younger patients. In an area of clinical practice with a sparse evidence base, these ongoing studies have the potential to provide greater clarity for clinicians seeking to appropriately manage this common condition in younger patients, but not yet in the older age group.…”