Bisoprolol and AFIB

281

Antiarrhythmic Effect of Bisoprolol, a Highly Selective β1-Blocker, in Patients With Paroxysmal Atrial

FibrillationHaruhisa 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 thesuppression of sympathetic activity. We evaluated the antiarrhythmic effects of a highlyselective β1-blocker, bisoprolol, in patients with diurnal paroxysmal atrial fibrillation (P-AF).

A total of 136 patients with symptomatic diurnal P-AF were enrolled. Patients weredivided into a diurnal-specific P-AF group and a diurnal & nocturnal P-AF group, as wellas into a bisoprolol single use group and a combined use group with an antiarrhythmicdrug. The effects of bisoprolol were evaluated in 3 categories: subjective symptomimprovement, quality of life (QOL) improvement, and elimination of P-AF episode inHolter electrocardiograms (ECGs). For patients with effective treatment, a long-termeffect up to 24 months was evaluated.

Five patients (3.7%) discontinued bisoprolol due to side effects. Following adminis-tration of bisoprolol, 109 patients (80%) experienced subjective symptom improvement,103 patients (76%) experienced QOL improvement, and elimination of P-AF episodes inECGs was observed in 84 patients (62%). The elimination rate of P-AF episodes in ECGswas 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 andthe combined use group. A long-term suppressive effect by bisoprolol was observed in 70of 83 patients (84%).

The results demonstrate that bisoprolol has an antiarrhythmic effect against sympa-thetic diurnal P-AF, improving subjective symptoms and QOL and eliminating P-AF epi-sodes in ECGs. (Int Heart J 2008; 49: 281-293)

Key words: β-blocker, Paroxysmal atrial fibrillation, Antiarrhythmic effect, Sympatheticnerve

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, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.This study was supported in part by a Grant-in-Aid (18300157) for Scientific Research from the Ministry of Education, Cul-

ture, 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, 2008.Revised and accepted March 31, 2008.

282 Int Heart JMay 2008ISHIGURO, ET AL

PAROXYSMAL atrial fibrillation (P-AF) is one of the most common arrhyth-mias in daily practice. In general, P-AF is not a type of arrhythmia with a poorprognosis, but it is an arrhythmia that may lower the quality of life (QOL) bycausing certain symptoms such as palpitations, or even lead to serious complica-tions such as cerebral infarction. For the treatment of P-AF, either pharmacologi-cal treatment or catheter ablation is used, with the former treatment being carriedout in most patients.

The pharmacological treatment of P-AF is largely divided into rhythm con-trol therapy and rate control therapy. When rhythm control therapy is selected,according to the recent guidelines for antiarrhythmic drug treatment, class I anti-arrhythmic drugs are recommended for administration.1,2)

Due to their atrio-ventricular conduction suppressive effect, in the field ofarrhythmia, β-blockers are mainly used to regulate heart rate; ie, to treat tach-yarrhythmia.3) However, an antiarrhythmic action by β-blockers is also antici-pated as an antagonism for high sympathetic nerve activity.4) Regarding theantiarrhythmic action of β-blockers, many studies have been conducted on ven-tricular arrhythmias.5-8) In these studies, it has been demonstrated that administra-tion of β-blockers suppressed life-threatening ventricular arrhythmic episodeswith a consequent reduction in the incidence of cardiac death. However, onlyvery few studies investigated supraventricular arrhythmias, and more impor-tantly, there are few reports on P-AF in the literature.

In the present study, using bisoprolol, the most selective β1-blocker,9) theantiarrhythmic effects in patients with confirmed diurnal episodes of P-AF wereinvestigated, taking into consideration the involvement of sympathetic activitiesand the concomitant use of class I antiarrhythmic drugs. In addition, in thepatients in whom bisoprolol proved effective in a short-term evaluation, the long-term suppressive effects by continuous administration were evaluated.

METHODS

Study population: A total of 136 consecutive patients (74 men, 62 women, meanage, 67 ± 14 years) who visited Kyorin University Hospital between January2003 and October 2005 were enrolled. They complained of symptoms such aspalpitations, and had a diurnal P-AF episode in a 12-lead electrocardiogram(ECG) or 24-hour Holter ECG, and were indicated for pharmacological treat-ment. 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 forthe treatment of P-AF were also enrolled. P-AF was defined as a condition inwhich AF spontaneously recovered to sinus rhythm within 24 hours after theonset.

