The study did not meet its primary objective of demonstrating that fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652; Prevention of Syncope Trial 2 [POST 2]; NCT00118482).

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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.

Circulating plasma endothelin-1 and copeptin levels are not significantly different among populations of controls, syncope patients and seizure patients.