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............................................................................................................................................................................. dopaminergic drugs, is key in the prevention of recurrence of syncope. In a small randomized trial260 performed in 58 patients (mean age 74 ± 11 years) affected by vasodepressor reflex syncope diagnosed by tilt testing or CSM, who were taking on average 2.5 hypotensive drugs, discontinuation or reduction of the vasoactive therapy caused a reduction of the rate of the primary combined endpoint of syncope, presyncope, and adverse events from 50 to 19% (hazard ratio 0.37) compared with a control group who continued hypotensive therapy during a follow-up of 9 months. In the Systolic Blood Pressure Intervention Trial,261 patients at high cardiovascular risk who were already using antihypertensive drugs targeting a systolic BP of 120 mmHg had an approximately twofold risk of syncope vs. the control group targeting a systolic BP of 140 mmHg. In a short-term randomized trial262 conducted in 32 patients affected by CSS, withdrawal of vasodilator therapy reduced the magnitude of the vasodepressor reflex induced by CSM.

There is moderate evidence that discontinuation/reduction of hypotensive therapy targeting a systolic BP of 140 mmHg should be effective in reducing syncopal recurrences in patients with hypotensive susceptibility. Further research is likely to have an important impact on our confidence in the estimate.

5.2.3 Physical counter-pressure manoeuvres Isometric muscle contractions increase cardiac output and arterial BP during the phase of impending reflex syncope. Three clinical studies119,120,263 and one prospective multicentre randomized trial121 assessed the effectiveness of physical counter-pressure manoeuvres (PCM) of the legs or arms and showed that they allowed the patient to avoid or delay losing consciousness in most cases. In the Physical Counterpressure Manoeuvres Trial (PC-Trial),121 223 patients aged 38 ± 15 years with recurrent reflex syncope and recognizable prodromal symptoms were randomized to receive standardized conventional therapy alone or conventional therapy plus training in PCM. Actuarial recurrence-free survival was better in the PCM group (log-rank P=0.018), resulting in a relative risk reduction of 39% (95% CI 11–53). No adverse events were reported. A limitation of this treatment is that it cannot be used in patients with short or absent prodrome and that PCM are less effective in patients older than 60 years.264 An instruction sheet on how to perform PCM can be found in the Web Practical Instructions section 9.2.

There is moderate evidence that PCM is effective in reducing syncopal recurrences in patients <60 years old with longlasting recognizable prodromal symptoms.

5.2.4 Tilt training In highly motivated young patients with recurrent vasovagal symptoms triggered by orthostatic stress, the prescription of progressively prolonged periods of enforced upright posture (so-called tilt training) has been proposed to reduce syncope recurrence.265 While some studies suggested modest benefit with outpatient tilt training,266,267 most controlled trials reported no significant effect.268–272 Moreover, this treatment is hampered by the low compliance of patients in continuing the training programme for a long period. There is sufficient evidence from multiple trials that tilt training has little efficacy in reducing recurrence of syncope in young patients with long-lasting recognizable prodromal symptoms. Further research is unlikely to have an important impact on our confidence in the estimate.

5.2.5 Pharmacological therapy Pharmacological therapy may be considered in patients who have recurrent syncope despite education and lifestyle modifications including training in PCM. Many drugs have been tested in the treatment of reflex syncope, for the most part with disappointing results. While results have been satisfactory in uncontrolled trials or shortterm controlled trials, several long-term placebo-controlled prospective trials have not shown a benefit of the active drug over placebo, with some exceptions.

5.2.5.1 Fludrocortisone Fludrocortisone, by increasing renal sodium reabsorption and expanding plasma volume, may counteract the physiological cascade leading to the orthostatic vasovagal reflex.273 The mechanism of action can be compared with that of saline infusion, which has also proved effective in acute tilt test studies.274 The Prevention of Syncope Trial (POST) 2275 enrolled 210 young (median age 30 years) patients with low–normal values of arterial BP and without comorbidities, and randomized them to receive fludrocortisone (titrated at a dosage of 0.05–0.2 mg once per day) or placebo. The primary endpoint showed only a marginal non-significant reduction in syncope in the fludrocortisone group compared with the placebo group (hazard ratio 0.69, 95% CI 0.46–1.03; P=0.069), which became more significant when the analysis was restricted to patients who achieved 0.2 mg/day dose stabilization at 2 weeks. The clinical benefit of fludrocortisone therapy was modest: at 12 months, 44% of patients in the fludrocortisone arm continued to suffer syncope, a rate only slightly lower than the 60.5% rate observed in the placebo arm. In the meantime, a similar number of patients discontinued fludrocortisone therapy owing to side effects, thus equating the benefit/risk ratio. Fludrocortisone should not be used in patients with hypertension or heart failure. Fludrocortisone was ineffective in a small randomized double-blind trial in children.276

There is moderate evidence that fludrocortisone may be effective in reducing syncopal recurrences in young patients with lownormal values of arterial BP and without comorbidities. Further research is likely to have an important impact on our confidence in the estimate of effect.

5.2.5.2 Alpha-agonists As failure to achieve proper vasoconstriction of the peripheral vessels is common in reflex syncope, alpha-agonist vasoconstrictors (etilefrine and midodrine) have been used. Etilefrine has been studied in a large randomized placebo-controlled double-blind trial.277 During follow-up, patients treated twice daily with etilefrine 25 mg or placebo showed no difference in the frequency of syncope or the time to recurrence. Midodrine [usually 2.5–10 mg, three times daily (t.i.d)] has proved effective in small studies but none satisfied the criteria of a pivotal clinical trial. A recent systematic review of these trials278 Downloaded from academic.oup.com/eurheartj/article/39/21/1883/4939241 by guest on 07 October 2026