(Circulation. 1996;93:973-981.)
© 1996 American Heart Association, Inc.
Articles |
Risk Factors for Syncope Recurrence After a Positive Tilt-Table
Test in Patients With Syncope
From the Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada.
Correspondence to Dr Robert Sheldon, Division of Cardiology, Calgary General Hospital, 841 Centre Ave E, Calgary, Alberta, Canada T2E 0A1.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Recent work with head-up tilt-table testing has suggested that many patients with syncope may have recurrent neurally mediated episodes of bradycardia, hypotension, or both. The purpose of this study was to determine how to identify patients at high risk of a recurrence of neuromediated syncope after a positive isoproterenol/tilt-table test.
|
Methods and Results A cohort of 101 drug-free patients in a
university hospital outpatient clinic with syncope and a positive
isoproterenol/tilt-table test underwent baseline assessment of
demographic variables, symptomatic burden, and
hemodynamic and clinical responses to tilt testing. The
primary outcome measure was the time to the first recurrent syncopal
spell. The actuarial probabilities of remaining syncope free after 1
and 2 years were 72% and 60%, respectively.
Multivariate proportional hazards analysis
demonstrated that the most powerful predictor of a recurrence
of syncope was the logarithm of the number of preceding syncopal spells
(P<.001). Other predictive variables included the
duration of syncopal symptoms, tilt-test symptomatic
outcome, and trough heart rate. The probability of a recurrence
of syncope also varied with the logarithm of the frequency of preceding
spells (P=.008). The median frequency of pretest spells was
0.3/month; after the tilt test, the median frequency dropped 
90% to
0.03 per month.
Conclusions The risk of a recurrence of syncope after a positive tilt-table test can be predicted with simple pretest and intratest variables.
Key Words: syncope • prognosis • follow-up studies • tilt-table tests
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Recurrent syncope is a common clinical problem and a significant diagnostic and therapeutic challenge. Recent work with head-up tilt-table testing has suggested that many patients with syncope have recurrent episodes associated with variable combinations of bradycardia and hypotension.1 2 3 4 This has been variably described as vasovagal syncope, bradycardia/hypotension syndrome, or neuromediated syncope. Attention is focused increasingly on how best to treat patients with recurrent neuromediated syncope. To counsel patients and to plan clinical trials, we need to know which patients are at high risk of recurrent syncope after tilt-table testing and, conversely, which patients are at such low risk of recurrent syncope that they could be managed conservatively without drug therapy.
At this time, there are no data that can be used to identify high- or low-risk patients and little data documenting the clinical course of drug-free patients after tilt-table testing. The purpose of the present study was to determine how to identify patients at high risk of recurrent neuromediated syncope after a positive isoproterenol/tilt-table test. Specifically, we used univariate and multivariate analyses to determine which pretest clinical variables and intratest tilt-table variables were significant risk factors for recurrent neuromediated syncope.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patient Population
The global patient population consisted of 338 sequentially consenting patients referred for assessment of syncope who underwent tilt-table testing if they had had (1) two or more syncopal episodes, (2) one syncopal episode and four or more presyncopal episodes, or (3) a single episode of syncope causing serious injury. Patients with structural heart disease, documented ventricular tachycardia, or bifascicular block also underwent ambulatory ECG and programmed electrical stimulation with a previously described protocol.5 Tilt-table tests and electrophysiological studies were performed on separate days. No patients underwent tilt-table testing while taking ß-adrenoceptor–blocking agents,6 disopyramide, or drugs with anticholinergic activity.
Tilt-Table
Test
Patients underwent tilt-table
testing in a quiet room after
they had fasted for 4 to 8 hours. They were comfortably restrained on
an electric tilt table. Instrumentation consisted of a
peripheral intravenous cannula and automatic
and manual sphygmomanometric blood pressure cuffs, but
intra-arterial cannulation was not performed. Our
previously published protocol7 8 was used. The
limitations
of this approach with regard to the generalizability of our findings
are reviewed in "Discussion." The test ended after frank syncope
during an infusion of 5 µg/min isoproterenol or to a total of 10
minutes in the head-up position with either presyncope or no
symptoms. Heart rate, blood pressure, and symptoms were recorded
each minute. Based on our previous work,7 tilt tests were
considered to be positive if they ended in syncope or in presyncope and
a drop in rate–systolic pressure product to 
9000
mm Hg/min. We stress that tilt tests ended only with syncope or at the
end of a 10-minute head-up tilt. Because presyncope was not a cause
for stopping the test before the end of a 10-minute period, the two
positive test outcomes (syncope and presyncope) can be assessed as
separate prognostic risk factors for clinical outcome.
