Shinshu Med J, 68⑴：31～39, 2020

Do the Efficacy and Safety of Treatment with Landiolol,
an Ultra-short-acting β1-Selective Blocker, Differ in the Urgent
Management of Rapid Atrial Fibrillation between
Patients Complicated with Cardiac Versus Non-cardiac Disease ?
Hiroshi Kamijo, Yuichiro Kashima＊, Kanako Takeshige
Kenichi Nitta and Hiroshi Imamura
Department of Emergency and Critical Care Medicine, Shinshu University School of Medicine

Purpose : Atrial fibrillation (AF) is highly prevalent in patients with non-cardiac diseases and in patients withcardiac disease. However, only a few studies have evaluated the characteristics of patients with AF complicatedwith non-cardiac diseases. We aimed to investigate whether the safety and efficacy of landiolol, an ultra-shortacting β1-selective blocker for controlling rapid heart rate (HR), for patients with AF differed between thosewith cardiac disease and those with non-cardiac diseases.
Materials and Methods : All AF patients with HRs ≥ 120 beats/min who received continuous intravenous landiolol administration were included in this study (n＝133). The patients were divided into the cardiac (n＝55) andnon-cardiac (n＝78) disease groups. Successful HR control was defined as an HR＜110 beats/min and a ≥ 20 ％decrease in HR in 2 hr after landiolol initiation.
Results : Landiolol significantly decreased the HRs of patients with rapid AF in both groups (cardiac : 145±17 to103±22 beats/min, P＜0.001 ; non-cardiac : 145±18 to 114±23 beats/min ; P＜0.001). The proportion of patientsachieving the efficacy endpoint was higher in the cardiac group than in the non-cardiac group (58.2 ％, n＝32 vs.
35.9 ％, n＝28 ; P＝0.02). No intergroup difference was noted in the incidence of adverse events. C-reactive protein levels were independent factors associated with non-effective landiolol responses (odds ratio : OR, 0.958 ;
95 ％ CI, 0.920－0.997 ; P＝0.04). A non-effective landiolol response was significantly and independently associated with 30-day mortality (Hazard ratios : HzR, 5.043 ; 95 ％ CI, 1.516-16.777 ; P＜0.01).
Conclusions : Landiolol may be a therapeutic option for the acute control of rapid AF in patients with either
cardiac or non-cardiac complications, especially in those without marked inflammation. Shinshu Med J 68 : 31―
39, 2020(Received for publication August 1, 2019 ; accepted in revised form August 23, 2019)
Key words : atrial fibrillation, non-cardiac disease, inflammation, landiololＩchronic obstructive pulmonary disease5）, obstructive

Introduction

sleep apnea6）, chronic kidney disease7）, and critical

Currently, there is increasing evidence of a highillnesses8）. Although the prevalence of AF in patients

incidence of atrial fibrillation (AF) in patients with

with non-cardiac diseases is often underestimated,1）2）

non-cardiac diseases

3）4）, including cancer , sepsis ,several studies have reported that AF is commonly
observed in patients with non-cardiac diseases and＊Corresponding author : Yuichiro Kashima
Department of Emergency and Critical Care Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : ykashima@shinshu-u.ac.jp

No. 1, 2020

its presence increases the mortality rates associatedwith such patients3）-10）.
The guidelines of the American Heart Associationand the European Society of Cardiology recommend
31

Kamijo・Kashima・Takeshige et al.

digitalis, amiodarone, and β-blockers for acute1）
2）

rate-control therapy in patients with AFof patients with primary diagnoses of a cardiac dis-

. However,ease upon admission, including ischemic heart dis-

only a few studies regarding AF associated withease, infective endocarditis, acute decompensatednon-cardiac diseases have been conducted andheart failure, any arrhythmia, and valvular heart

the treatment of AF in the context of non-cardiac

disease. The non-cardiac group consisted of patients

disease complications is mainly based on studies in-with primary non-cardiac disease diagnoses upon1）

volving patients with cardiac diseases . Additionally,

admission, without a history of cardiac disease. The

amiodarone and digitalis have long half-lives ; thus,

surgical subgroups included patients with AF deter-adjusting the dose according to the patient’s condi-

