Tohoku J. Exp. Med., 2016, 240, 259-268
The EXPAND Study
259
Study Design and Baseline Characteristics of the EXPAND Study:
Evaluation of Effectiveness and Safety of Xa Inhibitor,
Rivaroxaban for the Prevention of Stroke and Systemic Embolism
in a Nationwide Cohort of Japanese Patients Diagnosed as
Non-Valvular Atrial Fibrillation
Takanori Ikeda,1 Hirotsugu Atarashi,2 Hiroshi Inoue,3 Shinichiro Uchiyama,4
Takanari Kitazono,5 Takeshi Yamashita,6 Wataru Shimizu,7 Masahiro Kamouchi,8
Koichi Kaikita,9 Koji Fukuda,10 Hideki Origasa,11 Ichiro Sakuma,12 Keijiro Saku,13
Yasuo Okumura,14 Yuichiro Nakamura,15 Hideo Morimoto,16 Naoki Matsumoto,17
Akihito Tsuchida,18 Junya Ako,19 Nobuyoshi Sugishita,20 Shogo Shimizu21 and
Hiroaki Shimokawa10
1
Department of Cardiovascular Medicine, Toho University Faculty of Medicine, Tokyo, Japan
Department of Cardiovascular Medicine, Nippon Medical School Tama-Nagayama Hospital, Tokyo, Japan
3
Saiseikai Toyama Hospital, Toyama, Toyama, Japan
4
Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan
5
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyusyu University,
Fukuoka, Fukuoka, Japan
6
Cardiovascular Institute Hospital, Tokyo, Japan
7
Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
8
Department of Health Care Administration and Management, Kyusyu University Graduate School of Medical
Sciences, Fukuoka, Fukuoka, Japan
9
Department of Cardiovascular Medicine, Kumamoto University, Kumamoto, Kumamoto, Japan
10
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi,
Japan
11
Department of Biostatistics and Clinical Epidemiology, Toyama University, Toyama, Toyama, Japan
12
Hokko Memorial Hospital, Sapporo, Hokkaido, Japan
13
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Fukuoka, Japan
14
Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
15
Nakamura Cardiovascular Clinic, Itoshima, Fukuoka, Japan
16
Department of Medicine, Fukagawa Municipal Hospital, Fukagawa, Hokkaido, Japan
17
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
18
Division of Cardiology, JR Sapporo Hospital, Sapporo, Hokkaido, Japan
19
Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
20
Sugishita Clinic, Gujo, Gifu, Japan
21
Mashiko Hospital, Kawaguchi, Saitama, Japan
2
The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and
systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the
nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the
real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective,
non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in
non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were
enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline
demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%,
and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent)
AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension,
congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and
Received August 26, 2016; revised and accepted October 28, 2016. Published online November 30, 2016; doi: 10.1620/tjem.240.259.
Correspondence: Takanori Ikeda, M.D., Ph.D., Department of Cardiovascular Medicine, Toho University Faculty of Medicine, 6-11-1
Omorinishi, Ota-ku, Tokyo 143-8540, Japan.
e-mail: ikety5@gmail.com
259
T. Ikeda et al.
260
20.2%, respectively. The proportions of patients with a CHADS2 score ≤ 1 and a CHA2DS2-VASc score ≤ 1
were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up
period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate
treatment with rivaroxaban for Japanese patients with non-valvular AF.
Keywords: anticoagulants; atrial fibrillation; Japanese; real world evidence; stroke
Tohoku J. Exp. Med., 2016 December, 240 (4), 259-268. © 2016 Tohoku University Medical Press
Introduction
Atrial fibrillation (AF) is the most common cardiac
arrhythmia (Wolf et al. 1996). Several non-vitamin K oral
anticoagulants (NOACs) have recently been launched for
the prevention of ischemic stroke and systemic embolism in
patients with non-valvular AF (Savelieva and Camm 2014).
The Japanese Circulation Society (JCS) Guidelines 2013
for pharmacotherapy of AF recommended to control the
optimal prothrombin time international normalized ratio
(PT-INR) range in case of warfarin use for non-valvular AF.