Definitions
"Syncope" was defined as a transient
state of
unconsciousness characterized by spontaneous recovery or by recovery
during the supine position. "Presyncope" was defined as a state
of lightheadedness usually associated with one or more symptoms of
decreased vision, the sensation of hearing voices distantly, slow
response times to verbal stimuli, nausea, vomiting, or partial loss of
postural tone and which substantially reproduced the clinical
presyncope of the patient. "Duration of symptoms" refers to the
number of months elapsed between the first historical syncopal spell
and the diagnostic tilt-table test.
Interventions
After tilt-table testing and a brief rest
period, all
patients underwent counseling regarding the diagnosis, probable
pathophysiology, lack of mortality, and uncertain
symptomatic prognosis of neuromediated syncope. All
patients were reassured, counseled on recognizing their presyncopal
prodromal symptoms, and urged to take specific appropriate postural
maneuvers when presyncopal. Throughout this study, we recognized the
lack of level I to IV studies9 demonstrating drug
efficacy. The lack of certainty about the efficacy of any form of
pharmacological therapy was discussed, and no patients were urged to
accept empiric drug therapy. All patients who were started on drug
therapy did so at their own request. Throughout the study, we used
ß-adrenergic–blocking agents (when not contraindicated) for
initial attempts at treatment. Thus, although patients were started on
drug treatment at their request, ß-blockers were selected as the
particular pharmacological therapy by the investigators. The
differences between the treated and untreated populations are described
in "Results."
Follow-up
All patients were asked to notify the syncope
clinic of their
first recurrence of syncope, and all patients were also
contacted every 6 months by telephone. We defined the following end
points. The primary end point was the first recurrent syncopal spell in
patients who did not receive pharmacological therapy from the day of
the tilt test and who had a subsequent syncopal spell. Presyncope was
not an end point (see "Discussion"). Patients who did not have a
recurrent syncopal spell and had not received drug treatment were
censored on the date of last contact with the clinic. Patients who
crossed over from no treatment to treatment for any reason and had had
no recurrent syncope by that time were censored on the date of
crossover.
Statistical Analysis
We first determined whether a variable
was normally
distributed or skewed. The skewed distributions were analyzed
after natural logarithmic transformation. Mean (±SD) and median values
were calculated for continuous variables, and frequencies were
measured for categorical variables. Differences between groups were
examined for statistical significance with a two-sample
t test for continuous variables (using a logarithmic
transformation on skewed distributions as appropriate) and by Fisher's
exact test for categorical variables. P values are
two-tailed without adjustment for multiple P values.
Kaplan-Meier estimates of syncope-free survival were used to
illustrate the overall syncope-free survival rate and to assess the
prognostic effect of variables.
Proportional Hazards Model
Because most of the variables were
continuous, the
association of each variable with the probability of remaining
syncope-free was assessed first with a univariate Cox
proportional hazards regression model,10 which was then
used for multivariate analysis. All
variables were entered into the multivariate model
regardless of their significance in the univariate
analysis. The statistical significance of each variable in
the hazards models was evaluated with the Z statistic for
the regression coefficient. Variables significant at
P<.10 were retained in the proportional hazards model. All
two-way interactions between the variables were assessed for
statistical significance. A Martingale residual
analysis11 was used to assess the most appropriate
functional form for the continuous variables, and Schoenfeld
residuals12 were used to test the assumption of
proportional hazards. The instantaneous relative risks for dichotomous
variables were calculated from the exponential of the estimated
regression coefficient ß of the variable, with all other
variables in the model remaining constant. The instantaneous
relative risk for a continuous variable for an increase in n units
of that variable is exp(ß)n.
Predictive Model
One goal of the present study was to develop
a model that
would enable clinicians to predict the clinical outcome of patients
based on pretest and intratest variables. Smooth continuous
estimates of modeled survivor function were necessary for construction
of this predictive model. The survivor function first was calculated
from the proportional hazards model.13 The survivor
function is a step function, similar to a Kaplan-Meier estimate.
Smoothed survivor functions were calculated by fitting the Weibull
distribution S(t)=exp[-(
t)
] to the
survivor step
function. The Weibull distribution was selected for several reasons.
First, it is closely related to the exponential Poisson distribution,
which assumes the randomness of outcomes in a population and has proved
to be useful in outcome studies with supraventricular
arrhythmias. Second, it fit the data better than other
equations (see below). Third, it allows a continuous estimate of
changes in relative risk of outcomes over time. Note that a Weibull
distribution with =1 is a conventional exponential distribution.
