doi: 10.1161/hc2601.091708
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(Circulation. 2001;104:52.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Permanent Cardiac Pacing Versus Medical Treatment for the Prevention of Recurrent Vasovagal Syncope
A Multicenter, Randomized, Controlled Trial
From the Dipartimento di Malattie Cardiovascolari, Ospedale "S. Filippo Neri," Rome, Italy.
Correspondence to Dr Fabrizio Ammirati, Via Attilio Friggeri 95, 00136 Rome, Italy. E-mail fabamm{at}openaccess.it
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope.
Methods and
Results—Patients from 14 centers were
randomized to receive either a DDD pacemaker provided with rate-drop
response function or the ß-blocker atenolol at the dosage of 100 mg
once a day. Inclusion criteria were age >35 years, 
3 syncopal spells
in the preceding 2 years, and positive response to tilt table testing
with syncope occurring in association with relative bradycardia. The
primary outcome was the first recurrence of syncope after
randomization. Enrollment was started in December 1997, and the first
formal interim analysis was performed on July 30, 2000. By that
time, 93 patients (38 men and 55 women; mean age, 58.1±14.3 years) had
been enrolled and randomized, although follow-up data were available
for all patients (46 patients in the pacemaker arm, 47 patients in the
pharmacological arm). The interim analysis showed a significant
effect in favor of permanent cardiac pacing (recurrence of
syncope in 2 patients [4.3%] after a median of 390 days) compared
with medical treatment (recurrence of syncope in 12 patients
[25.5%] after a median of 135 days; OR, 0.133; 95% CI, 0.028 to
0.632; P=0.004). Consequently,
enrollment and follow-up were terminated.
Conclusions—DDD pacing with rate-drop response function is more effective than ß-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope.
Key Words: syncope • pacing • ß-blockers
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Vasovagal syncope represents a common disorder of the autonomic cardiovascular regulation.1 2 Even if this condition is not life threatening, patients with recurrent vasovagal syncope may show a substantial physical and psychosocial morbidity.3 4 Consequently, highly symptomatic subjects with excessive lifestyle difficulties are usually considered for a specific treatment.4 5 In general, the available therapeutic options for vasovagal syncope can be broadly classified as long-term pharmacological therapy and permanent dual-chamber cardiac pacing.4 5 6 Although medical therapy should be effective in preventing the development of the vasovagal reflex, cardiac pacing is expected to contrast the reflex just after its appearance. In particular, many pharmacological agents have been proposed as effective in the prevention of vasovagal syncope, even if only 3 drugs—atenolol, midodrine, and paroxetine—have shown some efficacy in
1 prospective,
randomized, controlled clinical
trial.7 8 9
As a matter of fact, in clinical practice, ß-blockers currently
represent the most widely prescribed drug class in patients
with recurrent vasovagal
spells.5 6 On the
other hand, after several observational
studies,10 11 2
randomized, controlled trials have suggested that cardiac pacing may
represent a reasonable therapeutic alternative in highly
symptomatic vasovagal
fainters.12 13
However, despite the existence of substantial literature on both
pharmacological and pacing treatment, the relative efficacy of any
specific option in patients with recurrent vasovagal spells is still a
matter of
dispute.4 5 6 Accordingly, this clinical investigation was designed and undertaken to compare the effects of medical therapy and cardiac pacing in patients with recurrent vasovagal syncope. The ß-blocker atenolol was considered the pharmacological agent, whereas a dual-chamber pacemaker with rate-drop response (RDR) function was chosen for pacing treatment.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patients
The study cohort consisted of 93 patients (38 men and 55 women; mean age, 58.1±14.3 years) with recurrent vasovagal syncope. These patients were recruited from consecutive subjects referred to the 14 participating centers from December 1997 to April 2000 for the evaluation of unexplained syncope. Syncope was defined as a sudden transient loss of consciousness with inability to maintain postural tone and with spontaneous recovery.14 15 In each patient, the cause of syncope was established according to a standardized diagnostic workup and by adhering to previously reported diagnostic criteria.16 17 In fact, all patients were considered to have been affected by vasovagal syncope when presenting with the following features16 17 : (1) no clinical or laboratory evidence of any cardiac, neurologic, or metabolic cause for the recurrent syncopal spells and (2) positive response to head-up tilt testing.
