β 1 -Blocker, in Patients With Paroxysmal Atrial

Transcription

1 Antiarrhythmic Effect of Bisoprolol, a Highly Selective β 1 -Blocker, in Patients With Paroxysmal Atrial Fibrillation Haruhisa ISHIGURO, 1 MD, Takanori IKEDA, 1 MD, Atsuko ABE, 1 MD, Takehiro TSUKADA, 1 MD, Hisaaki MERA, 1 MD, Kentaro NAKAMURA, 1 MD, Satoru YUSU, 1 MD, and Hideaki YOSHINO, 1 MD SUMMARY In the treatment of arrhythmia, β-blockers are mainly used to regulate the heart rate. However, β-blockers are also known as drugs with an antiarrhythmic effect due to the suppression of sympathetic activity. We evaluated the antiarrhythmic effects of a highly selective β 1 -blocker, bisoprolol, in patients with diurnal paroxysmal atrial fibrillation (P- AF). A total of 136 patients with symptomatic diurnal P-AF were enrolled. Patients were divided into a diurnal-specific P-AF group and a diurnal & nocturnal P-AF group, as well as into a bisoprolol single use group and a combined use group with an antiarrhythmic drug. The effects of bisoprolol were evaluated in 3 categories: subjective symptom improvement, quality of life (QOL) improvement, and elimination of P-AF episode in Holter electrocardiograms (ECGs). For patients with effective treatment, a long-term effect up to 24 months was evaluated. Five patients (3.7%) discontinued bisoprolol due to side effects. Following administration of bisoprolol, 109 patients (80%) experienced subjective symptom improvement, 103 patients (76%) experienced QOL improvement, and elimination of P-AF episodes in ECGs was observed in 84 patients (62%). The elimination rate of P-AF episodes in ECGs was higher in the diurnal P-AF group than in the diurnal & nocturnal P-AF group (P = 0.042). There was no significant difference between the bisoprolol single use group and the combined use group. A long-term suppressive effect by bisoprolol was observed in 70 of 83 patients (84%). The results demonstrate that bisoprolol has an antiarrhythmic effect against sympathetic diurnal P-AF, improving subjective symptoms and QOL and eliminating P-AF episodes in ECGs. (Int Heart J 2008; 49: ) Key words: nerve β-blocker, Paroxysmal atrial fibrillation, Antiarrhythmic effect, Sympathetic From the 1 Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan. Address for correspondence: Takanori Ikeda, MD, Second Department of Internal Medicine, Kyorin University School of Medicine, Shinkawa, Mitaka, Tokyo , Japan. This study was supported in part by a Grant-in-Aid ( ) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant from the Fukuda Memorial Foundation for Medical Research (Dr. Ikeda). Received for publication February 27, Revised and accepted March 31,