The
survivor function in Fig 1 is well fit by a Weibull
distribution with =0.566 with a 95% confidence interval of 0.543
to
0.588, indicating that a simple exponential distribution would not
adequately fit the data.
|
Smooth estimated survivor functions for individuals with nonzero covariates were then calculated with one coefficient from the proportional hazards model. The proportional hazards regression model with pretest variables was used to produce a model that can predict the risk of a recurrence of syncope within the first 12 or 24 months after a tilt-table test. The baseline hazard function was estimated with a Weibull distribution, and the combination of values of the two clinical variables (number of spells and duration of symptoms) were calculated to solve the proportional hazards equation for each specified risk.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Of the 338 patients in the global population, 196 had a positive tilt-table test. Of these, 52 received empiric therapy with ß-adrenoceptor blockers and 10 were treated with other medications. An additional 33 were lost to follow-up. The 101 patients who did not receive drug therapy form the basis of this report. The baseline clinical characteristics and tilt-test variables of the 43 patients lost to follow-up or treated with other medications closely resemble the characteristics of the 153 patients who either did not receive pharmacological therapy (101) or received ß-blockers (52), although these 153 patients had an insignificantly lower geometric mean number of syncopal spells (7.1; confidence interval, 5.3 to 9.4) than did the excluded patients (12.5; confidence interval, 7.3 to 21.4) (P=.074).
The baseline clinical characteristics and tilt-test variables of the 52 patients treated with ß-blockers closely resemble the characteristics of the 101 study patients, although the patients who elected to be treated were older (44±21 versus 36±19 years; P=.03) and had fainted more frequently. The patients who subsequently received ß-blockers had had a geometric mean frequency of 0.55 spells per month (confidence interval, 0.30 to 0.92), whereas untreated patients had had a geometric mean frequency of 0.31 spells per month (confidence interval, 0.23 to 0.41) (P=.04).
The clinical and tilt-table test variables of the study
population are shown in Table 1. The population
consisted of 43 men and 58 women with a mean age of 36±19 years
(range, 11 to 89 years). They had had a geometric mean of 6 syncopal
spells over a geometric mean of 21 months with a geometric mean
frequency of 0.3 syncopal spells per month. During the tilt test, 49
patients developed syncope and 52 patients developed presyncope. Table
2 shows the distribution of patients according to their
historical number of syncopal spells or duration of symptoms. Although
many patients (46 of 101) had 3 spells, there was a substantial
population (33 of 101) with >10 spells. Similarly, although many
patients (33 of 101) had had symptoms for 10 months, there were many
others (51 of 101) with symptoms lasting >30 months.
|
Of the 101 patients in this study, 28 had a syncopal spell at some time
after a positive tilt-table test, whereas 73 did not have recurrent
syncope. The probability of remaining free of syncope is shown in Fig
1A. The step function indicates the Kaplan-Meier estimate of
the
survivor function (with 95% confidence intervals). The smooth curve
indicates the survivor function of the Weibull distribution that
provided the closest fit to the data. There is a steady decline in the
probability of remaining syncope free with time. This probability after
1, 2, and 3 years was 0.72, 0.62, and 0.51, respectively.
The populations of patients with and without a recurrence of
syncope are compared in a univariate analysis in
Table 1. Patients with a recurrence of syncope were younger,
were more likely to be women, had more syncopal spells and a longer
duration of symptoms, and had a significantly higher peak heart rate
during tilt-table testing. There were no significant differences
between these two populations in any of the other tilt-table test
variables.
Univariate Analysis
The variables listed in Table
1 were subjected to a
univariate analysis of their prognostic value in
predicting the hazard of recurrent syncope after a positive
tilt-table test. The variables in Table 3 are
those that reached a statistical difference of P<.1 and
those that became significant in a subsequent
multivariate proportional hazards analysis. The
pretest variable that predicted a recurrence of syncope
most powerfully was the logarithm of the number of syncopal spells
preceding the tilt test (P<.001). Other pretest
variables that had prognostic significance were the logarithm of
age, the logarithm of the duration of symptoms, and the frequency of
syncopal spells. Of the tilt-table test variables listed in
Table 1, only peak heart rate was a significant univariate
predictor of a recurrence of syncope (P=.019). Two
other variables, a polynomial transformation of trough heart rate
and syncope as an outcome, were not significant univariate
predictors of outcome but were identified subsequently as significant
predictors in a multivariate proportional hazards
analysis (Table 4).
|
|
Kaplan-Meier estimates of the
probability of remaining free of syncope
for four different groups of subjects are presented in Fig 1B.