Optimal PT-INR range for patients older than 70 years and
those under 70 years is 1.6-2.6 and 2.0-3.0, respectively
(Inoue et al. 2014). Among them, rivaroxaban was
approved in January 2012, and was available since April
2012 in Japan. It is an orally direct inhibitor of factor Xa
with considerably fewer interactions with other drugs or
food (Carter and Plosker, 2013), requires no routine coagulation monitoring and thus overcomes drawbacks of warfarin (Savelieva and Camm, 2014). Based on rivaroxaban
pharmacokinetics in Japanese subjects and lower anti-coagulation preference in Japan, particularly in elderly patients,
the optimal dose regimen for Japanese AF patients was considered (Tanigawa et al. 2013). Approved dosage of rivaroxaban was 15 mg once daily for adult patients with nonvalvular AF, 10 mg once daily in patients with moderate
renal impairment defined as creatinine clearance (CCr) of
30(15)-49 mL/min.
The ROCKET AF Trial (Rivaroxaban Once Daily Oral
Direct Factor Xa Inhibition Compared with Vitamin K
Antagonism for Prevention of Stroke and Embolism Trial
in Atrial Fibrillation) is a global randomized, double-blind,
controlled phase III trial, which evaluated the effectiveness
and safety of rivaroxaban 20 mg once daily versus doseadjusted warfarin in 14,264 patients with non-valvular AF
(Patel et al. 2011). Patients with a CCr of 39 to 49 mL/min
were assigned to receive fixed-dose rivaroxaban 15 mg
daily at randomization in the ROCKET AF Trial (Patel et
al. 2011). The ROCKET-AF Trial demonstrated that rivaroxaban has the non-inferiority to warfarin in the incidence
rate of stroke and systemic embolism in patients with nonvalvular AF and that the overall rate of major bleeding and
non-major bleeding in the rivaroxaban group was similar to
that in the warfarin group (Patel et al. 2011). The
J-ROCKET AF Trial, a randomized, double-blind, controlled phase III trial, was conducted to evaluate the effectiveness and safety of rivaroxaban 15 mg once daily versus
dose-adjusted warfarin in 1,280 Japanese patients with non-
valvular AF (Hori et al. 2012). Patients with a CCr of 30 to
49 mL/min were assigned to receive fixed-dose rivaroxaban
10 mg daily at randomization in the J-ROCKET AF Trial
(Hori et al. 2012). The J-ROCKET Trial demonstrated that
rivaroxaban has the non-inferiority to warfarin in the rate of
the primary safety outcomes of major and non-major clinically relevant bleeding and that rivaroxaban use was associated with a significantly greater reduction in ischemic
stroke than warfarin (Hori et al. 2012).
These two pivotal clinical trials of rivaroxaban clearly
showed the effectiveness and safety of rivaroxaban in
patients with non-valvular AF. However, there may be limitations due to the carefully-selected and well-managed
study populations in those clinical trials. The number of
patients without a history of ischemic stroke, TIA, or nonCNS systemic embolism, and with only 2 of the risk factors, was limited to less than 10% of the total patients (Hori
et al. 2012), and the patients with a CHADS2 score of 0 or 1
were not included in these two trials (Patel et al. 2011; Hori
et al. 2012). Thus, the clinical evidence for this population
remains unclear. In the real-world clinical practice, it is
evident that rivaroxaban is widely administered to non-valvular AF patients with various demographic and clinical
characteristics compared with those in the clinical trials.
Thus, in order to address the clinical utility of rivaroxaban in Japanese non-valvular AF patients, we aimed to
conduct a multicenter, prospective, non-interventional,
observational cohort study, named the EXPAND Study
(Evaluation of effectiveness and safety of Xa inhibitor for
the Prevention of stroke And systemic embolism in a
Nationwide cohort of Japanese patients Diagnosed as nonvalvular atrial fibrillation). Here, we report the study
design and baseline demographic and clinical characteristics of the 7,164 patients enrolled in the EXPAND Study
during the registration period between November 2012 and
June 2014.
