Impact of bisoprolol transdermal patch on early recurrence during the blanking period after atrial fibrillation ablation

Abstract Background Early recurrences of atrial arrhythmias (ERAAs) after ablation may require therapeutic intervention. The optimal medical therapy that prevents ERAAs requires clarification. This study aimed to compare the incidence of ERAAs between patients who received or did not receive bisoprolol transdermal patches (BTPs) at 3 months postablation. Methods This single‐center retrospective study enrolled 203 consecutive patients with paroxysmal atrial fibrillation (AF) who had undergone their first ablation, comprising 59 in the BTP group and 144 in the non‐BTP group. Follow‐up assessments were conducted monthly for 3 months. We evaluated the incidence of ERAAs. Results During the initial 1‐week observational period, the rate of ERAAs was lower in the BTP group (5.0%) than that in the non‐BTP group (18.8%) (P = .013). At 3 months postablation, the rate of ERAAs was lower in the BTP group (6.8%) than that in the non‐BTP group (25.7%) (P = .002). The cumulative freedom from ERAAs was significantly lower in the BTP group than in the non‐BTP group (log‐rank: P = .003). Administering BTPs was an independent factor that protected against ERAAs (odds ratio 0.181, [95% confidence interval 0.059‐0.559], P = .003). Conclusion BTPs may prevent ERAAs after ablation.


| INTRODUC TI ON
Atrial fibrillation (AF) ablation is an increasingly utilized and effective treatment option for patients with symptomatic AF. Early recurrences of atrial arrhythmias (ERAAs) often occur within the first 3 months of AF ablation, that is, during the "blanking period." ERAAs are not associated with long-term ablation failure, 1 but they can be highly symptomatic and require therapeutic intervention. Although ERAAs may predict long-term arrhythmia recurrences, 2 the optimal medical therapy that prevents ERAAs during the blanking period requires clarification.
In January 2019, the world's first bisoprolol transdermal patch (BTP) (Bisono ® Tape; Toa Eiyo, Tokyo, Japan), which contains the selective β1 blocker, bisoprolol, became available for the treatment of tachycardia related to AF in Japan ( Figure 1). As a transdermal drug delivery system, BTP is associated with several advantages compared with oral bisoprolol, including more stable concentrations of the drug in the plasma and reduced likelihoods of rapid changes in the blood pressure and heart rate. 3,4 Moreover, removal of BTPs is easy if hypotension or bradycardia occurs, 4 and they can be administered immediately after AF ablation, even if a patient's arousal from anesthesia is delayed. The efficacy of BTPs at preventing ERAAs after ablation, however, has not been reported; therefore, we aimed to investigate whether BTPs prevent ERAAs in patients after ablation.

| Patients
This was a single-center retrospective study of patients who underwent AF ablation at Akashi Medical Center. Between January 2018 and June 2019, 219 patients underwent their first ablation for paroxysmal AF. We excluded patients with poor cardiac function, which was defined as a left ventricular ejection fraction <35%, severe bradycardia without a permanent pacemaker, including atrioventricular block types two and three, sinoatrial blocks, and sick sinus syndrome, concomitant inflammatory conditions, including active infections, inflammatory arthritis, and connective tissue disease, malignancies, and those who were dependent on hemodialysis or unable to attend follow-up assessments at the study site. After excluding 16 patients, the final analysis included 203 patients ( Figure 2). From January 2019 when BTPs have become available for the treatment of AF, our institution routinely administered BTPs in the catheter laboratory immediately after ablation to prevent ERAAs unless there were contraindications. As a result, 59 patients were administered BTPs and they were enrolled into the BTP group. On the other hand, the patients who underwent ablation between January 2018 and December 2018 were assigned into the non-BTP group.

This study was approved by the Akashi Medical Center's Ethics
Committee, and it was performed in accordance with the tenets of the Declaration of Helsinki.

| Consent
Informed consent was obtained in the form of opt-out on the website.

| Antiarrhythmic drug administration
Until December 2018, physicians could use antiarrhythmic drugs (AADs) after AF ablation to avoid the incidence of ERAAs during the blanking period. The type of AAD used, the dosage, and the timing of the administration were at the operating physician's discretion. BTPs have become available for the treatment of AF since January 2019, and our institution routinely administers BTPs in the catheter laboratory immediately after ablation to prevent ERAAs. The use of BTP was continued for 3 months after AF ablation, and, if possible, other AADs were discontinued before AF ablation. Although the BTP dosage was essentially 4 mg, which is equivalent to 2.5 mg of bisoprolol fumarate, it could be adjusted based on a patient's age, cardiac function, renal function, body weight, blood pressure, and heart rate.

