The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE)
Open accessAbstract
AIMS: Recently, some studies revealed the efficacy of pacemaker implantation in decreasing recurrences in patients with vasovagal syncope. As these studies were not blinded or placebo-controlled, the benefits observed might have been due to a bias in the assessment of outcomes or to a placebo effect of the pacemaker. We performed a randomized, double-blind, placebo-controlled study in order to ascertain if pacing therapy reduces the risk of syncope relapse. METHODS AND RESULTS: Twenty-nine patients (53 +/- 16 years; 19 women) with severe recurrent tilt-induced vasovagal syncope (median 12 syncopes in the lifetime) and 1 syncopal relapse after head-up tilt testing underwent implantation of a pacemaker, and were randomized to pacemaker ON or to pacemaker OFF. During a median of 715 days of follow-up, 8 (50%) patients randomized to pacemaker ON had recurrence of syncope compared to 5 (38%) of patients randomized to pacemaker OFF (p = n.s.); the median time to first syncope was longer in the pacemaker ON than in pacemaker OFF group, although not significantly so (97 [38-144] vs 20 [4-302] days; p = 0.38). There was also no significant difference in the subgroups of patients who had had a mixed response and in those who had had an asystolic response during head-up tilt testing. CONCLUSION: Our data were unable to show a superiority of active pacing versus inactive pacing in preventing syncopal recurrence in patients with severe recurrent tilt-induced vasovagal syncope.
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“Although earlier observational, open-label, and single-blind studies have been uniformly positive, the results of 2 subsequent double-blind studies in adults were negative.133–138”
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 [137]
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“In this study, and in the similarly designed SYNPACE trial, no reduction in syncope was seen [30] .”
From Evaluating and managing bradycardia (2020) · cites this paper as [30]
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“In general, pacing was ineffective in trials that enrolled patients without an asystolic tilt response. 299,300”
From 2018 ESC Guidelines for the diagnosis and management of syncope (2018) · cites this paper as [300]
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Citations
Cites
Guidelines on management (diagnosis and treatment) of syncope
Brignole, M. (2001) · European Heart Journal · doi:10.1053/euhj.2001.2739 · Cited by 951
Self-citationConnolly, S. J., Sheldon, R., Thorpe, K. E., Roberts, R. S., Ellenbogen, K. A., Wilkoff, B. L., Morillo, C., Gent, M., & for the VPS II Investigators (2003) · JAMA · doi:10.1001/jama.289.17.2224 · Cited by 500
The North American vasovagal pacemaker study (VPS)
Connolly, S., Sheldon, R., Roberts, R., & Gent, M. (1999) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(98)00549-x · Cited by 474
Sutton, R., Brignole, M., Menozzi, C., Raviele, A., Alboni, P., Giani, P., & Moya, A. (2000) · Circulation · doi:10.1161/01.cir.102.3.294 · Cited by 407
Self-citationManagement of Vasovagal Syncope: Controlling or Aborting Faints by Leg Crossing and Muscle Tensing
Krediet, C. T. P., van Dijk, N., Linzer, M., van Lieshout, J. J., & Wieling, W. (2002) · Circulation · doi:10.1161/01.cir.0000030939.12646.8f · Cited by 372
Bartoletti, A. (2000) · Europace · doi:10.1053/eupc.2000.0125 · Cited by 315
Ammirati, F., Colivicchi, F., & Santini, M. (2001) · Circulation · doi:10.1161/hc2601.091708 · Cited by 299
Impairment of physical and psychosocial function in recurrent syncope
Linzer, M., Pontinen, M., Gold, D. T., Divine, G. W., Felder, A., & Blair Brooks, W. (1991) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(91)90005-t · Cited by 296
Risk Factors for Syncope Recurrence After a Positive Tilt-Table Test in Patients With Syncope
Sheldon, R. S., Rose, S., Flanagan, P., Koshman, M. L., & Killam, S. (1996) · Circulation · doi:10.1161/01.cir.93.5.973 · Cited by 231
Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope
Brignole, M., Croci, F., Menozzi, C., Solano, A., Donateo, P., Oddone, D., Puggioni, E., & Lolli, G. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(02)02683-9 · Cited by 208
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- [19]19. Sheldon RS, Rose S, Flanagan P et al. Multivariate predictors of syncope recurrence in drug-free patients following a positive tilt table test. Circulation 1996;93:973-81.
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Items 301–321 of 321
Can, I., & Benditt, D. G. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-161-5_18
Alagiakrishnan, K. (2019) · Springer eBooks · doi:10.1007/978-3-030-30332-7_4
Block, C. L. (2019) · Journal of the American Veterinary Medical Association · doi:10.2460/javma.254.2.206
Vasovagal syncope in 2016: the current state of the faint
Chew, D. S., Raj, S. R., & Sheldon, R. S. (2016) · Interventional Cardiology · doi:10.4172/ica.1000661
KRUMERMAN, A. K., & Fisher, J. D. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-2856-5.00103-5
Gomes, J. A. (2020) · Springer eBooks · doi:10.1007/978-3-030-45066-3_30
Krahn, A. D. (2010) · Springer eBooks · doi:10.1007/978-1-84996-390-9_152
Magnano, M., Bissolino, A., Budano, C., Occhetta, E., & Rametta, F. (2022) · Minerva Cardiology and Angiology · doi:10.23736/s2724-5683.22.06131-2
Benditt, D. G., Lü, F., & Sakaguchi, S. (2009) · Wiley eBooks · doi:10.1002/9781444309768.ch42
Reflex Syncope and the Role of Cardiac Pacing: A Systematic Review and Meta-Analysis
Collin, C., & Solano, J. (2025) · Cureus · doi:10.7759/cureus.91874
“The SYNPACE trial [17], which used a sham pacing control, reported an OR of 1.60 (95% CI: 0.36-7.07), indicating no benefit and possible harm, though the result was not statistically significant.”
