(Circulation. 1999;99:1452-1457.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Etilefrine in Preventing Syncopal Recurrence in Patients With Vasovagal Syncope
A Double-Blind, Randomized, Placebo-Controlled Trial
From the Division of Cardiology, Ospedale Umberto I (A.R.), Mestre-Venice, Italy; Section of Arrhythmology, Ospedali Riuniti (M.B.), Lavagna-Genoa, Italy; Division of Cardiology, Royal Brompton National Heart and Lung Hospital (R.S.), London, UK; Division of Cardiology, Ospedale Civile (P.A.), Cento-Ferrara, Italy; Division of Cardiology, Ospedale Bolognini (P.G.), Seriate-Bergamo, Italy; Section of Arrhythmology, Ospedale S. Maria Nuova (C.M.), Reggio Emilia, Italy; and Division of Cardiology, Hospital General Universitari Vall d'Hebron (A.M.), Barcelona, Spain.
Correspondence to Antonio Raviele, MD, Divisione di Cardiologia, Ospedale Umberto I, 30174 Mestre (Venezia), Italy. E-mail araviele{at}TIN.IT
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Abstract |
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Background—Etilefrine is an
-agonist agent with a potent vasoconstrictor effect, which is
potentially useful in preventing vasovagal syncope by reducing venous
pooling and/or by counteracting reflex arteriolar vasodilatation. The
present multicenter, randomized, placebo-controlled study was
designed to evaluate the efficacy of this drug for the long-term
management of patients with recurrent vasovagal syncope. Methods and Results—In the 20 participating centers, 126 patients with recurrent vasovagal syncope (at least 3 episodes in the last 2 years) and a positive baseline head-up tilt response were randomly assigned to placebo (63 patients) or etilefrine at a dosage of 75 mg/d (63 patients) and were followed up for 1 year or until syncope recurred. The primary end-point of the study was the first recurrence of syncope. There were no differences between the 2 study groups in the patients' baseline characteristics. During follow-up, the group treated with etilefrine had a similar incidence of first syncopal recurrence to that of placebo group both in the intention-to-treat analysis (24% versus 24%) and in on- treatment analysis (26% versus 24%). Moreover, the median time to the first syncopal recurrence did not significantly differ between the 2 study groups (106 days in the etilefrine arm and 112 days in the placebo arm).
Conclusions—Oral etilefrine is not superior to placebo in preventing spontaneous episodes of vasovagal syncope. Randomized controlled studies are essential to assess the real usefulness of any proposed therapy for patients with vasovagal syncope.
Key Words: drugs • nervous system, autonomic • reflex • syncope • trials
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Introduction |
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The exact pathophysiological mechanism of vasovagal syncope is still unclear; nonetheless, a key component of the process seems to be an increase in venous pooling leading to a reduction in venous return with resultant paradoxical activation of ventricular mechanoreceptors, reflex sympathetic withdrawal, and arteriolar vasodilatation.1 2 3 4 5 6
-sympathetic agents are thought to prevent vasovagal syncope by 2
mechanisms.7 8 First, by increasing venous tone, these
drugs may reduce venous pooling and thus possibly avoid the paradoxical
activation of ventricular mechanoreceptors. Second, by
increasing arteriolar tone, they may counterbalance the profound reflex
vasodilatation and the hypotension that are ultimately responsible for
the syncope. Etilefrine is an -agonist agent with a potent
vasoconstrictor effect that was first used in 1990 for treatment of
vasovagal syncope. In a small, initial, open
study,9 the drug was shown to be effective
in preventing both tilt-induced and spontaneous episodes of vasovagal
syncope. However, subsequent studies performed with this and other
sympathetic agents yielded conflicting results.8 10 11 12
Thus, in 1994, a double-blind, randomized, placebo-controlled trial
(the Vasovagal Syncope International Study –VASIS)13 was
started in an attempt to establish the real value of etilefrine in the
treatment of vasovagal syncope. In this article, the main results of
this trial are reported and discussed. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Patients
The study cohort consisted of 126 patients with recurrent vasovagal syncope; they were recruited from a total of about 2000 patients referred to the 20 participating centers from September 1994 to September 1996 for evaluation of unexplained syncope by means of head-up tilt testing. To be included in the study, patients had to fulfill the following 2 criteria: at least 3 syncopal episodes in the previous 2 years, with the last episode occurring within 6 months of enrolment and with an interval between the first and last episode >6 months; and positive response to baseline head-up tilt testing.