Methods
Study design
The EXPAND Study is a multicenter, prospective, non-interventional, observational cohort study to evaluate the effectiveness and
safety of rivaroxaban for the prevention of stroke and systemic embolism in Japanese patients with non-valvular AF in the real-world clinical practice. In this study, eligible patients were consecutively
enrolled in 684 medical institutions during the registration period
between November 20, 2012 and June 30, 2014. The surveillance
was planned to be performed from November 20, 2012 to March 31,
2016. The information on each patient during the follow-up observa-
The EXPAND Study
tion was obtained by implementing the survey in all participating
medical centers at regular intervals (March 2013, September 2013,
March 2014, September 2014, March 2015, and March 2016). The
collected information included the baseline demographic and clinical
characteristics prior to the start of rivaroxaban treatment, and the follow-up observation data, such as physical/ medical conditions and
disease outcomes of the patients. If a patient was transferred to
another hospital or discontinued or completed the rivaroxaban treatment during the survey period, the information will be collected as
long as possible until the end of the survey.
This study was conducted in accordance with the principles of
the Declaration of Helsinki, the Ethical Guidelines for Clinical
Studies from the Japanese Ministry of Health, Labour and Welfare,
and all applicable laws and regulations in Japan. The protocol was
reviewed and approved by the Institutional Review Boards and/or
Ethics Committee at all the participating study sites. All subjects provided written informed consent before enrollment.
The study is registered with Clinical trials.gov., number
NCT02147444, and with the University Hospital Medical Information
Network clinical trials registry, number UMIN000009376.
Patients
Patients who met the following inclusion criteria were eligible;
male or female aged 20 years or older at enrollment, a diagnosis of
non-valvular AF, and use or future use of rivaroxaban. Exclusion criteria included the followings; a history of hypersensitivity to rivaroxaban or its components, bleeding (clinically significant intracranial
hemorrhage or gastrointestinal hemorrhage), liver diseases associated
with coagulation disorder or moderate-to-severe liver disorder classified into Child-Pugh class B or C, renal failure (defined as CCr of
< 15 mL/min), pregnancy or a possibility of pregnancy, use of human
immunodeficiency virus protease inhibitors, use of azole antifungal
agents excluding fluconazole, and acute bacterial endocarditis. We
excluded the cases treated with fluconazole to avoid any interactions
because rivaroxaban is a substrate of CYP3A4 and fluconazole is a
CYP3A4 inhibitor.
Assessment and endpoints
The primary effectiveness endpoint was a composite of symptomatic stroke (ischemic or hemorrhagic) and systemic embolism.
The secondary effectiveness endpoints included a composite of symptomatic stroke (ischemic or hemorrhagic), systemic embolism, myocardial infarction, and cardiovascular death, thus including symptomatic ischemic stroke, symptomatic hemorrhagic stroke, systemic
embolism, acute myocardial infarction/unstable angina, cardiovascular death, deep vein thrombosis/pulmonary thromboembolism, transient ischemic attack (TIA), and interventions/surgical treatment, and
all-cause mortality. The primary safety endpoint was major bleeding,
as defined by the International Society on Thrombosis and
Haemostasis (Schulman et al. 2005). The secondary safety endpoint
was non-major bleeding.
Sample size
The target sample size in this study was set to be 7,000 patients
based on the feasibility. In the RE-LY Trial (Randomized Evaluation
of Long-Term Anticoagulation Therapy Trial) (Connolly et al. 2009)
or the ARISTOTLE Trial (Apixaban for Reduction in Stroke and
Other Thromboembolic Events in Atrial Fibrillation Trial) (Granger et
al. 2011), the number of patients with CHADS2 ≤ 1 was approxi-
261
mately 3,000 to 4,000. Thus, the target number of patients with
CHADS2 ≤ 1 in this study was set to be 3,500. Additional 3,500
patients with CHAD2 ≥ 2 were also included in this study, so that the
patients with CHADS2 ≤ 1 and those with CHADS2 ≥ 2 accounted for
approximately 50% of the overall population as in the J-RHYTHM
Registry (Atarashi et al. 2011). As a result, we planned to include a
total of 7,000 patients with non-valvular AF in this study.