Patients with <6 syncopal spells over a duration of <24 months have a
1-year event-free probability of 0.94, whereas patients with 
6
syncopal spells over a duration 24 months have a probability of
remaining free of syncope after 1 year of only 0.54. Patients with <6
syncopal spells over a period 24 months and patients with 6
syncopal spells over a duration of <24 months have intermediate
probabilities of remaining free of syncope at 1 year of 0.66 and 0.71,
respectively. Thus, the simple pretest clinical characteristics of the
number of syncopal spells and the duration of symptoms are important
predictors of the probability of a recurrence of syncope.
Multivariate Analysis
The multivariate proportional hazards
analysis was performed in two stages. The first model included
only the pretest variables, whereas the second model considered
both pretest and intratest variables. In the first analysis
(Table 4, top), the variable log (spells and number) was a
powerful
predictor of a recurrence of syncope (P<.001). In
addition, there was a significant interaction (P=.008) of
this variable with log (duration of symptoms). This indicates that
the prognostic effect of each of these two variables must be
considered simultaneously. We have illustrated this
interactive effect in Fig 2A and 2B. This figure
depicts
the probability of remaining free of syncope for a modeled average
patient with various combinations of numbers of pretest syncopal spells
and durations of symptoms. A patient with a duration of symptoms of 6
months has a much higher likelihood of a recurrence of syncope
if he or she had had 17 syncopal spells preceding the tilt-table
test compared with a patient who had had only 2 preceding syncopal
spells. The probabilities of remaining free of syncope after 2 years in
these two modeled patients were 0.26 (17 spells) and 0.82 (2 spells),
respectively. In contrast, a patient with symptoms lasting 84 months
had 2-year probabilities of remaining free of syncope of 0.46 and 0.66
if he or she had had 17 and 2 preceding spells, respectively.
Interestingly, a patient with 7 syncopal spells had a probability of
remaining free of syncope that was independent of the duration of
symptoms. Both patients had probabilities of remaining free of syncope
after 2 years of 0.54 (Fig 2A and 2B).
|
The significant interaction of the number of syncopal spells and
duration of symptoms as predictors of a recurrence of syncope
indicates that the relation between these two variables is not as
straightforward as the simple frequency of symptoms. This interaction
is summarized in Fig 2C. The risk of a recurrence of syncope
for patients who had 7 syncopal episodes is independent of the duration
of symptoms. With this homogeneous group as baseline, we
estimated the instantaneous relative risk as a function of the total
number of previous syncopal episodes for five populations that have
histories of symptoms of 1, 6, 27, 84, and 240 months. These were the
5th, 25th, 50th, 75th, and 95th percentiles of durations. In Fig
2C, we
illustrate the risk for an individual with a given number of episodes
(horizontal axis) in a certain length of time (lines) relative to an
individual who had 7 episodes in the same length of time. The risk of a
recurrence of syncope increases linearly with the logarithm of
the total number of preceding syncopal episodes. The significant
interaction indicates that although the risk of a recurrence of
syncope always increases with the number of spells, the rate of
increase is much greater if the symptoms occurred over a short period
of time. For patients with <7 episodes, the relative risk is always
<1, indicating that individuals with <7 episodes are at less risk
than are patients with 7 episodes within the same period of time. In
addition, this relative risk decreases as the duration of symptoms
decreases. Conversely, for patients who have >7 episodes, the relative
risk increases rapidly as the duration of symptoms decreases.
The
effect of the interaction between the number of historical syncopal
spells and the duration of symptoms on prognosis is depicted in Fig
3. The independent variable is the probability of
remaining free of syncope throughout the first year after a positive
tilt-table test. Patients who have had few syncopal spells over a
short period of time are at much lower risk of a syncopal
recurrence than patients who have had a large number of
syncopal spells over a short period of time. The effect of a long
duration of symptoms is to smooth out (to some extent) the differences
in these risks.
|
Table 4 shows illustrative changes in
instantaneous
relative risks of a recurrence of syncope depending on pretest
clinical variables. For example, a doubling in the historical
number of syncopal spells increases the instantaneous relative risk of
syncope by 1.23- to 2.82-fold, depending on the duration of symptoms.
The 95% confidence intervals of these estimates are 1.00 to 1.52 and
1.49 to 5.38, respectively.