The preliminary diagnostic evaluation included history, physical examination, full routine laboratory tests, 12-lead ECG, exercise ECG, Doppler echocardiography, 24-hour ECG monitoring, carotid sinus massage, EEG, and duplex ultrasound scanning of the carotid arteries. When clinically indicated, CT scans and MRI of the central nervous system and cardiac electrophysiological study were also performed. When this diagnostic workup could not establish the cause of syncope, the patient underwent tilt table testing according to a previously described protocol.18 All patients were also questioned about the occurrence of trauma during syncopal spells. Syncope-related traumatic injuries were classified as previously described19 : major trauma (any fracture, head injury, or internal organ damage requiring hospital admission and surgical treatment) and minor trauma (any bruise, cut, and soft tissue injury).
Head-Up Tilt Testing
The test was performed in the morning in patients in
a fasting state. An electronically controlled tilt table with a
footboard for weight-bearing and restraining belts was used for the
procedure. Continuous ECG monitoring of heart rate and rhythm was
performed, whereas blood pressure was noninvasively measured beat to
beat by means of an Ohmeda Finapress 2300 photopletismographic device.
In 8 centers, such a device was not available, and blood pressure was
measured by a standard mercury sphygmomanometer at 5-minute intervals
throughout the test. Subjects were initially tilted at 60° for 30
minutes (control phase). Subsequently, if no symptoms occurred,
participants received 1.25 mg isosorbide dinitrate sublingually and
continued to be tilted for an additional 15 minutes (pharmacological
phase). The test was considered positive if syncope occurred in
association with hypotension, bradycardia, or both. In case of syncope,
the procedure was terminated by rapidly lowering the tilt table to the
horizontal position.
Patient Eligibility
To be included in the study, patients with recurrent
vasovagal syncope had to fulfill the following criteria: age >35
years; 3 syncopal spells in the preceding 2 years, with the last
episode occurring within 6 months of enrollment; and positive response
to tilt table testing with syncope occurring in association with
relative bradycardia. Relative bradycardia was defined as a trough
heart rate <60 bpm as previously
described.12
All enrolled patients provided written informed consent to take part in the investigation. Patients were excluded if a cause of syncope other than vasovagal was known or even suspected. Patients were also excluded in case of any historical, clinical, or laboratory evidence of cardiac, neurological, or metabolic disease. Other exclusion criteria included the need for any concomitant chronic pharmacological treatment for any cause and patient refusal to participate in the study.
Study Design
The study was planned as a multicenter, prospective,
randomized, controlled trial with parallel groups. The main goal of the
study was to compare the effects of pharmacological ß-blockade and
permanent dual-chamber cardiac pacing in the prevention of the
recurrence of vasovagal syncope. The study protocol was
approved by the ethics committee of all participating institutions.
Eligible patients were assigned to 1 of the 2 study arms according to a
central computer-generated randomization list: (1) treatment with
atenolol at the dosage of 100 mg once a day and (2) implantation of a
DDD pacemaker with RDR function (Medtronic Thera-I, model 7960,
Medtronic Inc).
Pharmacological Treatment
Pharmacological therapy was started immediately after
randomization at the dosage of 50 mg once a day. Subsequently, the drug
was titrated up to the full dosage of 100 mg once a day within 2 to 3
days. Titration decrements in atenolol to 50 mg/d were allowed during
follow-up in case of side effects. Compliance with pharmacological
therapy was assessed by pill counting. Patients who dropped out owing
to intolerable side effects, adverse reactions, or lack of adequate
response to treatment were taken as complete cases for the
intention-to-treat analysis.
Pacemaker Implantation and Programming
Pacemaker implantation was performed immediately
after randomization in all cases. The parameters of the RDR
algorithm were programmed after implantation and before discharge from
the hospital. The RDR programming was performed on the basis of heart
rate behavior during head-up tilt testing in every single patient as
previously described.20 In
addition, all pacemakers were programmed with a lower rate at 40 bpm
and a minimum AV delay of 200 ms to avoid inappropriate pacing and to
favor spontaneous cardiac rhythm.