2 282 ISHIGURO, ET AL Int Heart J May 2008 PAROXYSMAL atrial fibrillation (P-AF) is one of the most common arrhythmias in daily practice. In general, P-AF is not a type of arrhythmia with a poor prognosis, but it is an arrhythmia that may lower the quality of life (QOL) by causing certain symptoms such as palpitations, or even lead to serious complications such as cerebral infarction. For the treatment of P-AF, either pharmacological treatment or catheter ablation is used, with the former treatment being carried out in most patients. The pharmacological treatment of P-AF is largely divided into rhythm control therapy and rate control therapy. When rhythm control therapy is selected, according to the recent guidelines for antiarrhythmic drug treatment, class I antiarrhythmic drugs are recommended for administration. 1,2) Due to their atrio-ventricular conduction suppressive effect, in the field of arrhythmia, β-blockers are mainly used to regulate heart rate; ie, to treat tachyarrhythmia. 3) However, an antiarrhythmic action by β-blockers is also anticipated as an antagonism for high sympathetic nerve activity. 4) Regarding the antiarrhythmic action of β-blockers, many studies have been conducted on ventricular arrhythmias. 5-8) In these studies, it has been demonstrated that administration of β-blockers suppressed life-threatening ventricular arrhythmic episodes with a consequent reduction in the incidence of cardiac death. However, only very few studies investigated supraventricular arrhythmias, and more importantly, there are few reports on P-AF in the literature. In the present study, using bisoprolol, the most selective β 1 -blocker, 9) the antiarrhythmic effects in patients with confirmed diurnal episodes of P-AF were investigated, taking into consideration the involvement of sympathetic activities and the concomitant use of class I antiarrhythmic drugs. In addition, in the patients in whom bisoprolol proved effective in a short-term evaluation, the longterm suppressive effects by continuous administration were evaluated. METHODS Study population: A total of 136 consecutive patients (74 men, 62 women, mean age, 67 ± 14 years) who visited Kyorin University Hospital between January 2003 and October 2005 were enrolled. They complained of symptoms such as palpitations, and had a diurnal P-AF episode in a 12-lead electrocardiogram (ECG) or 24-hour Holter ECG, and were indicated for pharmacological treatment. They exhibited P-AF episodes at least twice within the previous 3 months. In the present study, patients who had been receiving an antiarrhythmic drug for the treatment of P-AF were also enrolled. P-AF was defined as a condition in which AF spontaneously recovered to sinus rhythm within 24 hours after the onset.

3 Vol 49 No 3 ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 283 Patients were excluded from the study if they received a pacemaker implant, underwent catheter ablation, had an acute myocardial infarction episode within a month, or when it was considered risky to receive β-blockers due to bradyarrhythmia, bronchial asthma, or hypotension. The clinical characteristics of the study patients are shown in Table I. Underlying diseases were detected in 90 patients (66.2%), with hypertension being the commonest (50.7%), followed by valvular disease (11.8%), diabetes mellitus (11%) and coronary heart disease (11%) with almost the same incidence rates. Lone AF, or underlying disease-free AF was observed in 42 patients (33.8%). Antiarrhythmic drugs had been used in 71 patients (52.2%) as follows: cibenzoline in 22 patients, propafenone in 19, pilsicainide in 17, disopyramide in 9, and amiodarone in 4. Thromboprophylaxis drugs were used in 64 patients as follows: warfarin in 29 patients, aspirin in 39, and both in 4. Other drugs included calcium Table I. Clinical Characteristics of the Study Patients n Age (years) Men Underlying disease Hypertension Valvular disease Diabetes mellitus Coronary artery disease Cardiomyopathy Hyperthyroidism Lone atrial fibrillation Heart rate (beats/minute) Systolic blood pressure Diastolic blood pressure Left atrial diameter (mm) Left ventricular ejection fraction (%) Antiarrhythmic drug therapy Cibenzoline Propafenone Pilsicainide Disopyramide Amiodarone Thromboprophylaxis drugs Warfarin Aspirin Warfarin and aspirin Other drugs Ca-antagonists ACE-inhibitor/ARB Digoxin ± (54.4%) 90 (66.2%) 69 (50.7%) 16 (11.8%) 15 (11.0%) 15 (11.0%) 8 (5.9%) 8 (5.9%) 46 (33.8%) 78.4 ± ± ± ± ± (52.2%) 22 (16.2%) 19 (14.0%) 17 (12.5%) 9 (6.6%) 4 (2.9%) 64 (47.1%) 29 (21.3%) 39 (28.7%) 4 (2.9%) 47 (34.6%) 34 (25.0%) 12 (8.8%)