The prognostic significance of pretest and
intratest variables in a
model that incorporates both types of variables is shown in Table
5 (bottom). The addition of intratest variables does
not change the prognostic value of the pretest variables, as can be
seen by the lack of change in the regression coefficients. In addition,
syncope as a tilt-test outcome (P=.062) and a polynomial
function of trough heart rate (P=.078 and
P=.10
for the linear and quadratic terms, respectively) both tended to
predict a recurrence of syncope. The data in Fig 4A show that
patients who develop syncope on a
tilt-table test have a 2-year probability of remaining free of
syncope of 0.45, whereas patients who develop only presyncope on a
tilt-table test have a 2-year probability of remaining fee of
syncope of 0.72. The quadratic nature of the predictive value of trough
heart rate is illustrated in Fig 4B. This model shows that
patients
with trough heart rates of 60, 80, and 100 beats per minute have a
2-year probability of remaining free of syncope of 0.63, 0.37, and
0.53, respectively. Fig 4C shows that the likelihood of a
recurrence of syncope is highest for patients with a trough
heart rate of 75 to 85 beats per minute and that this risk decreases
steadily with trough heart rates below or above this critical
range.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
These findings demonstrate that the risk of a recurrence of syncope after a positive isoproterenol/head-up tilt-table test can be estimated from a knowledge of two simple clinical variables—the number of pretest syncopal spells and the duration of the pretest symptoms. This estimate can be refined further based on whether patients faint or merely become presyncopal during the tilt-table test and based on the trough heart rate during symptoms. This information may prove useful in counseling patients about their risk of a recurrence of syncope, in determining which patients might be candidates for pharmacological therapy, and in determining which patients might be candidates for future interventional trials.
Until the advent of tilt-table testing, the diagnosis of idiopathic syncope frequently frustrated clinicians. Tilt-table testing has improved understanding of this syndrome, but in the absence of a gold standard, diagnostic criteria have remained a test of elusive sensitivity and contentious specificity.14 15 We elected to define a study population as patients with two diagnostic criteria: clinical syncope and symptoms that could be reproduced on isoproterenol/head-up tilt-table testing.
Choice of Clinical Outcome
Studies concerned with clinical
outcome (such as this one) are
critically dependent on the choice of outcome measure. In a study of
neuromediated syncope, these measures include syncope,
recurrences of presyncope and syncope, and objective measures
of quality of life. We chose syncope as an outcome because it is easily
quantifiable, is memorable, and was likely to have a high incidence due
to the highly symptomatic nature of our study population.
We chose to use the time to the first recurrence of syncope as
a primary end point because it seemed reasonable to ask patients to
defer medical therapy until that time as we anticipated that patients
might then request medical therapy and as first recurrence is
widely used as a primary outcome measure in arrhythmia trials.
This use is based in part on the temporally random recurrence
of supraventricular arrhythmias in study
populations.16 17 The close fit of the recurrence
data in this report to the Weibull distribution, which assumes a random
process, supports this assumption. Presyncope was not chosen due to
anticipated difficulties with quantifying its variable severity and
duration. Recurrent presyncope is likely to be a significant problem in
the lives of these patients. Although the quality of life in patients
with recurrent syncope is substantially and objectively
diminished,18 19 we did not use this as an end point
because we made no a priori assumptions that quality of life would
change after a positive tilt-table test.
Reduction in the Risk of a Recurrence of
Syncope
One surprising finding from the present study is the apparent
reduction in the risk of a recurrence of syncope after a
positive tilt-table test. In this population, the median frequency
of historical syncopal spells per month was 0.3; that is, half of the
population had fewer than 0.3 syncopal spells per month before
undergoing tilt-table testing and counseling. After this clinical
encounter, half of the population did not faint during 3 years of
follow-up. The cause for this apparently great reduction in the
likelihood of a recurrence of syncope after a tilt-table
test compared with the pretest history is unknown, but it may be due to
a combination of the natural history of the syndrome, reassurance,
counseling on the pathophysiology of syncope, and coaching on
appropriate postural maneuvers to prevent presyncope from progressing
to syncope. The data cannot rule out the possibility that some patients
have a great reduction in the frequency of syncopal spells, whereas
other patients have a much smaller reduction in the frequency of
spells. The data do suggest that the tilt test and clinical encounter
are themselves interventions. To test these hypotheses will require
randomized prospective studies.
Usefulness of Risk Assessment
These data provide the first
estimates of risk assessment in
neuromediated syncope. Recognizing the plethora of tilt-test
protocols that are now in use (see below), we suspect that most
investigators will focus on historical factors such as prognostic
markers. Risk assessment should prove helpful in counseling patients
about their prognoses, in deciding whether an attempt at
pharmacological or pacing therapy is warranted, and in designing
prospective clinical trials. Future trials, to be adequately powered,
should be carried out with subjects who have a sufficiently high risk
of recurrent syncope.