| Catheter ablation
All patients underwent contrast-enhanced multidetector computed tomography (MDCT) to evaluate their left atria (LAs) and pulmonary veins (PVs). Three-dimensional MDCT images of the LAs and PVs were reconstructed on a separate workstation and integrated using the PV isolation (PVI) was performed using 28-mm second-generation cryoballoon (CB) ablation, 28-mm fourth-generation CB ablation, or radiofrequency (RF) ablation. RF ablation was performed using an irrigated-tip catheter with the maximum temperature set at 50˚C and a power output of 20-35 W. The PVI endpoint was the creation of an entrance conduction block into the PV. After PVI, we performed the provocation of non-PV triggers by the administration of isoproterenol and/or atrial burst pacing. When non-PV triggers were not identified, additional ablation except for cavotricuspid isthmus (CTI) ablation was not performed. In contrast, when non-PV triggers were identified with reproducibility, the initiation of AF or atrial tachycardia (AT) was routinely targeted on ablation. Then, a linear ablation, superior vena cava (SVC) isolation, and/or non-PV trigger ablation were F I G U R E 1 A bisoprolol transdermal patch, which is the world's first transdermal patch that contains the selective β1 blocker, bisoprolol performed if additional ablation was needed. When triggers from the LA posterior wall were identified, posterior box was performed, creating a roof line and bottom line. If SVC triggers were identified, SVC isolation was performed. When non-PV triggers form other sites were identified, focal ablation was applied around the earliest ectopic site. If macroreentrant AT was present, the mechanisms were determined by electro-anatomical activation mapping or entrainment mapping, and linear ablation targeting the critical isthmus was performed.
If the AF did not dissipate or was inducible after these procedures, sinus rhythm was restored by transthoracic cardioversion.

| Follow-up
After the procedures, the patients remained hospitalized under continuous rhythm monitoring (dynascope DS-8900; Fukuda Denshi, Tokyo, Japan). After discharge, all patients attended monthly follow-up assessments for 3 months. At each hospital visit, the patients underwent 12-lead electrocardiography (ECG) examination and they were interviewed about any arrhythmia-related symptoms, namely palpitations, chest discomfort, dizziness, and nausea. Holter ECG was performed at the physician's discretion between 1 month and 3 months after AF ablation. Moreover, for patients who had cardiac implantable electrophysiological devices (CIEDs), including pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization therapy devices, and loop recorders, we checked for AF recurrences using the CIEDs.
An early recurrence (ER) was defined as any episode of AF or AT that lasted ≥30 s and occurred within 90 days of AF ablation.
We defined a very ER (VER) as a recurrence within 7 days of the AF ablation. VERs and ERs were classified as "definite" or "probable." A definite VER or ER classification required electronic confirmation using an ECG monitor, 12-lead ECG, Holter ECG, or a CIED. Probable VERs or ERs were defined as any arrhythmia-related symptoms that were not confirmed electronically.

| Statistical analyses
All data are presented as means and standard deviations (SDs) or proportions. The variables were compared using the Chi-square or Fisher's exact tests, as appropriate. Kaplan-Meier analysis was performed to assess recurrence-free survival, and the log-rank test was used to compare the groups. We performed a univariate analysis to identify potential factors associated with ERAAs, including clinical, medications, and ablation procedures. After a univariate analysis, all variables with P-value <.1 were entered en bloc into the multivariate model along with age and sex as background variables. Thereafter, we used the stepwise multiple regression logistic analysis to explore the influence of different variables on ERAAs and to adjust for covariates. All of the analyses were performed using IBM ® SPSS ® software, version 26 (IBM Corporation, Armonk, NY, USA), and a value of P < .05 was considered statistically significant.

| Patients' characteristics
The non-BTP group comprised 144 consecutive patients with paroxysmal AF whose mean age was 66.7 ± 10.0 years, and it included 108 men (75%); this group of patients underwent their first AF ablation between January and December 2018. The BTP group comprised 59 consecutive patients with paroxysmal AF whose mean age was 66.9 ± 12.7 years, and it included 38 men (64.4%); this group of patients underwent their first AF ablation and received BTPs between January and June 2019. Table 1 presents the patients' baseline characteristics. The groups did not differ regarding their epidemiological data, comorbidities, echocardiographic and computed tomography parameters, and laboratory data.   In addition, we analyzed the comparison of baseline characteristics, medications, and ablation procedures between patients with or without definite ERs as Table 3. BTP was administered significantly less frequently in patients with definite ER (n = 4; 9.8%) than in those without definite ERs (n = 55; 34%) (P = .002). However, Multivariate analysis was performed to identify independent risk and protective factors associated with ERAAs (

