Relationship between plasma dabigatran concentration and activated partial thromboplastin time in Japanese patients with non-valvular atrial fibrillation

Abstract

Activated partial thromboplastin time (aPTT) is recommended for monitoring anticoagulant activity in dabigatran-treated patients; however, there are limited data in Japanese patients. To clarify the relationship between plasma dabigatran concentration and aPTT, we analyzed plasma dabigatran concentration and aPTT at various time points following administration of oral dabigatran in a Japanese hospital.
We enrolled 149 patients (316 blood samples) with non-valvular atrial fibrillation (NVAF) who were taking dabigatran. Patients had a mean age of 66.6±10.0 years (range: 35-84) and 66% were men. Plasma dabigatran concentrations and aPTT were measured using the Hemoclot(®) direct thrombin inhibitor assay and Thrombocheck aPTT-SLA(®), respectively. Samples were classified into eight groups according to elapsed times in hours since oral administration of dabigatran.
Significantly higher dabigatran concentrations were observed in samples obtained from patients with low creatinine clearance (CLCr) (CLCr<50 mL/min). Dabigatran concentrations and aPTT were highest in the 4-h post-administration range. Additionally, there was a significant correlation between plasma dabigatran concentrations and aPTT (y=0.063x+32.596, r (2)=0.648, p<0.001). However, when plasma dabigatran concentrations were 200 ng/mL or higher, the correlation was lower (y=0.040x+38.034 and r (2)=0.180); these results were evaluated by a quadratic curve, resulting in an increased correlation (r (2)=0.668).
There was a significant correlation between plasma dabigatran concentrations and aPTT. Additionally, in daily clinical practice in Japan, plasma dabigatran concentrations and aPTT reached a peak in the 4-h post administration range. Considering the pharmacokinetics of dabigatran, aPTT can be used as an index for risk screening for excess dabigatran concentrations in Japanese patients with NVAF.

Full text

Original Article
Relationship between plasma dabigatran concentration and activated
partial thromboplastin time in Japanese patients with non-valvular
atrial fibrillation
Daiki Shimomura
a
, Yoshihisa Nakagawa, MD
b,
n
, Hirokazu Kondo, MD
b
,
Toshihiro Tamura, MD
b
, Masashi Amano, MD
b
, Yukiko Hayama, MD
b
, Naoaki Onishi, MD
b
,
Yodo Tamaki, MD
b
, Makoto Miyake, MD
b
, Kazuaki Kaitani, MD
b
, Chisato Izumi, MD
b
,
Masahiko Hayashida
c
, Aya Fukuda
a
, Fumihiko Nakamura, MD
a
, Seiji Kawano, MD
d
a
Department of Laboratory Medicine, Tenri Hospital, Tenri, Japan
b
Department of Cardiology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan
c
Tenri Institute of Medical Research, Tenri, Japan
d
Division of Laboratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
article info
Article history:
Received 4 November 2014
Received in revised form
15 November 2014
Accepted 18 November 2014
Available online 18 December 2014
Keywords:
Dabigatran
Anticoagulants
aPTT
Non-valvular atrial fibrillation
abstract
Background: Activated partial thromboplastin time (aPTT) is recommended for monitoring anticoagulant
activity in dabigatran-treated patients; however, there are limited data in Japanese patients. To clarify the
relationship between plasma dabigatran concentration and aPTT, we analyzed plasma dabigatran
concentration and aPTT at various time points following administration of oral dabigatran in a Japanese
hospital.
Methods: We enrolled 149 patients (316 blood samples) with non-valvular atrial fibrillation (NVAF) who
were taking dabigatran. Patients had a mean age of 66.6 710.0 years (range: 35–84) and 66% were men.
Plasma dabigatran concentrations and aPTT were measured using the Hemoclot
s
direct thrombin
inhibitor assay and Thrombocheck aPTT-SLA
s
, respectively. Samples were classified into eight groups
according to elapsed times in hours since oral administration of dabigatran.
Results: Significantly higher dabigatran concentrations were observed in samples obtained from patients
with low creatinine clearance (CLCr) (CLCro50 mL/min). Dabigatran concentrations and aPTT were
highest in the 4-h post-administration range. Additionally, there was a significant correlation between
plasma dabigatran concentrations and aPTT (y¼0.063xþ32.596, r
2
¼0.648, po0.001). However,
when plasma dabigatran concentrations were 200 ng/mL or higher, the correlation was lower
(y¼0.040xþ38.034 and r
2
¼0.180); these results were evaluated by a quadratic curve, resulting in an
increased correlation (r
2
¼0.668).
Conclusions: There was a significant correlation between plasma dabigatran concentrations and aPTT.
Additionally, in daily clinical practice in Japan, plasma dabigatran concentrations and aPTT reached a
peak in the 4-h post administration range. Considering the pharmacokinetics of dabigatran, aPTT can be
used as an index for risk screening for excess dabigatran concentrations in Japanese patients with NVAF.
&2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
1. Introduction
Dabigatran (Boehringer Ingelheim, Ingelheim, Germany) is a
direct thrombin inhibitor, which can be orally administered, and is
used to decrease the risk of ischemic stroke in patients with non-
valvular atrial fibrillation (NVAF). In early phase studies of dabiga-
tran in healthy men, plasma dabigatran concentrations were found
to rapidly increase and reach a peak value within 1.5–3 h after oral
administration of the drug [1–4]. However, the timing of peak
plasma dabigatran concentration in daily clinical practice is not
fully understood. When dabigatran was first approved for use,
monitoring of clotting time was considered unnecessary; however,
cases of large hemorrhage with a markedly prolonged clotting
time have been observed. Additionally, in certain situations, mon-
itoring of plasma concentrations and/or the anticoagulant action of
dabigatran is required as risk screening for effects of excess
dabigatran [5–7]. Therefore, it is recommended that activated
partial thromboplastin time (aPTT) be used as a parameter for
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/joa
Journal of Arrhythmia
http://dx.doi.org/10.1016/j.joa.2014.11.003
1880-4276/&2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
n
Corresponding author. Tel.: þ81 743 63 5611; fax: þ81 743 63 1530.
E-mail address: nakagawa@tenriyorozu.jp (Y. Nakagawa).
Journal of Arrhythmia 31 (2015) 183–188