mined postoperatively. The non-surgical subgroups

tion is difficult in some emergency settings. Landiolol,

included patients diagnosed with AF and treatedan ultra-short-acting β1-selective blocker (β1/β2with landiolol prior to any surgery performed during

receptor selectivity is as high as 251) with a half-life

hospitalization. Patient hemodynamic parametersof 4 min in human blood, is rapidly metabolized to its

were assessed using two-dimensional cardiac

inactive form in the blood and liver11）. Thus, landiolol

echocardiography ; non-cardiac disease patientsdecreases heart rate (HR) with less of an effect onwith a left ventricular ejection fraction (LVEF)＜50 ％blood pressure (BP), and its dosage can be easilyor those with a moderate to severe valvular heart

adjusted according to the patient’s hemodynamic

disease were excluded as an echocardiographic

response.

abnormality.

Fewer studies have evaluated the characteristics

Ｂ

Endpointsof patients with AF complicated with non-cardiac

The efficacy endpoint was assessed 2 hr after

disease, compared to those with AF and cardiac

landiolol administration ; the clinical outcome wasdisease. Questions remain regarding the differencesclassified as “effective” when the patient achieved anin the safety and effectiveness of β-blockers for the

HR＜110 beats/min and presented a ≥ 20 ％ decreaseurgent control of rapid HR in AF patients complicat-

from the baseline HR (HR immediately before landiolol

ed with cardiac versus non-cardiac diseases. There-

administration), based on a previous investigation12）.

fore, we investigated the efficacy and safety of pa-

The safety endpoint was defined as the incidence

tients treated with intravenous landiolol for theof adverse events related or unrelated to landiolol

urgent control of rapid HR in AF complicated withadministration, leading to its discontinuation. The

cardiac and non-cardiac disease.

clinical endpoint was 30-day mortality, defined as

ⅡＡMaterials and Methods

Study population
All patients with AF, who were admitted to Shinshu

University Hospital between January 2011 and Octoberall-cause mortality within 30 days after landiolol
administration. The protocol was approved by the
Ethics Committees at Shinshu University Graduate
School of Medicine.
Ｃ

Statistical Analyses

2016 and received continuous intravenous landiolol

Statistical analyses were performed using SPSS

were screened. The exclusion criteria were : age＜20

Ver. 22.0 (SPSS, Chicago, IL, USA). Unless otherwise

years, HR＜120 beats/min at the time of landiolol ini-stated, data are presented as means±standard devi-

tiation, non-cardiac disease patients with a history ofations when normally distributed and as medians

cardiac disease, electrical cardioversion or deathwith interquartile ranges (25th-75th percentiles) when

within 2 hr of landiolol administration, and inade-

non-normally distributed. Group differences werequate medical records. Patients treated with oral

evaluated using unpaired 2-tailed Student’s t-tests

β-blockers before landiolol initiation were included.

for normally distributed data and Mann-Whitney

The patients were assigned to either the cardiac

tests for non-normally distributed data. Paired, non-or non-cardiac group. The cardiac group consisted

normally distributed data were analyzed using the32

Shinshu Med J

Vol. 68

Landiolol in patients with non-cardiac disease

Wilcoxon signed-rank test. Categorical variables

were excluded from the multivariate analysis. Hazard

were evaluated using the chi-squared test or Fisher’sratios (HzRs), odds ratios (ORs), and 95 ％ confidence

exact test. Linear and logistic regression analyses

intervals (CIs) were also determined. P values＜0.05

were used to evaluate potential associations between

were considered statistically significant.

the variables and endpoints. Multivariate logistic re-Ⅲgression analysis was performed to identify factors

Results

associated with achieving the efficacy endpoint.

Among the 218 patients who received landiolol

Multivariate Cox’s proportional hazards analysis wasduring the study period, 85 were excluded for the

performed to determine the factors associated withfollowing reasons : age＜20 years (n＝6), HR＜120

all-cause 30-day mortality. If variables were missing

beats/min at the time of landiolol initiation (n＝for＞20 ％ of patients in the univariate analysis, they29), electrical cardioversion (n＝10) or death (n＝1)

Table 1 Baseline characteristics of the patients with atrial fibrillation complicated with cardiac or
non-cardiac disease