4 284 ISHIGURO, ET AL Int Heart J May 2008 antagonists (47 patients), angiotensin converting enzyme (ACE) inhibitor/angiotensin-ii receptor blocker (ARB) (34 patients), and digoxin (12 patients). Although patients with symptomatic diurnal P-AF were enrolled in the present study, the patients were evaluated after dividing them into a diurnal type group (n = 54) who had P-AF during the daytime (7:01-19:00) only and a diurnal & nocturnal type group (n = 82) who had P-AF during both the daytime and nighttime (19:01-7:00). In addition, depending on the concomitant use of an antiarrhythmic drug, the subjects were divided into a bisoprolol single use group (n = 65) and a combined use group (n = 71). The protocol was approved by the ethics committee of Kyorin University Hospital. Informed consent was obtained from all patients prior to enrollment into the study. Administration of bisoprolol: Bisoprolol was administered at 2.5 mg/day. However, if the patient weighed more than 80 kg or his systolic BP was higher than 140 mmhg, the dose was increased to 5.0 mg/day. Accordingly, a total of 46 patients (33.8%) received 5.0 mg/day. For the patients who had been receiving other antiarrhythmic drugs, bisoprolol was also administered while maintaining the dosage and administration of the former antiarrhythmic drug. When bisoprolol was considered effective, the administration was further continued for at least 24 months. Assessment of antiarrhythmic effects: The suppressive effects of P-AF were evaluated by the following 3 criteria: subjective symptom improvement, quality of life (QOL) improvement, and elimination of P-AF episode in 24-hour Holter ECGs. A short-term evaluation was carried out in the third month after the initial administration. When all of these criteria were satisfied, we considered that bisoprolol was effective. Evaluation of subjective symptoms. The subjective symptom improvement was evaluated by a symptom logbook recorded by the patient, and the logbook was checked regularly every two weeks while attending the outpatient clinic after starting oral bisoprolol. The strength and frequency of the symptoms were monitored, and when the symptoms improved, the condition was regarded as an improvement. Evaluation of QOL. The QOL improvement was evaluated by two aspects: limitation of physical activities and limitation of mental stresses. Briefly, we evaluated QOL by distributing questionnaires to the patients to fill out at 3 months after starting the initial oral administration. Limitation of physical activities and limitation of mental stresses were individually evaluated at 4 levels (significantly improved: 2 points, improved: 1 point, no change: 0 point, worsened: -1 point), and improvement was determined if the average score was greater than 1 point. Currently, AFQOQ 10) used in the J-Rhythm study 11) is extensively utilized in

5 Vol 49 No 3 ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 285 Japan, but we have developed our own simple QOL questionnaires since AFQOQ was not released yet when we designed the study. Evaluation of elimination of P-AF episode in ECGs. For evaluation of the actual elimination of P-AF episodes in ECG, 24-hour Holter ECG was used. It was necessary to confirm the presence of P-AF episodes in ECGs since Page, et al 12) reported that even symptomatic P-AF patients can show asymptomatic P-AF episodes in detailed Holter ECGs. The Holter ECG was recorded monthly starting at one month after the initial administration of bisoprolol to monitor the presence or absence of P-AF. Elimination of the P-AF episodes in ECGs was considered when the episode was not detected at all in Holter ECGs for 3 times in the first 3 months. Evaluation of long-term effectiveness of continuous administration: In the patients in whom administration of bisoprolol was effective for treatment of P-AF after the initial 3 months, the long-term suppressive effects on P-AF by continuous administration of bisoprolol were evaluated. The total follow-up period was 24 months. Three items; namely, the subjective symptoms, QOL, and Holter ECG were monitored and recorded 6, 12, 18, and 24 months after the initial administration. We concluded that bisoprolol was effective for the long-term suppression of P-AF if the patient did not show any subjective symptoms, worsening QOL, or P-AF episode. Statistical analysis: The data are presented as the mean ± SD. Student s t-test was used for statistical comparison of the patient background factors between the two groups, and the χ 2 test was used for comparison of the incidences. A P value < 0.05 was considered statistically significant. RESULTS Side effects following oral administration of bisoprolol were observed in 5 patients (3.7%), necessitating the discontinuation of administration. The side effects were severe bradycardia in 3 patients and edema in 2 patients. Figure 1 presents the antiarrhythmic effects of bisoprolol in all 136 patients. The subjective symptoms and QOL improved markedly; and the improvement rates were 80% (109 patients) and 76% (103 patients) of the patients, respectively. The actual elimination rate of P-AF episodes on Holter ECGs was 62% (84 patients). The effects on subjective symptoms were very similar to that on QOL (both 94%). When the changes in heart rate in the resting ECGs were compared between the patients with an improvement in subjective symptoms and those who did not experience any improvement, heart rates in the former patients were significantly reduced (P < ) (Figure 2). Comparison between diurnal P-AF group and diurnal & nocturnal P-AF group (Table II): When the diurnal & nocturnal P-AF group (n = 82) was compared

