Midodrine for the Prevention of Vasovagal Syncope

A Systematic Review and Meta-analysis

Lucy Y. Lei; Satish R. Raj; Robert S. Sheldon


Europace. 2022;24(7):1171-1178. 

In This Article

Abstract and Introduction


Aims: Vasovagal syncope (VVS) is a common clinical condition that lacks effective medical therapies despite being associated with significant morbidity. Current guidelines suggest that midodrine, a prodrug for an α1-adrenergic receptor agonist, might suppress VVS but supporting studies have utilized heterogeneous methods and yielded inconsistent results. To evaluate the efficacy of midodrine to prevent syncope in patients with recurrent VVS by conducting a systematic review and meta-analysis of published studies.

Methods and results: Relevant randomized controlled trials were identified from the MEDLINE, Embase, CENTRAL, and CINAHL databases without language restriction from inception to June 2021. All studies were conducted in clinical syncope populations and compared the benefit of midodrine vs. placebo or non-pharmacological standard care. Weighted relative risks (RRs) were estimated using random effects meta-analysis techniques. Seven studies (n = 315) met inclusion criteria. Patients were 33 ± 17 years of age and 31% male. Midodrine was found to substantially reduce the likelihood of positive head-up-tilt (HUT) test outcomes [RR = 0.37 (0.23–0.59), P < 0.001]. In contrast, the pooled results of single- and double-blind clinical trials (I 2 = 54%) suggested a more modest benefit from midodrine for the prevention of clinical syncope [RR = 0.51 (0.33–0.79), P = 0.003]. The two rigorous double-blind, randomized, placebo-controlled clinical trials included 179 VVS patients with minimal between-study heterogeneity (I 2 = 0%) and reported a risk reduction with midodrine [RR = 0.71 (0.53–0.95), P = 0.02].

Conclusions: Midodrine is effective in preventing syncope induced by HUT testing and less, but still significant, RR reduction in randomized, double-blinded clinical trials.


Syncope is a common clinical condition with a lifetime cumulative incidence of at least 35% and a high rate of recurrence following initial presentation.[1] Nearly 60% of all syncope cases are attributable to vasovagal syncope (VVS),[2,3] which is due to hypotension often caused by sympathetic withdrawal. Although syncope is generally benign, recurrent VVS is associated with frequent injuries,[4,5] psychological morbidities, and impaired patient quality of life.[6]

To date, there remain few effective medical therapies for the treatment of recurrent VVS current consensus guidelines provide weak recommendations for the use of beta-blockers, fludrocortisone, and midodrine for the management of recurrent VVS based on modest data supporting their effectiveness in selected patient populations.[2,3,7] This systematic review focuses on midodrine and provides an update on the systematic review performed by Izcovich et al.[8] in 2014, including the results of a recent, positive, randomized clinical trial.[9] Our review stresses studies with adequate blinding and clinical outcomes.

Midodrine is a selective α1-adrenergic receptor agonist pro-drug that is thought to enhance peripheral vascular tone and reduce venous pooling, thereby preventing syncope.[3] However, prior studies assessing the benefit of midodrine for syncope prevention have used heterogeneous methods in clinically disparate populations, providing inconsistent results and lower levels of evidence.[9–15] Therefore, the aim of this study was to evaluate the effectiveness of midodrine for the prevention of syncope in patients with recurrent VVS through a comprehensive systematic review and meta-analysis of published studies, with special consideration of the effect of study design on apparent drug benefit.