Journal of Cardiology 69 (2017) 591–595

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

Original article

Safety of low-dose dabigatran in patients with atrial fibrillation and

mild renal insufficiency
Hidehira Fukaya (MD, PhD), Shinichi Niwano (MD, PhD, FJCC)*, Jun Oikawa (MD, PhD),
Ryo Nishinarita (MD), Ai Horiguchi (MD), Hironori Nakamura (MD), Tamami Fujiishi (MD),
Tazuru Igarashi (MD), Naruya Ishizue (MD), Tomoharu Yoshizawa (MD, PhD),
Akira Satoh (MD, PhD), Jun Kishihara (MD, PhD), Masami Murakami (MD, PhD),
Junya Ako (MD, PhD, FJCC)
Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Background: Dabigatran etexilate (DE), an effective direct oral anticoagulant for patients with atrial
Received 3 February 2016 fibrillation (AF), should be carefully used in patients with renal insufficiency. Data on the safety of DE in
Received in revised form 15 April 2016 Japanese ‘‘real world’’ patients with mildly impaired renal function are limited. We hypothesized that
Accepted 6 May 2016
low-dose DE (110 mg, twice daily) could be safely used in Japanese AF patients with mildly impaired
Available online 1 July 2016
renal function compared to those with preserved renal function.
Methods and results: One hundred ninety-six consecutive AF patients taking low-dose DE were
Keywords:
retrospectively enrolled in this study, and were divided into two groups: preserved creatinine clearance
Atrial fibrillation
(CCr 50 ml/min; n = 127) and reduced CCr (30–49 ml/min; n = 69). Baseline characteristics including
Chronic kidney disease
Anticoagulation CHADS2, CHA2DS2-VASc, and HAS-BLED scores were evaluated. Activated partial thromboplastin time
Dabigatran (aPTT) was measured as a surrogate marker of the anticoagulant activity of DE, which was evaluated at
661 time points in total and the data were divided into five time windows after the last DE intake. The
incidence of bleeding complications was compared between the two groups of reduced and preserved
CCr. Reduced CCr group showed higher age (76.9  6.3 years vs. 67.6  6.7 years), higher CHADS2
(2.6  1.4 vs. 1.8  1.2), higher CHA2DS2-VASc (4.3  1.6 vs. 3.2  1.6), and higher HAS-BLED (2.3  1.0 vs.
2.0  1.0) scores in comparison with preserved CCr group (p < 0.01, respectively). There was no difference in
aPTT over the entire time windows between the two groups. The incidence of total bleeding events was not
significantly different between the two groups (reduced vs. preserved CCr = 2/69 vs. 2/127).
Conclusion: Low-dose DE was safe in AF patients with mildly reduced CCr.
ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction Dabigatran etexilate (DE), a direct thrombin inhibitor, has shown

Anticoagulation for patients with atrial fibrillation (AF) is
indispensable for the prevention of ischemic stroke and systemic
thromboembolism (STE). Several guidelines for AF management
[1–3] recommend anticoagulation based on the risk stratification of
ischemic stroke and STE. It has been reported that about one-third of
AF patients have chronic kidney disease (CKD) [4–6], and impaired
renal function is associated with a higher prevalence of AF [7,8].
* Corresponding author at: Department of Cardiovascular Medicine, Kitasato
University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa
252-0374, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8441.
E-mail address: shniwano@med.kitasato-u.ac.jp (S. Niwano).
non-inferiority to warfarin for the prevention of stroke and STE at low
doses (110 mg, twice daily, BID) and superiority at high doses
(150 mg, BID) [9]. Impairment of renal function affects the
pharmacokinetics of DE because it is excreted from urine by about
80% [10]. In the Randomized Evaluation of Long-Term Anticoagulant
Therapy (RE-LY) trial [9], the phase III trial of DE, AF patients with CKD
comprised only 20% of the study population, therefore, it is important
to elucidate that the safety of DE for the AF patients with mildly
impaired renal function. Moreover, there has been no clear evidence
whether DE is safe for Japanese ‘real world’ AF patients with mild
CKD. In this study, we hypothesized that low-dose DE (110 mg, BID)
could be safely used in Japanese AF patients with mildly impaired
renal function. We also evaluated the incidence of hemorrhagic
events and activated partial thromboplastin time (aPTT) data.

http://dx.doi.org/10.1016/j.jjcc.2016.05.011
0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
592 H. Fukaya et al. / Journal of Cardiology 69 (2017) 591–595

Methods Table 1
Baseline patient characteristics.

