Pacemakers are more commonly recommended than theophylline for sick sinus
syndrome (SSS) treatment. The positive effects of cilostazol on bradyarrhythmias
also have been reported. However, no comparison of cilostazol and theophylline
has been previously reported found. We retrospectively enrolled SSS patients, who
refused a pacemaker implantation. Theophylline or cilostazol was administered,
and the heart rate (HR) was evaluated in 4-8 weeks using a digital
sphygmomanometer and the electrocardiogram (ECG). A 200-400 mg of theophylline
or 100-200 mg of cilostazol were administered per day in 50 and 30 patients,
respectively. The baseline HR was 54.8
A decreasing heart rate (HR) in patients with sinus node dysfunction (SND) aggravates the symptoms related to bradycardia such as fatigue, dizziness, dyspnea, and syncope, which are indications for a permanent pacemaker implantation (Alt et al., 1985; Tung et al., 1994). However, some patients are reluctant to undergo permanent pacing due to the fear of having a device implanted in their body. Clinically, some patients may not have severe bradycardia requiring a pacemaker implantation but cannot be observed without some kind of treatment. Some helpful messages have been proposed in several studies (Ling and Crouch, 1998; Moriya et al., 2004; Sonoura et al., 2019; Verza et al., 1996) regarding pharmacological therapy to increase the HR in patients with sick sinus syndrome (SSS).
Theophylline and cilostazol have been shown to have positive chronotropic effects, which may be useful for relieving symptoms related to bradycardia in patients with SND. However, no previous studies or trials have been performed comparing the positive chronotropic effects of these two agents. Therefore, in this study, we compared the effects of theophylline and cilostazol on the HR in patients with SSS.
SSS was defined as SND (such as sinus bradycardia, sinus pauses, or tachycardia-bradycardia syndrome) combined with bradycardia-related symptoms such as fatigue, dizziness, dyspnea, or syncope. Sinus bradycardia was defined as an HR of less than 60 beats per minute (bpm) during sinus rhythm (Adán and Crown, 2003). A sinus pause was defined as a temporary absence of P waves and QRS complexes due to dysfunction of the sinus node for more than 2.5 seconds (Shaw and Southall, 1984), and tachycardia-bradycardia syndrome as an alternating presence of atrial origin tachycardias and brady-arrhythmias (Moss and Davis, 1974).
From January 2008 to December 2017, we sequentially and retrospectively enrolled patients with SSS, who refused a pacemaker implantation. The study was approved by the ethics committee at Chonnam National University Hospital, Gwangju, Korea (CNUH-2017-033). The patients were administered theophylline or cilostazol and underwent followed-up at our Cardiovascular Center. The patients who concomitantly used negative chronotropic agents such as beta-blockers, calcium channel blockers, and digoxin, discontinued the study drug during the follow-up, or were lost to follow-up, were excluded.
After exclusion of those patients, 50 patients were included in the theophylline group and 30 in the cilostazol group. Seventy patients had type I, 9 type II, and one type III SSS according to the Rubenstein classification (Rubenstein et al., 1972). Type III SSS (tachycardia-bradycardia syndrome) and type II SSS (sinus pause without tachycardia) were identified by the index 12-lead electrocardiograms (ECGs), and type I SSS was diagnosed by telemetry when the patients complained of symptoms during the hospitalization. Among the theophylline group, 15 patients were switched from theophylline to cilostazol, due to insufficient drug effects or adverse drug reactions to theophylline such as nausea, vomiting, or diarrhea (Fig. 1).
Study design. After the exclusion of the inelligible patients, 50 patients were included in the theophylline group and 30 in the cilostazol group. Among the theophylline group patients, 15 were switched from theophylline to cilostazol, due to insufficient drug effects or adverse drug reactions to theophylline such as nausea, vomiting, or diarrhea. The HR was evaluated in 4 - 8 weeks when the patients visited the outpatient clinic. The HR was measured by routine vital sign measurements and ECGs. Abbreviations: HR, heart rate
The HR was evaluated using the ECG (MAC-3500, GE Healthcare Co. Ltd., Chicago, IL, USA) and digital sphygmomanometry (HBP-9020, OMRON Co. Ltd, Kyoto, Japan) in the outpatient clinic. After the administration of theophylline or cilostazol, the HR was re-evaluated in 4-8 weeks at the out-patient clinic. The HR, maximum RR interval, and mean RR interval were compared.