| D ISCUSS I ON
To the best of our knowledge, this is the first investigation into the effects of BTPs on the prevention of ERAAs. The study generated several novel findings that showed the incidence of ERAAs was significantly lower in the BTP group than that in the non-BTP group, and that BTP might be a safe and effective means of preventing concentration of the drug in the plasma is more stable if it is administered transdermally, which may prevent rapid blood pressure and heart rate changes. 3,4 Moreover, if hypotension or bradycardia occurs, BTPs can be removed easily. 3 After cardiac and/or thoracic aortic surgery, BTPs were more effective at reducing the incidence of postoperative AF than orally administered bisoprolol fumarate. 12 Nonetheless, the efficacy of BTPs has not been described in the context of ablation. Immediately after surgery, patients are often unstable, and may become hypotensive or bradycardic. We selected BTPs as the pharmacological treatment for patients soon after AF ablation based on our reasoning that administering a drug with less potential to rapidly change the blood pressure and heart rate as soon as possible after ablation was desirable.
In the current study, the patients who were administered BTPs immediately after AF ablation showed significant reductions in the incidence of ERAAs compared with the patients who were not administered BTPs. The efficacy of BTPs at preventing ERAAs was confirmed not only immediately after ablation, but also during the short period after AF ablation without serious side effects. Hence, administering BTPs soon after AF ablation may be an effective and safe means to prevent ERAAs after AF ablation.
The mechanisms underlying ERAAs require full elucidation, but they could include inflammation during the acute phase after AF ablation, incomplete PVI, or the recovery of conduction in a previously isolated PV, non-PV triggers of AF, and a transient imbalance of the autonomic nervous system. 1,9,13 Many studies have shown that anti-inflammatory medications, namely corticosteroids or colchicine, reduce ERAAs. 9 These anti-inflammatory medications had adverse effects, including hyperglycemia, infections, and gastrointestinal bleeding. 14 Several investigators have reported that β-blockers might have anti-inflammatory effects and may attenuate the levels of inflammatory cytokines in heart failure, acute myocardial infarction, or dilated cardiomyopathy. 15 Landiolol controls the production of cytokines and other inflammatory regulators that may also help to prevent AF and reduce postoperative complications 16 ; therefore, the anti-inflammatory effects of BTPs may contribute to the prevention of ERAAs.
Several reports described β-blockers may have a relation to ectopic beats triggering AF and can suppress PV triggers. 17 Furthermore, β-blockers significantly suppress focal firing arising from the PV and non-PV sites, even in combination with a sodium channel-blocking agent. 18 We consider that β-blockers cannot directly prevent PV reconnection, but may reduce the incidences of ERAAs by suppressing PV triggering from the PV reconnection site and non-PV triggers of AF.
β-blockers may prevent excessive sympathetic nervous system activity. For example, the activation of the sympathetic nervous system plays an important role in the pathophysiology of AF postoperatively, and β-blockers prevent postoperative AF by inhibiting sympathetic tone. 19

| Limitations
The results of our study should be interpreted in the context of its in 91 patients (63.2%) in the non-BTP group and 37 patients (62.7%) in the BTP group between 1 month and 3 months after AF ablation.
However, even if patients received Holter ECG, we cannot deny the possibility of underdetection of ERAAs, because patients who had undergone the implantation of CIED were approximately 10% of all patients. The possibility of the underdetection of ERAAs was one of the limitations. Third, there was lack of uniform treatments and ablation procedure. AADs and/or β-blockers were not administered to all patients in the non-BTP group; however, BTPs were administered to all patients in the BTP group. Although oral bisoprolol fumarate, carvedilol, and AADs were not independent factors that protected from ERAAs by the univariate analysis, we cannot deny the possibility that lack of uniform treatments between the BTP and non-BTP groups might affect the results. CB ablation was significantly more often performed in the non-BTP group compared with BTP group. Although the multivariate analysis investigated that the CB was not an independent protective factor against the incidence of ERAAs, there was a possibility that the differences of ablation procedures had affected the incidences of ERAAs after ablation. In addition, we cannot deny the possibility of the influence of learning curve of ablation procedure. However, in almost cases of our study, well-experienced physicians basically performed ablation. Even when inexperienced physicians performed ablation, the instructors were fixed during study period. Moreover, the instructors were not changed between the BTP and non-BTP groups. As a result, there was no significant difference in the number of years of experience of the physicians between the BTP and non-BTP groups. Fourth, although the blood levels of bisoprolol might be stable in the patient with BTP than those with oral bisoprolol, we did not measure the blood levels of bisoprolol for each patient. Fifth, we could not reveal the mechanism that BTP was superior to oral β-blockers for the prevention of ERAAs. Finally, we could not determine the impact of BTPs on long-term improvements in this study, therefore further studies are warranted to evaluate whether the long-term use of BTPs reduces late clinical events.

| CON CLUS ION
The incidence of ERAAs after ablation in patients with paroxysmal AF was lower in the BTP group compared with that in the non-BTP group. BTP might be useful for preventing ERAAs after ablation.

ACK N OWLED G M ENT
None.

CO N FLI C T S O F I NTE R E S T
The authors declare no conflict of interest for this article.