Follow-Up and Outcome Measures
All subjects were asked to immediately note any
syncope recurrence. In addition, a clinical follow-up visit,
including physical examination and a 12-lead ECG, was scheduled on a
3-month basis. The primary end point of the study was the first
recurrence of syncope during follow-up. This outcome measure
was chosen because the time to first recurrence of syncope has
been shown to correlate with the eventual frequency of syncopal spells
in vasovagal fainters.21 For
all included patients, formal study participation ended in case of
recurrence of syncope.
As in previous studies,13 recurrences of minor symptoms such as presyncope, dizziness, or lightheadedness were neither collected nor considered in the analysis. In fact, syncope represents a memorable and easily quantifiable event, whereas other minor disturbances are far more difficult to define in terms of severity, duration, and clinical relevance.22
Statistical Analysis
The primary analysis of all outcomes was by
intention to treat. Moreover, an on-treatment analysis of the
primary end point was also performed. The recurrence of syncope
in the 2 treatment groups was tested with the OR of the 2-binomial
proportion analysis. The cumulative risk of recurrence
of syncope within each group was estimated by means of the Kaplan-Meier
method. The survival curves of the 2 different treatment groups were
than formally compared by use of the log-rank test.
Mean±SD and medians were calculated for continuous
variables, and frequencies were measured for categorical
variables. Differences between groups were analyzed by
unpaired Student’s t test for
continuous variables and 
2 for
categorical variables; a value of
P<0.05 was considered
significant.
Sample size calculation was based on an expected 15%/y
syncopal recurrence rate in the pharmacological arm and on an
expected 5%/y recurrence rate in the pacemaker arm.
Consequently, with an 
level of 0.05 and a test power of 0.80, the
resulting sample size was 60 patients in each treatment
group.
|
Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients had been enrolled, and follow-up data were available for all patients. The interim analysis showed a significant effect in favor of permanent cardiac pacing compared with medical treatment (P=0.004). Consequently, in accordance with the Study Safety and Efficacy Monitor, a decision was made to terminate enrollment and follow-up. The study results were than reported as of August 13, 2000.
During the recruitment period, 1743 potentially eligible
patients were initially screened. Among these 1743 patients, 93 (5.3%;
38 men and 55 women; mean age, 58.1±14.3 years) met all inclusion and
exclusion criteria, provided informed consent, and were randomized to 1
of the 2 treatment groups. Forty-seven patients were assigned to
pharmacological treatment with atenolol, and 46 patients were assigned
to receive a pacemaker. All patients were followed up for 60 days
after randomization, with a mean follow-up of 520±266 days. No patient
was lost to follow-up. During follow-up, 2 patients were not assessable
by on-treatment analysis. In fact, 1 patient in the pacemaker
arm refused pacemaker implantation just after randomization, and a
patient in the pharmacological arm discontinued treatment owing to
intolerable side effects. Thus, the on-treatment analysis was
performed on a total of 91 patients.
Baseline Characteristics
The baseline characteristics of the 2 groups were
similar and are shown in
Table 1
. Before enrollment, patients had had a
median of 7 (range 3 to 130) syncopal spells. During the preliminary
workup, all patients had a negative response to the carotid sinus
massage. In addition, 41 patients (44.0%) showed a positive response
to head-up tilt testing in the control phase, whereas in the remaining
52 patients (56.0%), tilt-induced syncope followed the pharmacological
provocation. A pure cardioinhibitory response to head-up
tilt testing (syncope in association with an asystolic pause
>3 seconds) was present in 56 patients (60.2%). Forty-seven
patients (50.5%) had 1 syncope-related traumatic injury in their
clinical histories. In 10 patients, the severity of physical injuries
had determined 1 hospital admission and surgical treatment (major
trauma). Patients with and without syncope-related trauma showed a
similar prevalence of asystolic response to tilt testing
(61.7% versus 58.7%).
|
Primary End Point
In the intention-to-treat analysis, syncope
recurred in 2 patients (4.3%) in the pacemaker arm after a median of
390 days (interquartile range, 360 to 420 days) and in 12 patients
(25.5%) in the pharmacological arm after a median of 135 days
(interquartile range, 15 to 250 days). The difference was found to be
highly significant (P=0.004)
(Table 2). The Kaplan-Meier actuarial estimates of first
recurrence of syncope after 6, 12, 24, and 36 months were 0%,
3.3%, 7.2%, and 7.2% in the pacemaker arm and 14.1%, 24.1%,
33.9%, and 33.9% in the pharmacological arm
(Figure 1). In the on-treatment analysis, similar
results were found
(Table 2). The Kaplan-Meier actuarial estimates of first
recurrence of syncope by on-treatment analysis are
shown in
Figure 2.
|
|
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Side Effects and Adverse Events
No local or systemic complications related directly to
pacemaker implantation were reported in any patient during the study.