The symptoms such as dyspnea, chest discomfort, syncope, and palpitations were compared between those before and after the administration of theophylline or cilostazol. The severity of the dyspnea was classified into 4 stages according to the New York Heart Association (NYHA) classification. Chest discomfort, syncope, and palpitations were classified as the presence or absence of symptoms.
All analyses were performed using SPSS® Statistics 18.0 for
Windows software (SPSS Inc., Chicago, IL, USA). The continuous baseline
characteristics were presented as the average values
Overall 80 patients were enrolled in this study (50 patients in the theophylline group and 30 in the cilostazol group). There was no significant difference between the two groups in terms of the age, sex, systolic blood pressure, previous history of hypertension, diabetes, dyslipidemia, and smoking (Table 1).
|Characteristics||Theophylline group (n = 50)||Cilostazol group (n = 30)||P value|
|Sex (Male: Female)||19:31||12:18||0.859|
|LV ejection fraction (%)||65.1
|Lowest heart rate (bpm)||43.3
|P-value calculated by a Student’s t-test for the continuous variables and Pearson’s chi-square test for the categorical variables. Abbreviations: bpm, beat per minute; DM, diabetes mellitus; DL, dyslipidemia; HTN, hypertension; LV, left ventricle; sBP systolic blood pressure|
Fifty patients were administered 200-400 mg of theophylline per day, and 30
patients, 100-200 mg of cilostazol per day. The baseline HR of the entire 80
patients was 51.9
The mean follow-up period was 31
Representative 12-lead ECGs of pre and post-treatment. A) Pre-treatment ECG showed a junctional rhythm with 47 bpm. Theophylline 400 mg was administered for 14 days. Post-treatment ECG showed a normal sinus rhythm with 71 bpm. B) Pre-treatment ECG showed a junctional rhythm with 46 bpm. Cilostazol 200 mg was administered for 14 days. Post-treatment ECG showed a normal sinus rhythm with 70 bpm. Abbreviations: bpm, beat per minute.
Comparison of the HR before and after the theophylline and cilostazol
administration. A) The HR evaluated by the ECG increased from 50.6
|HR at the clinic (bpm)||53.8
|HR on the ECG (bpm)||50.6
|Mean RR (ms)||1250.4
|HR at the clinic (bpm)||56.4
|HR on the ECG (bpm)||54.0
|Mean RR (ms)||1143.7
|P-value calculated by a paired t-test. Abbreviations: bpm, beat per minute; dBP diastolic blood pressure; ECG, electrocardiogram; HR, heart rate; OPD, out-patient department; PR, PR interval; RR, RR interval; sBP, systolic blood pressure|
Among the 50 patients in the theophylline group, 15 were switched from
theophylline to cilostazol. The drug-naive HR was 48.9
|Parameter||Baseline||Theophylline||Cilostazol||P value (B
||P value (T |
|HR on the ECG (bpm)||48.9
|Mean RR (ms)||1277.6
|P-value calculated by a paired t-test. Abbreviations: B, Baseline; bpm, beat per minute; C, Cilostazol; ECG, electrocardiogram; HR, heart rate; PR, PR interval; RR, RR interval; T, Theophylline|
Changes in the HR after switching from theophylline to cilostazol. The
baseline HR evaluated by the ECG was 48.9
Overall in the 80 patients, the dyspnea significantly improved after the
administration of theophylline or cilostazol (P
|Before||After||P value||Before||After||P value||Before||After||P value|
|Dyspnea (NYHA Fc)|
|P-value calculated by a Wilcoxon signed-rank test. Abbreviations: NYHA Fc, New York heart association function class|
In the 50 patients in the theophylline group, the dyspnea and palpitations
improved significantly. There were 2 class IV, 11 class III, and 13 class II
patients, and they improved to 0 class IV, 3 class III, and 12 class II patients
after the theophylline administration (P
In the 30 patients in the cilostazol group, the dyspnea and dizziness significantly improved. There was 1 class IV, 4 class III, and 6 class II patients, and they improved to 0 class IV, 1 class III, and 5 class II patients after the cilostazol administration (P = 0.002). Eleven patients experienced dizziness before the cilostazol administration, but only 2 after the cilostazol (P = 0.003). However, there was no significant improvement in the chest discomfort, syncope, or palpitations.