The risk of recurrent syncope based on clinical
history can be
estimated with the use of the diagram in Fig 5. The
probabilities of syncope in the first year (top) and the first 2 years
(bottom) are displayed as a function of both the number of preceding
syncopal spells and the duration of preceding symptoms. The boundaries
of these zones were calculated from the proportional hazards model as
described in "Methods." Four zones are displayed in which the
risk of recurrent syncope is <25%, 25% to 50%, 50% to 75%, and
>75%. Superimposed on these zones are single data points, each of
which represents one patient.
|
Fig 5 has three purposes.
First, the risk of a recurrence of
syncope for any patient after a positive tilt-table test can be
estimated directly from the figure. To use this figure, one simply
locates the position of any patient based on their number of syncopal
spells and duration of symptoms. For example, a patient with four
syncopal spells over a period of 2 months has a risk of at least one
additional syncopal spell of <25% in 1 year and of 25% to 50% in 2
years. Second, it can be used to estimate inclusion criteria and sample
size for future trials. For example, all patients with six or fewer
syncopal spells have a risk of recurrent syncope of <50% over 2
years, whereas patients with more than six syncopal spells have a risk
of syncope of >50% over 2 years. An interventional study of the
former population would require a much larger study size than would one
of the latter population. Third, it displays the relative proportion of
patients in each category in this population of patients, who
presented to a community-based tertiary care center. For
example, a study restricted to patients with >75% risk of syncope in
1 year might seem desirable, but only 5 of 101 patients in our study
population are in this category. Fig 5 therefore illustrates
not only
what is desirable but also what is feasible in trial design.
Study Limitations
The major limitations of the present study
are those of
generalizability. First, this report is focused on patients who had a
positive outcome to the isoproterenol/head-up tilt-table test
protocol used in our laboratory. Therefore, we cannot comment on the
long-term outcome of patients with a positive outcome to passive
prolonged head-up tilt testing,1 4 or to tilt testing
using one of a variety of other provocative agents, such as
nitroglycerin or a different dose of
isoproterenol.15 The use of isoproterenol remains a
controversial issue.14 These protocols have not been
compared directly with each other in a prospective controlled trial.
Although these limitations are particularly relevant when considering
the generalizability of the prognostic significance of the intratest
variables, they are also important because the sensitivity and
specificity of the various protocols may differ.20 21
Second, we did not examine the prognostic significance of a positive outcome to tilt-table testing. In the absence of a gold standard for the diagnosis of syncope, such a study would be difficult to perform and interpret because it would require establishing a pretest diagnosis of neuromediated syncope.
Third, we used syncope, not presyncope, as the outcome measure. The reasons for this include simplicity, quantifiability, memorability, and the impact of fear of syncope on quality of life. However, part of our clinical interaction with patients included teaching the specific physical maneuvers to abort the progression of presyncope to syncope. If successful, this would reduce the risk of syncope without reducing the clinical burden of presyncope.
In contrast to concerns with the
generalizability of the tilt-test
protocol, the population in this study probably is broadly
representative. The patients had a reasonably equal sex
distribution and a broad age range and presented with a wide
range of historical number of syncopal spells and duration of symptoms.
Although some patients had many spells and/or long durations of
symptoms, the majority had six or fewer syncopal spells and durations
of symptoms of 21 months (Tables 1 and 2).
Thus, the population was
composed of patients with a wide range of symptomatic
burdens.
Similarly, we focused on patients who elected to go home counseled but not treated with pharmacological agents and who were not lost to follow-up. This raises the possibility that selection bias might alter the findings. Although the patients who were lost to follow-up closely resembled the study patients, other unanticipated, unmeasured variables might exist. Similarly, the patients who elected to be treated were older and had had significantly more frequent syncopal spells than did the 101 untreated patients. However, in a separate analysis6 of a larger population consisting of these 101 drug-free patients and the subpopulation of the 52 patients who elected to be treated with ß-blockers, we showed that the multivariate risk factors reported here all became more highly significant as risk factors for recurrent syncope in the total population. Therefore, these identified risk factors appear to be significant not only for patients who elect not to be treated but also for those who wish to be treated with ß-blockers. These numerous issues, so typical in the weighing of the merit and generalizability of a retrospective study, can be addressed only in a prospective, inclusive natural history study or in the placebo arm of a large, randomized, controlled trial. This report provides the estimate of the probability of a recurrence of syncope that is necessary for the design of such a study or trial.
Finally, the large reduction in the risk of a recurrence of syncope in the population suggests that the clinical encounter that includes tilt testing is not neutral: the various nonpharmacological management strategies appear to have a salutary impact on the outcome of many patients.
