Background: About 25% of the population suffers from syncope, and 8% of the population experience recurrent episodes, which can cause physical injury and psychological morbidity.
Methods: We performed a meta-analysis of randomised trials of pacing, pharmacological and physical interventions for syncope. We assessed the effect of these therapeutic interventions on clinical syncope recurrence. We stratified the trials by whether the patient was blinded to the allocation arm.
Results: There were 49 eligible randomised clinical trials: 22 of pacing, 19 of pharmacological interventions and 8 of physical interventions.
Blinded trials were neutral for conventional pacing (relative risk [RR] of recurrent syncope 0.81, 95% CI 0.60–1.1; p=0.45) but favourable for closed-loop-stimulation (CLS) pacing (RR of recurrent syncope 0.21, 95% CI 0.12–0.34; p<0.001). Assessing non-placebo-controlled trials instead, virtually every category of therapy reported significant benefit. Three categories of therapy have been trialled with and without placebo control: the unblinded studies showed significantly different results from their blinded counterparts (dual chamber pacing p=0.017, beta blockers p=0.024, midodrine p=0.006).
Conclusion: The placebo effect of device implantation is more powerful than previously assumed. Unblinded randomised trials of conventional dual chamber pacing appeared to show remarkable efficacy. However, with placebo control, this efficacy is revealed to have been the placebo effect. Under blinded conditions, CLS pacing reduces risk of syncope recurrence by ~75%, whereas conventional pacing does not. Selective serotonin reuptake inhibitors and midodrine also show significant efficacy under blinded conditions. Without blinding, trials consistently show artefactually larger benefits. Therefore, all future trials of treatment for syncope should blind patients to the allocation arm.