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ISSUE3: International Study on Syncope of Uncertain Etiology 3

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00359203
Recruitment Status : Completed
First Posted : August 1, 2006
Results First Posted : November 18, 2013
Last Update Posted : September 30, 2015
Information provided by (Responsible Party):
Medtronic Bakken Research Center

July 31, 2006
August 1, 2006
May 22, 2013
November 18, 2013
September 30, 2015
September 2006
September 2011   (Final data collection date for primary outcome measure)
Syncope Recurrence Rate [ Time Frame: 2 years ]
Intention to treat analysis of percentage of patients with syncope recurrence at 2 years follow-up after study arm assignement
Primary end-point: first syncope recurrence.
Complete list of historical versions of study NCT00359203 on Archive Site
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Secondary end-points: findings at the time of syncopal recurrence in the control group (reproducibility of responses) and predictive value of Tilt Testing.
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ISSUE3: International Study on Syncope of Uncertain Etiology 3
ISSUE3: International Study on Syncope of Uncertain Etiology 3 Pacemaker Therapy for Patients With Asystolic Neurally-mediated Syncope
ISSUE 3 is a multi-center, prospective, randomised controlled double-blind study aimed to assess the effectiveness of pacemaker therapy for prevention of asystolic neurally-mediated syncope.
In asystolic neurally-mediated syncope (NMS) documented by Implantable Loop recorder (ILR), ISSUE-2, an observational trial, showed that pacemaker was effective in reducing the 1-year first syncope recurrence rate from 33% rate before implant (ILR phase 1) to 5% rate after implant (phase 2). Moreover, the control non-asystolic group still continued to have a 41% recurrence rate after the first recurrence of syncope, thus supporting the conclusion that the reduction with pacemaker was due to the beneficial effect of pacemaker itself and not to other factors. However a formal controlled trial is needed to confirm these findings.
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Device: Dual chamber pacemeker
Other Names:
  • Any model of Medtronic pacemakers with Rate Drop Respons algorhythm:
  • K700, K900, Enpulse, Advisa, Versa
  • Placebo Comparator: Dual chamber pacemaker
    Dual chamber pacemaker programmed ODO (switched OFF)
    Intervention: Device: Dual chamber pacemeker
  • Active Comparator: Dual chamber pacemeker
    Medtronic dual chamber pacemaker programmed ON and with Rate Drope Response programmed ON
    Intervention: Device: Dual chamber pacemeker
Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD, Wieling W, Beiras X, Deharo JC, Russo V, Tomaino M, Sutton R; 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 May 29;125(21):2566-71. doi: 10.1161/CIRCULATIONAHA.111.082313. Epub 2012 May 7.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
November 2012
September 2011   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Suspected or certain neurally-mediated syncope, based on the Guidelines recently published by the Task Force on Syncope of the European Society of Cardiology 2,3 (Appendix 1);
  • More than 3 syncope episodes in the last 2 years;
  • Clinical presentation of syncope of sufficient severity requiring treatment initiation in the physician's and patient's judgement.
  • Age > 40 years.
  • Negative carotid sinus massage.
  • Patients accept to have an ILR implantation.

Exclusion criteria:

  • Carotid sinus hypersensitivity
  • Suspected or certain 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;
  • Psychologically or physically (due to any other illness) or cognitively unfit for participation in the study according to the opinion of the investigator;
  • Patient compliance doubtful;
  • Patient geographically or otherwise inaccessible for follow-up;
  • Patient unwilling or unable to give informed consent;
  • Life expectancy <1 year.
Sexes Eligible for Study: All
40 Years and older   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
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Medtronic Bakken Research Center
Medtronic Bakken Research Center
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Principal Investigator: Michele Brignole, MD Ospedali del Tigullio, Lavagna
Medtronic Bakken Research Center
September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP