Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome
The THEOPACE Study: A Randomized Controlled Trial
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.
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).
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 β-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.
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.
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.
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
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.
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.
Primary analysis. Baseline characteristics and clinical end points were compared in the three groups by χ2 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 χ2 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.
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).
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⇓.
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.
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.
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⇓).
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.
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
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.
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.
Selected Abbreviations and Acronyms
|DDDR||=||dual-chamber rate-responsive pacing|
|NYHA||=||New York Heart Association|
|SSS||=||sick sinus syndrome|
- Received October 16, 1996.
- Revision received January 16, 1997.
- Accepted February 2, 1997.
- Copyright © 1997 by American Heart Association
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