Demographics
Age (years)
Male, n (％)
Weight (kg)
PAF, n (％)
History of cardiac disease, n (％)
Hemodynamic parameters
HR (beats/min)
SBP (mmHg)
DBP (mmHg)
LVEF (％)
Creatinine (mg/dL)
eGFR (mL/min/1.73ｍ2)
CRP (mg/dL)
Drugs, n (％)
Diuretics
Aldosterone antagonist
ARBs/ACE-inhibitors
Nitratesβ-blockers
Digitalis
Amiodarone
Statins
Inotropes and vasopressors, n (％)
Dopamine
Dobutamine
Noradrenaline
AF scores
CHA2DS2-VASc

Cardiac
N＝55

Non-cardiac
N＝78

P-value

73 ± 1238 (69.1)
58.0 ± 14.7
46 (83.6)
22 (35.6)

73 ± 1153 (67.9)
59.4 ± 13.8
57 (73.1)
0 (0)

0.68
0.91
0.49
0.20
＜0.001145 ± 17112 ± 2773 ± 2151.4 ± 17.6
1.02［0.81－1.56］

143 ± 18116 ± 2571 ± 15
66.4 ± 8.6
0.92［0.64－1.53］

0.94
0.25
0.95
＜0.001
0.39

50.6 ± 27.5
4.32［0.88－14.0］

59.1 ± 33.8
12.55 ± 9.89

0.14
0.01

37 (67.3)
9 (16.4)
27 (49.1)
22 (40.0)
24 (43.6)
12 (21.8)
6 (10.9)
19 (34.5)

24 (30.8)
5 (6.4)13 (16.7)
8 (10.3)
17 (21.8)
2 (2.56)
1 (1.28)
7 (8.9)＜0.0010.08＜0.001＜0.001
0.02
＜0.01
＜0.01
＜0.001

15 (27.3)
18 (32.7)
8 (14.5)

14 (17.9)
10 (16.3)
11 (14.1)

0.21
＜0.01
0.77

3.3 ± 1.8

0.11

3.8 ± 1.6thth

Data are presented as means ± SD or medians and interquartile ranges［25 －75 percentiles］. PAF, paroxysmal
atrial fibrillation ; HR, heart rate ; SBP, systolic blood pressure ; DBP, diastolic blood pressure ; LVEF, left ventricularejection fraction ; eGFR, estimated glomerular filtration rate ; CRP, C-reactive protein ; ARBs, angiotensin II receptor
blockers ; ACE, angiotensin-converting enzyme

No. 1, 202033

Kamijo・Kashima・Takeshige et al.

Fig. 1 Primary diagnosis at admission for patients with atrial fibrillation (AF) complicated with cardiac
diseases is shown for (A) all patients, (B) surgical patients, and (C) non-surgical patients.
ADHF, acute decompensated heart failure ; AMI, acute myocardial infarction ; IE, infective endocarditis ;AP, angina pectoris ; VF, ventricular fibrillation ; AS, aortic stenosis ; AR, aortic regurgitation.

within 2 hr after landiolol administration, inadequate(n＝40) subgroups (Fig. 1B, C, respectively). In the

medical records (n＝2), non-cardiac patients with a

non-cardiac group, aortic dissection (27 ％) was thehistory of cardiac disease (n＝23), and an echocardio­

most common primary diagnosis, followed by cancer

graphic abnormality (n＝14). Thus, 133 patients were

(23 ％), infectious disease (17 ％), cerebrovascular dis­

included in the analysis.

ease (11 ％ ), and trauma (5 ％ ) ; other diagnoses in­

Table 1 summarizes the baseline characteristics ofcluded pulmonary disease, gastrointestinal disease,the patients assigned to the cardiac (n＝55) and non-endocrine disease, acute renal failure, orthopedic dis­cardiac (n＝78) disease groups. Compared with theease, and leukemia (Fig. 2A). Infectious disease, can­non-cardiac group, the cardiac group demonstrated

cer and cerebrovascular diseases were common ina significantly greater use of oral β-blockers, diuretics,

both the surgical and non-surgical subgroups (Fig.

angiotensin-converting enzyme (ACE) inhibitors,

2B, C, respectively).