monitoring anticoagulant activity in dabigatran-treated patients
[1,8,9]. The relationship between aPTT and dabigatran therapy has
recently gained a lot of attention; however, there are limited data
in Japanese patients [10–14].
Therefore, this study aimed to evaluate the correlation between
dabigatran concentration and aPTT prolongation in Japanese NVAF
patients in daily clinical practice. Additionally, the time-dependent
change of these parameters according to the elapsed time after
oral dabigatran administration was investigated.
2. Material and methods
2.1. Study population
We measured plasma dabigatran concentrations and aPTT in
316 samples obtained from 149 patients with NVAF who were
receiving oral dabigatran therapy without concomitant use of
other anticoagulants from November 2012 to December 2013 in
Tenri Hospital. Blood sampling was performed at least one week
after patients initiated dabigatran therapy. The precise elapsed
time after oral administration of dabigatran was calculated as the
difference in time between a patient taking dabigatran and the
time of blood sampling. On the day of blood sampling, we asked
patients to come to the hospital after having breakfast and taking
dabigatran as prescribed. A laboratory medical technologist
recorded the last time of taking dabigatran according to the
patient. The present protocol was examined and approved by the
Ethical Review Board in Tenri Hospital (IRB approval number
#568, approval date 21 August 2013), and all participants provided
written informed consent before their participation in the study
according to the guidelines established in the Declaration of
Helsinki. Plasma dabigatran concentrations were measured using
the Hemoclot
s
thrombin inhibitor assay (Hyphen Biomed, France)
and aPTT was measured using aPTT-SLA
s
(Sysmex, Kobe, Japan) as
the reagent. The standard median of the aPTT reagent used in the
present assessment was 30.75 s.
2.2. Data analyses
Continuous variables were described as mean7standard
deviation or median and interquartile range (25th–75th percen-
tile), depending on the normality of the distribution. Comparisons
were made with the χ
2
test for categorical variables, as appro-
priate, and with the Mann–Whitney Utest for continuous vari-
ables. Interpretation of the intensity of the relationship between
plasma dabigatran concentrations and aPTT was performed using
Pearson's correlation coefficient method. A pvalue o0.05 was
considered statistically significant. These analyses were performed
using Stat Flex (Artech, version 6, Osaka, Japan).
3. Results
3.1. Baseline characteristics
Patients had a mean age of 66.6 710.0 years (range: 35–84)
and 66% were men. Analyses were performed based on samples,
and there were no significant differences between the baseline
characteristics of patients and samples (Table 1). The dosage of
dabigatran was 110 mg twice a day in 259 (82%) samples and
150 mg twice a day in 57 (18%) samples. The mean value of
creatinine clearance (CLCr) based on the Cockcroft-Gault formula
was 75.8725.4 mL/min, and CLCr o50 mL/min was observed in
40 (13%) samples. No samples were obtained from patients with
CLCro30 mL/min. Prescription of a P-glycoprotein (PGP) inhibitor
was observed in 55 (17%) samples: verapamil (n¼35), cyclosporine