Five patients (10.8%) in the pacemaker group reported 1 episode of
palpitations, possibly related to inappropriate pacemaker intervention.
Twelve patients (26.0%) in the pharmacological group reported mild to
moderate side effects such as fatigue, depression, anxiety, and
impotence. These symptoms were considered to be directly related to the
atenolol treatment. A titration decrement to 50 mg was then required in
9 patients (19.5%). Only 1 patient required premature pharmacological
treatment discontinuation owing to intolerable side
effects.
No deaths or major syncope-related traumatic injuries occurred during the investigation. Four patients had minor syncope-related traumatic injuries (1 in the pacemaker group and 3 in the pharmacological group).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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In clinical practice, the long-term therapeutic approach to vasovagal syncope markedly differs among patients. The only interventions warranted in case of sporadic spells are represented by reassurance and education regarding the avoidance of known triggering events and the awareness of evasive, protective actions. Additional therapies are deemed necessary when frequent recurrences impair quality of life, threaten employment, and impart an increased risk of traumatic injuries.4 5 6 23 In general, pharmacological treatment is usually considered the first option for the prevention of recurrent vasovagal episodes, even if the evidence in favor of such an approach is scarce.5 6 Moreover, long-term compliance with drug therapy is far from satisfactory, with side effects or adverse reactions causing frequent withdrawals.5 6 Conversely, recent studies have suggested that cardiac pacing may significantly relieve symptoms in specific subsets of highly symptomatic vasovagal fainters.4 12 13
This study represents the first randomized, controlled trial to allow comparison of the effects of medical treatment and pacemaker therapy in patients with recurrent vasovagal syncope. The main finding of this clinical investigation is that in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope, dual-chamber cardiac pacing is more effective than ß-blockers in reducing the likelihood of a recurrence of syncope. Indeed, although pacemaker therapy was associated with a 93% actuarial probability of remaining free of syncopal recurrences after 3 years, in medically treated patients, this probability was reduced to <67% after the same period of time.
Pacemaker therapy was found to be more effective in this trial than in several previous studies.10 12 However, the effects of pacing in this study are comparable to those reported in the recently published Vasovagal Syncope International Study (VASIS), which included patients with similar baseline clinical features.13 As for medical treatment, the effect of ß-blockade in preventing recurrences of syncope in this trial was comparable to that reported in previous observational studies addressing the same issue.24 Overall, ß-blockers have been associated with a likelihood of recurrence of syncope of 10%/y to 20%/y, depending on the symptom burden of treated patients. Moreover, in patients with cardioinhibitory vasovagal syncope, ß-blockers may occasionally worsen the tendency toward syncope (the so-called "prosyncope" phenomenon),17 even if such an adverse event has rarely been reported and has never been noted in large series.24
This clinical trial further contributes to the emerging evidence in favor of cardiac pacing for the prevention of recurrence of vasovagal syncope. Most practicing clinicians tend to consider pacing therapy as a "no-return" approach, which should be the last resort for severely symptomatic patients refractory to conventional medical therapy. However, the impact of medical treatment on the symptom burden of recurrent vasovagal syncope has not been clearly demonstrated.4 5 Conversely, cardiac pacing is consistently showing an unexpected efficacy in the specific subset of patients with a high recurrence rate.
Study Limitations
As in the recently published VASIS, the results
of the present study may have been influenced by a
lower-than-expected recruitment rate of potentially eligible
patients.13 In fact, as in
VASIS, a bias in encouraging and favoring the acceptance of
randomization, as well as the subsequent pacemaker implantation, by
older, highly symptomatic patients with an
asystolic response to tilt testing (considered the worst or
most severe cases) might have been possible. In fact, the proportion of
randomized patients to potentially eligible subjects and the mean age
and baseline clinical characteristics of the study populations in this
investigation and in VASIS are similar.