angiotensin II receptor blockers (ARBs), nitrates,

The proportion of patients achieving the efficacy

digitalis, amiodarone, statins, and intravenous dobu­

endpoint are shown in Fig. 3. Overall, landiolol ad­

tamine. LVEF and C-reactive protein (CRP) levels

ministration significantly decreased HRs 2 hr after

were significantly higher in the non-cardiac group

administration as 45.1 ％ (n＝60) of patients achieved

than in the cardiac group (51.4±17.6 vs. 66.4±8.6 ％,the efficacy endpoint. The proportion of patients

P＜0.001 and 4.32［ 0.88－14.0 ］vs. 12.55±9.89, P＝achieving the primary efficacy endpoint was higher

0.01, respectively).

in the cardiac (58.2 ％, n＝32) than in the non-cardiac

The primary diagnoses on admission for the pa­

group (35.9 ％, n＝28, P＝0.02 ; Fig. 3A). Although notients in the cardiac and non-cardiac groups aredifference was noted in the proportion of surgicalshown in Fig. 1, 2, respectively. In the cardiac group,

patients achieving the efficacy endpoint between thethe most common primary diagnoses were acute de­cardiac and non-cardiac groups (60.0 ％ , n＝9 vs.

compensated heart failure (31 ％) and acute myocar­

42.9 ％ , n＝21, P＝0.24 ; Fig. 3B), the proportion ofdial infarction (27 ％) ; other diagnoses included infec­

non-surgical patients achieving the efficacy endpoint

tive endocarditis, angina pectoris, arrhythmias, andwas significantly higher in the cardiac group than in

valvular heart disease (Fig. 1A). A similar tendency

the non-cardiac group (57.5 ％, n＝23 vs. 24.1 ％, n＝

was observed in the surgical (n＝15) and non-surgical

7, P＝0.02 ; Fig. 3C).

34

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Vol. 68

Landiolol in patients with non-cardiac disease

Fig. 2 Primary diagnosis at admission for patients with atrial fibrillation complicated with non-cardiac
diseases is shown for (A) all patients, (B) surgical patients, and (C) non-surgical patients.

Fig. 3 Effects of landiolol in controlling rapid heart rate in patients with atrial fibrillation (AF). The
proportion of (A) all patients, (B) surgical patients, and (C) non-surgical patients who achieved
the efficacy endpoint (based on both a heart rate＜110 beats/min and a ≥ 20 ％ decrease in HR
from baseline at 2 hr after the intravenous administration of landiolol).

The baseline and post-treatment changes in HR

in the cardiac group than in the non-cardiac group

and BP 2 hr after landiolol administration are shown(27.2 ± 16.8 ％ vs. 20.9 ± 12.4 ％, P＝0.03). However,in Table 2. There was no difference in HR between

among the surgical patients, no difference in HR

the cardiac and non-cardiac group at baseline (P＝reduction was noted between the two groups,

0.94), but landiolol significantly decreased the HRs ofwhereas among the non-surgical patients, the HR

the patients, from the baseline value 2 hr after its

reduction was significantly greater in the cardiac

administration in both the cardiac and non-cardiac

group than in the non-cardiac group. There wasgroups. The HR reduction was significantly greater

no significant change in BP after administration of

No. 1, 202035

Kamijo・Kashima・Takeshige et al.
Table 2Pre-and post-treatment hemodynamic parameters associated with landiolol administration
Cardiac group

HR (beats/min)
Overall％ reduction
Surgical subgroup％ reduction
Non-surgical subgroup％ reduction
SBP (mmHg)％ reduction
DBP (mmHg)％ reduction
Restoration of sinus rhythm, n (％)
Landiolol administration
Maximum dose (µg/kg/min)
Administration time (h)Non-cardiac group

Pre

Post

Pre

Post

145 ± 17103 ± 22a

145 ± 18114 ± 23a

P-value27.2 ± 16.8
148 ± 18
104 ± 22a29.1 ± 15.8
141 ± 16102 ± 23a

20.9 ± 12.4
142 ± 16108 ± 18a0.03

23.2 ± 11.8

0.38

26.7 ± 17.2b
112 ± 27
113 ± 24
－4.48 ± 25.1
73 ± 2167 ± 14
1.34 ± 28.9
15 (27.3)

17.1 ± 12.6
116 ± 25
111 ± 180.80 ± 24.2
72 ± 1668 ± 15
1.50 ± 22.6
12 (15.4)

