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(Circulation. 1997;96:260-266.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome
The THEOPACE Study: A Randomized Controlled Trial
From the Division of Cardiology, Ospedale Civile, Cento (P.A., N.P., R.C.); the Section of Arrhythmology, Department of Cardiology, Ospedale S Maria Nuova, Reggio Emilia (C.M., G.L.); and the Section of Arrhythmology, Department of Cardiology, Ospedali Riuniti, Lavagna (M.B., G.G.), Italy.
Correspondence to Dr Paolo Alboni, Division of Cardiology, Ospedale Civile, 44042 Cento (Fe), Italy.
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Abstract |
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Background Pacemakers and theophylline are currently being used to relieve symptoms in patients with sick sinus syndrome (SSS). However, the impact of either therapy on the natural course of the disease is unknown. We conducted a randomized controlled trial to prospectively assess the effects of pacemakers and theophylline in patients with SSS.
Methods and Results One hundred seven patients with symptomatic SSS (age, 73±11 years) were randomized to no treatment (control group, n=35), oral theophylline (n=36), or dual-chamber rate-responsive pacemaker therapy (n=36). They were followed for up to 48 months (mean, 19±14 months). During follow-up, the occurrence of syncope was lower in the pacemaker group than in the control group (P=.02) and tended to be lower than in the theophylline group (P=.07). Heart failure occurred less often in patients assigned to pacemaker therapy and theophylline than in control patients (both, P=.05), whereas the incidence of sustained paroxysmal tachyarrhythmias, permanent atrial fibrillation, and thromboembolic events did not show any apparent difference among the three groups. Heart rate was higher in the theophylline group than in the control group. Both pacemaker therapy and theophylline improved symptom scores after 3 months of treatment; however, a similar improvement was observed in the control group.
Conclusions In patients with symptomatic SSS, therapy with theophylline or dual-chamber pacemaker is associated with a lower incidence of heart failure; pacemaker therapy is also associated with a lower incidence of syncope. The therapeutic benefits of pacemakers and theophylline on symptoms are partly a result of spontaneous improvement of the disease.
Key Words: arrhythmia • pacemakers • syncope • theophylline
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Introduction |
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Definition of the clinical course in SSS is difficult. Patients with this disease are generally old and frequently have a concomitant heart disease. Various symptoms presumably related to the presence of a sinus node dysfunction may be superimposed; in addition, syncope generally comes unexpectedly and unpredictably.1 2 At present, the natural history of SSS is largely unknown.
Permanent pacing is currently being used as the elective therapy to relieve symptoms in patients with SSS; however, controlled studies assessing the impact of this therapy on the natural course of the disease are lacking.
In unpaced patients with SSS, dizziness and syncope did not evidence prognostic implications; total mortality and sudden death did not seem to be higher than in the general population; moreover, ventricular pacing did not seem to reduce mortality.3 These observations provided the rationale to test oral theophylline as an alternative to pacemaker therapy; this drug proved to be efficacious in increasing resting and exercise sinus rate as well as to reduce symptoms and cardiac pauses during follow-up in patients with SSS.4 5 6 7 8 9 Like pacemaker therapy, theophylline has not been investigated in controlled studies.
We performed a randomized, controlled trial to assess the effects of oral theophylline and of a permanent pacemaker on the symptoms and complications of SSS (the THEOPACE study).
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Methods |
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THEOPACE is a study in which patients with symptomatic SSS were recruited according to a prospective, randomized, controlled design. Patients who met the entry criteria were randomized to one of the following arms: (1) no treatment (control group), (2) oral theophylline, and (3) permanent DDDR. Randomization was central and was achieved by computer-generated assignment. Disclosure of data for analysis of end points in the three groups was performed after the last enrolled patient had completed 12 months of follow-up.
The institutional review board of the three hospitals participating in the trial approved the protocol; the study design was approved by the Ethics Committee of the Provincia di Ferrara. All the patients enrolled in this trial provided signed informed consent.
Recruitment of Patients
Patients were recruited between January 1991 and June 1994 from
subjects referred to our institutions from the emergency room,
inpatient service, and outpatient clinic of arrhythmias. The
study was terminated in June 1995.
Patients were evaluated for randomization if they met all of the
following criteria: (1) age 
45 years; (2) mean resting sinus rate
<50 bpm and/or intermittent sinoatrial block in more than one standard
ECG recorded during diurnal hours on different days; and (3)
symptoms attributable to sinus node dysfunction, such as syncope or
dizziness and/or easy fatigue or effort dyspnea. The latter was
attributed to sinus node dysfunction on the basis of the general
clinical evaluation, including the response of heart rate during
exercise test.
