Journal of Cardiology 62 (2013) 121–126

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Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Original article

Bleeding events and activated partial thromboplastin time with dabigatran in

clinical practice
Mihoko Kawabata (MD, PhD) a,∗ , Yasuhiro Yokoyama (MD, PhD) b , Tetsuo Sasano (MD, PhD) c ,
Hitoshi Hachiya (MD, PhD) a , Yasuaki Tanaka (MD) a , Atsuhiko Yagishita (MD) a , Koji Sugiyama (MD) a ,
Tomofumi Nakamura (MD) a , Masahito Suzuki (MD) a , Mitsuaki Isobe (MD, PhD, FJCC) a ,
Kenzo Hirao (MD, PhD) b
a
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
b
Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan
c
Department of Biofunctional Informatics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Dabigatran has demonstrated promising results for the prevention of strokes in patients with
Received 28 December 2012 non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially
Received in revised form 20 February 2013 in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively
Accepted 21 March 2013
examine the relationship between the bleeding events and activated partial thromboplastin time (APTT)
Available online 14 May 2013
values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors
would contribute to the APTT values.
Keywords:
Methods and results: A total of 139 NVAF patients (112 men, 65 ± 11 years) were included. We evaluated
Atrial fibrillation
Anticoagulants
the influence of the putative etiological variables and the bleeding score, HAS-BLED score, on APTT values:
Thrombosis age greater than 70 years, renal function, gender, dose of dabigatran, and the concomitant prescription
of a P-glycoprotein inhibitor. There were 50 patients with an age of ≥70 years (36.0%). A P-glycoprotein
inhibitor was administered in 18 patients. During the observation period (median 120 days) there was
1 episode of asymptomatic cerebral infarction. There were no intrinsic major bleeding events, however,
11 patients had minor hemorrhagic events. The results of the APTT measurements exhibited a variety of
values both among inter- and intra-individuals. On multivariable analysis, significant associations were
found between the following risk factors and the APTT values: creatinine clearance, dose of dabigatran,
and concomitant use of a P-glycoprotein inhibitor. The minor bleeding events did not correlate with the
APTT values, nor HAS-BLED score.
Conclusions: The APTT values became prolonged under dabigatran usage and exhibited a remarkable
diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding
arose irrespective of the APTT values even within the range of the APTT values not exceeding 80 s.
© 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction assessments may assist in the clinical management by indicat-

Dabigatran etexilate, an oral direct thrombin inhibitor, has
recently been used for the prevention of strokes and systemic
emboli in patients with non-valvular atrial fibrillation (NVAF)
[1,2]. It rapidly undergoes hydrolysis to its active form, dabi-
gatran. Due to a fixed dosing and predictable pharmacology,
routine laboratory coagulation monitoring under dabigatran is
deemed unnecessary. Commonly available global coagulation-time
∗ Corresponding author at: Department of Cardiovascular Medicine, Tokyo
Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Tel.: +81 358035231; fax: +81 358030131.
E-mail address: mihoko kawabata.cvm@tmd.ac.jp (M. Kawabata).
ing severe accumulation of dabigatran. It has been reported that
activated partial thromboplastin time (APTT) may be useful for a
qualitative assessment and is correlated with the plasma concen-
tration of dabigatran [3,4].
Anticoagulation therapy for thromboprophylaxis has another
aspect of serious hemorrhage. As dabigatran has been used widely,
there have been episodes of major bleeding due to dabiga-
tran, including in some patients whose APTT values exhibited an
excessive prolongation (>80 s), which resulted in death due to
uncontrolled bleeding. Elderly patients with impaired renal func-
tion or low body weight tended to have severe bleeding due to the
prescription of dabigatran [5–8]. On the other hand, a wide distri-
bution of APTT values in Japanese NVAF patients under dabigatran
therapy was observed [9]. The bleeding risk estimation is important

