Selective serotonin reuptake inhibitors for debilitating vasovagal syncope: looking for copper and finding gold

Funding Acknowledgements Type of funding sources: None. Background Despite its benign course, recurrent and unpredictable vasovagal syncope (VVS) may be disabling. Even though a non-pharmacological approach is generally regarded as first-line, a variety of drugs might also be of use. In this respect, the clinical value of selective serotonin reuptake inhibitors (SSRIs) is still a matter of debate. Purpose To perform a meta-analysis aimed at evaluating the extent to which SSRIs might reduce VVS recurrences in susceptible patients. Methods We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library and Google Scholar for prospective studies, addressing the effect of SSRIs on the recurrence rate of VVS in predisposed patients, published up until December 31st, 2020. In order to be included in the quantitative analysis, studies were required to encompass a positive head-up tilt table (HUTT) test for VVS diagnosis and a minimum patient follow-up of 6 months. The primary endpoint was recurrent spontaneous VVS, whereas secondary endpoints included the efficacy outcome of HUTT test-induced VVS and the safety outcome of drug discontinuation for adverse effects. Randomized controlled trials (RCTs) and studies including the most represented SSRI drug were further investigated separately, with respect to the primary endpoint. Study-specific odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random-effects model. Results 3 RCTs (2 placebo-controlled and 1 both placebo- and active-controlled) and 1 non-randomized prospective study, encompassing 222 and 127 patients, respectively, were regarded as eligible for quantitative evaluation. Patient follow-up ranged between 6 and 24 months. 131 patients were allocated to the SSRI arm, which featured fluoxetine as the most represented element (97 cases). The absolute number of events for each outcome may be reported as follows: primary efficacy endpoint, 57; secondary efficacy endpoint, 68 (only 2 RCTs reporting); secondary safety endpoint, 4 (only 2 RCTs reporting). In the main analysis, SSRIs were not found to significantly reduce VVS recurrence rate (OR 0.48, 95% CI 0.13-1.81, P 0.28, i2 74%). This null result was, however, single-handedly driven by the only non-randomized study included (OR 4.5, 95% CI 0.85-23.8). Likewise, fluoxetine was not able to significantly reduce the primary efficacy endpoint (OR 0.7, 95% CI 0.12-4.12, P 0.7, i2 78%), while SSRIs only numerically cut HUTT test-induced VVS events (OR 0.66, 95% CI 0.24-1.84, P 0.43, i2 59%). Nevertheless, when only RCTs are considered, SSRIs exerted a meaningful reduction in VVS recurrence rate, with no heterogeneity (OR 0.25, 95% CI 0.12-0.5, P 0.0001, i2 0%). In addition, drug discontinuation for safety reasons was rare and comparable between the SSRI and the placebo arms (OR 1.51, 95% CI 0.21-10.74, P 0.59, i2 0%). Conclusion SSRIs do represent one more safe pharmacological option to reduce syncope recurrences in patients with otherwise refractory VVS. Abstract Figure.