Study population and evaluation parameters Reduced CCr Preserved CCr p-Value

Male: n (%) 37 (54) 84 (66) 0.09

This study was approved by the ethical committee of clinical Age (year-old) 76.9  6.3 67.6  6.7 <0.01
studies in Kitasato University. Consecutive AF patients prescribed Body weight (kg) 51.9  9.4 64.0  9.8 <0.01
low-dose DE (110 mg, BID) from April 2011 to August 2015 in Serum creatinine (mg/dL) 1.03  0.23 0.85  0.20 <0.01
Creatinine clearance (ml/min) 41.5  6.8 74.8  4.8 <0.01
Kitasato University Hospital were retrospectively enrolled in this
Congestive heart failure: n (%) 26 (38) 22 (17) <0.01
study. The patients were divided into two groups: patients with Hypertension: n (%) 46 (67) 76 (60) 0.35
preserved renal function (creatinine clearance: CCr 50 ml/min; Age >75: n (%) 44 (64) 26 (20) <0.01
preserved CCr group) and patients with reduced renal function Age between 65 and 75: n (%) 21 (30) 66 (52) <0.01
(30  CCr < 50 ml/min: reduced CCr group). Since DE was not Diabetes mellitus: n (%) 9 (13) 31 (24) 0.59
Prior stroke or TIA: n (%) 20 (29) 26 (20) 0.18
recommended in patients with severe renal insufficiency Vascular disease: n (%) 17 (25) 24 (19) 0.35
(CCr <30 ml/min), such patients were excluded from this Liver or kidney dysfunction: n (%) 8 (12) 14 (11) 0.10
study. CCr was estimated by Cockcroft–Gault equation as Bleeding tendency: n (%) 1 (1) 6 (5) 0.24
follows: CCr = {(140 age)  (weight in kg)  (0.85 if female)}/ Co-prescription of antiplatelets: n (%) 18 (26) 19 (15) 0.07
Aspirin 13 (19) 16 (13) 0.24
(72  serum creatinine) [11].
P2Y12 inhibitor 5 (7.2) 3 (2.4) 0.09
All patients had undergone basic physical examination, Co-prescription of PPI: n (%) 35 (51) 61 (48) 0.72
electrocardiography, chest X-ray, and echocardiography at base- CHADS2 score 2.6  1.4 1.8  1.2 <0.01
line. The evaluation of baseline characteristics included age, CHA2DS2-VASc score 4.3  1.6 3.2  1.6 <0.01
gender, body weight, serum creatinine (sCr), CCr, past medical HAS-BLED score 2.3  1.0 2.0  1.0 <0.01

history, CHADS2 [12] and CHA2DS2-VASc score [2] as the risk
stratification of ischemic stroke, and HAS-BLED score [13] as the
risk stratification of hemorrhagic events.
aPTT was evaluated as the surrogate maker for the anticoagu-
lant activity of DE [14]. Patients without data for aPTT were
excluded from the study population. Because the aPTT data could
be influenced by the timing of blood sampling after DE intake, the
aPTT data were divided into five time windows, i.e. 1–2, 3–4, 5–6,
7–8, >9 h after DE intake, and were compared between the two
groups (reduced and preserved CCr). The aPTT data of >9 h were
considered as the trough of DE concentration.
As in the safety outcome, incidence of hemorrhagic complica-
tions was also evaluated over the entire observation. Major
bleeding was defined as decrease in hemoglobin level >2.0 g/dL,
transfusion >2 units of blood, or symptomatic bleeding in a
critical area or organ as same as the definitions used in the RE-LY
trial [9].
Statistical analyses
All parameters were described as mean value  standard
deviation and were compared by using unpaired Student t-test
and one-way ANOVA test. Chi-square test was used for discrete
variables. A two-sided p-value <0.05 was considered statistically
significant. All analyses were performed with JMP software (SAS,
Cary, NC, USA).
TIA, transient ischemic attack; PPI, proton pump inhibitor.
Results
Study population and baseline patient characteristics
Three hundred twenty-five consecutive patients prescribed
low-dose DE from April 2011 to August 2015 were identified for
the primary enrollment in this study, but 129 patients were
excluded because of lack of aPTT or CCr data. Finally, 196 patients
were enrolled in this study (69 and 127 patients in reduced and
preserved CCr groups, respectively: Fig. 1). Table 1 shows baseline
characteristics in both groups. Reduced CCr group showed
significantly higher age (76.9  6.3 years vs. 67.6  6.7 years),
higher CHADS2 (2.6  1.4 vs. 1.8  1.2), higher CHA2DS2-VASc score
(4.3  1.6 vs. 3.2  1.6), and higher HAS-BLED score (2.3  1.0 vs.
2.0  1.0) compared with preserved CCr group (p < 0.01, respective-
ly). The proportion of concomitant prescription of antiplatelet agents
(26% vs. 15%) or proton pump inhibitor (51% vs. 48%) were not
different between the groups.
aPTT data over the time course after DE intake
Fig. 2 shows the aPTT data, as the surrogate marker of the
anticoagulant activity of DE, over the time course after DE intake in

