PHARMACOLOGICAL NOREPINEPHRINE TRANSPORTER INHIBITION FOR THE PREVENTION OF VASOVAGAL SYNCOPE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Vasovagal syncope is a common clinical problem that significantly reduces quality of life yet lacks effective medical therapies. Pharmacological norepinephrine transporter (NET) inhibition increases sympathetic tone, leading to suggestions that it might be able to prevent hypotension and syncope. The objective of this systematic review and meta-analysis was to evaluate the ability of selective NET inhibitors – reboxetine, sibutramine, and atomoxetine – to prevent syncope in healthy subjects and patients with recurrent VVS. We conducted a systematic search and meta-analysis of studies in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL without language restriction from database inception to March 2019. We included all randomized controlled trials that compared the effect of selective NET inhibitors versus placebo in healthy and VVS populations. Studies were required to report a dichotomous outcome of syncope or a predefined syncope surrogate. Four studies (101 subjects) met criteria for inclusion. The mean study size was 25 (range 11-56) participants. Three studies tested the ability of NET inhibition to prevent induced syncope induced by tilt-table testing in healthy subjects (I2 = 0%). NET inhibition drastically reduced the likelihood of positive test outcomes (Relative Risk (RR) = 0.14; 95% CI: 0.04-0.48; p = 0.002). One study (the Prevention of Syncope Trial 6) examined the efficacy of NET inhibition in patients with recurrent vasovagal syncope and found a similar effect of atomoxetine in preventing syncope induced by tilt-table testing (RR = 0.49; 95% CI: 0.28-0.86; p = 0.01). NET inhibition is very effective at the prevention of syncope induced by tilt-table testing in both healthy participants and patients with recurrent vasovagal syncope. Pharmacological NET inhibition holds promise as a potential treatment for recurrent syncope given the 51% relative risk reduction in vasovagal syncope patients. A formal randomized controlled clinical trial is necessary to properly assess the clinical relevance of NET inhibition as an effective treatment for vasovagal syncope.