6 286 ISHIGURO, ET AL Int Heart J May 2008 Figure 1. Antiarrhythmic effect of bisoprolol in all 136 patients. Symptom indicates improvement of subjective symptoms; QOL, improvement on QOL; and ECG, elimination of P-AF on ECGs. Figure 2. Comparison of the changes in heart rate between the patients with improvement in subjective symptoms and those who did not claim any improvement with administration of bisoprolol. with the diurnal P-AF group (n = 54), there were no differences in the structural factors except that the diurnal P-AF group showed significantly higher resting heart rates (P = 0.003).

7 Vol 49 No 3 ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 287 Figure 3 shows comparisons of the subjective symptom improvement, QOL improvement, and elimination of P-AF in EGG between the two groups. Improvement in the subjective symptoms was observed in 45 patients (83%) in the diurnal P-AF group and in 64 patients (78%) in the diurnal & nocturnal P-AF group, and the difference between the two groups was not significant. For QOL, improvement was observed in 43 patients (80%) in the diurnal P-AF group and in 60 patients (73%) in the diurnal & nocturnal P-AF group, and the difference between the two groups was not significant. Regarding the elimination of P-AF episodes in ECGs, episode elimination was observed in 39 patients (72%) in the diurnal P-AF group and in 45 patients (55%) in the diurnal & nocturnal P-AF group, and the episode elimination was significantly higher in the former group (P = 0.042). Comparison between bisoprolol single use group and combined use (with an antiarrhythmic drug) group (Table II): There were no differences between the two groups, with the exceptions that the left ventricular ejection fraction rate was significantly higher (P = 0.019) and the anticoagulant therapy was significantly Table II. Comparisons of Clinical Characteristics Between Diurnal P-AF Group and Diurnal & Nocturnal P-AF Group and Between Bisoprolol Single Use Group and the Combined Use (With an Antiarrhythmic Drug) Group P-AF subgroups P-AF subgroups Diurnal P-AF group Diurnal & nocturnal P-AF group P Single use group Combined use group P n Age (years) Men Underlying disease Hypertension Diabetes mellitus Coronary artery disease Valvular disease Cardiomyopathy Hyperthyroidism Lone atrial fibrillation Heart rate (beats/minute) Systolic blood pressure Diastolic blood pressure Left atrial diameter (mm) Left ventricular ejection fraction (%) Thromboprophylaxis drugs Warfarin Aspirin Other drugs ACE-inhibitor/ARB Ca-antagonists Digoxin ± (51.9%) 32 (59.3%) 26 (48.1%) 6 (11.1%) 3 (5.6%) 7 (13.0%) 1 (1.9%) 3 (5.6%) 22 (40.7%) 82.0 ± ± ± ± ± (42.6%) 8 (14.8%) 17 (31.5%) 13 (24.1%) 17 (31.5%) 6 (11.1%) ± (56.1%) 58 (70.7%) 43 (52.4%) 9 (11.0%) 12 (14.6%) 9 (11.0%) 7 (8.5%) 5 (6.1%) 24 (29.3%) 76.0 ± ± ± ± ± (50.0%) 21 (25.6%) 22 (26.8%) 21 (25.6%) 30 (36.6%) 6 (7.3%) ± (49.2%) 43 (66.2%) 33 (50.8%) 9 (13.8%) 8 (12.3%) 8 (12.3%) 3 (4.6%) 3 (4.6%) 22 (33.8%) 79.0 ± ± ± ± ± (36.9%) 9 (13.8%) 16 (24.6%) 15 (23.1%) 20 (30.8%) 6 (9.2%) ± (59.2%) 47 (66.2%) 36 (50.7%) 6 (8.5%) 7 (9.9%) 8 (11.3%) 5 (7.0%) 5 (7.0%) 24 (33.8%) 77.8 ± ± ± ± ± (56.3%) 20 (28.2%) 23 (32.4%) 19 (26.8%) 27 (38.0%) 6 (8.5%)