AF Paents prescribed DE (110 mg, BID)

From April 2011 to August 2015 in Kitasato University Hospital
(n=325)

129 paents were excluded

· missing data of aPTT, sCr, BW
· contraindicaon of DE (CCr < 30 ml/min)

Matched 196 paents

30 ≤ CCr < 50 ml/min CCr ≥ 50 ml/min

Reduced CCr group (n= 69) Preserved CCr group (n=127)

Fig. 1. Flow chart of this study. One hundred ninety-six patients out of 325 patients prescribed DE from April 2011 to August 2015 were enrolled in this study and divided into
two groups based on CCr. AF, atrial fibrillation; DE, dabigatran etexilate; aPTT, activated partial thromboplastin time; sCr, serum creatinine; BW, body weight; CCr, creatinine
clearance.
 H. Fukaya et al. / Journal of Cardiology 69 (2017) 591–595 593

Reduced CCr group Thromboembolism events were not observed in either group in
80 Preserved CCr group the entire study.

* : p<0.05 vs. trough in each group

* Discussion
*
60 * *
In this study, we evaluated whether low-dose DE (110 mg, BID)
was safe in Japanese AF patients with mild CKD. Our findings are as
aPTT (sec)

follows: (1) aPTT data as the surrogate marker of DE serum

40 concentration did not show any differences between the reduced
CCr and the preserved CCr groups regardless of the timing of blood
sampling, such as peak and trough points; (2) the incidence of
20 hemorrhagic complications was not different between the two
groups.

0 Prevalence of AF with CKD

trough 1-2 3-4 5-6
Time after DE intake (h)
Fig. 2. aPTT data along the time course after DE intake in the reduced and preserved
CCr groups. aPTT data were significantly prolonged in 1–2 and 3–4 h time window
after DE intake compared with the respective trough points (p < 0.05), and
gradually shortened along the time course. There were no significant differences in
aPTT data between the reduced and preserved CCr groups at all evaluation
windows. DE: dabigatran etexilate; aPTT, activated partial thromboplastin time;
CCr, creatinine clearance.
both groups. Evaluation points were 661 in total from 196 patients.
The aPTT data showed significant prolongation in 1–2 and 3–4 h
time window after DE intake compared with the trough data in
both groups (p < 0.05, respectively). They gradually shortened along
the time course in both groups, which was considered to be consistent
with a previous report of DE pharmacokinetics [15]. There were no
significant differences in aPTT data between the reduced and
preserved CCr groups at each evaluation time window [reduced vs.
preserved CCr group = 38.5  6.8 vs. 36.8  7.1 (trough), 49.9  10.3 vs.
48.7  17.4 (1–2 h), 49.4  8.4 vs. 49.1  10.6 (3–4 h), 44.0  11.2 vs.
41.8  9.1 (5–6 h), 41.4  5.2 vs. 41.5  9.6 (7–8 h), N.S., respectively].
Incidence of hemorrhagic complications
7-8
Since AF and CKD basically share risk factors such as
hypertension, diabetes mellitus, and congestive heart failure
[17,18], the comorbidity of AF and CKD is common. Aging is also
an important risk factor for AF and CKD. Approximately 10% of
people over 80 years have AF in the USA [19]. The prevalence of AF
in Japan is also increasing [20], which is projected to affect 1% of the
total population in Japan by 2050. Likewise, the elderly population
also has a higher prevalence of CKD [21]. It has been reported [22]
that glomerular filtration rate (GFR) is reduced by 0.37 ml/min/
1.73 m2 per year even without other coexisting diseases, i.e. elderly
patients potentially have CKD. Anticoagulation therapy concur-
rently has risk of bleeding complications, which can sometimes be
fatal. Notably CKD patients are potentially exposed to higher risk of
hemorrhagic complications under anticoagulation therapy [23–
25]. In this study, the reduced CCr group was associated with
significantly higher age, higher CHADS2 and CHAD2S2-VASc scores
as thromboembolic risk scores, and higher HAS-BLED score as a
bleeding risk score compared with the preserved CCr group, and
those tendencies were consistent with previous reports [23–25]. In
anticoagulation therapy to prevent stroke and STE in AF, we should
intensively pay attention to the comorbidity of CKD and evaluate
severity of renal dysfunction, especially when prescribing DOACs.

