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)
Open accessAbstract
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.
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Implantable loop recorders improve care only in the subset of patients who are older, have asystole documented on the recorder, and had negative tilt test results, probably because many diagnoses are vasovagal syncope.
“However, the devices have been shown to improve care in only the subset of patients who are older, have asystole documented on the ILR, and whose tilt test results were negative, probably because many of the diagnoses are of vasovagal syncope.”
From 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (2015) · cites this paper as [112]
The Conclusions (page unavailable) report that cardiac pacing was very effective in patients with ILR-documented asystole and a negative tilt test. The claim instead assigns that benefit to the implantable loop recorder, which the Study protocol (page unavailable) used to document events before pacemaker treatment. The Conclusions say evidence for pacing in tilt-positive patients was insufficient, not that benefit is possible only in the tilt-negative group; they do not give vasovagal diagnoses as the reason for the difference. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese patients appear to benefit from permanent pacing.
“These patients appear to benefit from permanent pacing.105–112”
From 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (2015) · cites this paper as [112]
The Abstract says permanent pacing reduced recurrent syncope in patients with documented asystole. However, the Discussion reports no observed benefit in the tilt-test-positive subgroup; the apparent benefit was greatest in tilt-test-negative patients. The unqualified reference to “these patients” therefore extends beyond the subgroup for which this analysis found benefit. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA recent ISSUE-3 subanalysis showed that syncope recurrence for patients with asystole, with or without syncope, was 5% with negative tilt test results and 55% with positive tilt test results, similar to controls without pacing.
“A recent subanalysis of ISSUE-3 showed that the syncope recurrence rate for patients with asystole, with or without syncope, was 5% for patients with negative tilt test results and 55% for those with positive tilt test results, which is similar to the results observed in controls without pacing.112”
From 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (2015) · cites this paper as [112]
The Results report 21-month syncope recurrence estimates of 5% after a negative tilt test and 55% after a positive tilt test among patients with ILR-documented asystole who received pacemakers. They also say the positive-tilt rate was similar to that in untreated controls. The passages do not establish the claim’s additional qualifier that the documented asystole occurred “with or without syncope.” (LLM, conf=0.82)
Experimental — accuracy not yet measuredCardiac pacing effectively prevents syncopal recurrences in this syndrome.
“Cardiac pacing effectively prevents syncopal recurrences.112,139,140”
From 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope (2015) · cites this paper as [112]
The Discussion (page not specified in our copy) concludes that pacing is very effective in patients with a negative tilt test, but says syncope can frequently recur when the test is positive. The unqualified claim omits that distinction and overstates the effectiveness reported for the full study population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients with an asystolic response during tilt testing fared no better than those with nonasystolic responses.
“Patients with an asystolic response during tilt testing fared no better than those with nonasystolic responses.”
Typically, the vasovagal reflex is both hypotensive and cardioinhibitory, and emerging evidence indicates that tilt-table testing identifies patients with predominant reflex hypotension.
“Typically, the vasovagal reflex is both hypotensive and cardioinhibitory, and there is emerging evidence that tilt-table testing identifies patients with predominant reflex hypotension.112”
In a substudy of ISSUE-3, an asystolic response during tilt testing predicted a similar asystolic form during spontaneous ILR-documented syncope, with a positive predictive value of 86%.
“In a substudy of the ISSUE-3 trial, 302 an asystolic response during tilt testing predicted a similar asystolic form during spontaneous ILR-documented syncope, with a positive predictive value of 86%.”
From 2018 ESC Guidelines for the diagnosis and management of syncope (2018) · cites this paper as [302]
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Self-citation
- Authors
- Brignole, M., Donateo, P., Tomaino, M., Massa, R., Iori, M., Beiras, X., Moya, A., Kus, T., Deharo, J. C., Giuli, S., Gentili, A., & Sutton, R.
- Affiliations
- Imperial College Healthcare NHS Trust (GB)
- From the Department of Cardiology, Ospedali del Tigullio, Lavagna, Italy (M.B., P.D.); Department of Cardiology, Ospedale di Bolzano, Bolzano, Italy (M.T.); Department of Cardiology, Ospedale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy (R.M.); Department of Cardiology, Arcispedale S. Maria Nuova, Reggio Emilia, Italy (M.I.); Hospital Xeral de Vigo, Vigo, Spain (X.B.); Hospital Universitario Vall d’Hebron, Barcelona, Spain (A.M.); Hopital du Sacre-Coeur de Montreal, Montreal, Canada (T.K...
- Venue
- Circulation: Arrhythmia and Electrophysiology
- Published
- 2014-02
- Volume
- 7
- Issue
- 1
- Pages
- 10-16
- ISSN
- 1941-3084 (ISSN-L)
- 1941-3149
- OpenAlex
- W1992774660
- Semantic Scholar
- 457099f23f964fb86e736f90097ed8a6560b5467
- Cited by
- 127
- References
- 26
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 22 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 16 · 2016: 12 · 2015: 9 · 2014: 11
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Arrhythmia and Electrophysiology (publishedVersion)
- PubMed (publishedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac pacing and defibrillation studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- neurally mediated syncope, cardiac pacing, pacemaker therapy, tilt table test, asystole, syncope recurrence, implantable loop recorder, predictive value
- MeSH terms
- Aged, Cardiac Pacing, Artificial, Double-Blind Method, Europe, Female, Heart Arrest, Heart Rate, Humans, Male, Middle Aged, Predictive Value of Tests, Recurrence, Time Factors, Treatment Outcome, Tilt-Table Test, Syncope, Vasovagal
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