Criteria for exclusion included the following: very severe SSS, namely, symptomatic resting sinus rate <30 bpm or sinus pauses >3 seconds in standard ECGs recorded during diurnal hours or heart failure refractory to treatment with ACE inhibitors and diuretics; recent (within the previous 3 months) myocardial infarction or stroke or other acute diseases; very severe general diseases, likely to be fatal in <2 years; significant renal or hepatic disease (serum creatinine >2 times upper limit of normal; serum glutamic oxaloacetic acid transferase and/or total bilirubin >2 times upper limit of normal); history of documented sustained ventricular tachyarrhythmias; bradycardia secondary to transient causes (effect of drugs, etc); prior use of theophylline; a need for ß-blockers or calcium antagonists (verapamil or diltiazem); other definite or potential causes of syncope in patients complaining of syncopal attacks, as previously reported10 ; patient refusal; or follow-up not possible.
Patients with syncope and a positive response to carotid sinus massage or head-up tilt test without a typical history of neurally mediated syncope were included, because it has been shown that an abnormal neural reflex plays a major role in causing syncope in subjects with sinoatrial disease.10 11
During the recruitment period, 162 patients were evaluated for inclusion. Of these, 12 (7%) were not enrolled because of very severe SSS and 43 for one or more of the other exclusion criteria. Therefore, 107 patients met the inclusion criteria and underwent randomization.
End Points
The following parameters served as end points:
occurrence of the first episode of syncope, development of overt heart
failure, thromboembolic events (stroke and peripheral
embolus), development of permanent AF, and symptom scores as assessed
by a self-administered questionnaire. In case of development of
permanent AF, the patients were still followed, but the heart rate and
other variables of the Holter recording were not reported
for analysis. In case of death, the cause was obtained by
interviewing the doctors who cared for the patients and by reviewing
hospital and necropsy reports.
Patients were allowed to receive nitrates, diuretics, ACE inhibitors and other antihypertensive medications, aspirin, and anticoagulants as indicated. After randomization, antiarrhythmic drugs were not administered; these drugs could then be administered if the patient complained of palpitations.
During follow-up, the patients were withdrawn from the control or the theophylline arm if they developed syncope, overt heart failure, poorly tolerated episodes of sustained paroxysmal tachyarrhythmia that were drug refractory or not manageable with antiarrhythmic drugs, or any other event (eg, myocardial infarction) requiring reevaluation of the therapy. In case of thromboembolism, the decision on whether to leave the patient in the assigned arm was left to the investigator's best judgment. Owing to the permanent nature of pacemaker treatment, patient withdrawal from the pacemaker arm was not possible.
Procedures
All diagnostic investigations, theophylline
titration, and pacemaker implantation were performed during
hospitalization. At baseline evaluation, the following examinations
were carried out: history, physical examination, resting ECG, chest
radiograph, standard laboratory tests for hematologic
parameters; thyroid, renal, and hepatic function; 24-hour
Holter recording; echocardiogram; carotid sinus massage; tilt
test; electrophysiological study; exercise
test; and symptom score measurements. During long-term follow-up, the
effects of treatment were evaluated by means of medical visit,
resting ECG, symptom score assessments, and 24-hour Holter
recording.
Symptom score assessments. Subjective perception of physical functional capacity was assessed by a self-administered semiquantitative questionnaire. The scale was constructed to address the symptoms of SSS. Each patient was asked to quantify symptoms of fatigue, dizziness, and palpitation by means of a score scale (0, absent; 1, rare and mild; 2, frequent and mild; 3, rare and severe; 4, frequent and severe; 5, incessant). Functional capacity was assessed objectively according to the NYHA classification.
Electrophysiological study. An invasive electrophysiological study was performed with standard techniques to evaluate sinus node function and atrioventricular conduction during the basal state and after pharmacological autonomic blockade.12 13 A basal corrected sinus node recovery time >500 ms and an intrinsic corrected sinus node recovery time >385 ms was considered abnormal.14 In the patients complaining of syncope, atrial and ventricular programmed stimulation was performed.