The diagnosis of vasovagal syncope was based, in addition to a positive tilt test result, on the exclusion of all other possible causes of syncope by means of a systematic work-up. This included, in all patients, careful history and physical examination, full neurological assessment, standard laboratory tests, supine and orthostatic blood pressure measurements, 12-lead surface ECG, bilateral bedside and upright carotid sinus massage, 24-hour Holter recording, and 2-dimensional echocardiography. Other diagnostic investigations, such as exercise stress testing, electrophysiological study, cardiac catheterization, electroencephalogram, Doppler flowmeter analysis of neck vessels, and CT scan or MRI of the brain were performed only when clinically indicated.
Exclusion criteria included moderate or severe hypertension not
controlled by drugs, recent (<6 months) acute myocardial infarction or
angina pectoris, class III or IV NYHA functional class, other common
contraindications to the use of -sympathetic agents,
concomitant severe chronic disease (eg, diabetes mellitus, neurological
disease, terminal neoplasia), use of drugs that can favor or prevent
vasovagal syncope (eg, nitrates, beta-blocking agents), age <18 years,
weight <50 kg, pregnancy, and refusal to participate in the study. All
eligible patients were informed as to the nature of the trial and gave
their written consent before enrolment.
Study Design
The study was planned as a double-blind, randomized, controlled
trial with parallel groups. The study protocol was approved by the
Ethics Committee in each participating center. Eligible patients were
assigned, according to a central computer-generated randomization list,
to one of the 2 study arms: placebo or etilefrine at a dosage of 25 mg
3 times a day (1 capsule every 8 hours). Randomization was stratified
by balanced blocks of 4 patients. Several blocks, sufficient to cover
all patients, were assigned to each center. Etilefrine and placebo
(Boehringer Ingelheim) were provided as 25 mg capsules
identical in shape, color, and size.
After 3 to 6 days of treatment, a second head-up tilt test was performed in the same manner as the baseline test. Regardless of the response obtained, the patients continued with the treatment initially established and were followed up. The reason for repeating the head-up tilt test was to establish the short-term reproducibility of the test as well as its value in predicting the efficacy of long-term therapy with etilefrine (a posteriori analysis).
During follow-up, examinations were performed every 3 months. At each examination an accurate history, a physical examination and an ECG were performed; in particular, a record was kept of any syncopal or presyncopal recurrence, associated traumas, side-effects, variations in treatment from the initial dosage, and other concomitant therapy. Titration decrements in etilefrine or placebo to 25 mg twice a day (2 capsules a day) was permissible. Drug compliance was assessed by pill counting. The follow-up duration was 1 year or until syncope recurred. Predefined criteria of withdrawal from the study included major protocol violations, poor patient cooperation or noncompliance in returning for examination and/or administration of drug medication, occurrence of serious adverse events (defined as untoward medical events requiring hospitalization or producing temporary or permanent invalidation or life-threatening or fatal), pregnancy, and the patients' refusal to continue. Patients who dropped out because of intolerable adverse experiences, lack of adequate therapeutic response resulting in intolerable signs and/or symptoms, or unacceptable risk were considered complete cases for the intention-to-treat analysis.
Study End-Points
The primary study end-point was the first recurrence of
syncope during follow-up. Secondary end-points were the
recurrence of presyncope, the total number of presyncopal
episodes, and the usefulness of etilefrine in preventing tilt-induced
syncope (short-term study).
Head-Up Tilt Testing Protocol
Head-up tilt testing was always performed in the morning, after
overnight fasting, in a quiet, slightly darkened room. The procedure
was performed by means of an electronically controlled tilt table with
a footboard for weight-bearing. Blood pressure was measured by means of
an Ohmeda Finapress 2300 (Ohmeda) photoplethysmographic device
that provides noninvasive beat-to-beat determination of finger
arterial pressure by the Penaz volume-clamp
method.14
Initially (first 24 patients), head-up tilt testing was performed without drug challenge, according to the Westminster protocol (passive tilting at 60° for 45 minutes).15 Beginning in March 1995, in an attempt to increase the recruitment rate, sublingual nitroglycerin provocation16 was added. If syncope did not develop during the initial unmedicated phase at 60° for 45 minutes, 300 µg of nitroglycerin was administered sublingually, and patients continued to be tilted at 60° for an additional 20 minutes. The end-points of head-up tilt testing were positive response (see below) and completion of the protocol.