8 288 ISHIGURO, ET AL Int Heart J May 2008 Figure 3. Comparisons of antiarrhythmic effects of bisoprolol between diurnal P-AF group and diurnal & nocturnal P-AF group. lower in the bisoprolol single use group (n = 65) than in the combined use (with an antiarrhythmic drug) group (n = 71). Figure 4 shows comparisons of the subjective symptom improvement, QOL improvement, and elimination of P-AF episodes in ECGs between the two groups. Subjective symptom improvement was observed in 53 patients (80%) in the single use group and in 57 patients (80%) in the combined use group, and the difference between the two groups was not significant. QOL improved in 48 patients (74%) in the single use group and in 55 patients (78%) in the combined use group, and the difference between the two groups was not significant. In addition, the elimination of P-AF episodes in ECGs was observed in 41 patients (63%) in the single use group and in 43 patients (61%) in the combined use group, and the difference between the two groups was not significant. Long-term suppressive effect by continuous administration: In the 83 patients in whom bisoprolol proved effective in the short-term evaluation, ie, the patients who demonstrated subjective symptom improvement, QOL improvement, as well as elimination of P-AF episodes in ECGs, the long-term suppressive effects on P-AF by continuous administration were evaluated. During follow-up, one patient experienced symptomatic bradycardia due to bisoprolol. Withdrawal of the drug was necessary in this patient and the patient was excluded from the longterm evaluation. Suppressive effects on P-AF at 6, 12, 18, and 24 months after the

9 Vol 49 No 3 ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 289 Figure 4. Comparisons of antiarrhythmic effects of bisoprolol between single use group and combined use group. Figure 5. Long-term suppressive effect by continuous administration in patients in whom bisoprolol was effective in the short-term evaluation. initial administration were detected in 79 (95%), 76 (92%), 72 (87%), and 70 (84%) of 83 patients, respectively, indicating that the suppressive effects of bisoprolol on P-AF were still strong at 24 months. There were no clear differences between the two groups when the patients were divided into the bisoprolol single use group and the combined use group (with an antiarrhythmic drug) (Figure 5).