(n¼9), diltiazem (n¼5), atorvastatin (n¼3), and amiodarone
(n¼3). Patients receiving 110 mg of dabigatran, compared with
those receiving 150 mg, had a significantly higher age, lower
values of estimated glomerular filtration rate (eGFR) and CLCr,
lighter weight, and were mostly women. Higher plasma dabiga-
tran concentrations and longer aPTT values were observed in
patients taking 150 mg dabigatran compared with patients taking
110 mg; however, this difference was not significant (Table 2).
3.2. Effect of reduced renal function on dabigatran concentrations
Significantly higher dabigatran concentrations were observed
in samples from patients with reduced renal function (CLCr o
50 mL/min) compared with those with normal renal function
(CLCrZ50 mL/min) (120 [69–219] and 81 [40–152] ng/mL, respec-
tively, p¼0.009) (Table 3). aPTT values appeared to be elongated in
patients with reduced renal function compared with those with
normal renal function but the difference was not significant.
3.3. Elapsed time after oral administration of dabigatran
The median elapsed time after oral administration of dabiga-
tran to blood sampling was 169 min (115–300 min), and in 87% of
the samples, this time ranged from 0 to 240 min. In 286 (91%)
samples, dabigatran was administered to patients between 5:00
am and 9:00 am. Samples from patients who were administered
dabigatran during this time period, were classified into eight
groups according to elapsed time from administration, ranging
from 0 to 6 h (groups 1–7) and after 7 h (group 8). Further analyses
and comparisons were performed among these eight groups.
There was no significant difference dosage of dabigatran among
the eight groups.
3.4. Distribution of dabigatran concentrations and aPTT
The median dabigatran concentration was 89 ng/mL (41–165
ng/mL), and 54 (17%) samples had dabigatran concentrations of
200 ng/mL or higher (Table 2 and Fig. 1A). When the median
dabigatran concentration for each of the eight groups was com-
pared, the 4-h range group showed the highest value of 133 ng/mL,
followed by 111 ng/mL in the 3-h range group, and 98 ng/mL in the
5-h range group (Fig. 2A).
The median aPTT was 38.7 s (34.4–44.7 s) and none of the
samples showed an aPTT of Z60 s (Table 2 and Fig. 1B). When the
median values of aPTT were compared among the eight groups,
the 4-h range group showed the highest value of 43.0 s, followed
by 39.7 s in the 3-h range group, and 38.4 s in the 2-h range group
(Fig. 2B).
3.5. Relationship between plasma dabigatran concentrations and
aPTT
There was a significant correlation between dabigatran con-
centration and aPTT (y¼0.063xþ32.596, r
2
¼0.648, po0.001)
(Fig. 3A). Additional analysis was performed for two levels of
plasma dabigatran concentrations: o200 ng/mL and Z200 ng/mL.
The regression line was y¼0.077xþ31.605 (r
2
¼0.535) for
o200 ng/mL (n¼262) and showed a significant linear relationship
(po0.001). For Z200 ng/mL (n¼54), the regression line was
y¼0.040xþ38.034 (r
2
¼0.180), which again showed a linear rela-
tionship (p¼0.001), but the slope was diminished and the correla-
tion value was lower compared with that for o200 ng/mL (Fig. 3B).
Therefore, we evaluated this relationship by quadratic curve:
y¼0.0001x
2
þ0.097xþ31.016. A better correlation value of
D. Shimomura et al. / Journal of Arrhythmia 31 (2015) 183–188184

