Preventative Effects of Bisoprolol Transdermal Patches on Postoperative
Atrial Fibrillation in High-risk Patients undergoing Non-cardiac Surgery:
A subanalysis of the MAMACARI Study
Takayuki Iwano, MDa; Hironobu Toda, MDa; Kazufumi Nakamura, MD, FJCCa,*; Kazuyoshi
Shimizu, MDb; Kentaro Ejiri, MDa; Yoichiro Naito, MDc; Hisatoshi Mori, MDd; Takuro Masuda,
MDa,e; Toru Miyoshi, MD, FJCCa; Masashi Yoshida, MDa; Yukiko Hikasa, MDb; Hiroshi
Morimatsu, MDb; Hiroshi Ito, MD, FJCCa on behalf of the MAMACARI Investigators.

aDepartment of Cardiovascular Medicine, Okayama University Graduate School of Medicine,

Dentistry and Pharmaceutical Sciences, Okayama, Japan; bDepartment of Anesthesiology,
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama, Japan; cDepartment of Cardiology, Fukuyama City Hospital, Fukuyama, Japan;
dDepartment of Cardiology, Tsuyama Chuo Hospital, Tsuyama, Japan; and eDepartment of

Cardiology, Himeji Red Cross Hospital, Himeji, Japan*Correspondence author at Department of Cardiovascular Medicine, Okayama University
Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho,
Kita-ku, Okayama 700-8558, Japan
Tel: +81-86-235-7351, fax: +81-86-235-7353, e-mail: ichibun@cc.okayama-u.ac.jp

Key words: perioperative atrial fibrillation, non-cardiac surgery, bisoprolol

Word count for the body of the text: 2797
Total numbers of tables and figures: 2 tables, 2 figures,1

Abstract
Background: Perioperative atrial fibrillation (POAF) after non-cardiac surgery is a risk factor
for cardiovascular events including stroke and death. The aim of this subanalysis of the
MAMACARI study, a multicenter randomized control study on the effectiveness of abisoprolol transdermal patch for prevention of perioperative myocardial injury in high-riskpatients undergoing non-cardiac surgery, was to identify the predictors of POAF after noncardiac surgery in high-risk patients and to determine changes in blood pressure and heart
rate during bisoprolol patch administration in the perioperative period.
Methods and Results: Patients aged over 60 years with hypertension and a high revised
cardiac risk index (≥2) who were scheduled to undergo non-cardiac surgery were randomly
assigned to a bisoprolol patch group (n=120) or a control group (n=120). We divided thepatients into two groups: patients with POAF (POAF group; n=16) and patients without POAF
(non-POAF group; n=206). Multivariate analysis showed that bisoprolol patch therapy (OR:0.30, 95% CI: 0.092-0.978) and surgery time of 250 minutes or more (OR: 4.99, 95% CI: 1.3718.2) were independently associated with POAF. Although systolic blood pressure did not
differ significantly between the two groups throughout the perioperative period, treatment
with a bisoprolol patch significantly reduced heart rate throughout the perioperative period
compared with that in the control group.
Conclusions: Low dose of a bisoprolol patch in the perioperative period was effective forprevention of POAF after non-cardiac surgery in high-risk patients, while long surgery time
was an independent risk factor for POAF. It is expected that low dose of a bisoprolol patch
can prevent POAF without causing hypotension.

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Introduction
It has been reported that postoperative atrial fibrillation (POAF) occurred in 5-15% of
patients who underwent non-cardiac surgery [1, 2]. Recent studies have revealed thatpatients with POAF after non-cardiac surgery have significantly increased risks of stroke,
myocardial infarction and death [3, 4]. Therefore, prevention of POAF after non-cardiac
surgery is needed.
We previously reported the results of the MAMACARI study, a multicenter,
prospective randomized controlled study that was carried out to investigate theeffectiveness of bisoprolol transdermal patches for prevention of perioperative myocardial
injury in high-risk patients undergoing non-cardiac surgery [5]. In that study, patients aged
>60 years with hypertension and a high revised cardiac risk index (≥2) who were scheduled
to undergo non-cardiac surgery were randomly assigned to a bisoprolol patch or control
group. POAF after non-cardiac surgery occurred in 10.9% of the patients in the control
group. Several studies have been carried out to identify possible risk factors for POAF after
non-cardiac surgery [6-8], and advanced age and male sex were reported to be predictors of
POAF. However, predictors of POAF after non-cardiac surgery in those high-risk patientsremain unknown.
A bisoprolol patch, a newly developed form of a beta-blocker in Japan, wasdesigned to deliver bisoprolol through the skin to produce stable blood concentrations.
However, it is uncertain whether the use of a bisoprolol path is effective for prevention of
POAF. In the MAMACARI study, we showed that the use of bisoprolol patches in the
perioperative period is safe for high-risk patients undergoing non-cardiac surgery. However,
it is not clear whether bisoprolol patches cause significant changes in blood pressure andheart rate in the perioperative period.
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The aim of this subanalysis of the MAMACARI study was to identify the predictors of
POAF in high-risk patients undergoing non-cardiac surgery and to determine changes inblood pressure and heart rate during bisoprolol patch administration in the perioperative
period.