Definitions
Syncope was defined as sudden transient loss of consciousness,
with inability to maintain postural tone, and with spontaneous
recovery. Presyncope was defined as the complex of premonitory signs
and symptoms of imminent syncope (eg, severe light-headedness, severe
weakness, transient graying of vision, or hearing loss) with difficulty
in maintaining postural tone. A positive response to head-up tilt
testing was defined as reproduction of the spontaneous syncope
in association with hypotension, bradycardia, or both (decrease in
systolic blood pressure >50% and decrease in heart rate
>30% of the maximal value observed in the upright position). During
the drug-free phase of the test, the occurrence of isolated hypotension
was considered sufficient to classify the response as positive. During
the pharmacological phase, both hypotension and bradycardia of
relatively rapid onset (occurring within 5 minutes) were
required.16 The positive response to head-up tilt testing
was defined as cardioinhibitory when a marked bradycardia
(
40 bpm for >10 seconds) or prolonged asystole (
3 seconds)
occurred at the time of syncope.13 The positive response
was defined as vasodepressor or mixed when isolated hypotension or
hypotension associated with only mild bradycardia (>40 bpm) or brief
asystole (<3 seconds) was observed.13
Sample Size Calculation
The formula used to compute the sample size17 is
reported in Appendix 1. The sample size calculation was based on the
results of a preliminary study9 that suggested an expected
15% 1-year syncopal recurrence rate in the placebo group and
an expected 5% 1-year syncopal recurrence rate in the
etilefrine group. With an alpha level of 0.05 and a test power of 0.80,
the resulting sample size was 137 patients for each treatment group;
this was increased to 180 patients on account of the number of dropouts
anticipated.
For ethical and administrative problems, formal interim analysis was planned and performed in September 1996, after the first 70 patients had concluded 1-year follow-up. This interim analysis revealed a lack of evidence of etilefrine efficacy, and it was estimated that, even with a considerably greater number of patients (360 or more), it would have been practically impossible to show any significant difference between etilefrine and placebo. Thus, the Steering Committee decided to stop recruitment.18 The final statistical analysis was performed on the 126 patients who had already been enrolled at the time of interim analysis. With this number of patients the test power is 0.50.
Statistical Analysis
The primary analysis of the results of the study was by
intention-to-treat but we also made an on-treatment analysis of
the primary end-point in enrolled patients (with >70% compliance)
while they were on study medication or within 3 days of early permanent
discontinuation. The recurrence of syncope in the 2 treatment
groups was tested by using the odds ratio of the 2-binomial proportion
analysis. Moreover, the time to the first syncopal
recurrence was analyzed by means of Kaplan-Meier
curves. Means (±SD) and medians were calculated for continuous
variables, and frequencies were measured for categorical
variables. Differences between groups were examined for statistical
significance by a 2-sample Student's t test for continuous
variables and by Fisher's exact test for categorical
variables. P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Patient Characteristics
The trial profile shows overall patient numbers throughout the study (Figure 1
). Screening logs were not
maintained throughout the trial, but we used data from tilt laboratory
records to calculate that, during the study recruitment period,
about 2000 patients with unexplained syncope were referred for tilt
testing evaluation and that about 250 of these (approximately 12%) met
eligibility criteria. Of these, 126 of the eligible patients gave their
informed consent to take part (
6% of the source population). Of
the 126 enrolled patients, 63 were randomly assigned to the etilefrine
arm and 63 to the placebo arm. The baseline characteristics of
randomized patients in the 2 study groups were broadly similar
(Table 1). The patients were
followed up for a maximum of 1 year (mean, 262 days). During the
follow-up, 13 patients (5 in the etilefrine group and 8 in the placebo
group) were not assessable by on-treatment analysis owing to
poor (<70%) drug compliance or >3 days' drug discontinuation. Thus,
the efficacy analysis was performed only on a total of 113
patients. Outcome events are summarized in Table 2.
