Transdermal bisoprolol for prevention of postoperative atrial fibrillation: A systematic review and meta‐analysis

Abstract Background The transdermal patch of bisoprolol available in Japan has been reported to demonstrate superior efficacy in preventing postoperative atrial fibrillation, possibly surpassing its oral counterpart. However, there has been no systematic review and meta‐analysis assessing the efficacy of transdermal bisoprolol. Methods A comprehensive systematic literature search was conducted on PubMed, Embase, and Cochrane to identify all relevant studies assessing the efficacy of transdermal bisoprolol in preventing postoperative atrial fibrillation. The search covered studies from inception up to December 4, 2023. For data analysis, Review Manager (RevMan) 5.4 software was employed, using a random‐effects model to calculate risk ratios (RR) and 95% confidence intervals (CI). Results Three studies, comprising a total of 551 patients (transdermal bisoprolol 228 and control 323), were included. There was a decreased risk of postoperative atrial fibrillation or atrial tachyarrhythmias in patients treated with transdermal bisoprolol (RR 0.43, 95% CI 0.27–0.67, p = .0002, I 2 = 0%). Conclusion Transdermal administration of bisoprolol has consistently shown efficacy, and this pooled analysis supports its effectiveness. The heterogeneity of the included studies limits certain interpretations. Future randomized clinical trials may elucidate the superiority of transdermal administration over oral administration.


| INTRODUC TI ON
Postoperative atrial fibrillation (POAF) is observed in 5%-60% of postsurgical patients, with a higher incidence following cardiac and valve surgeries. 1Although many cases spontaneously convert to normal sinus rhythm, 2 POAF is linked to adverse outcomes, such as stroke and death. 3ta-blockers have been employed to prevent POAF in both cardiac 4 and noncardiac surgeries. 5Bisoprolol, a selective beta-1 receptor blocker without intrinsic sympathomimetic activity, not only controls heart rate but also exhibits antiarrhythmic effects in atrial fibrillation, potentially through the suppression of sympathetic activity. 6Recent advances in electrophysiology, such as cardioneuroablation, underscore the role of steady autonomic nervous system regulation in suppressing atrial fibrillation. 7In light of these findings, hypothesizing that maintaining a more stable serum betablocker concentration would offer superior POAF prevention seems plausible.
Transdermal bisoprolol patch (TBP) (Bisono ® Tape; Toa Eiyo, Tokyo, Japan) offers advantages over oral bisoprolol fumarate (OBF) by ensuring a steady serum concentration.This could be beneficial in POAF prevention, considering that minimizing autonomic variability through autonomic denervation reduces atrial fibrillation recurrences. 7Hypothetically, TBP may outperform OBF in preventing POAF by potentially minimizing autonomic variability by maintaining steadier serum concentrations.Indeed, Okamura et al. (2019)  8 demonstrated the superiority of the transdermal formula over the oral formula in preventing POAF.In this context, we conducted a comprehensive literature review on the efficacy of TBP.

| Search strategy
An extensive search of the literature was conducted using the databases PubMed, Embase, and Cochrane, gathering all studies available from their start dates up to December 4, 2023.The search terms used included "bisoprolol," "transdermal," and "atrial fibrillation," in various word forms, applied across all texts.

| Study selection
Two reviewers (AGK and SB) independently conducted a thorough evaluation of the study articles.We included all studies that evaluated the efficacy of TBP in preventing POAF with a comparison group.
Case reports or abstracts with insufficient data were excluded, along with single-arm studies that only evaluated the efficacy of TBP.Five studies [8][9][10][11][12] from Japan evaluating the effect of TBP in POAF were retrieved.Three studies [8][9][10] were included in the review.Two studies 11,12 only included patients who received TBP, thereby being removed from the comparative analysis.The meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Figure 1).

| Statistical analysis
The pooled analysis was conducted using Review Manager (RevMan) 5.4 software, applying a random-effects model for the calculation of risk ratios (RRs) and 95% confidence intervals (CIs).Statistical significance was determined by an overall p-value below .05.The I 2 test was used to evaluate heterogeneity.

| Study characteristics
The analysis comprised one multicenter randomized controlled study 9 and two single-center retrospective studies, 8,10       participants in each arm.The measured outcome was AF onset within 30 days postsurgery.

| Overall
The pooled analysis of both subgroups revealed a decreased risk of either postoperative atrial fibrillation or atrial tachyarrhythmias in patients treated with transdermal bisoprolol, risk ratio 0.43, 95% CI 0.27-0.67,p = .0002,I 2 = 0%.Despite heterogeneity of the three studies in terms of type of surgery/procedure and comparison group, statistical heterogeneity of the outcome between the TBP arm and the control arms was 0%.In the test for subgroup differences between cardiac and noncardiac surgeries versus catheter ablation, the heterogeneity (I 2 ) was 12.8%, indicating low variability among the subgroups.Each study yielded statistically and clinically significant results, as illustrated in Figure 2.