Methods
Study design
The design of the MAMACARI study (UMIN000016908) has been described elsewhere [5].
The principal study was a multicenter, prospective randomized controlled, open-label study
conducted from November 2014 to February 2019. That study was approved by the Ethics
Committee of Okayama University Graduate School of Medicine, Density, andPharmaceutical Sciences and other hospitals. The study was approved by the local medical
ethics committee (application number of Ethical Committee of Okayama University m07015;
Effects of Bisoprolol Transdermal Patches for Prevention of Perioperative Myocardial Injury
in High-risk Patients Undergoing Non-cardiac Surgery: MAMACARI study) and all patientsprovided written informed consent. This trial was conducted in compliance with the
Declaration of Helsinki.

Participants
The protocol of the study was described previously [5]. Patients were eligible for the study ifthey were aged ≥60 years, had hypertension and a revised cardiac risk index (RCRI) of ≥2,
and were scheduled to undergo elective non-cardiac surgery under general anesthesia. RCRI
is determined by assigning one scoring point for each of the following six criteria: high-risk

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type of surgery, history of ischemic heart disease, history of congestive heart failure, historyof cerebrovascular disease, preoperative treatment with insulin, and preoperative serum
creatinine >2.0 mg/dL [9]. A total of 240 patients were registered and randomly assigned toa bisoprolol group or a control group. Intention to treat analysis was conducted for 222
patients. Patients receiving beta blockers were excluded from the enrollment criteria andwere not included in this study. Similarly, cases in which the oral medication was switched toa patch were not included. In this trial, administration of 4 mg/day of bisoprolol in a patch
form was started 7 days before surgery and was continued until 7 days after surgery. If theinitiation dose of the bisoprolol patch was not tolerated, the dose was reduced to 2 mg/day
and administration was stopped if this lower dose was not tolerated. The median bisoprolol
dose used was 2 mg in the bisoprolol patch group. According to the protocol, the bisoprolol
patch was discontinued on the 8th day after surgery, but in cases in which it was clinicallynecessary to continue administration of bisoprolol by the patch after the 8th day,administration could be continued at the discretion of the attending physician.

Definition of POAF
POAF was defined as onset of atrial fibrillation (AF) that occurred within 30 days after
surgery [3]. Patients with paroxysmal AF were included in this study, but those with chronic
AF were excluded. In this study, ECG monitoring was performed for several days after
surgery. After the ECG monitoring was discontinued, arrhythmia was detected on the basisof the patient's symptoms and vital signs.

Statistical analysis

5Continuous variables are presented as mean ± standard deviation or median (interquartile
range) as appropriate. Categorical variables are presented as frequency or proportion (%).
Differences between the two groups were evaluated using the chi-square test for categoricalvariables and Student’s t-test for continuous variables. Associations of variables wereassessed by Pearson’s correlation coefficients. Changes in systolic blood pressure and heart
rate within POD 3 from registration were evaluated using analysis of covariance (ANCOVA),and the adjusted mean and 95% CI for each group were calculated. The independent
relationship between POAF and use of a bisoprolol patch was assessed by multivariate
logistic regression analysis, adjusting for variables at baseline with a p value of < 0.05 in
univariate analysis (bisoprolol patch, surgery time). P < 0.05 was considered to be significant.
All statistical analyses were performed using SPSS 27.0 for Windows (IBM, Armonk, NY,
USA).

Results
Flow diagram of patients in this study
The MAMACARI study started in November 2014 and ended in February 2019, and fiveinstitutions in Japan were involved in the study [5]. A total of 240 patients undergoing noncardiac surgery were randomly assigned to a bisoprolol patch group or a control group. The
flow diagram of patients in this study is shown in Fig. 1. A few patients were excluded
because of cancellation or postponement of surgery for various reasons. Intention to treat
analysis was performed for 112 patients in the bisoprolol patch group and 110 patients inthe control group. POAF occurred in 4 patients in the bisoprolol patch group and in 12
patients in the control group. We summarized the details of the 16 cases of POAF in
Supplementary Table 1. Occurrence of POAF in the bisoprolol patch group was significantly
6lower than that in the control group (bisoprolol group: 3.6% vs control group: 10.9%;
P=0.035) (Fig. 2A).