When comparing the two drugs in terms of the symptom improvement, cilostazol had a significantly better results for the dizziness than theophylline (Table 5). In terms of the side effects of the drugs, there were 5 patients with nausea, 0 with diarrhea, 3 with headaches, 3 with new arrhythmias (e.g.: atrial fibrillation, flutter, or premature atrial complexes), and 1 with numbness of the extremities in the theophylline group. There were 4 patients with headaches and 1 with diarrhea in the cilostazol group (Table 6).
|Dyspnea||20 (40%)||30 (60%)||10 (33%)||20 (67%)||0.551|
|Chest discomfort||3 (50%)||3 (50%)||3 (60%)||2 (40%)||0.74|
|Dizziness||5 (26%)||14 (74%)||9 (82%)||2 (18%)||0.003|
|Syncope||3 (100%)||0 (0%)||1 (100%)||0 (0%)||NA|
|Palpitations||4 (100%)||0 (0%)||3 (75%)||1 (25%)||0.285|
|P-value calculated by a Chi-square test. Abbreviations: NA, not available|
After a median follow-up of 2 years and 9 months, there was no significant difference in the clinical course between the two groups (Table 6).
|Theophylline group (n = 50)||Cilostazol group (n = 30)|
|CV hospitalization||1 HF, 1 AMI||2 UAP|
|Abbreviations: AMI, acute myocardial infarction; CV, cardiovascular; HF, heart failure; UAP, unstable angina|
SND is often related to age-dependent, progressive, and degenerative fibrosis of the sinus nodal tissue and surrounding atrial myocardium. SSS is a clinical syndrome characterized by SND. However, historically, SND used to be referred to as SSS. In the present study, when we emphasized the histopathologic characteristics, we used “SND”. When the symptoms were emphasized, we used “SSS”.
The increment in the HR is helpful for improving symptoms such as general weakness, fatigue, dizziness, and syncope in patients with SSS (Alt et al., 1985; Tung et al., 1994). Permanent pacemaker implantations are the most frequently used and most effective treatment option and are almost always considered as a first-line treatment. Therefore, only a few studies have investigated the effectiveness of the pharmacological therapy for SSS, and thus far, the diversity of the various pharmacological therapies for these patients is still low.
There have been many reports on the positive chronotropic effects of theophylline, which acts to block adenosine and leads to an increase in sinus node automaticity and atrioventricular (AV) conduction (Gambhir et al., 1995; Szentmiklosi et al., 1980). Several studies have shown that theophylline improves the severity of bradycardia-related symptoms in newborn babies, and that theophylline increases the HR in patients with late advanced AV block complicated with acute myocardial infarction and who undergo heart transplantations (Altun et al., 1998; Ellenbogen et al., 1988; Myers et al., 1980; Shannon et al., 1975). Thus, this agent could be used to increase the HR in patients with SND. However, a prospectively assessed randomized controlled trial (THEOPACE) has revealed that permanent pacemakers are more effective than theophylline in reducing the occurrence of syncope (Alboni et al., 1997). Cilostazol, a phosphodiesterase-III (PDE-III) inhibitor, was first developed in Japan for the treatment of symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. Cilostazol has anti-platelet effects and positive hemodynamic effects on peripheral circulatory defects by the selective inhibition of cyclic nucleotide PDE-III in platelets and vascular smooth muscle. Therefore, this agent is first treatment option for vascular inflammatory diseases, such as coronary artery disease or peripheral arterial occlusive disease (Kambayashi et al., 2003; Kawamura et al., 1985; Liu et al., 2001; Shintani et al., 1985).