r
2
¼0.668 was observed with this regression curve compared with
the regression line (Fig. 3C).
4. Discussion
4.1. Major findings
The main findings of this study are as follows: there was a
significant correlation between the concentration of dabigatran
and aPTT; peak dabigatran concentrations and the longest aPTT
values were observed in the 4-h post dabigatran administration
range; and significantly higher dabigatran concentrations were
observed in patients with reduced renal function compared with
those with normal renal function.
4.2. Measurement of dabigatran concentrations
Liquid chromatography-tandem mass spectrometry (LC–MS/
MS) is considered the most precise method for measuring plasma
dabigatran concentrations [1]; however, LC–MS/MS requires high
expenditure and extensive procedures for sample pretreatment
[1]. The LC–MS/MS system and coagulation assays were previously
evaluated [2,8,15,16], and a good correlation was observed
between the clotting time measured by the Hemoclot
s
direct
thrombin inhibitor assay and plasma dabigatran concentrations
measured using the LC–MS/MS system [15]. Therefore, the mea-
surements obtained by the Hemoclot
s
direct thrombin inhibitor
assay can be considered the estimated plasma concentration of
dabigatran.
Our study indicates that measurement of plasma concentra-
tions with Hemoclot
s
is ideal for monitoring the risk of bleeding
due to excess accumulation of dabigatran. However, the expense of
Hemoclot
s
direct thrombin inhibitor assay is not reimbursed by
the Japanese social insurance system. On the other hand, monitor-
ing with aPTT could be performed in any hospital in Japan and
therefore it is important to clarify the relationship between
dabigatran concentration and aPTT prolongation in a clinical
setting. Our data showed a significant relationship between serum
dabigatran concentration and aPTT, thereby supporting the use of
aPTT as a surrogate test for dabigatran concentration.
4.3. Reduced renal function
We confirmed that higher dabigatran concentrations were
observed in patients with reduced renal function (CLCr, 30–50
mL/min). Stangier et al. reported that, after oral administration of a
single dose of 150 mg dabigatran, the area under the curve values
Table 1
Baseline characteristics.
Patient Sample pValue Dosage of dabigatran pValue
n¼149 n¼316 110 mg 2150mg2
n¼259 (82%) n¼57 (18%)
Elapsed time after oral administration (min) 203 (130–345) 169 (115–300) 0.072 160 (112–290) 200 (120–355) 0.12
Age (year) 66.6710.0 67.679.4 0.40 69.178.8 60.4 78.8 o0.001
Males, n(%) 98 (66%) 202 (64%) 0.70 154 (60%) 48 (84%) o0.001
Weight (kg) 62.7710.3 62.9 710.3 0.97 61.679.5 69.1711.4 o0.001
eGFR (mL/min/1.73 m
2
) 69.6716.0 67.7715.6 0.19 66.9715.7 71.7714.2 0.019
Creatinine (mg/dL) 0.8270.19 0.8370.20 0.66 0.8370.21 0.84 70.15 0.34
Creatinine clearance (mL/min) 77.8725.1 75.8725.4 0.27 72.5723.7 90.9 727.7 o0.001
Creatinine clearance o50 mL/min, n(%) 14 (9%) 40 (13%) 0.31 37 (14%) 3 (5.3%) 0.064
P-glycoprotein inhibitor, n(%) 19 (13%) 55 (17%) 0.20 49 (19%) 6 (11%) 0.13
Values are expressed as mean7standard deviation, median and interquartile range, or number (n) and %.
eGFR¼Estimated glomerular filtration rate.
Table 2
Dabigatran concentrations and activated partial thromboplastin time (aPTT) according to the dabigatran dosage.
Total Dosage of dabigatran pValue
n¼316 110 mg 2150mg2
n¼259 (82%) n¼57 (18%)
Plasma concentrations of dabigatran (ng/mL) 89 (41–165) 79 (40–150) 128 (54–183) 0.09
aPTT (s) 38.7 (34.4–44.6) 38.3 (34.6–44.5) 39.7 (33.4–45.4) 0.80
Values are expressed as median and interquartile range.
Table 3
Dabigatran concentrations and activated partial thromboplastin time (aPTT) according to renal function.
Total Creatinine clearance pValue
n¼316 Z30–o50 mL/min Z50 mL/min
n¼40 (13%) n¼276 (87%)
Dose of dabigatran, 150 mg 2/day, n(%) 57 (18%) 3 (7.5%) 54 (20%) 0.064
Elapsed time after oral administration (min) 169 (115–300) 143 (109–266) 172 (115–306) 0.35
Plasma concentrations of dabigatran (ng/mL) 89 (41–165) 120 (69–219) 81 (40–152) 0.009
aPTT (s) 38.7 (34.4–44.6) 44.0 (36.2–47.0) 38.3 (34.3–44.5) 0.16
Values are expressed as median and interquartile range, or number (n) and %.
D. Shimomura et al. / Journal of Arrhythmia 31 (2015) 183–188 18 5