InfluentialHolzenthal, R. W., & Pes, A. M. (2004) · INFM-OAR (INFN Catania) · doi:10.5281/zenodo.169326
Gao, L., Yu, X., Li, H., & Yuan, Y. (2020) · Figshare · doi:10.6084/m9.figshare.12292022
Vo, T. D., Kieu, N. T., Tran, L. U. P., Tran, C. D., Nguyen, T. T., & Dao, B. T. T. (2025) · Journal of Arrhythmia · doi:10.1002/joa3.70257
“Current evidence also suggests that clinical and hemodynamic characteristics, such as sex, burden of prior syncopal episodes, magnitude of blood pressure drop, and duration of asystole during tilt testing—may influence the likelihood of recurrence after pacemaker implantation [11].”
InfluentialAksu, T. (2026) · Indian Pacing and Electrophysiology Journal · doi:10.1016/j.ipej.2026.01.005
Sbarra, F., Pagnoni, G., Darroudi, S., Moscetti, L. I., Vicenzi, A., Bolognesi, M. G., Coppi, F., Rossi, L., & Aschieri, D. (2026) · IJC Heart & Vasculature · doi:10.1016/j.ijcha.2026.101903
“Subsequent blinded trials, including VPS II and SYNPACE, failed to demonstrate a significant benefit of pacing [9,10], underscoring the critical role of blinding in syncope trials.”
Endovascular stimulation as a therapeutic strategy for the treatment of cardiopulmonary disorders
Jia, Y., Moscato, F., & Haberbusch, M. (2026) · Journal of Neural Engineering · doi:10.1088/1741-2552/ae6bf2
“Cardiac pacemakers have been used to address bradycardia in NCS but show limited efficacy in preventing recurrent episodes [46, 47].”
Syncope and the heart: When to suspect and how to act?
Ruzieh, M., Hamdan, M. H., & Goldberger, Z. D. (2026) · Heart · doi:10.1136/heartjnl-2025-326964
“…episodes (syncope with ≥3 s or ≥6 s without syncope) on implantable loop recorders 30 but not in the subgroup of patients with asystole during TTT. 31 Other trials, such as VPS II (n=100) 28 and SYNPACE (n=29), 29 failed to show significant benefit when patient selection was based only on TTT.”
Cardioneuroablation for Reflex Syncope and Functional Bradyarrhythmias: A State-of-the-Art Review
Antonio, R. S., Almonte, I., Filloy, C. G., Mercé, J., Rodríguez‐García, J., Rodríguez-Silva, J., Rodríguez-García, M. L., Chauca, A., Marco, A. D., Dallaglio, P., et al. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15156012
“…reasked under double-blind conditions, comparing pacemaker ON with pacemaker OFF in patients who had all been implanted, the effect largely disappeared—VPS II found no significant reduction in recurrent syncope, and SYNPACE could not demonstrate superiority of active over inactive pacing [62,63].”
From Mechanism to Management in Vasovagal Syncope: An Integrative Review
Laranjo, S. M., Oliveira, M., & Rocha, I. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15197360
“When the comparison was made double-blind, by implanting every patient and randomising the pacemaker on or off, the benefit evaporated, for neither the Second Vasovagal Pacemaker Study nor the SYNPACE trial found an advantage of active pacing [76,77].”
Management und Therapie der vasovagalen Synkope
Aydin, M. A., & Willems, S. (2012) · Der Kardiologe · doi:10.1007/s12181-011-0394-3
To Pace or not to Pace for Neurally Mediated Syncope: Do We Know the Answer? A Positive View
Giada, F., & Raviele, A. (2004) · Springer eBooks · doi:10.1007/978-88-470-2137-2_85
Self-citation
Metadata
- Authors
- RAVIELE, A., GIADA, F., MENOZZI, C., SPECA, G., ORAZI, S., GASPARINI, G., SUTTON, R., & BRIGNOLE, M.
- Affiliations
- Santa Maria Nuova Hospital (IT)
- Royal Brompton Hospital (GB)
- Corresponding author
- RAVIELE, A
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-10
- Volume
- 25
- Issue
- 19
- Pages
- 1741-1748
- ISSN
- 0195-668X (ISSN-L)
- OpenAlex
- W1982517883
- Semantic Scholar
- fc5273c9844e2031f629c06b5ca6a054616c5cd2
- Cited by
- 323
- References
- 28
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 17 · 2020: 15 · 2019: 13 · 2018: 12 · 2017: 23 · 2016: 16 · 2015: 12 · 2014: 23 · 2013: 21 · 2012: 17
- FWCI
- 17.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › 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
- vasovagal syncope, permanent cardiac pacing, pacemaker implantation, syncope recurrence, head-up tilt
- MeSH terms
- Cardiac Pacing, Artificial, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pacemaker, Artificial, Prospective Studies, Treatment Outcome, Tilt-Table Test, Syncope, Vasovagal, Secondary Prevention
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