Comparing Physical, Pharmacological, Pacemaker, and Cardioneuroablation Therapies for Patients with Vasovagal Syncope: A systematic review and network meta-analysis

Background: Vasovagal syncope (VVS) represents the most frequent syncope subtype, but evidence comparing treatment strategies remains limited. This network meta-analysis (NMA) evaluates physical, pharmacological, pacemaker, and cardioneuroablation (CNA) therapies for VVS. Methods: We conducted a Bayesian NMA of randomized controlled trials (RCTs) from PubMed, Embase, and Web of Science. The primary outcome was spontaneous syncope recurrence, and the secondary outcome was head-up tilt test (HUTT) positivity. Network geometry and treatment rankings were evaluated using Surface Under the Cumulative Ranking values. Results: A total of 49 RCTs involving 2,798 patients assigned to various treatments were included. For spontaneous syncope recurrence, CNA OR = 0.077, 95% CrI (0.015, 0.403), pacing OR = 0.075, 95% CrI (0.023, 0.22), pharmacological OR = 0.33, 95% CrI (0.11, 0.94), and physical OR = 0.27, 95% CrI (0.13, 0.57) therapies were all superior to conventional therapy. Regarding HUTT outcomes, only pharmacological OR = 5.5, 95% CrI (2.6, 12.0) and physical OR = 12, 95% CrI (2.9, 50.0) therapies showed significant differences compared with placebo. Subgroup analysis identified dual-chamber pacing with closed-loop stimulation (DDD-CLS) as the highest-ranked therapy. Midodrine was the superior pharmacological option, and selective serotonin reuptake inhibitors demonstrated efficacy. Conclusions: This NMA supports a stratified management approach for VVS. Physical and conventional therapies should be first-line. DDD-CLS pacing shows superior efficacy for cardioinhibitory VVS, while midodrine is the preferred pharmacological option. Although CNA demonstrates promise, it is constrained by limited direct evidence and should be considered hypothesis-generating, underscoring the need for head-to-head RCTs with long-term follow-up.