Patients underwent carotid sinus massage and tilt test as previously described.10 11
Therapeutic Procedures
A DDDR stimulator was implanted in all patients randomized to
the pacemaker arm. The device was programmed at a basic rate of 60 to
70 bpm, at an upper sensor rate of 110 to 140 bpm, and with
atrioventricular interval long enough to possibly avoid
asynchronous ventricular activation. Patients randomized to
the theophylline arm received the drug at a dosage of 550 mg/d in two
doses with a slow-release tablet. Serum theophylline level was
determined after 5 days of treatment, and the initial dosage was
appropriately decreased in case of serum theophylline level >15
ng/mL.8 15
Follow-up
The patients were enrolled in a long-term phase and were seen at
the outpatient clinic every 3 months. The follow-up visit included a
medical visit and resting ECG. Information on clinical status,
symptoms, drug treatments, adherence to the study regimen, and side
effects were recorded at each visit. In particular, the patient was
asked whether in the previous 3 months he had had episodes of
paroxysmal tachyarrhythmia, defined as rapid
palpitation lasting >5 minutes with abrupt onset and termination. This
question was included to define the number of patients affected by
clinically relevant paroxysmal tachyarrhythmia,
probably but not certainly of atrial origin. After 3 and after 12
months, a 24-hour Holter recording was repeated. The
questionnaire and the NYHA class were reevaluated by the same
cardiologist in each center after 3 months. In patients assigned to
pacemaker therapy, a change of parameters programmed at
time of enrollment was made if necessary. In patients assigned to
theophylline, serum drug levels were determined every 3 months. Dosage
modifications of the drug were made as necessary to eliminate symptoms
and limit side effects.
Definitions
Syncope was defined as a transient loss of consciousness with
inability to maintain postural tone. AF was defined as permanent if
recorded at two consecutive follow-up visits. Overt heart failure
was defined as the appearance or worsening of dyspnea or
peripheral edema requiring hospitalization, during which
the signs of pump failure were present. Stroke was diagnosed when
neurological symptoms of presumably cerebral ischemic origin
persisted for >24 hours. A peripheral embolus was
diagnosed if typical from the clinical point of view or if verified
during angiographic investigation or at embolectomy.
Statistical Analysis
Primary analysis. Baseline characteristics
and clinical end points were compared in the three groups by
2 or Fisher's exact test (two-tailed) for
discrete variables and by ANOVA and two-tailed t test
for continuous variables. The rate of occurrence of syncope during
follow-up was estimated by means of Kaplan-Meier survival curves, and
curves were compared by log-rank test. Semiquantitative assessment of
symptoms was compared at 3 months after randomization by
2 test for heterogeneity in the
three groups. Holter data were compared at 3 and 12 months after
randomization, and resting heart rates (in standard ECG) were compared
at 3, 6, and 12 months after randomization in the no-treatment and
theophylline arms. Patients who did not have those examinations because
of withdrawal or death were excluded from analysis. The
differences were adjusted for baseline values by ANCOVA. It has been
demonstrated16 that the adjusted difference
represents the appropriate tool for reducing variability in the
outcome by taking into account baseline values. Baseline values were
estimated by the AM procedure of BMDP statistical
software.17 18
Secondary analysis. An interpatient comparison of
symptom scores and heart rates (in standard ECG and Holter
recording) at enrollment and after 3 months was also performed
by use of the Mc Nemar test for discrete variables and paired
t test for continuous variables. All analyses
were performed with BMDP statistical software for Windows and SPSS for
Windows.17 19 Significance was established at
P
.05.
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Results |
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Patients
The baseline characteristics of patients are reported in Table 1
. The three groups were similar with regard to
age, sex, incidence of underlying heart disease, syncope, heart
failure, sinoatrial block, and bradycardia-tachycardia
syndrome. Patients in the three groups were also comparable relative to
the distribution of anticongestive, antiarrhythmic, and antithrombotic
drugs. The distribution of these drugs in the three groups was similar
during the follow-up as well. In particular, warfarin or aspirin was
administered to 5, 4, and 5 patients in the control, theophylline, and
pacemaker arms, respectively. Sinus node function
parameters were similar in the three groups (Table 2). Mean age and follow-up for the total population were
73±11 years and 19±14 months, respectively. Owing to the withdrawal
of some of the patients in the nonsurgical arms, the mean follow-up
period was longer in the pacemaker arm (23±13 months; maximum, 48
months) than in the theophylline arm (16±13 months; maximum, 47
months) (P=.03) and in the no-treatment arm (18±15 months;
maximum, 48 months) (P=.08).
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Carotid sinus massage and tilt tests were performed in 60 of the 63 patients complaining of syncope and in 33 of the 44 patients without episodes of syncope. At least one test was positive in 46 patients (77%) with syncope and in 12 (36%) without syncope (P=.0001).
In the patients assigned to theophylline, serum theophylline levels were 12±5 ng/mL at the steady state and 10±4 ng/mL after 3 months; they remained almost stable throughout the follow-up period.