0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jjcc.2013.03.010
122 M. Kawabata et al. / Journal of Cardiology 62 (2013) 121–126
in clinical management. Among some bleeding scores, Hyper-
tension, Abnormal renal/liver function, Stroke, Bleeding history
or predisposition, Labile international normalized ratio, Elderly
(>65 years), Drugs/alcohol concomitantly (HAS-BLED) score was
used in the guidelines [10,11].
In this study we examined the relationship between the bleed-
ing events and APTT values under dabigatran usage in everyday
clinical practice. Moreover, we investigated which factors would
contribute to the APTT values.
Methods
NVAF patients treated with dabigatran between April 2011
and July 2012, and who were followed until October 2012 were
included. The follow-up was ceased when dabigatran was discon-
tinued or the patient transferred to another hospital. We checked
the clinical and demographic data, including the other medications,
incidence of side effects, and APTT values (normal range, 25–27 s),
which were obtained from the medical records. Major bleeding
was defined as intrinsic bleeding associated with a reduction in
the hemoglobin level of ≥2.0 g/dl, or which required hospitaliza-
tion. Other bleeding was defined as minor bleeding. CHA2 DS2 -VASc
score was evaluated for risk stratification of thromboembolism in
all subjects [12,13]. The Ethical Committee at Tokyo Medical and
Dental University granted permission for this study.
Since the effect of dabigatran on the APTT values might be
thought to indicate large differences among individuals [9], the
mean APTT-value in each patient was used for the analysis, so as
not to be affected by specific subjects whose APTT values had been
measured much more frequently than others.
The renal function was evaluated using creatinine clearance
(Ccr) (ml/min) [calculated by (140 − age [years]) × body weight
(kg)/72/serum creatinine (Scr) (mg/dl), and ×0.85 if female] [14]
and estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2 )
[calculated by 194 × Scr−1.094 × age (years)−0.287 , and ×0.739 if
female] [15], and those mean values in each patient were also used
for the analysis like the APTT values.
In Japan, the recommended dose of dabigatran is 150 mg twice
daily, and 110 mg twice daily can be considered in patients with
an age ≥70 years, moderate renal impairment (Ccr 30–50 ml/min),
history of gastrointestinal bleeding, or those taking a concomitant
P-glycoprotein inhibitor. The drug should be contraindicated in
patients with severe renal impairment (Ccr < 30 ml/min).
In this study, the dose of dabigatran and the sampling time of
the APTT values were determined by each of the physicians in their
daily clinical practice. We evaluated the influence of the putative
etiological variables and HAS-BLED score on the APTT values retro-
spectively: age greater than 70 years, renal function, gender, dose
of dabigatran, and the concomitant prescription of a P-glycoprotein
inhibitor. If there was a change in the dose of dabigatran or the
prescription of a P-glycoprotein inhibitor during the observation
period, the APTT value data in those patients were obtained for each
of those situations. Among the P-glycoprotein inhibitors, ketocona-
zole, amiodarone, verapamil, and quinidine were included in this
study [16–20]. The relationship between the bleeding events and
APTT values under dabigatran was also examined.
Statistical methods
All data are expressed as the mean ± standard deviation (SD)
or numbers and percentages of patients. A multivariate analysis
was performed using multiple linear regression analyses to deter-