| DISCUSS ION
Postoperative atrial fibrillation (POAF) poses a clinical challenge, affecting a notable percentage of postsurgical patients, especially after cardiac and valve surgeries. 1While many cases spontaneously revert to normal sinus rhythm, the association between POAF and adverse outcomes, including stroke and death, underscores the need for effective prevention strategies.Evidence suggests that minimizing autonomic variability through vagal and sympathetic denervation is associated with a reduction in atrial fibrillation recurrences. 7This insight guides our exploration of the potential benefits of maintaining a more stable blood bisoprolol concentration through transdermal administration.Our study supports the advantages of transdermal bisoprolol patch (TBP) in preventing POAF.

| Study limitations
Our study's interpretability is hindered by the variability in surgical procedures, control groups, and outcome measures across the included studies.This variability affects the consistency of the findings and their applicability to different surgical contexts.

| CON CLUS ION
In conclusion, our study supports the potential of transdermal bisoprolol as a superior preventive measure against postoperative atrial fibrillation (POAF).The sustained suppression of sympathetic tone through the transdermal patch may introduce a clinically relevant avenue for exploration.Future randomized clinical trials may elucidate the nuanced efficacy of transdermal bisoprolol over oral bisoprolol in diverse surgical and procedural contexts.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no competing interests to declare.

R E FE R E N C E S
with a total of 551 patients-228 in the TBP arm and 323 in the control arm.Heterogeneity existed among the three studies in terms of the type of surgery, control group, and outcome measures.Detailed characteristics of the included studies and patients are listed in Tables 1, 2.F I G U R E 1 Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flowchart.

3. 1 . 1 |
Cardiac and noncardiac surgeries Okamura et al. (2019) 8 conducted a single-center retrospective study in Tokyo, Japan, from April 2016 to February 2018, involving 108 participants undergoing cardiac/thoracic aortic surgery.The study compared TBP 4 mg or lower from POD 1 to discharge to no TBP (OBF 2.5 mg or lower), with 49 participants in the TBP arm and 59 in the control (OBF) arm.The outcome measured was the new onset of AF (>30s).
Iwano et al. (2021), 9 a subanalysis of the MAMACARI trial with baseline characteristics stated in Toda et al. (2020), 13 is a multicenter randomized controlled study conducted in Okayama, Japan, from November 2014 to February 2019.It included 240 participants aged ≥60 with hypertension and a revised cardiac risk index score ≥2 scheduled for noncardiac surgery.Patients receiving beta-blockers and patients with chronic AF were excluded.The study compared TBP 4 mg or lower from 7 days pre-surgery to POD 7 to no TBP, with 120 Suzuki et al. (2021) 10 is a single-center retrospective study in Akashi, Japan, from January 2018 to June 2019, involving 203 participants with paroxysmal AF undergoing their first ablation, with LVEF ≥35%.The study compared TBP 4 mg or dose adjusted to no TBP immediately after AF ablation for 3 months, with 59 participants in the TBP arm and 144 in the control arm.The control arm could have received either OBF or other antiarrhythmics instead of TBP, including OBF (32.6%), carvedilol (15.3%), atenolol (1.4%), verapamil (1.4%), bepridil (2.8%), flecainide (11.1%), and amiodarone (0.7%).The measured outcome was early recurrences of atrial arrhythmias within 90 days post-AF ablation (blanking period).

2 , 3 6 F I G U R E 2
Bisoprolol, a beta-1 receptor blocker without intrinsic sympathomimetic activity, is commonly used for ventricular rate control in atrial fibrillation.It also demonstrates an antiarrhythmic effect, likely achieved by suppressing sympathetic activity, particularly in maintaining sinus rhythm for patients with a history of atrial fibrillation mediated by sympathetic tone.Forest plot of outcomes.CI, confidence interval; M-H, Mantel-Haenszel; TBP, transdermal bisoprolol patch.| 439 KIM et al.
Iwano et al. (2021), 9 however, did not compare TBP with OBF but instead evaluated TBP against no beta-blocker treatments.Despite these discrepancies, all included studies consistently demonstrated the efficacy of TBP in preventing POAF.Both Okamura et al. (2019) 8 and Suzuki et al. (2021) 10 suggested TBP's superiority over OBF in this context.
TA B L E 1 (Continued)TA B L E 2 Baseline characteristics of study patients.Okamura et al. (