Despite randomization, there was a trend for pacemaker
patients to be older and to have had more syncope-related traumatic
injuries. However, both variables have never been found to
influence the recurrence rate of syncope in patients with
vasovagal fainting. In addition, all other baseline characteristics
were well balanced
(Table 1
).
As in previous studies,13 no data concerning the recurrences of presyncope or lightheadedness in the study population were collected. However, although cardiac pacing therapy is known to be less effective in reducing such minor symptoms,12 no data are available as to the effects of medical treatment on these events. Moreover, these symptoms are often nonspecific and notably difficult to define and quantify in the long term.22
The study was not blinded. Consequently, a bias in the assessment of outcome cannot be excluded, even if most of the outcome events were witnessed (8 of 14, 57.1%) or were associated with minor injuries (4 of 14, 28.5%).
Finally, patients knew the therapy, and the pharmacological group did not undergo a surgical procedure with its consequent psychological impact. Accordingly, part of the benefit of pacing therapy may derive from a possible "pacemaker placebo" effect.25
Conclusions
Dual-chamber cardiac pacing provided with the RDR
function is more effective than pharmacological ß-blockade in
reducing the likelihood of recurrence of syncope in patients
showing a relative bradycardia during tilt-induced syncope. However,
because patients included in this study showed a mean age >50 years
and a high prevalence of asystolic response to tilt testing,
according to the results of this trial, pacing treatment should
probably be reserved for the subset of older, highly
symptomatic vasovagal fainters with clear evidence of
tilt-induced cardioinhibition. Further investigations are needed to
define the specific indications and possible deleterious long-term
effects of pacing therapy in patients with recurrent vasovagal
syncope.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Study Investigators
The Syncope Diagnosis and Treatment (SYDIT) Study Investigators were as follows (the number of randomized patients is given in parentheses): D. Cornacchia, Ospedale degli Infermi, Faenza (2); G. Pulitanò, Policlinico Madonna della Consolazione, Reggio Calabria (6); M. Del Greco, Ospedale S. Chiara, Trento (1); S. Orazi, Ospedale Provinciale, Rieti (11); C. Pignalberi, Policlinico Campus Biomedico, Roma (8); M. Mariani, Ospedale Parodi-Delfino, Colleferro (7); C. Bianchi, Ospedale CTO, Roma (8); F. Ammirati and F. Colivicchi, Ospedale S. Filippo Neri, Roma (14); M. Rolloni, Ospedale Santissimo Gonfalone, Monterotondo (6); E. Faletra, Aurelia Hospital, Roma (7); G. Limongelli, Ospedale Villa Betania, Roma (5); M. Modica, Ospedale IDI, Roma (4); A. Ammirati, Ospedale Bambino Gesù, Presidio di Palidoro, Roma (6); and P. Gelfo, Ospedale S. Maria Goretti, Latina (8). The Organizing Committee was made up of M. Santini (chairman), F. Ammirati, F. Colivicchi, S. Orazi, and C. Pignalberi. The External Safety and Efficacy Monitor was M. Zoni Berisso.
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Acknowledgments |
|---|
We would like to thank Francesco De Seta, PhD, and Massimiliano Pepe, PhD, for their technical assistance during the study.
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Footnotes |
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1 The Appendix lists the SYDIT Study Investigators.
Received January 17, 2001; revision received April 11, 2001; accepted April 11, 2001.
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References |
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|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. Kosinski D, Grubb B, Temesey-Armos P. Pathophysiological aspects of neurocardiogenic syncope: current concepts and new perspectives. Pacing Clin Electrophysiol. 1995;18:716–724.[Medline] [Order article via Infotrieve]
2. Benditt DG. Neurally mediated syncopal syndromes: pathophysiological concepts and clinical evaluation. Pacing Clin Electrophysiol. 1997;20(pt 2):572–584.
3. Linzer M, Pontinen M, Gold DT, et al. Impairment of physical and psychosocial function in recurrent syncope. J Clin Epidemiol. 1991;44:1037–1043.[Medline] [Order article via Infotrieve]
4. Sheldon R. Role of pacing in the treatment of vasovagal syncope. Am J Cardiol. 1999;84:26Q–32Q.[Medline] [Order article via Infotrieve]
5.
Benditt DG, Fahy
GJ, Lurie KG, et al. Pharmacotherapy of neurally mediated syncope.