Withdrawal From the Study and Mortality
During follow-up, 18 patients in the control arm were withdrawn
from the study because they developed syncope (n=8), overt heart
failure (n=6), or poorly tolerated episodes of paroxysmal
tachyarrhythmia (n=2); 2 other patients in this group
dropped out at their own wish. In the theophylline arm, 15 patients
were withdrawn because of syncope (n=6), overt heart failure (n=1),
poorly tolerated episodes of paroxysmal tachyarrhythmia
(n=1), patient's wish (n=3), and side effects of the drug, mainly
gastric intolerance (n=4). There were 2 deaths from noncardiac causes
in the control arm, 2 deaths from noncardiac causes in the theophylline
arm, and 5 deaths in the pacemaker arm (1 sudden, 1 from pump failure,
and 3 from noncardiac causes). The differences were not statistically
significant.
Clinical Events During Follow-up
The clinical events during follow-up are reported in Table 3.
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Syncope. Eight patients (23%) in the control arm, 6 (17%)
in the theophylline arm, and 2 (6%) in the pacemaker arm had syncope
during the follow-up. Of the latter, 1 patient had a positive tilt
test. In patients assigned to pacemaker therapy, the incidence of
syncope was lower than in control patients (P=.02) and
tended to be lower than in those assigned to theophylline
(P=.07) (Figure). During the follow-up
period, the first episode of syncope occurred after 8±8 months in
control patients, after 12±9 months in theophylline patients, and
after 5±2 months in pacemaker patients (P=NS). Fourteen of
the 16 patients who suffered from syncope during follow-up had already
complained of syncopal episodes at the time of randomization.
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Development of overt heart failure. Six patients (17%) in the control arm, 1 (3%) in the theophylline arm, and 1 (3%) in the pacemaker arm developed overt heart failure during follow-up. The incidence of overt heart failure was significantly lower in the theophylline arm and in the pacemaker arm than in the control arm (P=.05).
Paroxysmal tachyarrhythmias and permanent atrial fibrillation. All patients were in sinus rhythm at the time of randomization. Nine patients (26%) in the control arm, 10 (28%) in the theophylline arm, and 10 (28%) in the pacemaker arm complained of sustained paroxysmal tachyarrhythmia during follow-up (P=NS). Of the 29 patients who complained of paroxysmal tachyarrhythmia during follow-up, 20 already had bradycardia-tachycardia syndrome at the time of randomization.
Four patients (11%) in the control arm, 2 (6%) in the theophylline arm, and 3 (9%) in the pacemaker arm developed permanent AF during follow-up (P=NS). Of the 9 patients who developed permanent AF during follow-up, 7 already had bradycardia-tachycardia syndrome at randomization.
Thromboembolism. Thromboembolic events occurred in 1 patient (3%) in the control arm, 3 (9%) in the theophylline arm, and 3 (9%) in the pacemaker arm (P=NS). Of the 7 patients who had thromboembolic events during follow-up, 3 already had bradycardia-tachycardia syndrome at the time of randomization, and 1 of these had developed permanent AF before the event.
Symptoms
There were no significant differences in the NYHA class score or
in the fatigue, dizziness, and palpitation scores among the three
groups of patients at the time of randomization and after 3 months
(Table 4).
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Heart Rates
At the time of randomization, there were no significant
differences among the three groups in resting heart rate evaluated by
standard ECG (Table 1
); maximum exercise heart rate (Table 1); or
minimum, mean, and maximum heart rates evaluated by 24-hour Holter
recording (Table 5). During follow-up, resting
heart rate was always higher in the theophylline group than in the
control group, and the differences reached statistical significance at
3 months (Table 5). Heart rates evaluated by 24-hour Holter
recording also showed a trend toward higher values in the
theophylline group than in the control group (Table 5). The number of
premature supraventricular and ventricular
beats and the number of patients with cardiac pauses >2.5 seconds did
not show significant differences among the three groups.
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Discussion |
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In this study, the clinical and electrophysiological characteristics of the total population show that we are dealing with subjects with relevant sinus node dysfunction. In fact, 59% of the patients had already experienced at least one syncopal episode at the time of randomization, and 42% presented with bradycardia-tachycardia syndrome. Basal and intrinsic corrected sinus node recovery time were prolonged in 57% and 87% of the patients, respectively; in addition, patients suffered from chronotropic incompetence. In common clinical practice, patients with similar characteristics receive pacemakers as a definitive therapy.
The main finding of the present study is that in patients with symptomatic SSS, pacemaker therapy reduces the incidence of syncope and overt heart failure and oral theophylline reduces the incidence of overt heart failure.
