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)

Background— In the Third International Study on Syncope of Uncertain Etiology (ISSUE-3), cardiac pacing was effective in reducing recurrence of syncope in patients with presumed neurally mediated syncope (NMS) and documented asystole but syncope still recurred in 25% of them at 2 years. We have investigated the role of tilt testing (TT) in predicting recurrences. Methods and Results— In 136 patients enrolled in the ISSUE-3, TT was positive in 76 and negative in 60. An asystolic response predicted a similar asystolic form during implantable loop recorder monitoring, with a positive predictive value of 86%. The corresponding values were 48% in patients with non–asystolic TT and 58% in patients with negative TT ( P =0.001 versus asystolic TT). Fifty-two patients (26 TT+ and 26 TT–) with asystolic neurally mediated syncope 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 non–asystolic responses during TT ( P =0.53). Conclusions— Cardiac pacing was effective in neurally mediated syncope 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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01463358.