mine the presence of an association between the APTT values and
variables tested, using the previously mentioned covariables. A uni-
variate analysis of the factors associated with bleeding events was
performed with the t-test for continuous variables and the Chi2
test for nominal variables. Then a logistic regression analysis was
performed to determine the independent predictors of bleeding
events. p-Values of <0.05 were considered statistically significant.
SPSS version 11.0.1 software (SAS Institute, Cary, NC, USA) was used
for all statistical analyses.
Results
A total of 139 NVAF patients (112 men and 27 women, mean age
65 ± 11 years) were included in this study. There were 50 patients
with an age of ≥70 years (36.0%). The CHA2 DS2 -VASc score ranged
from 0 to 6, and 75 patients (54.0%) had a score of ≥2. The pre-
scribed dose of dabigatran was 300 mg/day in 60, 220 mg/day in 72,
150 mg/day in 5, and 110 mg/day in 2. A reduced dose was applied
because of a high age, renal impairment, or concomitant use of a P-
glycoprotein inhibitor. The mean eGFR was 68 ± 15 ml/min/1.73 m2
and the mean Ccr was 96 ± 41 ml/min. The median follow-up dura-
tion was 120 days (range 1–546, average 149 days). Among the
aforesaid P-glycoprotein inhibitors only verapamil was given in 18
(12.9%). The baseline characteristics of the patients are shown in
Table 1.
Over the course of the follow-up period, an 86-year-old male
taking clarithromycin, a P-glycoprotein inhibitor, had asymp-
tomatic cerebral infarction. His CHA2 DS2 -VASc score was 2 and
HAS-BLED score 1. Although he received 75 mg dabigatran twice
daily, he decreased it to 75 mg once daily due to subcutaneous
bleeding and nasal bleeding by his own decision. As the onset
of cerebral infarction was unknown, the exact dose of dabiga-
tran related to this event was unclear. The APTT was 35–40 s
with 75 mg dabigatran twice daily before the cerebral infarc-
tion, however, it prolonged to 60.7 s after the event with the
same dose of dabigatran. As a result, dabigatran was switched to
warfarin.
Adverse effects occurred in 32 (23%) patients including
15 patients who discontinued dabigatran because of side effects.
There were no major bleeding events. Only one patient had an
intracranial bleeding event, however, it was traumatic subarach-
noid hemorrhage (SAH). He was a 50-year-old man and took his
first dabigatran dose of 150 mg and had some alcohol. He then fell
down, and had a transient loss of consciousness. He was diagnosed
with brain contusion and SAH. At that time his APTT value was
40.4 s. No increase in the intracranial bleeding occurred after that
and no symptoms remained. Other recorded adverse effects were
minor bleeding events in 10 patients (subcutaneous bleeding in
3, hemorrhage in the fundus of the eye, subconjunctival hemor-
rhage, and hemorrhoidal bleeding in 2 each, and hematuria, and
nasal bleeding in 1 each), dyspepsia in 14, liver dysfunction in 3,
Table 1
Baseline characteristics of our population.
Study population (n = 139)
Age (years) 65 ± 11
Male (%) 81
Type of AF (%) (paroxysmal/persistent) 51/49
Daily dose of dabigatran 3/52/4/1
300 mg/220 mg/150 mg, 110 mg (%)
CHA2DS2-VASc score, ≥2 points (%) 1.8 ± 1.3, 54
Hemoglobin (mg/dl) 14 ± 2
eGFR (ml/min/1.73 m2 ) 68 ± 15
Ccr (Cockcroft-Gault) (ml/min) 96 ± 41
Body weight (kg) 68 ± 14
Antiplatelet drugs (%) 12
P-glycoprotein inhibitor (%) 13
Follow-up duration (days) 149 ± 125
The values are the mean ± SD or %. AF, atrial fibrillation; Ccr, creatinine clearance;
eGFR, estimated glomerular filtration rate.
 M. Kawabata et al. / Journal of Cardiology 62 (2013) 121–126 123