ANTIARRHYTHMIC EFFECT OF BISOPROLOL IN P-AF 283Vol 49No 3

Patients were excluded from the study if they received a pacemaker implant,underwent catheter ablation, had an acute myocardial infarction episode within amonth, or when it was considered risky to receive β-blockers due to brad-yarrhythmia, bronchial asthma, or hypotension.

The clinical characteristics of the study patients are shown in Table I. Under-lying diseases were detected in 90 patients (66.2%), with hypertension being thecommonest (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: cibenzo-line in 22 patients, propafenone in 19, pilsicainide in 17, disopyramide in 9, andamiodarone 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

nAge (years)MenUnderlying disease

HypertensionValvular diseaseDiabetes mellitusCoronary artery diseaseCardiomyopathyHyperthyroidism

Lone atrial fibrillationHeart rate (beats/minute)Systolic blood pressureDiastolic blood pressureLeft atrial diameter (mm)Left ventricular ejection fraction (%)Antiarrhythmic drug therapy

CibenzolinePropafenonePilsicainideDisopyramideAmiodarone

Thromboprophylaxis drugsWarfarinAspirinWarfarin and aspirin

Other drugsCa-antagonistsACE-inhibitor/ARBDigoxin

13666.6 ± 14.674 (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 ± 11.8

130.6 ± 16.674.2 ± 9.936.8 ± 5.861.9 ± 7.571 (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%)


antagonists (47 patients), angiotensin converting enzyme (ACE) inhibitor/angio-tensin-II receptor blocker (ARB) (34 patients), and digoxin (12 patients).

Although patients with symptomatic diurnal P-AF were enrolled in thepresent study, the patients were evaluated after dividing them into a diurnal typegroup (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 andnighttime (19:01-7:00). In addition, depending on the concomitant use of an anti-arrhythmic 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 UniversityHospital. Informed consent was obtained from all patients prior to enrollmentinto the study.Administration of bisoprolol: Bisoprolol was administered at 2.5 mg/day. How-ever, if the patient weighed more than 80 kg or his systolic BP was higher than140 mmHg, the dose was increased to 5.0 mg/day. Accordingly, a total of 46patients (33.8%) received 5.0 mg/day. For the patients who had been receivingother antiarrhythmic drugs, bisoprolol was also administered while maintainingthe dosage and administration of the former antiarrhythmic drug. When biso-prolol was considered effective, the administration was further continued for atleast 24 months. Assessment of antiarrhythmic effects: The suppressive effects of P-AF wereevaluated by the following 3 criteria: subjective symptom improvement, qualityof life (QOL) improvement, and elimination of P-AF episode in 24-hour HolterECGs. A short-term evaluation was carried out in the third month after the initialadministration. When all of these criteria were satisfied, we considered that biso-prolol was effective.

Evaluation of subjective symptoms. The subjective symptom improvementwas evaluated by a symptom logbook recorded by the patient, and the logbookwas checked regularly every two weeks while attending the outpatient clinic afterstarting oral bisoprolol. The strength and frequency of the symptoms were moni-tored, 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 eval-uated QOL by distributing questionnaires to the patients to fill out at 3 monthsafter starting the initial oral administration. Limitation of physical activities andlimitation of mental stresses were individually evaluated at 4 levels (significantlyimproved: 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, AFQOQ10) used in the J-Rhythm study11) is extensively utilized in


Japan, but we have developed our own simple QOL questionnaires since AFQOQwas not released yet when we designed the study.