Circulation. 1999;100:1242–1248.
6. Calkins H. Pharmacologic approaches to the therapy for vasovagal syncope. Am J Cardiol. 1999;84:20Q–25Q.[Medline] [Order article via Infotrieve]
7. Mahanonda N, Bhuripanjo K, Kangkate C, et al. Randomized, double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J. 1995;130:1250–1253.[Medline] [Order article via Infotrieve]
8.
Ward CR, Gray JC,
Gilroy JJ, et al. Midodrine: a role in the management of
neurocardiogenic syncope.
Heart. 1998;79:45–49.
9.
Di Girolamo E, Di
Iorio C, Sabatini P, et al. Effects of paroxetine hydrochloride, a
selective serotonin reuptake inhibitor, on
refractory vasovagal syncope: a randomized, double-blind,
placebo-controlled study. J Am Coll
Cardiol. 1999;33:1227–1230.
10.
Petersen MEV,
Chamberlain-Webber R, Fitzpatrick AP, et al. Permanent pacing for
cardioinhibitory malignant vasovagal syndrome.
Br Heart J. 1994;71:274–281.
11. Benditt DG, Sutton R, Gammage MD, et al. Clinical experience with Thera DR rate drop response pacing algorithm in carotid sinus syndrome and vasovagal syncope. Pacing Clin Electrophysiol. 1997;20(pt 2):832–839.
12.
Connolly SJ,
Sheldon R, Roberts RS, et al. The North American Vasovagal Pacemaker
Study (VPS): a randomized trial of permanent cardiac pacing for the
prevention of vasovagal syncope. J Am
Coll Cardiol. 1999;33:16–20.
13.
Sutton R,
Brignole M, Menozzi C, et al. Dual-chamber pacing in the treatment of
neurally mediated tilt-positive cardioinhibitory syncope:
pacemaker versus no therapy: a multicenter randomized study.
Circulation. 2000;102:294–299.
14. Day SC, Cook EF, Funkenstein H, et al. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med. 1982;73:15–23.[Medline] [Order article via Infotrieve]
15. Eagle KA, Black HR, Cook EF, et al. Evaluation and prognostic classification of patients with syncope. Am J Med. 1985;79:455–460.[Medline] [Order article via Infotrieve]
16. Calkins H, Shyr Y, Frumin H, et al. The value of clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block and neurocardiogenic syncope. Am J Med. 1995;98:365–373.[Medline] [Order article via Infotrieve]
17. Grubb BP Neurocardiogenic syncope. In: Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management. Armonk, NY: Futura Publishing; 1998:73–108.
18. Ammirati F, Colivicchi F, Biffi A, et al. Head-up tilt testing potentiated with low-dose sublingual isosorbide dinitrate: a simplified time-saving approach for the evaluation of unexplained syncope. Am Heart J. 1998;135:671–676.[Medline] [Order article via Infotrieve]
19.
Oh JH, Hanusa B,
Kapoor WN. Do symptoms predict cardiac arrhythmias and
mortality in patients with syncope? Arch
Intern Med. 1999;159:375–380.
20. Ammirati F, Colivicchi F, Toscano S, et al. DDD pacing with rate drop response function versus DDI with rate hysteresis pacing for cardioinhibitory vasovagal syncope. Pacing Clin Electrophysiol. 1998;21(pt 2):2178–2181.
21. Malik P, Koshman ML, Sheldon RS. Timing of first syncope recurrence predicts syncope frequency following a positive tilt table test. J Am Coll Cardiol. 1997;29:1284–1289.[Abstract]
22.
Sheldon R, Rose
S, Flanagan P, et al. Risk factors for syncope recurrence after
a positive tilt-table test in patients with syncope.
Circulation. 1996;93:973–981.
23.
Fenton AM,
Hammill SC, Rea RF, et al. Vasovagal syncope.
Ann Intern Med. 2000;133:714–725.
24. Sheldon R, Rose S, Flanagan P, et al. Effect of beta blockers on the time to first syncope recurrence in patients after a positive tilt test. Am J Cardiol. 1996;78:536–539.[Medline] [Order article via Infotrieve]
25.
Benditt DG.
Cardiac pacing for the prevention of vasovagal syncope.
J Am Coll Cardiol. 1999;33:21–23.