Table 2
Patients with minor bleeding events.

Patient Type of bleeding Dose of dabigatran Ccr eGFR HAS-BLED APTT (s) P-glycoprotein Body
(years/gender) (mg/day) (ml/min) (ml/min/1.73 m2 ) score inhibitor weight (kg)

66, male Hemorrhoidal 220 79.6 68.8 1 33.7 No 67

86, male Nasal, 150 45 69 1 39.7 Yes 48
subcutaneous (clarithromycin)
64, male Hemorrhoidal 220 88.7 84.2 1 34 No 61
78, female Subcutaneous 300 54.1 61.6 1 No No 51
50, male Traumatic SAH 300 103.4 79.5 0 40.4 No 67
65, male In the fundus of 300 62.3 51.7 1 48.6 No 67
the eye
75, male Subconjunctival 220 62.4 58.1 1 54.6 No 67
69, male In the fundus of 220 63.2 65.4 2 54.3 No 57
the eye
68, male Hematruia 220 59.2 53.7 1 No No 63
69, female Subcutaneous 220 58.5 57.4 1 59 Yes (verapamil) 53
68, male Subconjunctival 300 62.2 64.9 1 74.3 Yes (verapamil) 56

APTT, activated partial thromboplastin time; Ccr, creatinine clearance; eGFR, estimated glomerular filtration rate; SAH, subarachnoid hemorrhage.

and skin rash, pancytopenia, cough, and diarrhea in 1 each. Table 2
shows the patients who had minor bleeding events. The APTT val-
ues which were obtained just before or after the minor bleeding
events are described.
APTT values
A total of 401 APTT values were obtained in 123 patients (1–16
data values per patient). The dose of dabigatran was changed in
14 and the concomitant use of verapamil was altered in 6 patients,
so 2 different mean APTT values were obtained from 20 patients.
At last 143 mean APTT values were analyzed in this study. Fig. 1
shows the scatter plots of the APTT values and age (at doses of
300 mg/day (a) and 220 mg/day (b), respectively), which exhibit a
wide range of values. There were 17 patients who had their APTT
measured more than 5 times around similar sampling time with
the same dose of dabigatran. Their standard deviation ranged from
1.8 to 11.2 s.
At a dose of 300 mg/day, the mean APTT values that were
derived numbered 48 (average 41.0 s) in the morning and 26 in the
afternoon (average 42.6 s), while at a dose of 220 mg/day, 46 data
values were obtained in the morning (average 42.4 s) and 35 in
the afternoon (average 46.1 s) (Fig. 2). There were 22 patients who
had their APTT values examined both in the morning and in the
afternoon. The APTT values were more prolonged in the morning
in some patients, however, in others they were more prolonged in
the afternoon (Fig. 3).
Influential factors of the APTT values
A multivariable analysis showed that Ccr, dose of dabigatran,
and concomitant use of a P-glycoprotein inhibitor were indepen-
dent factors related to the APTT values (Table 3). By a univariate
analysis, only Ccr and body weight significantly correlated with the
minor bleeding events (Table 4). The APTT values were not associ-
ated with the minor bleeding events. These same variables were
then entered into a multivariable model to evaluate the presence
of an association with the minor bleeding events, however, this

Fig. 1. Distribution of activated partial thromboplastin time (APTT) values in rela-
tion to the patients’ age (a) at a dabigatran dose of 300 mg/day and (b) 220 mg/day,
respectively. The APTT-values exhibited a wide range of values.
Fig. 2. The activated partial thromboplastin time (APTT) values in the morning and
afternoon at a dabigatran dose of 300 mg/day and 220 mg/day, respectively. At a dose
of 300 mg/day, the mean APTT value was 41.0 ± 8.6 s in the morning and 42.6 ± 10.6 s
in the afternoon, while at a dose of 220 mg/day, it was 42.4 ± 10.7 s in the morning
and 46.1 ± 10.4 s in the afternoon.
124 M. Kawabata et al. / Journal of Cardiology 62 (2013) 121–126

association did not reach statistical significance (p = 0.19 for Ccr and
p = 0.57 for body weight).