0.98
0.10

3.60［0.40－11.3］
37［9.5－113］

3.00［1.66－4.70］
47［21－107］

0.65
0.65

149 ± 20123 ± 22a
0.01
0.26

Data are presented as means ± SD or medians and interquartile ranges［25th－75th percentiles］. “a” indicates thatlandiolol significantly decreased HR from baseline, 4 h after administration in both the cardiac and non-cardiac
groups (P＜0.001) ; “b” indicates that the HR reduction was significantly greater in the cardiac group than in the noncardiac group (P＝0.01) ; HR, heart rate ; SBP, systolic blood pressure ; DBP, diastolic blood pressure.

Table 3Adverse events in patients with atrial fibrillation treated with landiolol

Age (y)Sex

Diagnosis

Adverse event

Landiolol dose at event (μg/kg/min)

53
83
78
65
88

Male
Male
Male
FemaleMale

Dilated cardiomyopathy
Acute myocardial infraction
Angina pectoris
Acute aortic dissection
Acute renal failure

Oliguria
Dyspnea
Hypotension
Hypotension
Sinus arrest

1.13
9.02
2.20
2.50
4.46

landiolol.
Five adverse events were observed in patientstreated with landiolol and no intergroup differenceswere noted (Table 3).

non-effective landiolol response (OR, 0.958 ; 95 ％ CI,
0.920-0.997 ; P＝0.04).
Univariate and multivariate Cox’s proportional
hazards analyses for an association between a non-

Univariate and multivariate analyses for independent

effective landiolol response and 30-day mortality arefactors associated with achieving the efficacy endpoint,

shown in Table 5. Using variables associated withincluding significant variables between the cardiac

efficacy endpoint achievement, we made several

and non-cardiac groups, are shown in Table 4. The

models and evaluated the association between amultivariate logistic regression analysis showed that

non-effective landiolol response and all-cause 30-day

cardiac disease and postoperative AF were indepen­

mortality. Potential associations between these vari­dent factors associated with achieving the efficacy

ables and non-effective landiolol responses wereendpoint (OR, 2.877 ; 95 ％ CI, 1.216-6.807 ; P＝0.02

evaluated using linear and logistic regression ana­

and OR, 2.753 ; 95 ％ CI, 1.239-6.118 ; P＝0.01, respec­

lyses ; no significant associations were found. The

tively). In contrast, the CRP level (per 1 mg/dL in­

univariate Cox’s proportional hazards analysis re­crease) was an independent factor associated with avealed that the risk of mortality increased by 453 ％36

Shinshu Med J

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Landiolol in patients with non-cardiac disease
Table 4 Univariate and multivariate analysis of factors associated with achieving the efficacy endpoint
Univariate analysis
Variables
Age
Male
Cardiac disease
Postoperative AF
Oral β-blockers
CRP (per 1 mg/dL increase)
Dopamine
Dobutamine
Noradrenaline
Digitalis
LVEF

Multivariate analysis

OR (95 ％ CI)

P value1.009 (0.979－1.039)
1.215 (0.605－2.440)
2.056 (1.025－4.122)
1.546 (0.801－2.983)
2.241 (1.070－4.694)
0.964 (0.930－0.998)
1.086 (0.487－2.423)
1.468 (0.660－3.264)
1.033 (0.406－2.626)
0.545 (0.179－1.660)
0.998 (0.976－1.021)

0.57
0.58
0.04
0.19
0.03
0.04
0.84
0.35
0.95
0.29
0.85

OR (95 ％ CI)

P value

2.877 (1.216－6.807)
2.753 (1.239－6.118)
1.763 (0.797－3.898)
0.958 (0.920－0.997)

0.02
0.01
0.16
0.04

OR, odds ratio ; CI, confidence interval ; AF, atrial fibrillation ; CRP, C-reactive protein ; LVEF, left
ventricular ejection fraction

Table 5 Multivariate Cox regression analyses of association between a non-effective
landiolol response and the 30-day mortality
Non-effective landiolol response
Endpoint : 30-day mortality
Model 1
Univariate
Model 2Adjusted for age and sex
Model 3Adjusted for age, sex, and CRP levels
Model 4
Adjusted for age, sex, and non-cardiac disease
Model 5Adjusted for age, sex, CRP levels, and non-cardiac disease