Cilostazol is considered to have positive chronotropic effects via several
speculated mechanisms (MacDonald et al., 2020; Mangoni and Nargeot, 2008).
Firstly, Fischmeister et al. (2006) revealed that cyclic adenosine
monophosphate (cAMP) plays an important role in the beta-adrenergic receptors
that stimulate the HR. Gs-protein (stimulatory G-protein) activation (e.g., via
Therefore, it was considered that cilostazol would be a reasonable pharmacological treatment for SSS by increasing the HR, and several studies on that have been performed. Ueda et al. (2001) evaluated 24-hour ambulatory ECG monitoring after cilostazol administration and revealed that the HR increases and the frequency of sinus pauses decreases after cilostazol administration.
The present study compared the positive chronotropic effects between theophylline and cilostazol, and although the HR significantly increased after the administration of theophylline and cilostazol, there was no difference between the two groups. Moreover, the symptoms such as dyspnea, chest discomfort, and dizziness improved after the administration of theophylline and cilostazol. Interestingly, in terms of the dizziness, cilostazol resulted in a significant improvement when compared to theophylline. We believed that the max RR interval increment, which is shown in Table 2, could explain the significant improvement in the dizziness in the cilostazol group. Also, as we described above, it might be a result of the positive chronotropic and vasodilation effects.
Theophylline has a narrow therapeutic index, and theophylline toxicity may occur at toxic levels. That includes symptoms from mild gastrointestinal symptoms such as nausea, vomiting, and diarrhea to severe and fatal cardiac arrhythmias or a central nervous system manifestation such as seizures. In this study, nausea was the most frequent adverse effect. Therefore, regular evaluation of the serum theophylline level may be required and helpful to minimize the adverse drug reactions (Gaudreault and Guay, 1986). However, the optimum dose of cilostazol has been determined (100 mg twice daily) and there is no need to monitor the serum levels. The vasodilation effect of cilostazol causes some side effects such as headaches and diarrhea, but they are almost always mild symptoms and improve after conservative treatment and the discontinuation of the cilostazol (Liu et al., 2001). In this study, there were 4 patients with headaches and 1 with diarrhea in the cilostazol group. The headaches disappeared by their next clinic visit.
This study had some limitations. First, the study was a retrospective and single center-based study, so selection bias and recall bias may have occurred and the baseline patient characteristics could have influenced the outcome. Second, we did not control the dosage of theophylline and cilostazol, so it may have been difficult to accurately investigate the effects of both agents. Further, since we used the ECG to evaluate the patient’s HR, the HR only reflected that at the time of the ECG. Twenty-four hour ambulatory ECG monitoring may be required to evaluate the continuous HR, including the circadian rhythms, in the patients. In the overall patients, the symptoms improved significantly and also tended to improve when the patients were divided into the theophylline and cilostazol groups, however, some improvements in the overall patients were not statistically significant. This may have been due to the lack of an adequate number of patients or because the symptoms were subjective, and we did not classify the severity of the symptoms.
In conclusion, this study suggested that cilostazol, like theophylline, might be used for supportive management in patients with SSS, especially when the patients do not want a pacemaker or their symptoms are not very severe. Moreover, there are some advantages to using cilostazol. Since SSS frequently occurs in elderly patients and they tend to have comorbid peripheral arterial occlusive disease, there may be an advantage of using cilostazol in elderly patients. However, further studies are needed due to several limitations of this study.
ITJ was a major contributor to the writing of the manuscript. NY contributed to the design, literature search, experimental studies, data acquisition, data analysis, manuscript preparation, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. HKJ contributed to the literature search, experimental studies, data analysis, statistical analysis, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. KHL contributed to the manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. HWP contributed to the conception of the work, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. JGC contributed to the conception of the work, definition of the intellectual content, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. All authors read and approved the final manuscript.
The study was approved by the ethics committee at Chonnam National University Hospital, Gwangju, Korea (CNUH-2017-033), where exempted informed consent from enrolled patients because of retrospective study protocol.
We gratefully acknowledge Mr. John Martin, RN, BSN, for the linguistic assistance with the manuscript.
The authors declare that there are no conflicts of interest regarding the publication of this article.