Effects of Permanent Pacemaker
In patients with sinus node dysfunction, retrospective
studies2 20 21 22 23 24 25 suggested that atrial or dual-chamber
pacemakers were associated with lower incidence of permanent AF,
thromboembolism, heart failure, and mortality than single-chamber
ventricular pacemakers. In similar patients, a recent
prospective randomized trial26 showed that atrial pacing
was associated with a lower incidence of permanent AF and
thromboembolism compared with single-chamber ventricular
pacing. Because of the absence of a control group, these studies could
not clarify whether differences in clinical outcome are related to a
beneficial effect of atrial stimulation or to a detrimental effect of
single-chamber ventricular pacing.
In the present study, the incidence of thromboembolism, paroxysmal
tachyarrhythmias, and evolution toward permanent AF
during follow-up did not show apparent differences between the patients
treated with dual-chamber stimulation and the control patients (Table 3). This finding suggests that the higher incidence of complications
previously reported in patients receiving single-chamber
ventricular pacemakers may be related to detrimental
effects of this pacing modality. However, it must be noted that the
episodes of paroxysmal tachyarrhythmia reported by our
patients are not unequivocally of atrial origin; moreover, atrial
tachyarrhythmia can also be asymptomatic.
Therefore, it is not possible to draw final conclusions on the effects
of dual-chamber pacemakers on the rate of occurrence of atrial
tachyarrhythmias. Moreover, it must be pointed out that
the study may be underpowered to detect significant differences in the
incidence of AF and thromboembolism.
It is commonly accepted that a permanent pacemaker reduces syncopal
attacks in patients with SSS, but this has not been demonstrated. In
fact, the natural history of syncopal recurrences appears to be
variable and unpredictable,1 2 and a therapeutic
efficacy can be evaluated only in controlled trials. In the present
study, dual-chamber pacing was associated with a significant reduction
of syncopal episodes (Figure). As has been reported in retrospective
studies,27 28 syncope occurred more frequently in patients
who had already experienced at least one episode before pacemaker
implantation. The prevalence of positive responses to carotid sinus
massage and tilt test was significantly higher in patients who at the
time of enrollment had experienced syncope than in those who had not,
thus confirming the contribution of abnormal neural reflexes in the
pathophysiology of this event in patients with sinoatrial
disease.10 11 Permanent pacemakers may abolish syncope
because of failure of intrinsic sinus node automaticity as well as
carotid sinus hypersensitivity,29 whereas there is no
definitive demonstration of their efficacy in the prevention of
vasovagal syncope.30 Syncopal episodes occurred during
follow-up in 6% of our paced patients. It should be noted that pacing
that is successful in treating bradycardia-induced symptoms may not be
efficacious in preventing syncope that originated in an abrupt fall in
peripheral resistance, a common final pathway for the
vasovagal mechanism. We implanted DDDR pacemakers, which seem to
represent the best mode of stimulation in patients with
syncopal attacks and/or chronotropic incompetence.
Compared with control patients, those receiving pacemaker therapy
presented a significant reduction of overt heart failure during
follow-up (Table 3). Patients with episodes of heart failure before
randomization were equally distributed in the three groups and
accounted for 
15% of the whole population, a finding
consistent with previous reports.20 21 22 31 The
beneficial effect of dual-chamber pacing in these patients appears to
be related to the increase in heart rate and, very likely, to the
preservation of atrioventricular synchrony.
Effects of Theophylline
There have been a number of reports substantiating a positive
chronotropic effect of theophylline. The most probable mechanism by
which the drug exerts this action appears to be the antagonism of the
cardiac effects of adenosine, which has been shown to depress
sinus node automaticity.32 33
Electrophysiological investigations showed that
theophylline improves sinus node function in subjects with sinus
bradycardia and enhances atrioventricular nodal
conduction.6 34 The drug diminished the frequency and
severity of bradycardia in newborn infants with spells of
apnea-bradycardia.4 5 In patients with severe sinus
bradycardia after heart transplantation, oral theophylline increased
the donor heart rate by 50%, avoiding pacemaker
implantation.7 In noncontrolled studies performed in
patients with symptomatic SSS, oral theophylline increased
resting and exercise heart rate, improved symptoms, and reduced cardiac
pauses during follow-up.6 8 9
In the present study, oral theophylline therapy was initiated at a
dosage of 550 mg/d, the most appropriate on the basis of our previous
experiences.8 15 Like patients assigned to pacemaker
therapy, patients receiving theophylline presented a lower
incidence of overt heart failure than those receiving no therapy (Table 3). The increase in heart rate and a slight positive inotropic
action35 36 37 may account for this drug effect in patients
with SSS. It has been proposed that SSS is an
adenosine-mediated disease38 ; the results of the
present study partly support this hypothesis.