10 290 ISHIGURO, ET AL DISCUSSION Int Heart J May 2008 P-AF is an arrhythmia frequently observed along with certain underlying diseases such as valvular disease, ischemic heart disease, cardiomyopathy, and hypertensive heart disease, but it is also often induced by elevated autonomic nervous function and stresses. Therefore, P-AF can be classified into a high vagal nerve activity type or high sympathetic nerve activity type, or nocturnal P-AF or diurnal P-AF depending on the effects on the autonomic nervous activities. 1,2) It is known that administration of a drug that blocks autonomic nervous function increases the suppressive effect of P-AF when pharmacological treatment is selected. 1,2) In the present study, using bisoprolol, which is an excellent heart selective β-blocker, we investigated the efficacy on P-AF in diurnal P-AF patients. We found that the administration of bisoprolol effectively suppressed P-AF in 62% of the patients, indicating a high antiarrhythmic effect of bisoprolol on P-AF. Furthermore, this effect was observed upon single use of bisoprolol, especially in the diurnal P-AF. The long-term effect of bisoprolol was also indicated. When pharmacological treatment is chosen for P-AF to regulate the cardiac rhythm, a Na-channel or K-channel blocker is selected in many patients. However, many studies have reported that the use of these drugs to suppress AF resulted in worsening prognosis although the drugs exhibit strong antiarrhythmic effects ) In addition to a worsening prognosis, these drugs may induce a risk of serious ventricular arrhythmia, eg, torsade de points, as a side effect. Recently, the effectiveness of β-blockers in the treatment of persistent AF has been reevaluated since several large-scale studies revealed that rate control therapy using a drug such as a β-blocker proved not to be inferior to rhythm control therapy using an antiarrhythmic drug in terms of the incidence of serious events such as cerebral infarction. 3,17) Some studies investigated the correlation between β-blocker administration and the incidence of AF. Bruce, et al 18) reported that the use of β-blockers lowered the incidence of new AF episodes in elderly people based on their epidemiological study (relative risk = 0.61). Nasr, et al 19) suggested that the use of β-blockers suppressed new episodes of AF in patients with heart failure. Haghjoo, et al 20) reported that administration of a β-blocker (carvedilol) was effective in suppressing AF after coronary artery bypass graft surgery. These studies did not directly investigate the suppression of a preexisting P-AF condition, but they indicated that β-blockers suppressed AF episodes. A study investigated the effect on rhythm control in persistent AF patients who underwent electrical defibrillation using metoprolol, a β 1 -blocker similar to bisoprolol. 21) The results revealed that administration of metoprolol was effective in preventing AF recurrence.

11 Vol 49 No 3 ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 291 There are two reports comparing the suppressive effect of a β-blocker with that of an antiarrhythmic drug in P-AF patients. Steeds, et al 22) compared the β- blocker atenolol, and sotalol which is a class III antiarrhythmic drug having a β- blocking function, in symptomatic P-AF patients. Both showed a similar level of P-AF suppression. Plewan, et al 23) compared the suppression of P-AF recurrence in persistent AF patients who underwent electrical defibrillation, and demonstrated that bisoprolol administration had a similar effect to that of sotalol administration in terms of suppressing P-AF recurrence. Furthermore, they concluded that administration of bisoprolol was more effective than administration of sotalol because of the lower incidence of side effects observed in the patients treated with bisoprolol. Bisoprolol is the most selective β-blocker in the heart and a highly sympatholytic drug. 4) When the sympathetic tone is increased, norepinephrine is released from the sympathetic nerve terminals to stimulate β-(β 1 ) receptors in the cardiac muscle, following which G-protein is activated to activate adenyl cyclase to eventually act on calcium channels, which decrease the action potential duration of the atrial muscle cells to increase the risk of AF episodes by shortening the refractory phase. 4) Therefore, β-blockers are effective at suppressing AF due to their β 1 selectivity. In addition, a recent study has indicated that a lipid soluble β- blocker is more effective than a water soluble β-blocker in terms of cardiac muscle protection, 24) and bisoprolol is considered to have a similar effect since it is also a lipid soluble drug. Furthermore, atrial muscle remodeling is also believed to be involved in AF episodes, and bisoprolol is expected to suppress the remodeling of atrial muscle due to its antioxidative effect. In this manner, bisoprolol is a suitable β-blocker for the suppression of P-AF. As another advantage of using bisoprolol, as demonstrated in the present study, even if arrhythmia was not suppressed, bisoprolol is expected to be effective in regulating the cardiac rate with consequent improvement of the subjective symptoms and the QOL of the patient. Thus, the administration of bisoprolol is still useful. Study limitations: There were several limitations in the present study. First, the study enrolled P-AF patients who demonstrated P-AF during daytime. Therefore, this increased the efficacy of bisoprolol administration. In other words, the efficacy would have been lower if all P-AF patients were targeted. Second, the QOL was assessed by the simple questionnaires that we developed. The use of detailed questionnaires might have resulted in slightly different conclusions. Third, placebo or other β-blockers were not used as a control. Haghjoo, et al 20) reported that carvedilol was more effective than metoprolol for prevention of atrial fibrillation after coronary artery bypass graft surgery. Thus, the use of a

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