Statistical analysis
The analyses for effectiveness of rivaroxaban were performed
based on the followings; the incidence rate (% per year) of the primary effectiveness endpoint, the incidence rate of each secondary
effectiveness endpoint, the incidence rates of the primary and secondary effectiveness endpoints by the CHADS2 or a CHA2DS2-VASc
score, the incidence rate of the primary effectiveness endpoint by the
presence or absence of complication or medical history, and analysis
of prognostic factors associated with the onset of the primary and secondary effectiveness endpoints. The CHADS2 score (ranging from 0
to 6 points) and CHA2DS2-VASc score (0 to 9 points) were used to
assess the risk of cerebral infarction (ischemic stroke) in patients with
non-valvular AF, where higher scores indicate a greater risk of ischemic stroke (Gage et al. 2001; European Heart Rhythm Association et
al. 2010).
The analyses for safety of rivaroxaban were performed based
on the followings; the incidence rates (% per year) of major and nonmajor bleeding, the incidence rate of major and non-major bleedings
by a HAS-BLED score (Pisters et al. 2010), and the analysis of baseline prognostic factors associated with the development of the primary and secondary safety endpoints. The HAS-BLED score (0 to 9
points) was used to assess the risk of bleeding, with higher scores
representing a higher risk of bleeding (Lip et al. 2011). The labile
prothrombin time-international normalized ratio was not counted in
this study.
The difference in the incidence rate between the patient populations were analyzed by the chi-squares test or log-rank test, with a
2-sided significance level of 5%.
Results
A total of 7,178 patients were enrolled in this study
from 684 institutions in Japan, and 7,164 of them were considered to be eligible for effectiveness and safety analyses.
The baseline demographic and clinical characteristics of the
patients are summarized in Table 1.
The proportion of female patients was 32.2%, and that
of elderly patients aged ≥ 75 years 40.9%, that of patients
weighed < 50 kg 13.9%, and that of patients with CCr < 50
mL/min 21.8%. As for complication and medical history,
patients with hypertension accounted for 70.9%, those with
congestive heart failure (CHF) 25.9%, those with diabetes
mellitus 24.3%, and those with a history of stroke/TIA/systemic embolism 24.1% (ischemic stroke, 20.2%).
Regarding the CHADS2 score, patients with the score 2
accounted for 29.0% and those with score ≤ 1 37.3% (Table
2). As for the CHA2DS2-VASc score, patients with the
score 3 accounted for 23.1%, those with the score 2 18.4%,
and those with the score ≤ 1 13.6% (Table 2). With respect
to the HAS-BLED score, patients with the score 1
accounted for 48.3%, those with the score 2 28.5%, and
T. Ikeda et al.
262
Table 1. Baseline Demographic and Clinical Characteristics of Patients.
Patients (n = 7,164)
n
%
Male
4,856
67.8
Female
2,308
32.2
Gender
Age (year-old), mean (SD)
71.6 (9.4)
< 65
1,441
20.1
65 - 74
2,793
39.0
2,930
40.9
≥ 75
Body weight (kg), mean (SD)
< 50
62.8 (12.5)
957
13.9
50 - 59
1,866
27.1
≥ 60
4,058
59.0
CHADS2 score, mean (SD)
Creatinine clearance (mL/min), mean (SD)
< 30
2.1(1.3)
69.7 (26.2)
134
2.0
30 - 49
1,352
19.8
≥ 50
5,341
78.2
Paroxysmal
3,210
44.8
Non-paroxysmal (persistent/permanent)
3,953
55.1
2,843
39.7
Any complication or medical history
6,728
93.9
Hypertension
5,078
70.9
Congestive heart failure
1,859
25.9
Diabetes mellitus
1,740
24.3
Peripheral arterial disease
187
2.6
History of myocardial infarction
298
4.2
Angina pectoris
831
11.6
Deep venous thrombosis
37
0.5
Pulmonary embolism
18
0.3
Type of AF
History of warfarin use
Comorbidity/medical history
Aortic aneurysm
95
1.3
2,998
41.8
413
5.8
1,725
24.1
1,579
22.1
1,444
20.2
135
1.9
History of TIA
219
3.1
History of systemic embolism
59
0.8
4,297
60.0
437
6.1
Dyslipidemia
Liver dysfunction
History of stroke/TIA/systemic embolism
History of stroke
History of ischemic stroke
History of hemorrhagic stroke
Therapy of AF
Pharmacotherapy
Non-pharmacotherapy
AF, atrial fibrillation; TIA, transient ischemic attack.