Fig. 1. (A) Distribution of plasma dabigatran concentrations and elapsed time after dabigatran oral administration. (B) Distribution of activated partial thromboplastin time
(aPTT) and elapsed time after dabigatran oral administration.
Fig. 2. (A) Distribution of plasma dabigatran concentrations according to elapsed time after dabigatran oral administration (hour range). (B) Distribution of activated partial
thromboplastin time (aPTT) according to elapsed time after dabigatran oral administration (hour range). Values are expressed as median and interquartile range.
D. Shimomura et al. / Journal of Arrhythmia 31 (2015) 183–188186

for the plasma concentration-time were 1.5-, 3.2-, and 6.3-fold
higher in people with a CLCr of 50–80 mL/min, 30–50 mL/min,
and o30 mL/min, respectively, compared with values in healthy
people [17]. Therefore, dabigatran is regarded as a contraindication
for patients with CLCro30 mL/min. However, there are no specific
recommendations to reduce the dose of dabigatran in patients
with reduced renal function and therefore, a reliable method for
monitoring dabigatran use is greatly anticipated to ensure its safe
use in patients with reduced renal function.
4.4. Timing of peak dabigatran concentrations and peak aPTT after
administration
Early phase studies of dabigatran have shown that dabigatran
concentrations rapidly increase and reach a peak value within 1.5–
3 h after oral administration [1–4]. The timing of peak dabigatran
concentration in the present study was approximately 2 h later
compared with previous studies in which blood sampling was
performed in healthy men with an empty stomach [1,18].A
possible reason for the difference observed between the studies
could be a delay in dabigatran absorption in our study since most
of the patients administered dabigatran after breakfast. Our result
is consistent with that of Stangier's study, which demonstrated
that plasma dabigatran concentrations reached a peak value 2 h
after oral administration when dabigatran was administered on an
empty stomach, but reached a peak value 2 h later, when it was
administered after a meal [18].
4.5. Correlation between plasma dabigatran concentrations and
aPTT
The sensitivity of dabigatran depends on the type of aPTT
reagent [9,19–21], which could be a possible explanation for the
differences observed between studies. The regression line between
the plasma concentration of dabigatran and aPTT in this study for
all samples, showed a significant linear relationship with a
moderate correlation. When the concentration of dabigatran was
o200 ng/mL, plasma dabigatran concentrations and aPTT showed
a moderate correlation (r
2
¼0.535), which suggested that dabiga-
tran concentrations are able to be estimated by aPTT. However,
when plasma dabigatran concentrations exceeded 200 ng/mL, the
slope was diminished and the correlation value decreased to
r
2
¼0.180, suggesting that aPTT does not prolong in proportion to
the plasma dabigatran concentration. When aPTT exceeds 45.2 s,
corresponding to a dabigatran concentration of 200 ng/mL, it is
plausible that dabigatran concentrations could be higher than
expected. Plasma concentrations of dabigatran exceeding 200 ng/
mL, as measured by Hemoclot
s
, have been reported to be related
to hemorrhagic events [5], and this relationship has been
described in the European Heart Rhythm Association Practical
Guide on the use of new oral anticoagulants [22]. These findings
suggested that it was better to estimate the plasma concentration
of dabigatran from aPTT on the regression quadratic curve rather
than the regression line, especially for high plasma concentrations
of dabigatran.
4.6. Clinical implications
To monitor the risk of bleeding due to excessive accumulation
of dabigatran, measurement of the trough dabigatran value imme-
diately before its administration is reasonable. However, it is also
reasonable to monitor peak dabigatran concentration for a period
after breakfast, since the half-life of dabigatran concentration is as
short as 12 h and dabigatran is administered after breakfast by
many patients. Our study clarified the pharmacokinetics and the
timing of peak dabigatran concentration and peak aPTT in daily
clinical practice.
4.7. Study limitations
First, our database consisted of a cohort from a single hospital,
and therefore, the results should be carefully interpreted since the
patients' backgrounds, the criteria for use, and patient manage-
ment in one hospital might be different from that in other
institutions. The second limitation of the study was the absence
of hemorrhagic events, which meant that we were not able to
analyze how high dabigatran concentrations and related high aPTT
predispose the risk of hemorrhagic events.
5. Conclusions
There was a significant correlation between plasma dabigatran
concentrations and aPTT. Plasma dabigatran concentrations and
Fig. 3. Relationship between plasma dabigatran concentrations and activated partial thromboplastin time (aPTT). (A) Regression line of dabigatran concentrations.
(B) Regression line at two levels of plasma dabigatran concentrations: o200 ng/mL and Z200 ng/mL. (C) Regression curve between plasma dabigatran concentrations
and aPTT.
D. Shimomura et al. / Journal of Arrhythmia 31 (2015) 183–188 18 7

aPTT reached a peak in the 4-h post administration range.
Considering the pharmacokinetics of dabigatran, aPTT could be
used as a parameter in risk screening for excess effects in Japanese
patients who are taking dabigatran. Further studies are required to
establish an ideal method for monitoring the safe use of
dabigatran.
Funding
This research received no grants from any funding agency in
the public, commercial or not-for-profit sectors.
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgments
We are indebted to the outstanding efforts of the laboratory
medical technologists in Tenri Hospital for data collection and
blood sampling.
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