Evaluation of elimination of P-AF episode in ECGs. For evaluation of theactual elimination of P-AF episodes in ECG, 24-hour Holter ECG was used. Itwas necessary to confirm the presence of P-AF episodes in ECGs since Page, etal12) reported that even symptomatic P-AF patients can show asymptomatic P-AFepisodes in detailed Holter ECGs. The Holter ECG was recorded monthly start-ing at one month after the initial administration of bisoprolol to monitor the pres-ence or absence of P-AF. Elimination of the P-AF episodes in ECGs wasconsidered when the episode was not detected at all in Holter ECGs for 3 times inthe first 3 months. Evaluation of long-term effectiveness of continuous administration: In the pati-ents in whom administration of bisoprolol was effective for treatment of P-AFafter the initial 3 months, the long-term suppressive effects on P-AF by continu-ous administration of bisoprolol were evaluated. The total follow-up period was24 months. Three items; namely, the subjective symptoms, QOL, and Holter ECGwere monitored and recorded 6, 12, 18, and 24 months after the initial adminis-tration. We concluded that bisoprolol was effective for the long-term suppressionof P-AF if the patient did not show any subjective symptoms, worsening QOL, orP-AF episode. Statistical analysis: The data are presented as the mean ± SD. Student’s t-test wasused for statistical comparison of the patient background factors between the twogroups, 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 5patients (3.7%), necessitating the discontinuation of administration. The sideeffects 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 improvementrates were 80% (109 patients) and 76% (103 patients) of the patients, respec-tively. The actual elimination rate of P-AF episodes on Holter ECGs was 62% (84patients). 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 comparedbetween the patients with an improvement in subjective symptoms and those whodid not experience any improvement, heart rates in the former patients were sig-nificantly reduced (P < 0.0001) (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


with the diurnal P-AF group (n = 54), there were no differences in the structuralfactors except that the diurnal P-AF group showed significantly higher restingheart rates (P = 0.003).

Figure 1. Antiarrhythmic effect of bisoprolol in all 136 patients. Symptom indicates improve-ment of subjective symptoms; QOL, improvement on QOL; and ECG, elimination of P-AF onECGs.

Figure 2. Comparison of the changes in heart rate between the patients with improvement in subjective symptoms and thosewho did not claim any improvement with administration of bisoprolol.


Figure 3 shows comparisons of the subjective symptom improvement, QOLimprovement, and elimination of P-AF in EGG between the two groups.Improvement in the subjective symptoms was observed in 45 patients (83%) inthe diurnal P-AF group and in 64 patients (78%) in the diurnal & nocturnal P-AFgroup, 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 in60 patients (73%) in the diurnal & nocturnal P-AF group, and the differencebetween the two groups was not significant. Regarding the elimination of P-AFepisodes in ECGs, episode elimination was observed in 39 patients (72%) in thediurnal P-AF group and in 45 patients (55%) in the diurnal & nocturnal P-AFgroup, 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 antiar-rhythmic drug) group (Table II): There were no differences between the twogroups, with the exceptions that the left ventricular ejection fraction rate was sig-nificantly 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 andBetween Bisoprolol Single Use Group and the Combined Use (With an Antiarrhythmic Drug) Group

P-AF subgroups P-AF subgroups

DiurnalP-AF group

Diurnal & nocturnalP-AF group P Single use

groupCombined use

group P

n Age (years)MenUnderlying disease

HypertensionDiabetes mellitusCoronary artery diseaseValvular diseaseCardiomyopathyHyperthyroidism

Lone atrial fibrillationHeart rate (beats/minute)Systolic blood pressureDiastolic blood pressureLeft atrial diameter (mm)Left ventricular ejection fraction (%)Thromboprophylaxis drugs

WarfarinAspirin

Other drugsACE-inhibitor/ARBCa-antagonistsDigoxin

5466.8 ± 16.228 (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 ± 12.4

130.0 ± 18.672.4 ± 8.935.7 ± 5.762.6 ± 6.723 (42.6%)

8 (14.8%)17 (31.5%)

13 (24.1%)17 (31.5%)

6 (11.1%)

8266.4 ± 13.546 (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 ± 10.8

131.0 ± 15.175.6 ± 10.537.4 ± 5.761.4 ± 8.141 (50.0%)21 (25.6%)22 (26.8%)

21 (25.6%)30 (36.6%)

6 (7.3%)

0.8980.6270.1690.6270.9810.1000.7270.1070.8960.1690.0030.7190.0820.1050.3990.4010.1350.561