The EXPAND Study
Table 2. Prevalence of Patients by Baseline CHADS 2,
CHA2DS2-VASc or HAS-BLED Scores.
Patients
%
CHADS2 score (n = 7,164)
0
10.1
1
27.2
2
29.0
3
18.7
4
10.2
5
3.9
6
0.9
CHA2DS2-VASc score (n = 7,164)
0
3.1
1
10.5
2
18.4
3
23.1
4
20.7
5
13.6
6
7.0
7
2.6
8
0.8
9
0.1
HAS-BLED score (n = 6,698)
0
12.0
1
48.3
2
28.5
3
9.4
4
1.7
5
0.1
6 to 9
0.0
those with the score ≥ 3 11.2% (Table 2).
Discussion
The EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with
non-valvular AF. In Japan, the EXPAND Study could help
to answer medical questions at least in part that came up
and were not possible to answer until now with clinical trials. In the EXPAND Study, we will investigate effectiveness and safety of rivaroxaban such as in patients with early
phase of cerebral infarction, those received antiplatelet
drugs concomitantly or complicated with vascular diseases,
in terms of stroke prevention (primary/secondary), risk factor, and type of AF.
Comparison with the two previous clinical trials of rivaroxaban
As compared with the ROCKET AF (Patel et al. 2011),
and the J-ROCKET AF (Hori et al. 2012) Trials, the
EXPAND Study is characterized by the following patient
characteristics; the proportion of paroxysmal and non-par-
263
oxysmal (persistent and permanent) AF was similar in the
EXPAND Study, while that of paroxysmal AF was lower
compared with ROCKET AF. Creatinine clearance was
comparable between the EXPAND Study and the ROCKET
AF Trial. Regarding comorbidities, the patients enrolled in
the previous 2 trials had higher percentages compared with
the EXPAND Study. Comorbidities of the East Asian
cohort of the ROCKET AF Trial had similar distribution as
in the J-ROCKET AF Trial compared with the previous 2
trials. Incidentally, the East Asian cohort of the ROCKET
AF Trial did not include Japanese patients and a secondary
analysis included the randomized patients from 73 sites in 4
geographic areas in the East Asia (China, Korea, Taiwan,
and Hong Kong) who participated in the full ROCKET AF
study (Wong et al. 2014) (Table 3).
Patients with the CHADS2 score ≤ 1 were not enrolled
in the ROCKET AF (Patel et al. 2011) or J-ROCKET AF
(Hori et al. 2012), while 37.3% of patients who were
enrolled in EXPAND had the CHADS2 score ≤ 1. This
indicates that a higher proportion of high-risk patients were
enrolled in the ROCKET AF and J-ROCKET AF Trials
compared with the EXPAND Study, resulting in the higher
proportion of patients with comorbidities.
Comparison with the two observational studies on non-valvular AF in Japan
Although the J-ROCKET AF or ROCKET AF Trial
did not include low-risk patients (the CHADS2 score of 0 or
1), the EXPAND Study included those patients in 37.3% of
the cohort (Fig. 1A). In the Japanese J-RHYTHM Registry,
patients with CHADS2 ≤ 1 and those with CHADS2 ≥ 2
accounted for approximately 50% of the overall population
(Atarashi et al. 2011). This is because the J-RHYTHM
Registry was performed mainly by cardiologists with AF
patients for primary prevention (Atarashi et al. 2011). In
contrast, the clinical characteristics of the EXPAND
patients are comparable with those of the Fushimi AF registry, another large-scale observational study on non-valvular
AF in Japan (Akao et al. 2013), which examined ~3,100 AF
patients from the community-based survey (Fig. 1A). In
the Fushimi AF registry, it is not clear whether the registry
reflects the risk distribution of thromboembolism in the
entire Japanese patient population. However, since major
participating sites of the registry are private clinics by general practitioners, it may reflect the real-world situation in
daily practice of AF. In the rivaroxaban post marketing surveillance (n = 10,038), the proportion of low-risk AF
patients was 36.2%, which is comparable with the present
study (Ogawa et al. 2014). Thus, the EXPAND Study can
be considered to reflect the real-world AF practice with
rivaroxaban.
