Clinical Autonomic Research

, Volume 22, Issue 6, pp 275–280 | Cite as

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

  • Satish R. RajEmail author
  • Peter D. Faris
  • Maureen McRae
  • Robert S. Sheldon
Research Article



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. A few 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 end point 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 end points 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.


POST 4 is registered with (NCT01456481).


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.


Vasovagal syncope Randomized clinical trial Quality of life 



This study was supported by a grant MOP-115124 from the Canadian Institutes of Health Research, Ottawa, Canada to RSS. AA Pharma (Vaughn, Ontario, Canada) provided the midodrine and placebo capsules.


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Satish R. Raj
    • 1
    Email author
  • Peter D. Faris
    • 2
  • Maureen McRae
    • 3
  • Robert S. Sheldon
    • 3
  1. 1.Division of Clinical Pharmacology, Departments of Medicine and PharmacologyVanderbilt UniversityNashvilleUSA
  2. 2.Alberta Health ServicesCalgaryCanada
  3. 3.Libin Cardiovascular Institute of AlbertaUniversity of CalgaryCalgaryCanada

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