International study on syncope of uncertain aetiology 3 (ISSUE 3): pacemaker therapy for patients with asystolic neurally-mediated syncope: rationale and study design

Aim To assess the effectiveness of pacing therapy for preventing syncope recurrence in patients with a high probability of cardio-inhibitory neurally-mediated syncope (NMS). Methods Study design: Multi-centre, prospective, double-blind, randomized placebo-controlled study. Inclusion criteria: Eligible patients are at least 40 years of age and have suffered, in the prior 2 years, >= 3 syncope episodes of suspected NMS (with the exception of carotid sinus syndrome), which is considered by the attending physician to have a severe clinical presentation requiring treatment initiation. Patients with positive and negative tilt testing are included. Exclusion criteria: Patients with one or more of the following are excluded: carotid sinus syndrome; suspected or definite heart disease and high likelihood of cardiac syncope; symptomatic orthostatic hypotension diagnosed by standing blood pressure measurement; loss of consciousness different from syncope (e.g. epilepsy, psychiatric, metabolic, drop-attack, TIA, intoxication, cataplexy); subclavian steal syndrome. Study protocol: Eligible patients receive an Implantable Loop Recorder and are followed tilt the first documented syncopal recurrence or a significant asystolic event. Those patients who have an asystolic pause (sinus arrest or AV block) > 6 s or a syncopal asystolic pause >= 3 s receive a dual-chamber pacemaker implantation and are randomized to active therapy (Pm ON) or to placebo therapy (Pm OFF). End-points: Primary end-point is the first syncope recurrence after pacemaker implant. Sample size and duration: A maximum of 710 patients are to be enrolled during an anticipated period of 2 years to allow randomization of 60 patients in the Pm ON arm and 60 in the Pm OFF arm (total 120).