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A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. Mark Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, D. L. Hayes, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2085 - 2105. [Full Text] [PDF]
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 Writing Committee Members, A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons Circulation, May 27, 2008; 117(21): 2820 - 2840. [Full Text] [PDF]
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Writing Committee Members, A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons Circulation, May 27, 2008; 117(21): e350 - e408. [Full Text] [PDF]
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M. P. Tan and S. W. Parry Vasovagal syncope in the older patient. J. Am. Coll. Cardiol., February 12, 2008; 51(6): 599 - 606. [Abstract] [Full Text] [PDF]
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 M. Brignole, F. Giada, A. Raviele, and J. J. Blanc Pacing for syncope: what role? which perspective? Eur. Heart J. Suppl., December 1, 2007; 9(suppl_I): I37 - I43. [Abstract] [Full Text] [PDF]
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 Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Europace, October 1, 2007; 9(10): 959 - 998. [Full Text] [PDF]
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Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Eur. Heart J., September 2, 2007; 28(18): 2256 - 2295. [Full Text] [PDF]
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S. Sud, G. J. Klein, A. C. Skanes, L. J. Gula, R. Yee, and A. D. Krahn Implications of mechanism of bradycardia on response to pacing in patients with unexplained syncope Europace, May 1, 2007; 9(5): 312 - 318. [Abstract] [Full Text] [PDF]
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M. Brignole, R. Sutton, W. Wieling, S.N. Lu, M.K. Erickson, T. Markowitz, N. Grovale, F. Ammirati, D.G. Benditt, and on behalf of the ISSUE 2 investigators Analysis of rhythm variation during spontaneous cardioinhibitory neurally-mediated syncope. Implications for RDR pacing optimization: an ISSUE 2 substudy Europace, May 1, 2007; 9(5): 305 - 311. [Abstract] [Full Text] [PDF]
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M. Brignole, R. Sutton, C. Menozzi, R. Garcia-Civera, A. Moya, W. Wieling, D. Andresen, D. G. Benditt, N. Grovale, T. De Santo, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope Eur. Heart J., September 2, 2006; 27(18): 2232 - 2239. [Abstract] [Full Text] [PDF]
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G. N. Theodorakis, D. Leftheriotis, E. G. Livanis, P. Flevari, G. Karabela, N. Aggelopoulou, and D. Th. Kremastinos Fluoxetine vs. propranolol in the treatment of vasovagal syncope: a prospective, randomized, placebo-controlled study. Europace, March 1, 2006; 8(3): 193 - 198. [Abstract] [Full Text] [PDF]
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J.-C. Deharo, C. Jego, A. Lanteaume, and P. Djiane An Implantable Loop Recorder Study of Highly Symptomatic Vasovagal Patients: The Heart Rhythm Observed During a Spontaneous Syncope Is Identical to the Recurrent Syncope But Not Correlated With the Head-Up Tilt Test or Adenosine Triphosphate Test J. Am. Coll. Cardiol., February 7, 2006; 47(3): 587 - 593. [Abstract] [Full Text] [PDF]
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 Additional Information JAMA, November 2, 2005; 294(17): E1 - E3. [Full Text] [PDF]
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B. P. Grubb Neurocardiogenic Syncope and Related Disorders of Orthostatic Intolerance Circulation, June 7, 2005; 111(22): 2997 - 3006. [Full Text] [PDF]
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 B. P. Grubb Neurocardiogenic Syncope N. Engl. J. Med., March 10, 2005; 352(10): 1004 - 1010. [Full Text] [PDF]
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Task Force members, M. Brignole, P. Alboni, D. G. Benditt, L. Bergfeldt, J.-J. Blanc, P. E. B. Thomsen, J. G. van Dijk, A. Fitzpatrick, S. Hohnloser, et al. Guidelines on management (diagnosis and treatment) of syncope - Update 2004: The task force on Syncope, European Society of Cardiology Eur. Heart J., November 2, 2004; 25(22): 2054 - 2072. [Full Text] [PDF]