Treatment with theophylline was associated with an incidence of syncopal episodes, thromboembolic events, sustained paroxysmal tachyarrhythmias, and evolution toward permanent AF similar to that in control patients. However, because during follow-up, paroxysmal tachyarrhythmias occurred almost exclusively in subjects who presented with bradycardia-tachycardia syndrome at the time of randomization, it should be noted that the drug at the dosage we used did not increase paroxysmal tachyarrhythmias in these patients. Because of side effects, drug discontinuation was required in 11% of patients, a finding consistent with previous reports.39
Symptoms
In previous noncontrolled studies,2 4 5 6 7 8 9 20 21 22 23 24 28 31
permanent pacemakers and oral theophylline were reported to reduce
symptoms in patients with SSS. In the present study, DDDR
pacemakers and oral theophylline did not evidence different effects on
symptoms compared with "no treatment" (Table 4). To clarify this
point, we performed an interpatient comparison of symptom scores and
heart rates between enrollment and third-month visit (Tables 4 and 5).
In control patients, a subjective improvement is evident, as documented
by a significant reduction of dizziness and by a trend toward a
reduction of fatigue (Table 4). These findings were associated with a
significant increase in resting, mean, and maximum heart rates (Table 5). This aspect of the natural history of SSS has been
suspected1 2 but not clearly demonstrated, because the
course of symptoms and heart rate has not been prospectively
investigated in unpaced patients. These results suggest that patients
with SSS generally call for medical attention when they are
symptomatic for bradycardia-related symptoms such as
syncope, dizziness, and easy fatigue; during this time, the heart rate
appears to be low. Subsequently, in the vast majority of these
patients, heart rate increases spontaneously and symptoms diminish. In
our study design, it is not possible to define exactly when this
spontaneous improvement occurs; however, after 3 months it is clearly
evident. These fluctuations of heart rate and of clinical pattern in
patients with SSS have no obvious explanation; the autonomic nervous
system most likely plays a major role.
Conclusions
In patients with SSS, dual-chamber pacemakers reduce the
occurrence of syncope, whereas oral theophylline does not appear to be
effective; therefore, when syncope represents a relevant
clinical problem, pacemaker implantation is the first choice of
treatment. Dual-chamber pacemakers and oral theophylline reduce the
occurrence of overt heart failure, and both treatments therefore appear
to be indicated in patients with SSS and episodes of heart failure. A
higher mortality has been reported after administration of some
positive inotropes in patients with heart failure40 41 ;
theophylline has a slight positive inotropic action, and the effect of
the drug on survival has not been investigated. The present study
is not powered to look at mortality; however, a trend toward higher
death rates did not emerge.
Dual-chamber pacemakers and oral theophylline reduce the minor symptoms of SSS, as previously demonstrated in noncontrolled studies2 4 5 6 7 8 9 20 21 22 23 24 28 31 ; however, the benefits of these treatments are actually due, at least in part, to a spontaneous improvement of the patient's clinical picture.
These conclusions are not valid for patients with very severe SSS, namely, symptomatic resting sinus rate <30 bpm or sinus pauses >3 seconds on standard ECGs recorded during diurnal hours or heart failure refractory to treatment with ACE inhibitors and diuretics, who were not included in the study and treated with pacemaker implantation.
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Selected Abbreviations and Acronyms |
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Received October 16, 1996; revision received January 16, 1997; accepted February 2, 1997.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Gann D, Tolentino A, Samet P.
Electrophysiologic evaluation of elderly patients with sinus
bradycardia: a long term follow-up study. Ann Intern
Med. 1979;90:24-29.
-
Sasaki Y, Shimotori M, Akahane K, Yonekura H, Hirono
K, Endoh R, Koike S, Kawa S, Furuta S, Homma T. Long-term
follow-up of patients with sick sinus syndrome: a comparison of
clinical aspects among unpaced, ventricular inhibited
paced, and physiologically paced
groups. Pacing Clin Electrophysiol. 1988;11:1575-1583.[Medline]
[Order article via Infotrieve]
-
Shaw DB, Holman RR, Gowers JI. Survival in
sino-atrial disorder (sick sinus syndrome). Br Med
J. 1980;280:139-141.
-
Shannon DC, Gotay F, Stein IM, Roger MC, Todras ID,
Moylan FMB. Prevention of apnea and bradycardia in
low-birthweight infants. Pediatrics. 1975;55:583-594.