Discussion

This study was an assessment of the bleeding events and the

APTT values with dabigatran among NVAF patients in clinical
practice. The APTT values were prolonged under dabigatran usage
and exhibited a variety of values. On multivariable analysis, signifi-
cant associations were found between the following risk factors and
the APTT values: creatinine clearance, dose of dabigatran, and con-
comitant use of a P-glycoprotein inhibitor. In this study there were
no patients with an excessive APTT prolongation, nor any intrin-
sic major bleeding events. The minor hemorrhagic events did not
correlate with the APTT values.
Dabigatran, with its convenient oral administration, may
improve the adherence and quality of life in patients, which could
result in a reduction in the rate of strokes in NVAF patients [1,2].
It is expected that dabigatran will likely extend its administra-
tion in elderly patients. However, major bleeding events have been
reported in this frail elderly population [5–8]. Dabigatran is elim-
inated predominantly (85%) by the kidneys, and renal functional
impairment is likely to cause drug overexposure due to prolonged
excretion rates and accumulation of the drug [21]. At the same time,
there is an inverse relationship between the renal function and age
[14]. An impaired renal function, often in the presence of a nor-
mal serum creatinine level, is common yet frequently overlooked
Fig. 3. The comparison of the activated partial thromboplastin time (APTT) values among elderly patients. A low body weight also further exagger-
in the morning and in the afternoon in 22 patients. ates the magnitude of the under ascertainment of an impaired renal
function [22]. Therefore, the risk of major overdosage of dabigatran
in this population is much increased causing severe bleeding. In this
study Ccr which includes the body weight in its formula, but not
Table 3
Multivariate analysis of the correlates of the activated partial thromboplastin time-
eGFR which does not contain the body weight in the equation, was
values. revealed as an independent factor which affected the APTT values.
We highlighted that not only the renal function but also the body
p value
weight is an important key point in the prescription of dabigatran
Age greater than 70 years 0.856 in the elderly population. In this study the correlation between the
Creatinine clearance (Cockcroft-Gault) 0.001
APTT values and the patient’s age was not obvious. One of the rea-
Estimated glomerular filtration rate 0.947
Gender 0.876 sons might be that the dose of dabigatran was determined due to
Dose of dabigatran 0.024 patient’s age, so there was an artificial bias.
Concomitant P-glycoprotein inhibitor <0.0001 Since dabigatran etexilate is a substrate of P-glycoprotein [16], it
HAS-BLED score 0.203
has few drug interactions except for that involving P-glycoprotein
agents. Inhibitors of P-glycoprotein such as ketoconazole, amio-
darone, verapamil, and quinidine may increase the peak plasma
concentrations of dabigatran [17,18], while atorvastatin, also a
Table 4 P-glycoprotein inhibitor, results in no significant change in the
Univariate predictive factors of minor bleeding events in the overall population. pharmacokinetic parameters of dabigatran [19]. For that reason
Bleeding group No bleeding p value we included only ketoconazole, amiodarone, verapamil, and quini-
(n = 11) group (n = 128) dine as concomitant P-glycoprotein inhibitors, and among them
Age (years) 69 ± 9 65 ± 11 0.11 just verapamil was given in this study. The presence of verapamil
Male (%) 82 80 0.91 was an independent factor which influenced the APTT-values. NVAF
Daily dose of 243 ± 50 252 ± 51 0.1 patients who have an indication for dabigatran might also need
dabigatran (mg)
rate control for AF, and from this point of view verapamil might
APTT (s) 41.4 ± 13.3 42.0 ± 10.2 0.27
eGFR 64.9 ± 10.1 66.6 ± 15.8 0.22 frequently be given together. We should pay thorough attention in
(ml/min/1.73 m2 ) such cases.
Ccr 67.1 ± 16.8 83.0 ± 33.8 0.001 The only patient who had asymptomatic cerebral infarc-
(Cockcroft-Gault) tion during the observation period received clarithromycin, a
(ml/min)
Body weight (kg) 59.7 ± 7.1 67.6 ± 14.4 0.003
P-glycoprotein inhibitor. He also had two minor bleeding events.
HAS-BLED score 1.0 ± 0.4 0.7 ± 0.7 0.21 The APTT values in this patient were unsteady and finally dabiga-
