Third International Study on Syncope of Uncertain Etiology - ISSUE 3


Data on permanent pacing in patients with neurally mediated syncope (NMS) have been discouraging. For example, in ISSUE-2, there was no impact of pacing in unselected patients with NMS. However, on subgroup analysis, patients with asystolic NMS did demonstrate a significant reduction in recurrent syncope with pacing. The current trial sought to systematically study if patients with NMS and documented asystole on implantable loop recording would benefit from permanent pacemaker (PPM) implantation or not.


PPM implantation would be superior to no PPM in patients with NMS and documented asystole.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥40 years
  • Neurally mediated syncope based on history
  • ≥3 syncopal events in the past 2 years
  • Presentation severe enough to warrant treatment
  • Documented asystole on implantable loop recorder monitoring

    Number of screened applicants: 511
    Number of enrollees: 77
    Duration of follow-up: 2 years
    Mean patient age: 63 years
    Percentage female: 54%


  • Nonsyncopal loss of consciousness
  • Symptomatic orthostatic hypotension
  • Cardiogenic syncope
  • Carotid sinus syncope

Primary Endpoints:

  • First recurrence of syncope

Drug/Procedures Used:

Patients with neurally mediated syncope underwent loop recorder implantation. Those with evidence of asystolic syncope ≥3 seconds or nonsyncopal asystole ≥6 seconds underwent PPM placement. Patients were then randomized to having the PPM turned on (DDD-RDR) or off (ODO).

Concomitant Medications:

Antihypertensive (39%), psychiatric (8%)

Principal Findings:

A total of 77 patients were randomized, at 29 hospitals in nine countries, 38 to PPM on and 39 to PPM off. Baseline characteristics were fairly similar between the two arms. About 12% had evidence of structural heart disease. The median total number of events in these patients was seven, with approximately five in the past 2 years. Approximately 80% had evidence of asystole ≥3 seconds and syncope; the mean length of asystole was 11 seconds. Presentation was atypical in 56% of the patients, and about 8% presented with major injuries related to fainting (fractures, concussion, etc.). In patients in whom tilt-table testing was performed (85%), it was positive in only 58%.

The incidence of first syncope recurrence was significantly lower in the PPM on arm as compared with the PPM off arm at 24 months (25% vs. 57%, p = 0.039). This corresponded to a hazard ratio of 0.43 (95% confidence interval 0.19-0.96). Procedure-related complications were infrequent, with lead dislodgements in four patients and subclavian vein thrombosis in one patient.


The results of this trial indicate that dual-chamber permanent pacing is effective in reducing recurrence of syncope in patients ≥40 years with severe asystolic NMS. It also highlights the utility of an implantable loop recorder in these patients. Of note, only 9% of patients with NMS in this study actually qualified based on implantable loop recording. Further, symptoms had to be severe to warrant treatment—most patients with NMS have a benign/mild presentation.


Brignole M, Menozzi C, Moya A, et al., on behalf of the International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker Therapy in Patients With Neurally Mediated Syncope and Documented Asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): A Randomized Trial. Circulation 2012;125:2566-71.

Presented by Dr. Michele Brignole at ACC.12 & ACC-i2 with TCT, Chicago, IL, March 26, 2012.

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

Keywords: Follow-Up Studies, Syncope, Vasovagal, Thrombosis, Tilt-Table Test, Heart Arrest, Confidence Intervals, Subclavian Vein

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