Characteristics of patients and predictors of POAF
Characteristics of the patients are shown in Table 1. Eleven patients underwent thoracic
surgery including lobectomy. Thirteen patients underwent non-cardiac surgery with surgery
time of more than 250 minutes, and the majority of patients with POAF had longer surgery(P=0.009). Bisoprolol patch treatment was performed for a significantly larger proportionalof patients in the non-POAF group than in the POAF group (P=0.040). There was no left atrial
dilation in either group. In the POAF group, 6 patients (38%) had a history of PAF, while 5
patients (2%) in the non-POAF group had a history of PAF. There was a clear significant
difference (P <0.001) between the two groups. Of the 11 patients with a history of PAF, 4
were in the bisoprolol patch group and 7 were in the control group, and there was no
statistically significant difference (P = 0.34).
Multivariate analysis showed that bisoprolol patch therapy (OR: 0.30, 95% CI: 0.090.98) and surgery time of 250 minutes or more (OR: 4.99, 95% CI: 1.37-18.24) wereindependently associated with POAF (Table 2).

Changes in blood pressure and heart rate in patients with a bisoprolol patch
Changes in systolic blood pressure and heart rate during the perioperative period are shownin Fig. 2B and C. There was no significant difference in systolic blood pressure between thetwo groups during the perioperative period. On the other hand, heart rate was increased
after surgery in the control group, but it was not increased after surgery in the bisoprolol

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group. Treatment with a bisoprolol patch significantly reduced heart rate throughout theperioperative period compared with that in the control group.

Discussion
Two major new findings were obtained in the present study. First, bisoprolol patch therapy
was found to be associated with reduction in the risk of POAF after non-cardiac surgery inhigh-risk patients. To our knowledge, this is the first report on the efficacy of bisoprolol
patch therapy for prevention of POAF in non-cardiac surgery. Second, treatment with abisoprolol patch did not reduce systolic blood pressure, but it significantly reduced heart
rate throughout the perioperative period compared with that in the control group. It is
expected that the use of a bisoprolol patch can prevent POAF without causing hypotension.
POAF is caused by the combination of multiple mechanisms and factors. The stressof surgery increases heart rate and release of catecholamines. Clinical circumstances such as
hypovolemia, intraoperative hypotension, anemia, trauma, and pain can also affectsympathetic activity [2]. Therefore, beta-blockers would be effective for prevention of POAF.
However, there are several problems about using beta-blockers in the perioperative period.
In the POISE trial, which showed that beta-blockers significantly reduced the incidence of
perioperative myocardial infarction, clinically significant new POAF was found in 2.2% of thepatients in the metoprolol group and in 2.9% of the patients in the placebo group (HR: 0.76,
95% CI: 0.58-0.99) [10]. These results suggest that preoperative metoprolol administration
may prevent the development of POAF. However, compared to the placebo group,
perioperative beta-blockade was also found to significantly increase the risk of stroke,
clinically significant hypotension and bradycardia. Furthermore, the metoprolol group had asignificantly higher risk of mortality. The problem with this trial was that administration of a8relatively high dose of long-acting metoprolol just before surgery, without titration, caused
serious hypotension and stroke. The advantages and disadvantages of administering betablockers in the perioperative period need to be recognized. To overcome the limitations ofprevious studies on perioperative beta-blockers, several points including the trial design andthe dosage and route of administration require consideration. A bisoprolol transdermal
patch, a newly developed form of a beta-blocker in Japan, is designed to deliver the drug
through the skin. The use of a bisoprolol transdermal patch has several benefits. First, it
enables stabilization of blood concentrations of bisoprolol, making hemodynamic instability
less likely. Sairaku et al. reported that administration of bisoprolol through the transdermalroute resulted in a more constant blood level and was less likely to cause a spike
concentration than was administration through the oral route [11]. Second, a bisoprolol
patch can be used in patients with gastrointestinal disease who are undergoing abdominal
surgery, for whom perioperative oral treatment would be difficult. Third, a bisoprololtransdermal patch can be safely and effectively used in patients with atrial fibrillation andheart failure. Momomura et al. suggest that a bisoprolol patch can be used safely
by switching from oral bisoprolol in patients with chronic heart failure [12]. Yamashita et al.
reported that 4 and 8 mg/day of bisoprolol patch treatment had heart rate-reducing effects
similar to those of bisoprolol oral formulation at doses of 2.5 mg and 5 mg in patients withpersistent or permanent atrial fibrillation, respectively, and that the incidence of adverse
events did not differ between the bisoprolol patch and oral formulation groups [13].
However, there have been few studies on the safety of bisoprolol patch treatment inpatients undergoing non-cardiac surgery in which perioperative changes in blood pressureand heart rate were monitored. We monitored perioperative changes in blood pressure andheart rate and we found that the use of a bisoprolol patch is safe. In this study, a bisoprolol
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patch reduced only heart rate without reducing systolic blood pressure, which is a risk factorof stroke.
In the MAMACARI study, administration of 4 mg/day of bisoprolol in patch form wasstarted 7 days before surgery and was continued until 7 days after surgery [5]. A 4-mg
bisoprolol patch is equivalent to 2.5 mg of oral bisoprolol. If the initiation dose of thebisoprolol patch was not tolerated, the dose was reduced to 2 mg/day and administration
was stopped if this lower dose was not tolerated. Eventually, the median dose of bisoprolol
actually administered was 2 mg in the bisoprolol patch group. This study showed that thislow dose (2 mg/day) might be sufficient for prevention of POAF. Further studies are needed
to clarify the appropriate dose of a bisoprolol patch.
Prolonged operative time is associated with an increase in the risk of complications
across various surgical specialties and procedure types [14]. This study also showed thatsurgery time of 250 minutes or more was independently associated with POAF after noncardiac surgery in high-risk patients. Further study is needed to evaluate the effects ofreducing operating time on the incidence of POAF.
There are several reports showing that withdrawal of beta-blockers after cardiac
surgery results in sympathetic nerve activity, increasing the risk of atrial fibrillation [14]. In
this study, no cases of POAF developed after discontinuation in the bisoprolol patch group.
However, it is necessary to determine whether treatment with a bisoprolol patch should becontinued or discontinued several days after surgery for each case, and after discontinuationof treatment with the bisoprolol patch, attention should be paid to tachyarrhythmia,
especially atrial fibrillation.

