Midodrine and Fludrocortisone for Vasovagal Syncope
Midodrine and Fludrocortisone for Vasovagal Syncope
Syncope is a common condition which can disturb daily functions of the patients and impair
 their quality of lives. It contributes to 0.8 to 2.4% of the visits of emergency rooms.
 Noticeably, studies demonstrated that the lifetime prevalence of syncope is as high as 41%
 with a 13.5% recurrence rate.

 The cornerstone of the treatment of vasovagal syncope (VVS), the most common type of syncope,
 is lifestyle modifications and patient education to avoid potential triggers of syncope.
 These recommendations alleviate vasovagal spells in many patients; however, some patients
 experience life-disturbing vasovagal attacks despite compliance with these modifications.
 This fact underscores the importance of efficient pharmacological interventions as well.

 Currently, there is an ongoing controversy about the efficacy of midodrine and
 fludrocortisone as adjunct pharmacological interventions for the prevention of VVS. In the
 COMFORTS trial, we are going to evaluate the efficacy of midodrine, fludrocortisone, and
 lifestyle modifications for prevention of vasovagal attacks in patients with VVS.
Background: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle
 modifications; however, some patients incur life-disturbing attacks despite compliance with
 these treatments which underscores the importance of pharmacological interventions.

 Methods: In the COMFORTS trial, a multi-center randomized controlled trial, 1375 patients
 with VVS will be randomized into three parallel arms with a 2:2:1 ratio to receive midodrine,
 fludrocortisone, or just lifestyle modifications. All patients will receive recommendations
 for lifestyle modifications. In the pharmacological intervention arms, patients will receive
 5 mg of midodrine three times a day or 0.1 mg of fludrocortisone twice daily. In case of
 intolerance, the dosage will be cut by half. If the patient does not tolerate even the
 reduced dosage, the medication will be discontinued and the patient will be advised to use
 compression garments, practice tilt training exercises, or switch to the other medication.
 The patients will be followed on 3, 6, and 12 months after dose stabilization. Primary
 efficacy outcomes of the study is the time to the first syncopal episode. The secondary
 efficacy outcome are the recurrence rate of syncope, number of syncopal episodes and the
 quality of life of the patients which will be assessed by the 36-Item Short Form Survey
 questionnaire at the enrollment and 12 months after dose stabilization.
Inclusion Criteria:

 -  Vasovagal syncope as the cause of transient loss of consciousness (Clinical diagnosis
 AND Calgary Syncope Symptom Score ≥ -2; Head-up tilt test is not mandatory for
 diagnosis)

 -  ≥2 episodes of syncope during the last year

 -  Medication-naïve or have at least a 2-week washout period prior to randomization

 -  The capability of giving informed consent

 -  Signed written informed consent

 Exclusion Criteria:

 -  Other causes of transient loss of consciousness including orthostatic hypotension,
 postural tachycardia, carotid sinus hypersensitivity, or seizure

 -  Cardiac rhythm disorders including ventricular tachycardia, long QT syndrome, Brugada
 syndrome, arrhythmogenic right ventricular cardiomyopathy, complete heart block, and
 any conduction abnormality on electrocardiogram

 -  Severe valvular heart disease

 -  Hypertrophic cardiomyopathy

 -  Cardiac systolic dysfunction (ejection fraction≤40%)

 -  Obstructive coronary artery disease

 -  Hypertension

 -  Diabetes mellitus

 -  Cirrhosis

 -  Renal failure stage≥3

 -  Known intolerance or hypersensitivity to midodrine or fludrocortisone

 -  Urinary retention

 -  Pheochromocytoma

 -  Thyrotoxicosis

 -  Glaucoma

 -  Previous use of midodrine or fludrocortisone for treatment of VVS or another condition

 -  Pregnancy or breastfeeding