[Abstract/Free Full Text]
-
Meyers TF, Milsap RL, Krauss AN, Adult PAM,
Reindenberg MM. Low-dose theophylline therapy in idiopathic
apnea of prematurity. J Pediatr. 1980;96:99-103.[Medline]
[Order article via Infotrieve]
-
Benditt DG, Benson W Jr, Kreitt J, Dunningan A,
Pritzker MR, Crouse L, Scheinman MM. Electrophysiologic effects
of theophylline in young patients with recurrent
symptomatic bradyarrhythmias. Am
J Cardiol. 1983;52:1223-1229.[Medline]
[Order article via Infotrieve]
-
Ellenbogen KA, Szentpetery S, Katz MR.
Reversibility of prolonged chronotropic dysfunction with theophylline
following orthotopic cardiac transplantation. Am
Heart J. 1988;110:202-206.
-
Alboni P, Ratto B, Cappato R, Rossi P, Gatto E,
Antonioli GE. Clinical effects of oral theophylline in sick
sinus syndrome. Am Heart J. 1991;122:1361-1367.[Medline]
[Order article via Infotrieve]
-
Saito D, Matsubara K, Yamanari H, Obayashi N, Uchida
S, Maekawa K, Sato T, Mizuo K, Kobayashi H, Haraokaj S. Effects
of oral theophylline on sick sinus syndrome. J Am
Coll Cardiol. 1993;21:1199-1204.[Abstract]
-
Alboni P, Menozzi C, Brignole M, Paparella N, Lolli G,
Oddone D, Dinelli M. An abnormal neural reflex plays a role in
causing syncope. J Am Coll Cardiol. 1993;22:1130-1134.[Abstract]
-
Brignole M, Menozzi C, Gianfranchi L, Oddone P, Lolli
G, Bertulla A. Neurally mediated syncope detected by carotid
sinus massage and head-up tilt test in sick sinus syndrome.
Am J Cardiol. 1991;68:1032-1036.[Medline]
[Order article via Infotrieve]
-
Jose AD, Collison D. The normal range and
determinants of the intrinsic heart rate in man.
Cardiovasc Res. 1970;4:160-166.
[Abstract/Free Full Text]
-
Alboni P, Malacarne C, Pedroni P, Masoni A, Narula
OS. Electrophysiology of normal sinus node with and without
autonomic blockade. Circulation. 1982;65:1236-1242.
[Free Full Text]
-
Alboni P, Pirani R, Filippi L Scarfò S, De
Lorenzi E, Tomasi AM, Masoni A. Latent abnormalities of sinus
function in patients with organic heart disease and normal sinus node
on clinical basis. J Electrocardiol. 1984;17:385-392.[Medline]
[Order article via Infotrieve]
-
Alboni P, Paparella N, Cappato R, Pirani R,
Yiannacopulu P, Antonioli GE. Long-term effects of theophylline
in atrial fibrillation with a slow ventricular
response. Am J Cardiol. 1993;72:1142-1145.[Medline]
[Order article via Infotrieve]
-
Fleiss JL. Analysis of
covariance and the study of change. In: The
Design and Analysis of Clinical Experiments. New York, NY:
Wiley; 1986:186-219.
-
BMDP Statistical Software, Release 7.0.
1993.
-
Little RJA, Rubin DB. Statistical
Analysis With Missing Data. New York, NY: Wiley; 1986.
-
SPSS for Windows, Release 5.02. 1993.
-
Alt E, Völker R, Wirtzfeld A, Ulm K.
Survival and follow-up after pacemaker implantation: a comparison of
patients with sick sinus syndrome, complete heart block, and atrial
fibrillation. Pacing Clin Electrophysiol. 1985;8:849-855.[Medline]
[Order article via Infotrieve]
-
Alpert MA, Curtis JJ, Sanfelippo JF, Flaker GC,
Walls JT, Mukerji V, Villarreal D, Katti SK, Madigan NP, Morgan
RJ. Comparative survival following permanent
ventricular and dual-chamber pacing for patients with
chronic symptomatic sinus node dysfunction with and without
congestive heart failure. Am Heart J. 1987;113:958-965.[Medline]
[Order article via Infotrieve]
-
Rosenqvist M, Brandt J, Shüller H.
Long-term pacing in sinus node disease: effects of stimulation mode on
cardiovascular morbidity and mortality.
Am Heart J. 1988;116:16-20.[Medline]
[Order article via Infotrieve]
-
Santini M, Alexidou G, Ansalone G, Cacciatore G, Cini
R, Turitto G. Relation of prognosis in sick sinus syndrome to
age, conduction defects and modes of permanent cardiac pacing.
