The Benefit of Pacemaker Therapy in Patients With Presumed Neurally-Mediated Syncope and Documented Asystole Is Greater When Tilt Test Is Negative: An Analysis From the Third International Study on Syncope of Uncertain Etiology (ISSUE-3)

Study Questions:

How well did tilt testing (TT) perform in predicting recurrences of neurally-mediated syncope (NMS) in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3)?


The current study was a subgroup analysis of ISSUE-3, a multicenter, prospective, randomized study. The study enrolled patients >40 years old with frequent presumably NMS. All patients received an implantable loop recorder (ILR), and those with documentation of syncope with ≥3 seconds of asystole or ≥6 seconds of asystole without syncope were eligible to undergo pacemaker implantation. Tilt test (TT) was recommended, but its result was not considered in management decisions. The current analysis focuses on those patients who had TT performed.


In 136 patients enrolled in the ISSUE-3 study, TT was positive in 76 and negative in 60 patients. An asystolic response predicted a similar asystolic form during ILR monitoring, with a positive predictive value of 86%. The corresponding values were 48% in patients with nonasystolic TT and 58% in patients with negative TT (p = 0.001 vs. asystolic TT). Fifty-two patients (26 TT+ and 26 TT–) with asystolic NMS received a pacemaker. Syncope recurred in 8 TT+ and in 1 TT– patients. At 21 months, the estimated product-limit syncope recurrence rates were 55% and 5%, respectively (p = 0.004). The TT+ recurrence rate was similar to that seen in 45 untreated patients (control group), which was 64% (p = 0.75). The recurrence rate was similar between 14 patients with asystolic and 12 with nonasystolic responses during tilt testing (p = 0.53).


Cardiac pacing was very effective in NMS patients with documented asystolic episodes in whom TT was negative; conversely, there was insufficient evidence of efficacy from this data set in patients with a positive TT, even when spontaneous asystole was documented. Present observations are unexpected, and need to be confirmed by other studies.


The surprising result of this study may be due to patient selection. The ISSUE-3 population was older, had atypical presentation, and was enrolled based on the presence of a spontaneous asystolic event on ILR. Prior studies of NMS enrolled patients with TT+.

Clinical Topics: Arrhythmias and Clinical EP, Implantable Devices, SCD/Ventricular Arrhythmias

Keywords: Recurrence, Patient Selection, Neuroleptic Malignant Syndrome, Tilt-Table Test, Syncope, Pacemaker, Artificial, Heart Arrest, Triazoles

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