Hemorrhagic complications including thrombolysis in myo- DOAC for AF with CKD

cardial infarction major bleeding and other minor bleeding events
occurred in 2/69 in the reduced CCr group, and in 2/127 in the
preserved CCr group during 1059  457 days of the total
observational period. Antiplatelet agents have been reported as an
independent risk factor for bleeding under taking direct oral
anticoagulants (DOACs) [16], the proportion of co-prescription of
antiplatelets was not significantly different, and the incidence of
hemorrhagic complication events was not statistically different
between the two groups. Table 2 shows the detailed information of
the patients having hemorrhagic complications. Two cases in the
preserved CCr group had higher bleeding risk based on the HAS-BLED
score. Two cases in the reduced CCr group showed relatively low
body weight while HAS-BLED score does not show high risk of
bleeding.
Since DOACs are excreted through urination, warfarin was
preferred for AF patients with CKD patients in preventing stroke/
STE. However, Wieloch et al. reported [26] that decreasing
estimated GFR was inversely related to increasing major bleeding
risk in patients undergoing anticoagulation with warfarin. Besides,
anticoagulation with warfarin in Asians showed higher incidence
of intracranial hemorrhage (ICH) compared with the USA and
European countries [27]. Large clinical trials of DOAC indicated
that prevalence of ICH in DOACs was significantly less compared
with the warfarin group [27,28]. Considering the potential safety of
DOACs [27–29], the Japanese guideline [1] recommends antic-
oagulation with DOACs rather than with warfarin if AF patients
have an indication for DOACs. In this study, we focused on the AF

Table 2
The detailed characteristics of the patients complicated with hemorrhagic events.

Type of bleeding Age Gender BW (kg) sCr (mg/dL) CCr (ml/min) Type of AF CHADS2 CHA2DS2-VASc HAS-BLED

Reduced CCr group

Case 1 Hemosputum 70 Female 35.7 0.65 45.4 Paroxysmal 1 3 2
Case 2 Intracranial hemorrhage 82 Male 44.5 0.88 40.7 Chronic 3 4 2
Preserved CCr group
Case 3 Intracranial hemorrhage 47 Male 129 1.61 103.5 Chronic 3 3 4
Case 4 Subdural hematoma 67 Female 50.7 0.66 66.2 Paroxysmal 3 5 4