In conclusion, the present study identifies significant clinical and tilt-test variables that predict recurrent syncope after a positive tilt-table test in patients with a previous history of syncope. These findings should help decide which patients might be treated pharmacologically and which patients have such a low risk of recurrent syncope that they could be treated expectantly.
|
Acknowledgments |
|---|
This work was supported by grants from the Medical Research Council of Canada (PG11188) and the Calgary General Hospital Research and Development Committee.
Received September 6, 1995; revision received October 2, 1995; accepted October 6, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Almquist A, Goldenberg IF, Milstein S, Chen MY, Chen X, Hansen R, Gornick GC, Benditt DG. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med. 1989;320:346-351. [Abstract]
2. Abi-Samra F, Malony JD, Fouad-Tarazi FM, Castle LW. The usefulness of head-up tilt testing and hemodynamic investigations in the work-up of syncope of unknown origin. PACE Pacing Clin Electrophysiol. 1988;11:1202-1214. [Medline] [Order article via Infotrieve]
3. Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol. 1989;63:58-65. [Medline] [Order article via Infotrieve]
4. Fitzpatrick A, Sutton R. Tilting towards a diagnosis in recurrent unexplained syncope. Lancet. 1989;1:658-660. [Medline] [Order article via Infotrieve]
5. Mitchell LB, Wyse DG, Duff HJ. Programmed electrical stimulation studies of ventricular tachycardia in humans: the role of ventricular functional refractoriness in tachycardia induction. J Am Coll Cardiol. 1986;8:567-575. [Abstract]
6. Sheldon RS, Rose S, Flanagan P, Koshman ML, Killam S. Age-dependent effect of beta blockers on the clinical outcome of patients following a positive isoproterenol-tilt table test. Can J Cardiol. 1994;10:79C. Abstract.
7. Sheldon RS, Killam S. Methodology of isoproterenol-tilt table testing in patients with syncope. J Am Coll Cardiol. 1992;19:773-779. [Abstract]
8. Sheldon R. Evaluation of a single-stage isoproterenol-tilt table test in patients with syncope. J Am Coll Cardiol. 1993;22:114-118. [Abstract]
9. Cook DJ, Guyatt GH, Laupacis A, Sachett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1992;102:3055-3115.
10. Cox DR. Regression models and life-tables (with discussion). JR Stat [Soc B]. 1972;34:187-220.
11.
Therneau TM, Grambsch PM, Fleming TR.
Martingale-based residuals for survival models.
Biometrika. 1990;77:147-160.
12.
Schoenfeld D. Partial residuals for the
proportional hazards regression model. Biometrika. 1982;69:239-241.
13. Oakes DR, Oakes D. Analysis of Survival Data. London, UK: Chapman & Hall; 1984.
14. Kapoor W, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol: a nonspecific test. Ann Intern Med. 1992;116:358-363.
15. Kapoor WN. Methodology of upright tilt table testing. Eur J Cardiac Pacing Electrophysiol. 1992;2:242-246.
16. Pritchett ELC, Lee KL. Designing clinical trials for paroxysmal atrial tachycardia and other paroxysmal arrhythmias. J Clin Epidemiol. 1988;41:851-858. [Medline] [Order article via Infotrieve]
17. Greer SG, Wilkinson WE, McCarthy EA, Pritchett ELC. Random and nonrandom behavior of symptomatic paroxysmal atrial fibrillation. Am J Cardiol. 1989;64:339-342. [Medline] [Order article via Infotrieve]
18. Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. Impairment of physical and psychosocial function in recurrent syncope. J Clin Epidemiol. 1991;44:1037-1043. [Medline] [Order article via Infotrieve]
19. Linzer M, Gold DT, Pontinen M, Divine GW, Felder A, Brooks WB. Recurrent syncope as a chronic disease: preliminary validation of a disease-specific measure of functional impairment. J Gen Intern Med. 1994;9:181-186. [Medline] [Order article via Infotrieve]