In addition, the J-RHYTHM Registry (Atarashi et al.
2011) and Fushimi AF Registry (Akao et al. 2013) showed
similar patient characteristics to our EXPAND patients in
terms of the type of AF, creatinine clearance, and comorbidities (Tables 4 and 5). Furthermore, the distribution of
T. Ikeda et al.
264
Table 3. Comparison with the Two Previous Clinical Trials of Rivaroxaban.
ROCKET AF
Trial
J-ROCKET AF
Trial
EXPAND
Study
East Asia
cohort
(n = 7,131)
(n = 468)
(n = 639)
(n = 7,164)
Paroxysmal (%)
17.5
NA
NA
44.8
Non-paroxysmal
(persistent/permanent) (%)
81.1
NA
NA
55.1
(20.3/34.8)
Newly diagnosed or new onset
1.4
NA
NA
NA
67 (52-88)
(median) (IR)
64.0
NA
69.7±26.2
(mean ± SD)
NA
NA
22.1
19.8
Previous stroke/TIA/
systemic embolism (%)
54.9
65.0
63.8
24.1
Congestive heart failure (%)
62.6
38.9
41.3
25.9
Hypertension (%)
90.3
79.3
79.5
70.9
Diabetes mellitus (%)
40.4
38.3
39.0
24.3
Previous myocardial infarction (%)
16.6
3.6
7.0
4.2
Type of AF (%)
Creatinine clearance
Mean (range) (mL/min)
Range 30-49mL/min (%)
Comorbidity
AF, atrial fibrillation; TIA, transient ischemic attack; NA, not available.
the HAS-BLED score in the EXPAND Study is similar to
that in the J-RHYTHM Registry (Fig. 2) (Okumura et al.
2014). Thus, the patient demographic and clinical characteristics in the EXPAND Study are similar to those in the
previous 2 observational studies with Japanese AF patients,
and it is expected that the results of the EXPAND Study
will reflect the real-world clinical practice with rivaroxaban.
Validation of the CHA2DS2-VASc score
The European Society of Cardiology (ESC) Guidelines
2012 for the management of AF recommend the use of the
CHA2DS2-VASc score as a new assessment method to specify low-risk patients accurately (Camm et al. 2012). The
CHA2DS2-VASc score adds vascular diseases, 65 years or
older of age, and sex category (female sex), as additional
risk factors to the CHADS2 score, which leads to a greater
reduction in the number of patients with C CHA2DS2-VASc
score ≤ 1 than that with the CHADS2 score ≤ 1, and enables
us to stratify AF patients at low-risk more precisely. The
results of the J-RHYTHM Registry showed that the proportion of patients with the CHA2DS2-VASc score ≤ 1 (22%)
was lower compared with those with CHADS2 score ≤ 1
(50%) (Fig. 1A, B) (Atarashi et al. 2011; Okumura et al.
2014). The results of the Fushimi AF Registry also showed
that the proportion of patients with CHA2DS2-VASc score
≤ 1 (13.9%) was lower compared with those with CHADS2
score ≤ 1 (36.9%) (Akao et al. 2013). Similarly, the present
study showed that the proportion of patients with
CHA2DS2-VASc score ≤ 1 (13.6%) was lower than that of
patients with the CHADS2 score ≤ 1 (37.3%). These results
suggest that it is possible to apply CHA2DS2-VASc score to
Japanese AF patients in order to stratify the patients at lowrisk of ischemic stroke.
