STARS News & Events

New study provides “direct evidence” for effectiveness of midodrine for treating vasovagal syncope

A new study, published in the medical journal Annals of Internal Medicine, shows that midodrine, compared with placebo (i.e., a “fake” pill), significantly reduces episodes of syncope (aka fainting) in people with vasovagal (reflex) syncope. While previous studies have also indicated that midodrine may be beneficial for vasovagal syncope, the evidence that they provided was insufficient to definitively support the use of midodrine in this context.

Study authors Professor Robert Sheldon (University of Calgary, Calgary, Canada) and colleagues report that vasovagal syncope can be difficult to treat because “no current medications have high-quality evidence for effectiveness”. They add that midodrine “holds promise” because it could “prevent reduced cardiac output due to decreased preload, which is an early feature of the vasovagal reflex”. However, according to Sheldon et al, of the two randomised trials conducted before POST 4 began that looked at using midodrine for preventing clinical vasovagal syncope, one was small and assessed children and the other was not placebo-controlled. Therefore, they (along with other studies in this area) could not be classed as high-quality evidence — leading to weak recommendations in guidelines for syncope management.

To address the need for high-quality evidence, Sheldon et al conducted a double-blind randomised trial — in which neither the participants nor the investigators knew what treatment had been given — that compared the use of midodrine with that of placebo in people with vasovagal syncope. Of 133 participants (73% were female; mean age 32 years), 66 were in the midodrine group and 67 were in the placebo group. Prior to randomisation, they had a median of 21 syncope episodes over 14 years with a median frequency of 4.1 episodes. Both groups of participants received guideline-directed lifestyle advice (such as increased salt and fluid intake).

In the intention-to-treat analysis, participants assigned midodrine were significantly less likely to have a recurrence of syncope than those assigned placebo: 42% vs. 61%. “The number needed to treat to prevent one patient from having syncope was 5.3,” Sheldon et al state. They add midodrine was also associated with a significantly longer time to first recurrence of syncope compared with placebo (p=0.035). Furthermore, after a landmark dose-adjustment period of two weeks, the authors found that midodrine was associated with a 40% relative risk reduction of recurrent syncope that was statistically and clinically significant.

Summarising their findings, Sheldon et al state their study provides direct evidence for the effectiveness of midodrine for preventing recurrent vasovagal syncope in younger patients. “No previously published studies provided high-quality evidence for its clinical effectiveness… we designed this study to address the remaining gaps in our knowledge,” they explain.

In an accompanying commentary, Professor Michele Brignole notes: “Now that we have identified several effective therapies [for vasovagal syncope], we need to learn to best apply them to individual patients. It is time to move towards personalised mechanisms-specific medicine.”


For healthcare professionals:
Both Professor Sheldon and Professor Brignole will be speaking at the STARS Symposia at the Arrhythmia Alliance Virtual Heart Rhythm Congress 2021 (launching 3rd October). For more programme information and how to register, visit:

For patients
For more information about vasovagal syncope, click here to download the STARS Reflex Syncope (Vasovagal Syncope) here.


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