0.8410.5440.449

6565.7 ± 16.032 (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 ± 11.4

130.7 ± 19.074.6 ± 11.336.6 ± 5.863.6 ± 7.424 (36.9%)

9 (13.8%)16 (24.6%)

15 (23.1%)20 (30.8%)

6 (9.2%)

7167.3 ± 13.242 (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 ± 12.2

130.8 ± 14.073.8 ± 8.437.0 ± 5.860.4 ± 7.340 (56.3%)20 (28.2%)23 (32.4%)

19 (26.8%)27 (38.0%)6 (8.5%)

0.5020.2460.9960.9940.3190.6520.8520.5510.5510.9960.5320.8820.6480.6680.0190.0230.0420.320

0.6230.3780.874


lower in the bisoprolol single use group (n = 65) than in the combined use (withan antiarrhythmic drug) group (n = 71).

Figure 4 shows comparisons of the subjective symptom improvement, QOLimprovement, and elimination of P-AF episodes in ECGs between the twogroups. Subjective symptom improvement was observed in 53 patients (80%) inthe single use group and in 57 patients (80%) in the combined use group, and thedifference between the two groups was not significant. QOL improved in 48patients (74%) in the single use group and in 55 patients (78%) in the combineduse group, and the difference between the two groups was not significant. In addi-tion, 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 inwhom bisoprolol proved effective in the short-term evaluation, ie, the patientswho demonstrated subjective symptom improvement, QOL improvement, aswell as elimination of P-AF episodes in ECGs, the long-term suppressive effectson P-AF by continuous administration were evaluated. During follow-up, onepatient experienced symptomatic bradycardia due to bisoprolol. Withdrawal ofthe drug was necessary in this patient and the patient was excluded from the long-term evaluation. Suppressive effects on P-AF at 6, 12, 18, and 24 months after the

Figure 3. Comparisons of antiarrhythmic effects of bisoprolol between diurnal P-AF group anddiurnal & nocturnal P-AF group.


initial administration were detected in 79 (95%), 76 (92%), 72 (87%), and 70(84%) of 83 patients, respectively, indicating that the suppressive effects of biso-prolol on P-AF were still strong at 24 months. There were no clear differencesbetween the two groups when the patients were divided into the bisoprolol singleuse group and the combined use group (with an antiarrhythmic drug) (Figure 5).

Figure 4. Comparisons of antiarrhythmic effects of bisoprolol between single use group andcombined use group.

Figure 5. Long-term suppressive effect by continuous administration in patients in whom bisoprolol was effective in theshort-term evaluation.


DISCUSSION

P-AF is an arrhythmia frequently observed along with certain underlyingdiseases such as valvular disease, ischemic heart disease, cardiomyopathy, andhypertensive heart disease, but it is also often induced by elevated autonomic ner-vous function and stresses. Therefore, P-AF can be classified into a high vagalnerve activity type or high sympathetic nerve activity type, or nocturnal P-AF ordiurnal P-AF depending on the effects on the autonomic nervous activities.1,2) Itis known that administration of a drug that blocks autonomic nervous functionincreases the suppressive effect of P-AF when pharmacological treatment isselected.1,2)

In the present study, using bisoprolol, which is an excellent heart selectiveβ-blocker, we investigated the efficacy on P-AF in diurnal P-AF patients. Wefound that the administration of bisoprolol effectively suppressed P-AF in 62% ofthe patients, indicating a high antiarrhythmic effect of bisoprolol on P-AF. Fur-thermore, this effect was observed upon single use of bisoprolol, especially in thediurnal P-AF. The long-term effect of bisoprolol was also indicated.