BW, body weight; sCr, serum creatinine; CCr, creatinine clearance; AF, atrial fibrillation.
594 H. Fukaya et al. / Journal of Cardiology 69 (2017) 591–595
patients with mildly impaired renal function who are on DOACs, to
evaluate whether DE can be safely used in CKD patients by treating
AF patients with CKD. We demonstrated the safety of low-dose DE
in such a population.
DE for AF with CKD
In a sub-analysis of the RE-LY trial [30], DE was more effective in
higher CCr patients compared with the warfarin group, but the
superiority of DE tended to subside as CCr reduced. However, this
paper indicated that incidence of ICH, the most fatal complication
of anticoagulation, was clearly less with both doses of DE
compared with that in warfarin group regardless of renal function.
The effect of warfarin is known to exhibit racial differences [31], so
that the results of clinical trials in Western countries may not be
directly applicable in Japan. In fact, compared to non-Asian
populations, DE has documented more significant reduction in the
incidence of ICH compared with warfarin in Asian populations
[28]. Recently, Hori et al. reported the sub-analysis of RE-LY in
Asian patients with renal dysfunction [32]. In this Asian sub-
analysis, DE did not show any differences in efficacy and safety
endpoints independent of renal function compared with the
warfarin group.
In terms of bleeding, there were two patients who experienced
bleeding events in our study although they did not have any high
risk of bleeding complication except for their low body weight.
Large clinical trials [33,34] showed body weights in Japanese are
lower compared with Caucasians. The incidence of bleeding
complications in patients undergoing anticoagulation for AF
tended to be high in low body-weight patients both in DE and
warfarin groups in RE-LY sub-analysis [35]. Taken together, we
should pay more attention when using DE for low body weight
patients with renal insufficiency even if they do not have high HAS-
BLED scores.
In our present study, we evaluated aPTT changes as a surrogate
marker of anticoagulant activity of DE [14]. Several reports
documented that aPTT would be useful as a safety marker
[14,36] potentially helping us to prevent the excessive antic-
oagulation. Since the incidences of stroke/STE or hemorrhagic
complications were rare, we evaluated aPTT data as a surrogate
marker over the time course after DE intake in this study.
Shimomura et al. [14] reported that the concentration of DE
increased 3–4 h after DE intake and gradually decreased along the
time course. Consistent with their report [14], our results showed
significantly longer aPTT data in 1–2 h and 3–4 h time window
after DE intake compared with the trough data in both groups.
However, there was no significant difference in aPTT between the
reduced and preserved CCr groups. A previous paper indicated that
blood concentration of DE in CKD patients was higher due to its
excretion pathway. In accordance with published data [14], trough
data in reduced CCr group tended to be higher compared with that
in preserved CCr group in this study. Miyamoto et al. [37] reported
that the relationship between aPTT and CCr showed a weak inverse
correlation. Besides, since they evaluated all data in two doses of
DE together, i.e. 150 mg BID and 110 mg BID, there is no concrete
evidence in terms of the relation under low dose DE in mild CKD
patients. Our results suggested that DE did not excessively
accumulate under the low-dose usage (110 mg, BID), possibly
showing the safety of low-dose DE in Japanese ‘real world’ AF
patients with mildly impaired renal function.
Study limitations
First, this study was a single center, retrospective study, with a
limited patient number posing a risk for patient selection bias.
Physicians might have chosen DE for the AF patients with reduced
CCr who are still tolerant of DOACs. It should be noted that we
selected the patients prescribed 110 mg BID of DE in this study, so
this result could not apply to regular doses (150 mg BID) of DE.
Second, the time-dependent changes of aPTT in each individual
patient were not evaluated in this study, so we could not mention
the change rate of aPTT along the time course. Third, the incidences
of stroke/STE and bleeding complications were limited in this
study. To elucidate the safety of low-dose DE in mild CKD patients,
further studies with a larger number of patients are necessary.
Conclusion
Based on the aPTT data and incidence of bleeding complica-
tions, low-dose DE (110 mg, BID) was safe in AF patients with
mildly reduced CCr.
Funding
This research received no grant from any funding agency in the
public, commercial, or not-for-profit sectors.
Disclosure
J.A. received research funding from Kissei, Astellas, Mediphy-
sics, Ono, Bristol Myers, Pfizer, Boehringer Ingelheim, Kyowa Kirin,
Bayer, Daiichi-Sankyo, Eisai, Teijin, Kowa, Mochida, Abbott
Vascular, Asahi Intec, Astra Zeneca, Dainippon Sumitomo, Otsuka,
Tanabe Mitsubishi, Takeda, Japan Lifeline, and lecture fees from
Actelion, Sanofi, Tanabe-Mitsubishi, Takeda, Mochida, Shionogi,
Kaneka, Astra-Zeneca, Astellas, Volcano, Terumo, Eisai, Bristol-
Myers, St. Jude Medical, Kyowa-Kirin, Pfizer, Ono Pharmaceutical,
Abbott Vascular, Toa Eiyo, JIMRO, Kissei, Dainippon Sumitomo.
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