First-line pharmacological treatment of vasovagal syncope based on syndrome phenotype
Authors: Flevari P , Leftheriotis D , Kotsialou Z , Tzanni M , Deftereos S , Filippatos G 
Published: May 2024

Abstract

Background/Introduction
The pharmacological treatment of recurrent vasovagal syncope (VVS) remains suboptimal. A significant proportion of patients exhibit a specific, stress-related personality trait, defined as anxiety sensitivity; fluoxetine treatment seems more effective than placebo in initial studies, underpinning the importance of central mechanisms in VVS pathophysiology. In addition, midodrine is a proposed treatment for the hypotensive VVS phenotype (class IIb ESC indication), implying that peripheral mechanisms may be more important in the hypotensive VVS phenotype.

Purpose
The purpose of this study was 2-fold: a) to classify recurrent VVS episodes based on history, initial examination (including anxiety sensitivity questionnaire results) and head-up tilt testing into i) central type, ii) peripheral type, and b) to study the effect of fluoxetine in patients with recurrent central-type syncope as well as the effect of midodrine in patients with peripheral-type syncope.

Methods
Sixty-eight consecutive patients with at least 2 VVS episodes during the preceding 6 months and a positive head-up tilt test were studied, in a 2:1 randomized, single-blind, placebo-controlled way. They were initially classified into i) patients with central-type VVS, and ii) those with peripheral-type VVS based on history, clinical examination, tilt test characteristics, as well as a positive or negative 16-item anxiety sensitivity screening questionnaire. The first group (n=33) was randomized to fluoxetine vs placebo, while the second group (n=31) to midodrine vs placebo. During 2 years of follow-up, and after a 1-month blanking period, we assessed i) syncope/presyncope-free time in patients receiving fluoxetine (or midodrine) vs similar-type patients assigned to placebo treatment, ii) total number of patients who experienced syncope or presyncope between the respective groups.

Results
Fluoxetine vs placebo. In the intention-to-treat analysis the fluoxetine group exhibited more syncope-free time (14% vs 48%, p &lt;0.05) and similar results were observed regarding presyncope (22% vs 57%, p &lt;0.05). A significant difference was also observed between the two groups regarding the total number of patients who experienced syncope or presyncope during follow-up.
Midodrine vs placebo. Midodrine was more effective than placebo regarding presyncope (presyncope-free time 19% vs 45%, p&lt;0.05), while a non-significant difference was observed regarding syncope. However, a significant difference was observed between the two groups regarding the total number of patients who experienced syncope or presyncope during follow-up (p&lt;0.05).

Conclusions
Fluoxetine or midodrine seem superior to placebo as a first-line pharmacological treatment for recurrent VVS and a central or peripheral phenotype, respectively. Each substance may be an effective first-line pharmacological treatment for patients specifically selected by a simple, initial clinical assessment of VVS phenotype.