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Primary End-Point
In the intention-to-treat analysis, the group treated with
etilefrine had the same number of syncopal episodes as the placebo
group (15 patients, 24%). In the on- treatment analysis,
similar results were found. Median time to the first recurrence
of syncope was no different between the etilefrine group and the
placebo group (106 days versus 112 days). The Kaplan-Meier actuarial
estimates of first recurrence of syncope by intention-to-treat
analysis and by on-treatment analysis are shown in
Figures 2 and 3, respectively. The probability of
remaining free of syncope drops steadily and similarly in both
groups.
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Secondary End-Points
No statistical difference was observed between the 2 study groups
concerning the number of patients who had at least one presyncope
during follow-up and the total number of presyncopal episodes. On
repeated head-up tilt testing performed 3 to 6 days after the start of
treatment, etilefrine did not appear superior to placebo in preventing
tilt-induced syncope (negative response 52% in etilefrine group versus
45% in placebo group).
Variables Predictive of Syncopal Recurrence
In order to assess the value of some variables in predicting
the risk of syncopal recurrence during follow-up, the data of
all 126 patients enrolled were analyzed together (owing to the
lack of significant difference between the two study groups concerning
the primary end-point). Among the different variables examined,
many syncopal episodes (>6) and a positive response to repeated
head-up tilt testing on treatment were predictive of a higher risk of
syncopal recurrence (45% in patients with >6 episodes versus
20% in patients with 6 episodes, P<0.04; and 32% in
patients with positive response to repeated tilt test versus 15% in
patients with negative response, P<0.05; Table 3).
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Adverse Events
A total of 30 adverse events judged as possibly related to the
treatment were registered, 17 occurring in patients treated with
etilefrine and 13 occurring in the placebo group. The occurrence of
adverse events was comparable between the 2 treatment groups, the only
exception being psychiatric disorders, such as agitation, depression,
anxiety, and insomnia, which were exclusively observed in patients
treated with etilefrine (20% versus 0%). In particular, the incidence
of gastrointestinal discomfort, palpitations, and new onset or
worsening of hypertension, generally considered common side-effects of
therapy with -agonist agents, was not significantly higher in the
etilefrine group than in the placebo group. Overall, the majority of
adverse events were mild/moderate in severity. However, 7 patients (4
in the etilefrine group and 3 in the placebo group) discontinued
treatment prematurely because of adverse events. No deaths or serious
syncope-associated traumas occurred throughout the study.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Previous Studies
In recent years, several investigators have evaluated the utility of
-agonist medications in the treatment of vasovagal syncope, and
the reported results have usually been positive.8 9 10 11 12
However, the majority of the trials conducted with these drugs have
been open studies performed in small numbers of patients and have
involved different compounds, such as etilefrine, pseudoephedrine, and
midodrine. To date, there are only 2 small controlled trials that have
been performed with -agonist agents with discordant results. In the
Moya trial,10 no difference was observed between
etilefrine and placebo, whereas in the Ward trial,12
midodrine appeared to be clearly superior to placebo. It is noteworthy
that both these trials were essentially short-term studies designed to
test the efficacy of -agonist agents in preventing tilt-induced
syncope. Moreover, the dosage of etilefrine in the Moya study (10 mg, 3
times a day) was probably too low to achieve a marked vasoconstrictor
effect, as recognized by the same authors.10 Thus, at the
present time, we have insufficiently compelling data on the real
efficacy of long-term therapy with -agonist agents for the
prevention of spontaneous recurrences of vasovagal syncope. The
VASIS trial was a multicenter, double-blind, randomized,
placebo-controlled trial, which was planned in 1994 to answer this
question. The trial was prematurely interrupted in September 1996 after
the first interim analysis had been performed.
Main Findings
The main finding of the VASIS trial is the lack of superiority of
etilefrine over placebo in preventing spontaneous syncopal
recurrence. Indeed, the 63 patients treated with etilefrine at
the dosage of 25 mg 3 times a day showed exactly the same
recurrence rate during the first year following enrolment as
did the 63 patients treated with placebo (24%). Furthermore, the time
to the first syncope after the start of treatment, as well as the
incidence and the number of presyncopal episodes, were not
significantly different between the 2 study groups. These results
confirm those of 3 previous small randomized controlled trials
performed by Fitzpatrick et al,19 Brignole et
al,20 and Morillo et al.21 with other drugs,
and, like those results, strongly suggest caution in interpreting the
outcome of open studies that do not include a placebo or control group.