P-glycoprotein 27 12 0.14 tran was switched to warfarin. The co-administration of dabigatran
inhibitor (%) with clarithromycin might result in a possibility of increasing the
Data are expressed as the mean values ± SD, or number (%). APTT, activated par- plasma concentration of dabigatran, which is not so striking com-
tial thromboplastin time; Ccr, creatinine clearance; eGFR, estimated glomerular pared to other P-glycoprotein inhibitors such as verapamil [20]. The
filtration rate. use of dabigatran together with clarithromycin might have made it
difficult to have controlled the coagulation state in this patient.
 M. Kawabata et al. / Journal of Cardiology 62 (2013) 121–126
In previous reports the effects on APTT by dabigatran were con-
centration dependent, indicating that APTT prolonged more at a
peak concentration than at a trough concentration [4]. It is specu-
lated that APTT is altered according to the sampling time in clinical
practice. However, there was little difference in the APTT-values
obtained at the peak and trough levels or in the morning and
afternoon at the outpatient clinic in a previous report [9]. In our
population there were some patients who revealed longer APTT
values in the afternoon than in the morning and others showed
the opposite. Moreover, dabigatran demonstrated variable effects
on the APTT values even within individuals, thus this considerable
intraindividual variability might exceed the reported differences
between the peak and trough APTT values. Further, dabigatran
reaches a peak plasma concentration in 1.5–3 h [4,23], however, it
has been shown to be delayed to closer to 6 h following hip arthro-
plasty with a slower rate and extent of absorption [24]. Therefore,
we considered that the APTT value at any time was well worth eval-
uating in clinical practice and did not take the sampling time into
account. As dabigatran’s mean absolute bioavailability remains at
only 6.5% [16,25], such a large difference in its coagulation effect
might be observed.
Although the APTT results demonstrated a wide range of values
as in previous reports [3,4,9,16], there were no patients with an
excessive APTT prolongation or any intrinsic major bleeding in this
study. On the other hand, the APTT-results had no relationship to
the minor hemorrhagic events, nor HAS-BLED score as in a previous
report [26]. The HAS-BLED score is a practical bleeding risk score
in AF patients [10,11]. Another novel bleeding risk score is needed
for AF patients taking dabigatran or other novel oral anticoagulant
drugs in the future. Concomitant P-glycoprotein inhibitors should
be included in such a score.
Limitations
First, we did not assay the plasma concentration of dabiga-
tran. Second, our results were obtained retrospectively from an
unselected and limited population with a small number and short
observation period from a single center. Patients with a high risk
for a thromboembolism (high CHA2 DS2 -VASc score) or severe renal
dysfunction were not sufficiently evaluated. There were a few cases
taking dabigatran with doses that were not recommended. The pre-
scription of dabigatran was based not on any medical evidence but
only each physician’s decision. Therefore, the results should not
be directly extrapolated to all populations. The evaluation of more
patients with a longer observation time is needed in the future.
Third, this study essentially depended on the patients’ compliance.
Finally, the thrombin clotting time and ecarin clotting time are the
most sensitive clotting assays for the detection of dabigatran in
the blood [4]. However, they are not routinely available in clinical
practice, while APTT can be assessed easily and might be a practical
tool to take care of real-world AF patients.
Clinical implications
The APTT value would not be prolonged excessively as long as
the instructions for the prescription of dabigatran are followed, and
major bleeding would not occur within such APTT values. In the
determination of the dose of dabigatran, creatinine clearance or
concomitant use of a P-glycoprotein inhibitor should particularly
be assessed.
Conclusions
The APTT values prolonged under dabigatran usage and exhib-
ited a remarkable diversity. Although major bleeding did not occur
125
unless the APTT value was excessively prolonged, minor bleeding
arose irrespective of the APTT values even within the range of APTT
values not exceeding 80 s.
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