Hazard ratio (95 ％ CI)

P-value

5.530 (1.723－17.751)＜0.01

5.956 (1.834－19.347)＜0.01

5.504 (1.665－18.200)＜0.01

5.293 (1.613－17.369)＜0.01

5.043 (1.516－16.777)＜0.01

CI, confidence interval ; CRP, C-reactive protein(HzR, 5.530 ; 95 ％ CI, 1.723-17.751 ; P＜0.01) in thebased on studies involving cardiac disease ; there

presence of non-effective landiolol responses. Evenare few reports regarding AF complicated withafter adjusting for age, sex, CRP levels and non-non-cardiac disease1）. In the present study, AF was

cardiac disease, a non-effective landiolol response

observed among a more diverse range of diseases

was significantly and independently associated withthan was previously reported, especially among non-30-day mortality (HzR, 5.043 ; 95 ％ CI, 1.516-16.777 ;cardiac patients. Additionally, our results showed

P＜0.01)that landiolol was more effective for acute control ofⅣDiscussion

rapid HR in patients with AF and cardiac disease
than in patients with AF and non-cardiac disease ;Although treatment guidelines recommend digitalis,

however, landiolol significantly decreased the rapid

amiodarone, and β-blockers for acute rate-control

HR of AF in both cardiac and non-cardiac patients

1）
2）

therapy in patients with AF, the treatment of AF

in patients with non-cardiac disease has been mainly
No. 1, 2020

and was similarly safe in both groups.
The presence of non-cardiac disease and a high37

Kamijo・Kashima・Takeshige et al.

CRP level were independent factors associated with

sex, CRP level, and non-cardiac disease.

a non-effective landiolol response in this study.

This study has several limitations. First, it was a

Although several factors appear to contribute to theretrospective study and dose standardization was not

12）
-14）

, inflammation is apossible because of the heterogeneous usage of landi­

common denominator among these conditions andolol. Therefore, we could not evaluate the effect ofconcomitant presence of AF

15）

may be one of the most important factors , especially10）

inadequate dose adjustment on the non-effective re­in patients with non-cardiac disease . Moreover, oursponses. Second, because various diseases were ex­

results suggest that inflammation is associated withamined, especially among patients with non-cardiac

landiolol responses in patients with AF. Expectedly,

disease, the ability to affirm similarities in baseline

greater use of digitalis, amiodarone, ACE inhibitors

characteristics, medical therapy, and long-term clini­to lower systolic BP, ARBs, dopamine or dobutamine

cal outcomes was limited. Third, some patients in thewas found in the cardiac group ; however, these

non-cardiac group might have latent cardiac disease.

medication differences were not independent factors

However, one of the aims of this study was to clarify

associated with effective landiolol responses in thethe characteristics of rapid AF complicated withpresent study. A high CRP level was an independent

non-cardiac disease versus cardiac disease in a real-factor associated with non-effective landiolol re­world setting. Further prospective studies involving

sponses, suggesting that inflammation contributes toa larger number of patients are needed to confirm

the observed reduced efficacy of landiolol in both the

our results.

cardiac and non-cardiac groups. Since the mecha­Ⅴnisms of postoperative AF differ from those of non-Conclusions

postoperative AF, we investigated the separate

Landiolol was more effective for acute control ofgroups of patients. Postoperative AF was an inde­

rapid HR in patients with AF and cardiac disease

pendent factor associated with an effective landiolol

than in those with AF and non-cardiac disease ;response in this study.

however, landiolol significantly decreased the rapid

Although several reports suggest that the presence
3）-10）of AF has a negative impact on mortality

HR associated with AF in both groups of patients.

, previ­

The safety of landiolol was similarly high in bothous clinical studies, to our knowledge, have not at­groups and no between-group clinical outcome dif­

tempted to identify the predictive value of β-blocker

ferences were noted. Landiolol may be considered as

responses as a clinical outcome in patients with rapida therapeutic option for the acute control of rapid

AF accompanied by non-cardiac disease. Non-

AF complicated with either cardiac or non-cardiac

effective landiolol response was an independent anddiseases, especially in patients without high systemic

significant factor associated with all-cause 30-day

inflammation.

mortality in our study, even after adjusting for age,
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