Indeed, the frequently benign course of vasovagal syncope, with
relatively long periods of quiescence and asymptomatic
status regardless of the intervention, may give the false impression of
drug efficacy.
The relatively low recurrence rate of symptoms in our study population, despite the predicted high risk of relapses, is in agreement with the observations made by many authors20 21 22 and may be explained by the cyclic course of neurally mediated syncope, patient reassurance, a possible therapeutic action of repeated tilting,23 and the placebo effect of the treatment.
Minor Findings
Like other studies,10 19 20 21 the VASIS trial
documented a marked reduction in the incidence of positive responses to
repeated tilt testing on treatment, whether etilefrine or placebo was
administered, with no difference between the 2 study groups (52%
negative conversion of a positive tilt result with etilefrine and 45%
with placebo). This suggests a low short-term reproducibility of
positive tilt tests and discourages the use of serial head-up tilt
testing as a method for predicting the efficacy of a given therapeutic
intervention.24 It is noteworthy that the persistence of a
positive response to repeated tilt testing on treatment was able to
identify a subgroup of patients with a higher incidence of syncopal
recurrences during follow-up. Many previous syncopal episodes
(>6), in accordance with the data of Sheldon et al25 and
Grimm et al,26 was also predictive of a greater
probability of syncopal relapse. The identification of clinical
variables significantly associated with syncopal
recurrences is clearly of great value in detecting those
patients with vasovagal syncope who really need long-term
treatment.
Conclusions
In conclusion, the VASIS trial has clearly demonstrated that
etilefrine is not superior to placebo in preventing vasovagal syncope.
Moreover, it has taught us that today only randomized
placebo-controlled trials are able to assess the real efficacy of any
proposed treatment for patients with vasovagal syncope. Finally, it has
shown the limited value of tilt table testing in predicting a positive
outcome, which must caution us in the interpretation of other studies
using response to tilt table testing as therapy end-point.
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Footnotes |
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1 A complete list of the Vasovagal Syncope International Study (VASIS) Investigators appears in Appendix 2.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Formula used to compute sample size:
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/2=standard normal
distribution for error I type Z1-ß=standard normal
distribution for error II type |
Appendix 2 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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VASIS Participating Centers and Investigators
Ospedale Umberto I, Mestre-Venezia: Franco Giada, MD, Gianni Gasparini, MD; Ospedale S. Maria Nuova, Reggio Emilia: Gino Lolli, MD; Ospedale Bolognini, Seriate-Bergamo: Giuseppe Leoni, MD, Vittorio Giudici, MD; Ospedale Ferrari, Casarano-Lecce: Giacinto Pettinati, MD, Fernando De Sanctis, MD; Ospedale Civile, Mirano-Venezia: Federico Sartori, MD, Albino Zanocco, MD; Ospedale Nuovo S. Gerardo, Monza-Milano: Antonio Vincenti, MD, Sergio De Ceglia, MD; Ospedale Riuniti, Lavagna-Genova: Daniele Oddone, MD; Ospedale S. Maria delle Croci, Ravenna: Silvano Silvani, MD, Maurizio Piancastelli, MD; Ospedale Maggiore, Lodi-Milano: Mario Orlandi, MD, Egidio Marangoni, MD; Ospedale Civile, Borgomanero-Novara: Marco Zanetta, MD, Umberto Parravicini, MD; Ospedale Valduce, Como: Mauro Santarone, MD, Giovanni Foglia Manzillo, MD; Ospedale Fatebenefratelli, Roma: Massimo Fioranelli, MD; Ospedale Giuseppe Moscati, Avellino: Giuseppe De Fabrizio, MD, Francesco Rotondi, MD; Ospedale S. Orsola Fatebenefratelli, Brescia: Alessandra Marchetti, MD; Ospedale Civile, Cento-Ferrara: Maurizio Dinelli, MD; Ospedale Civile, Imperia: Giacomo Musso, MD, Antonello Ranise, MD; Ospedale Civile, Castelnuovo Garfagnana-Lucca: Eugenio Nannini, MD, Pier Romano Mariani, MD; Ospedale Silvestrini, Perugia: Pietro De Ciuceis, MD, Vincenzo Chiodini, MD; Ospedali Riuniti, Taranto: Vitantonio Russo, MD, Nicola Baldi, MD; Ospedali Riuniti, Salerno: Michele Di Mauro, MD, Andrea Campana, MD.