20. Kapoor WN. Diagnostic evaluation of syncope. Am J Med. 1991;90:91-106. [Medline] [Order article via Infotrieve]
21. Sheldon RS. Tilt table testing in the diagnosis and treatment of syncope. Cardiovasc Rev Resp. 1994;15:8-28.
This article has been cited by other articles:
 |
|
 |
|
  D. Sorajja, G. C. Nesbitt, D. O. Hodge, P. A. Low, S. C. Hammill, B. J. Gersh, and W.-K. Shen Syncope While Driving: Clinical Characteristics, Causes, and Prognosis Circulation, September 15, 2009; 120(11): 928 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Guida, M. Iacoviello, C. Forleo, A. Ferrara, S. Sorrentino, C. Balducci, M. Sarlo, and S. Favale Prevalence, timing, and haemodynamic correlates of prodromes in patients with vasovagal syncope induced by head-up tilt test Europace, September 1, 2009; 11(9): 1221 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
R. Sheldon, S. Connolly, S. Rose, T. Klingenheben, A. Krahn, C. Morillo, M. Talajic, T. Ku, F. Fouad-Tarazi, D. Ritchie, et al. Prevention of Syncope Trial (POST): A Randomized, Placebo-Controlled Study of Metoprolol in the Prevention of Vasovagal Syncope Circulation, March 7, 2006; 113(9): 1164 - 1170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Giada, I. Silvestri, A. Rossillo, P. G. Nicotera, G. F. Manzillo, and A. Raviele Psychiatric profile, quality of life and risk of syncopal recurrence in patients with tilt-induced vasovagal syncope Europace, January 1, 2005; 7(5): 465 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ector, R. Willems, H. Heidbüchel, and T. Reybrouck Repeated tilt testing in patients with tilt-positive neurally mediated syncope Europace, January 1, 2005; 7(6): 628 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dorian, M. Borggrefe, H. R. Al-Khalidi, S. H. Hohnloser, J. M. Brum, D. S. Tatla, J. Brachmann, R. J. Myerburg, D. S. Cannom, M. van der Laan, et al. Placebo-Controlled, Randomized Clinical Trial of Azimilide for Prevention of Ventricular Tachyarrhythmias in Patients With an Implantable Cardioverter Defibrillator Circulation, December 14, 2004; 110(24): 3646 - 3654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Sheldon, S. Rose, S. Connolly, and on behalf of the POST investigators Prevention of Syncope Trial (POST): a randomized clinical trial of beta blockers in the prevention of vasovagal syncope: Rationale and study design Europace, January 1, 2003; 5(1): 71 - 75. [Abstract] [PDF]
|
|
|
|
|
|
C.T. P. Krediet, N. van Dijk, M. Linzer, J. J. van Lieshout, and W. Wieling Management of Vasovagal Syncope: Controlling or Aborting Faints by Leg Crossing and Muscle Tensing Circulation, September 24, 2002; 106(13): 1684 - 1689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Menozzi, M. Brignole, R. Garcia-Civera, A. Moya, G. Botto, L. Tercedor, R. Migliorini, X. Navarro, and on behalf of the International Study on Syncope of Mechanism of Syncope in Patients With Heart Disease and Negative Electrophysiologic Test Circulation, June 11, 2002; 105(23): 2741 - 2745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. Kouakam, G. Vaksmann, E. Pachy, D. Lacroix, C. Rey, and S. Kacet Long-term follow-up of children and adolescents with syncope; predictor of syncope recurrence Eur. Heart J., September 1, 2001; 22(17): 1618 - 1625. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
F. Ammirati, F. Colivicchi, and M. Santini Permanent Cardiac Pacing Versus Medical Treatment for the Prevention of Recurrent Vasovagal Syncope : A Multicenter, Randomized, Controlled Trial Circulation, July 3, 2001; 104(1): 52 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Sheldon and S. Rose Components of clinical trials for vasovagal syncope Europace, January 1, 2001; 3(3): 233 - 240. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. J. Leor-Librach, B.-Z. Bobrovsky, S. Eliash, and E. Kaplinsky Computer-controlled heart rate increase by isoproterenol infusion: mathematical modeling of the system Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1478 - H1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Raviele, M. Brignole, R. Sutton, P. Alboni, P. Giani, C. Menozzi, and A. Moya Effect of Etilefrine in Preventing Syncopal Recurrence in Patients With Vasovagal Syncope : A Double-Blind, Randomized, Placebo-Controlled Trial Circulation, March 23, 1999; 99(11): 1452 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Connolly, R. Sheldon, R. S. Roberts, M. Gent, and on Behalf of the Vasovagal Pacemaker Study Investi The North American vasovagal pacemaker study (VPS) : A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope J. Am. Coll. Cardiol., January 1, 1999; 33(1): 16 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. N. Theodorakis, M. Markianos, E. G. Livanis, E. Zarvalis, P. Flevari, and D. T. Kremastinos Central Serotonergic Responsiveness in Neurocardiogenic Syncope : A Clomipramine Test Challenge Circulation, December 15, 1998; 98(24): 2724 - 2730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. SMITH Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine Heart, January 1, 1998; 79(1): 105 - 105. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||