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A. Raviele, F. Giada, C. Menozzi, G. Speca, S. Orazi, G. Gasparini, R. Sutton, M. Brignole, and for the Vasovagal Syncope and Pacing Trial Investi 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) Eur. Heart J., October 1, 2004; 25(19): 1741 - 1748. [Abstract] [Full Text] [PDF]
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G. Foglia-Manzillo, F. Giada, G. Gaggioli, A. Bartoletti, G. Lolli, M. Dinelli, A. Del Rosso, M. Santarone, A. Raviele, and M. Brignole Efficacy of tilt training in the treatment of neurally mediated syncope. A randomized study Europace, January 1, 2004; 6(3): 199 - 204. [Abstract] [Full Text] [PDF]
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Guidelines on Management (diagnosis and treatment) of syncope - update 2004: The Task Force on Syncope, European Society of Cardiology Europace, January 1, 2004; 6(6): 467 - 537. [Full Text] [PDF]
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E. Occhetta, M. Bortnik, R. Audoglio, C. Vassanelli, and for the INVASY Study Investigators Closed loop stimulation in prevention of vasovagal syncope. Inotropy controlled pacing in vasovagal syncope (INVASY): a multicentre randomized, single blind, controlled study Europace, January 1, 2004; 6(6): 538 - 547. [Abstract] [Full Text] [PDF]
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S. J. Connolly, R. Sheldon, K. E. Thorpe, R. S. Roberts, K. A. Ellenbogen, B. L. Wilkoff, C. Morillo, and M. Gent Pacemaker Therapy for Prevention of Syncope in Patients With Recurrent Severe Vasovagal Syncope: Second Vasovagal Pacemaker Study (VPS II): A Randomized Trial JAMA, May 7, 2003; 289(17): 2224 - 2229. [Abstract] [Full Text] [PDF]
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W. N. Kapoor Is There an Effective Treatment for Neurally Mediated Syncope? JAMA, May 7, 2003; 289(17): 2272 - 2275. [Full Text] [PDF]
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A. S. Kurbaan, T. J. Bowker, N. Wijesekera, A.-C. Franzen, D. Heaven, S. Itty, and R. Sutton Age and hemodynamic responses to tilt testing in those with syncope of unknown origin J. Am. Coll. Cardiol., March 19, 2003; 41(6): 1004 - 1007. [Abstract] [Full Text] [PDF]
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D. G. Benditt and M. Brignole Syncope: is a diagnosis a diagnosis? J. Am. Coll. Cardiol., March 5, 2003; 41(5): 791 - 794. [Full Text] [PDF]
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E. Occhetta, M. Bortnik, C. Vassanelli, and on behalf of the 'INVASY Italian feasibility Study The DDDR closed loop stimulation for the prevention of vasovagal syncope: results from the INVASY prospective feasibility registry Europace, January 1, 2003; 5(2): 153 - 162. [Abstract] [PDF]
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The Steering Committee of the ISSUE 2 study International Study on Syncope of Uncertain Etiology 2: the management of patients with suspected or certain neurally mediated syncope after the initial evaluation Rationale and study design Europace, January 1, 2003; 5(3): 317 - 321. [Abstract] [Full Text] [PDF]
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Committee Members, G. Gregoratos, J. Abrams, A. E. Epstein, R. A. Freedman, D. L. Hayes, M. A. Hlatky, R. E. Kerber, G. V. Naccarelli, M. H. Schoenfeld, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines) J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1703 - 1719. [Full Text] [PDF]
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G. Gregoratos, J. Abrams, A. E. Epstein, R. A. Freedman, D. L. Hayes, M. A. Hlatky, R. E. Kerber, G. V. Naccarelli, M. H. Schoenfeld, M. J. Silka, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines) Circulation, October 15, 2002; 106(16): 2145 - 2161. [Full Text] [PDF]
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W. N. Kapoor Current Evaluation and Management of Syncope Circulation, September 24, 2002; 106(13): 1606 - 1609. [Full Text] [PDF]
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A. Raviele Tilt-induced asystole: a useful prognostic marker or clinically unrelevant finding? Eur. Heart J., March 2, 2002; 23(6): 433 - 437. [Full Text] [PDF]
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A. Raviele, F. Giada, R. Sutton, P. Alboni, M. Brignole, A. Del Rosso, E. di Girolamo, R. Luise, and C. Menozzi The Vasovagal Syncope and Pacing (Synpace) trial: rationale and study design Europace, January 1, 2001; 3(4): 336 - 341. [Abstract] [PDF]
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