Am J Cardiol. 1990;65:729-735.[Medline]
[Order article via Infotrieve]
-
Hesselson AB, Parsonnet V, Bernstein AD, Bonavita
GJ. Deleterious effects of long-term single-chamber
ventricular pacing in patients with sick sinus syndrome:
the hidden benefits of dual-chamber pacing. J Am
Coll Cardiol. 1992;19:1542-1549.[Abstract]
-
Lamas GA, Pashos CL, Normand SLT, McNeil B.
Permanent pacemaker selection and subsequent survival in elderly
Medicare pacemaker recipients. Circulation. 1995;91:1063-1069.
[Abstract/Free Full Text]
-
Andersen HR, Thuesen L, Bagger JP, Vesterlund T,
Thomsen BEB. Prospective randomized trial of atrial versus
ventricular pacing in sick sinus syndrome.
Lancet. 1994;344:1523-1528.[Medline]
[Order article via Infotrieve]
-
Sgarbossa EB, Pinski SL, Jaeger FJ, Trohman RG, Maloney
JD. Incidence and predictors of syncope in paced patients with
sick sinus syndrome. Pacing Clin Electrophysiol. 1992;15:1055-1060.
-
Sgarbossa EB, Pinski SL, Maloney JD, Simmons TW,
Wilkoff BL, Castle LW, Throman RG. Chronic atrial fibrillation
and stroke in paced patients with sick sinus syndrome: relevance of
clinical characteristics and pacing modalities.
Circulation. 1993;88:1045-1053.
[Abstract/Free Full Text]
-
Brignole M, Menozzi C, Lolli G, Bottoni N, Gaggioli
G. Long-term outcome of paced and nonpaced patients with severe
carotid sinus syndrome. Am J Cardiol. 1992;69:1039-1043.[Medline]
[Order article via Infotrieve]
-
Sra JS, Iazayeri MR, Avitali B, Dhala A, Deshpande S,
Blanck Z, Akhtar M. Comparison of cardiac pacing with drug
therapy in the treatment of neurocardiogenic (vasovagal) syncope with
bradycardia or asystole. N Engl J Med. 1993;328:1085-1090.
[Abstract/Free Full Text]
-
Breivik K, Ohm OJ, Segadal L. Sick sinus
syndrome treated with permanent pacemaker in 109 patients: a follow-up
study. Acta Med Scand. 1979;206:153-159.[Medline]
[Order article via Infotrieve]
-
Szentimikl'osi AJ, Ne'meth N, Szegi J, Papp J,
Szekeres L. Effect of adenosine on sinoatrial and
ventricular automaticity on the guinea pig.
Arch Pharmacol. 1980;311:147-149.
-
Di Marco JP, Sellers TD, Berne RM, West GA,
Belardinelli L. Adenosine: electrophysiologic effects
and therapeutic use for terminating paroxysmal
supraventricular tachycardia.
Circulation. 1983;68:1254-1263.
[Abstract/Free Full Text]
-
Alboni P, Rossi P, Ratto B, Pedroni P, Gatto E,
Antonioli GE. Electrophysiologic effects of oral theophylline in
sinus bradycardia. Am J Cardiol. 1990;65:1037-1039.[Medline]
[Order article via Infotrieve]
-
Marcus ML, Skelton CL, Grauer LE, Epstein SE.
Effects of theophylline on myocardial mechanics. Am
J Physiol. 1972;222:1361-1368.
-
Murphy GW, Schreiner BF, Yu PN. Effects of
aminophylline on the pulmonary circulation and left
ventricular performance in patients with
valvular heart disease. Circulation. 1968;37:361-369.
[Abstract/Free Full Text]
-
Matthay RA, Berger HJ, Loke J, Gottschalk A, Zaret
BL. Effects of aminophylline upon right and left
ventricular performance in chronic obstructive
pulmonary disease. Am J Cardiol. 1978;65:903-910.
-
Watt AH. Sick sinus syndrome: an
adenosine-mediated disease. Lancet. 1985;1:786-788.[Medline]
[Order article via Infotrieve]
-
Rall TW. The methylxanthines. In: Gilman AG,
Goodman LS, eds. The Pharmacological Basis of
Therapeutics. New York, NY: McMillan Publishing Co; 1985:589.
-
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, Di
Bianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam V, Kukin ML.
Effect of oral milrinone on mortality in severe chronic heart
failure. N Engl J Med. 1991;325:1468-1475.[Abstract]
-
Cowely AJ, Skene AM. Treatment of severe heart
failure: quantity or quality of life? A trial of enoximone.
Br Heart J. 1989;72:266-230.
[Abstract/Free Full Text]
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