Study limitations
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This study has several limitations. First, because the study included only patients aged ≥ 60
years and with a high RCRI risk score who were scheduled to undergo non-cardiac surgery,the results cannot be applied to younger patients and to patients with lower RCRI risk
scores. Second, this study was carried out for only 30 days after surgery, and we could notevaluate the long-term efficacy of a bisoprolol patch for preventing POAF. Third, in thisstudy, POAF was defined as AF that developed within 30 days after surgery, with reference
to previous literature [3]. However, it is clear that the AF detection rate decreases after thecompletion of ECG monitoring, especially after discharge from the hospital, which is one of
the limitations of this study. One of the findings of this study was that most cases of POAF
occurred 3 days after surgery, suggesting the importance of preventing AF in the early
postoperative period. Further studies are required to determine the best method forpreventing POAF.

Conclusion
In conclusion, low dose of a bisoprolol patch in the perioperative period is effective forprevention of POAF after non-cardiac surgery in high-risk patients. It is expected that low
dose of a bisoprolol patch can prevent POAF without causing hypotension.

Acknowledgments
This trial was supported by MAMACARI investigators. We would like to acknowledge thepeople who worked with us on this project. We thank Kaoru Akazawa, Megumi Kondo and
Masayo Ohmori for their excellent technical assistance.

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Source of Funding
This study was funded in part by TOA EIYO LTD. (JP). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosures
Dr. Ito received a trust research/joint research fund from TOA EIYO LTD. (JP). The otherauthors have no conflict of interest to declare.

Appendix
MAMACARI investigators, in addition to the authors, are Kunihisa Kohno, Atsuyuki
Watanabe, Masao Hayashi, Takuro Masuda, Hideki Fujio, Kunihiko Hatanaka, Toshiaki
Kurasako, Naoki Mukohara, Hisatoshi Mori, Masatoshi Sugiyama, Takefumi Oka, Yoichiro
Naito, Hidekuni Hidaka, Mitsuru Munemasa, Koji Kabutan and Hiromi Matsubara.

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Figure legends
Fig. 1. Study flow chart. POAF, postoperative atrial fibrillation.
Fig. 2. Incidence of POAF and changes of systolic blood pressure and heart rate in the
perioperative period. A. Incidence of POAF (%) according to the study group. B and C.
Systolic blood pressure (B) and heart rate (C) at baseline, 1 day before surgery, and on
postoperative day (POD) 1 and POD 3. Data are expressed as means ± SD. POAF,
postoperative atrial fibrillation.

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