Therapeutic options for syncope: a meta-analysis of trials with and without placebo control

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: None. BACKGROUND: 8% of the population suffer recurrent episodes of syncope which can cause physical injury and psychological morbidity. The extent to which therapeutic options effectively reduce syncope recurrence beyond placebo remain unclear. METHODS: We performed a meta-analysis of randomised trials including pharmacological, cardiac pacing and physical interventions for syncope. We assessed the effect of these therapeutic interventions on clinical syncope recurrence. We stratified the trials by use of placebo control. RESULTS: There were 50 eligible trials: 22 pacing, 19 pharmacological and 9 of physical interventions including 3,975 patients. Trials assessing syncope recurrence with placebo control were neutral for Beta-Blockers (RR 1.11, 95% CI 0.85 to 1.45, p=0.36), Fludrocortisone, (RR 0.83, 95% CI: 0.63 to 1.11 p=0.83) and conventional dual-chamber pacing (RR 0.81, 95% CI 0.61 to 1.09 p=0.287). However, they were favourable for Selective Serotonin Reuptake Inhibitors [SSRIs] (RR 0.40, 95% CI 0.25 to 0.63 p<0.001), Midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and Closed-Loop-Stimulation (CLS) pacing (RR 0.21, 95% CI 0.12 to 0.34, p < 0.001). Non-placebo-controlled trials reported significant benefit for every category of therapy including conventional dual-chamber pacing, medicines (Beta-Blockers, Midodrine and Oral rehydration salts) and physical interventions including tilt-training. Three categories of therapy have been trialled with and without placebo control: the non-placebo-controlled studies showed significantly different results from their placebo-controlled counterparts (beta-blockers p=0.024, midodrine p=0.006, dual-chamber pacing p=0.017) (figure 2). CONCLUSION: Under placebo-controlled conditions, CLS pacing reduces risk of syncope recurrence by ~75%, whereas conventional pacing does not. SSRIs and midodrine also show significant efficacy under placebo-controlled conditions. Without placebo control, trials consistently show artefactually larger benefits. Future non-placebo-controlled trials for syncope should not be conducted. [Figure: see text] [Figure: see text]