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............................................................................................................................................................................. showed that the confidence in estimates was moderate because of imprecision and publication bias. The most frequent side effects that led to discontinuation of midodrine were supine hypertension, pilomotor reactions, and urinary problems (urinary retention, hesitancy, or urgency). The major limitation of midodrine is frequent dosing, which limits long-term compliance. Overall, these data suggest that chronic pharmacological treatment with alpha-agonists alone may be of little use in reflex syncope and that long-term treatment cannot be advised for occasional symptoms.

There are contrasting results from multiple trials that alphaagonists may be effective in reducing syncopal recurrences in patients with the orthostatic form of VVS. Further research is likely to have an important impact on our confidence in the estimate.

5.2.5.3 Beta-blockers Beta-blockers have been presumed to lessen the degree of ventricular mechanoreceptor activation owing to their negative inotropic effect in reflex syncope. This theory has not been supported by the outcome of clinical trials. Beta-blockers failed to be effective in VVS in two randomized double-blind controlled trials.279,280 A rationale for the use of beta-blockers in other forms of neutrally-mediated syncope is lacking. It should be emphasized that beta-blockers may enhance bradycardia in CSS.

There is sufficient evidence from multiple trials that betablockers are not appropriate in reducing syncopal recurrences. Desirable and undesirable effects are closely balanced.

5.2.5.4 Other drugs Paroxetine, a selective serotonin reuptake inhibitor, was effective in one placebo-controlled trial, which included highly symptomatic patients from one institution.281 This finding has not been confirmed in other studies and has no experimental support. Conversely, human studies with different subtypes of serotonin-receptor antagonists demonstrated a decreased tolerance to tilt.1,282 In a small randomized trial, benzodiazepine was as effective as metoprolol.283 A somatostatin analogue (octreotide)284 was used in a few patients affected by orthostatic intolerance and its effect cannot be properly evaluated.

5.2.5.5 Emerging new therapies in specific subgroups Low-adenosine phenotype. In a series of case reports, theophylline appeared effective in patients with recurrent sudden onset (pre)syncope who presented with the common biological characteristic of low circulating adenosine levels.285,286 Theophylline is a non-selective adenosine receptor antagonist that is potentially effective when adenosine is suspected to be involved in the mechanism of syncope. An intra-patient comparison between a period with and a period without theophylline therapy, with the support of prolonged ECG monitoring, showed that symptoms disappeared and the number of prolonged asystolic pauses was impressively reduced from a median of 1.11 per month during 13 months of no treatment to 0 per month during 20 months of theophylline treatment. Low-norepinephrine phenotype. A mismatch between sympathetic nerve activity and norepinephrine spillover is present in patients with orthostatic VVS.287 Norepinephrine transport inhibitors (reboxetine and sibutramine) lead to a selective increase in sympathetic tone during stress by inhibiting the reuptake of norepinephrine in sympathetic neuronal synapses. In double-blind, randomized, crossover fashion, reboxetine and sibutramine block or attenuate the vasovagal reflex during tilt testing.288 In an open-label prospective clinical study in seven very symptomatic patients who had not responded to any previous treatment, sibutramine achieved 94% suppression of syncopal episodes at 6 months.289

Ganglionic plexus ablation. Radiofrequency ablation of vagal ganglia located close to the sinus node and AV node was reported to abolish the vagal efferent output during VVS in some observational studies and case reports.290,291 However, owing to a weak rationale, small populations, weak documentation of follow-up results, procedural risks, and lack of control groups, the current evidence is insufficient to confirm the efficacy of vagal ganglia ablation.

5.2.6 Cardiac pacing Permanent pacemaker therapy may be effective if asystole is a dominant feature of reflex syncope. Establishing a relationship between symptoms and bradycardia should be the goal of the clinical evaluation of patients with syncope and a normal baseline ECG. The efficacy of pacing depends on the clinical setting. A comparative table of results in different settings is reported in the Supplementary Data Table 9. Figure 10 summarizes the recommended indication for pacing.

5.2.6.1 Evidence from trials in suspected or certain reflex syncope and electrocardiogram-documented asystole In two observational studies, cardiac pacing reduced syncope burden in patients with documented asystolic syncope by 92184 and 83%,200 but did not prevent all syncopal events. In the randomized double-blind Third International Study on Syncope of Uncertain Etiology (ISSUE)-3 trial,185 77 patients who had documentation, by means of ILR, of syncope with >_3-s asystole or >_6-s asystole without syncope were randomly assigned to receive either dual-chamber pacing with rate drop response or sensing only. During follow-up, the 2year estimated rate of syncope recurrence was 57% with pacemaker off and 25% with pacemaker on (log-rank P1⁄40.039). The risk of recurrence was reduced by 57%. In the ILR subgroup of the multicentre Syncope Unit Project (SUP) 2 study,292 the estimated rates of syncope recurrence with pacing were 11% at 1 year, 24% at 2 years, and 24% at 3 years, and were significantly lower than the corresponding rates observed in untreated control patients. The above evidence supports a class IIa recommendation

There is sufficient evidence that dual-chamber cardiac pacing should be considered to reduce recurrence of syncope when the correlation between symptoms and ECG is established in patients 40 years of age with the clinical features of those in the ISSUE studies.

5.2.6.2 Evidence from trials in patients with carotid sinus syndrome The evidence supporting the benefit of cardiac pacing in patients affected by cardioinhibitory CSS is limited to a few small controlled trials and retrospective observational studies. In a review293 including Downloaded from academic.oup.com/eurheartj/article/39/21/1883/4939241 by guest on 07 October 2026