VASIS Data Coordinating Center: Boehringer Ingelheim Italia, Milano: Elena Cicioni, ScD; Medical Statistics Service: Mauro Montanari, PhD, Paola Ambroso, BScD.
Received August 20, 1998; revision received November 18, 1998; accepted December 11, 1998.
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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 M. Brignole, J.-J. Blanc, R. Sutton, and A. Moya CHAPTER 26 Syncope ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
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S. Petkar and A. Fitzpatrick Tilt-table testing: transient loss of consciousness discriminator or epiphenomenon? Europace, June 1, 2008; 10(6): 747 - 750. [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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N. van Dijk, F. Quartieri, J.-J. Blanc, R. Garcia-Civera, M. Brignole, A. Moya, W. Wieling, and on behalf of the PC-Trial Investigators Effectiveness of Physical Counterpressure Maneuvers in Preventing Vasovagal Syncope: The Physical Counterpressure Manoeuvres Trial (PC-Trial) J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1652 - 1657. [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, P. Vardas, and for the International Study on Syncope of Uncertai Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope Eur. Heart J., May 1, 2006; 27(9): 1085 - 1092. [Abstract] [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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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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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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 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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 W. N. Kapoor Current Evaluation and Management of Syncope Circulation, September 24, 2002; 106(13): 1606 - 1609. [Full Text] [PDF]
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M. Brignole and E. Puggioni Exercise-related syncope: are athletes different from sedentary subjects? Eur. Heart J., July 2, 2002; 23(14): 1080 - 1082. [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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G Baron-Esquivias, A Pedrote, A Cayuela, J.I Valle, J.M Fernandez, E Arana, M Fernandez, F Morales, J Burgos, and A Martinez-Rubio Long-term outcome of patients with asystole induced by head-up tilt test Eur. Heart J., March 2, 2002; 23(6): 483 - 489. [Abstract] [Full Text] [PDF]
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A. Moya, M. Brignole, C. Menozzi, R. Garcia-Civera, S. Tognarini, L. Mont, G. Botto, F. Giada, and D. Cornacchia Mechanism of Syncope in Patients With Isolated Syncope and in Patients With Tilt-Positive Syncope Circulation, September 11, 2001; 104(11): 1261 - 1267. [Abstract] [Full Text] [PDF]
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Task Force on Syncope, European Society of Cardiol, M Brignole, P Alboni, D Benditt, L Bergfeldt, J.J Blanc, P.E Bloch Thomsen, J.G van Dijk, A Fitzpatrick, S Hohnloser, et al. Guidelines on management (diagnosis and treatment) of syncope Eur. Heart J., August 1, 2001; 22(15): 1256 - 1306. [Abstract] [PDF]
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 M. Bryce, S. R. Spielman, A. M. Greenspan, and M. N. Kotler Evolving Indications for Permanent Pacemakers Ann Intern Med, June 19, 2001; 134(12): 1130 - 1141. [Abstract] [Full Text] [PDF]
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A. H. Madrid, J. Ortega, J. G. Rebollo, J. G. Manzano, J. G. Segovia, A. Sanchez, G. Pena, and C. Moro Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study J. Am. Coll. Cardiol., February 1, 2001; 37(2): 554 - 559. [Abstract] [Full Text] [PDF]
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W. N. Kapoor Syncope N. Engl. J. Med., December 21, 2000; 343(25): 1856 - 1862. [Full Text] [PDF]
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A. M. Fenton, S. C. Hammill, R. F. Rea, P. A. Low, and W.-K. Shen Vasovagal Syncope Ann Intern Med, November 7, 2000; 133(9): 714 - 725. [Abstract] [Full Text] [PDF]
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R. Sutton, M. Brignole, C. Menozzi, A. Raviele, P. Alboni, P. Giani, and A. Moya Dual-Chamber Pacing in the Treatment of Neurally Mediated Tilt-Positive Cardioinhibitory Syncope : Pacemaker Versus No Therapy: A Multicenter Randomized Study Circulation, July 18, 2000; 102(3): 294 - 299. [Abstract] [Full Text] [PDF]
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 Prospective Trials Needed to Evaluate Treatments for Vasovagal Syncope Journal Watch Cardiology, May 21, 1999; 1999(521): 2 - 2. [Full Text]
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