When pharmacological treatment is chosen for P-AF to regulate the cardiacrhythm, a Na-channel or K-channel blocker is selected in many patients. How-ever, many studies have reported that the use of these drugs to suppress AFresulted in worsening prognosis although the drugs exhibit strong antiarrhythmiceffects.13-16) In addition to a worsening prognosis, these drugs may induce a riskof 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 reeval-uated since several large-scale studies revealed that rate control therapy using adrug such as a β-blocker proved not to be inferior to rhythm control therapy usingan antiarrhythmic drug in terms of the incidence of serious events such as cere-bral infarction.3,17)

Some studies investigated the correlation between β-blocker administrationand the incidence of AF. Bruce, et al18) reported that the use of β-blockers loweredthe incidence of new AF episodes in elderly people based on their epidemiologi-cal study (relative risk = 0.61). Nasr, et al19) suggested that the use of β-blockerssuppressed new episodes of AF in patients with heart failure. Haghjoo, et al20)

reported that administration of a β-blocker (carvedilol) was effective in suppress-ing AF after coronary artery bypass graft surgery. These studies did not directlyinvestigate the suppression of a preexisting P-AF condition, but they indicatedthat β-blockers suppressed AF episodes. A study investigated the effect onrhythm control in persistent AF patients who underwent electrical defibrillationusing metoprolol, a β1-blocker similar to bisoprolol.21) The results revealed thatadministration of metoprolol was effective in preventing AF recurrence.


There are two reports comparing the suppressive effect of a β-blocker withthat of an antiarrhythmic drug in P-AF patients. Steeds, et al22) 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 ofP-AF suppression. Plewan, et al23) compared the suppression of P-AF recurrencein persistent AF patients who underwent electrical defibrillation, and demon-strated that bisoprolol administration had a similar effect to that of sotalol admin-istration in terms of suppressing P-AF recurrence. Furthermore, they concludedthat administration of bisoprolol was more effective than administration ofsotalol because of the lower incidence of side effects observed in the patientstreated with bisoprolol.

Bisoprolol is the most selective β-blocker in the heart and a highly sym-patholytic drug.4) When the sympathetic tone is increased, norepinephrine isreleased from the sympathetic nerve terminals to stimulate β-(β1) receptors in thecardiac muscle, following which G-protein is activated to activate adenyl cyclaseto eventually act on calcium channels, which decrease the action potential dura-tion of the atrial muscle cells to increase the risk of AF episodes by shortening therefractory phase.4) Therefore, β-blockers are effective at suppressing AF due totheir β1 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 mus-cle protection,24) and bisoprolol is considered to have a similar effect since it isalso a lipid soluble drug. Furthermore, atrial muscle remodeling is also believedto be involved in AF episodes, and bisoprolol is expected to suppress the remod-eling of atrial muscle due to its antioxidative effect. In this manner, bisoprolol isa suitable β-blocker for the suppression of P-AF.

As another advantage of using bisoprolol, as demonstrated in the presentstudy, even if arrhythmia was not suppressed, bisoprolol is expected to be effec-tive in regulating the cardiac rate with consequent improvement of the subjectivesymptoms and the QOL of the patient. Thus, the administration of bisoprolol isstill useful.Study limitations: There were several limitations in the present study. First, thestudy enrolled P-AF patients who demonstrated P-AF during daytime. Therefore,this increased the efficacy of bisoprolol administration. In other words, the effi-cacy would have been lower if all P-AF patients were targeted.

Second, the QOL was assessed by the simple questionnaires that we devel-oped. The use of detailed questionnaires might have resulted in slightly differentconclusions.

Third, placebo or other β-blockers were not used as a control. Haghjoo, etal20) reported that carvedilol was more effective than metoprolol for prevention ofatrial fibrillation after coronary artery bypass graft surgery. Thus, the use of a


control drug was necessary to conclude that bisoprolol is the most effective β-blocker for arrhythmia.

Fourth, the bisoprolol-induced elimination of the P-AF episodes in ECGswas carried out by using monthly Holter ECG a total of 3 times. Although this isnot sufficient for evaluation purposes, considering most of the previous studiesexamined drug efficacy by simply judging the improvement of subjective symp-toms, our present study is valuable in that we have used 3 criteria; namely, thesubjective symptoms, QOL, and Holter ECGs. Conclusions: We have demonstrated that bisoprolol was effective as an antiar-rhythmic drug against diurnal symptomatic P-AF. Furthermore, this effect wasfurther intensified for P-AF episodes occurring only in the daytime, and it wasfully effective when used alone. Bisoprolol is also effective for long-term treat-ment, which makes it a good candidate for the suppression of diurnal P-AF.

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Bisoprolol and AFIB

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