Safety assessment
Regarding the safety of rivaroxaban, bleeding events
in the EXPAND protocol is classified into the following 2
categories; major and non-major bleeding. In contrast, in
the ROCKET AF Trial, bleeding events were classified into
the following 3 categories; (1) major bleeding (including
subcategories such as a decrease in hemoglobin ≥ 2 g/dl,
transfusion, critical bleeding, and fatal bleeding), (2) nonmajor clinically relevant bleeding, and (3) minor episodes
(Patel et al. 2011). The J-ROCKET AF Trial also had the
following 3 categories; (1) major bleeding, (2) non-major
The EXPAND Study
265
Fig. 1. Patient distribution by CHADS2 score and CHA2DS2-VASc score.
The prevalence (%) is shown on the top of each bar. A. Patient distribution by CHADS2 score. Adapted from Fushimi
AF Registry (Akao et al. 2013), J-RHYTHM Registry (Atarashi et al. 2011). B. Patient distribution by CHA2DS2-VASc
score. Adapted from Fushimi AF Registry (Akao et al. 2013) and J-RHYTHM Registry (Okumura et al. 2014) with
permission.
clinically relevant breeding, and (3) minor bleeding events
(Hori et al. 2012). Since bleeding is one of the important
outcomes in anti-coagulation therapy, we plan to use these
3 categories when analyzing bleeding events.
Conclusions
The findings of the EXPAND Study will help to establish an appropriate rivaroxaban treatment for Japanese
patients with non-valvular AF in the real-world clinical
practice. The first results from this study will be available
in 2017.
Acknowledgments
We would like to acknowledge all the physicians and
medical staff who supported this study.
Funding
The EXPAND Study is an investigator-initiated clinical
study based on the collaborative contract with Tohoku University Hospital and Bayer Yakuhin, Ltd. The company had no role
in the study design, conduct of the study, data collection, data
analysis, or preparation or submission of the manuscript.
T. Ikeda et al.
266
Table 4. Comparison with the Previous Observational Studies on Non-valvular AF in Japan (Clinical Characteristics).
J-RHYTHM
Registry
Fushimi AF
Registry
EXPAND
(n = 7,937)
(n = 3,183)
(n = 7,164)
Male
68.9
59.3
67.8
Female
31.1
40.7
32.2
69.7 (9.9)
74.2 (11.0)
71.6 (9.4)
< 75
65.8
46.3
59.1
≥ 75
34.2
53.7
40.9
NA
58.5(13.2)
62.8 (12.5)
< 50
NA
25.7
13.9
≥ 50
NA
74.3
86.1
1.7 (1.2)
2.1 (1.4)
2.1 (1.3)
NA
63.4 (31.6)
69.7 (26.2)
< 50
NA
35.6
21.8
≥ 50
NA
64.4
78.2
Paroxysmal
37.1
46.0
44.8
Non-paroxysmal
(persistent/permanent)
62.9
54.0
55.1
Warfarin use
87.3
48.5
NA
History of warfarin use
NA
NA
39.7
Study
Gender
Age (years), mean (SD)
Body weight (kg), mean
(SD)
CHADS2 score, mean (SD)
Creatinine clearance
(mL/min), mean (SD)
Type of AF
Anticoagulant therapy
AF, atrial fibrillation; NA, not available.
Conflict of Interest
T.I. has received research fund and/or lecture fees from
Nippon Boehringer Ingelheim, Bayer Yakuhin Ltd., BristolMyers Squibb, Pfizer, and Daiichi Sankyo Co., Ltd. H.A. has
received research fund and/or lecture fees from Daiichi Sankyo
Co., Ltd. H.I. received lecture fees from Daiichi Sankyo Co.,
Ltd., Bayer Yakuhin Ltd., and Bristol-Meyers Squibb. S.U. has
received research fund and lecture fees from Bayer Yakuhin,
Ltd., Nippon Boehringer Ingelheim and Daiichi Sankyo Co.,
Ltd. T.K. has received research fund from Mitsubishi Tanabe
Pharma Corporation, Daiichi Sankyo Co., Ltd., Astellas Pharma
Inc., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Chugai
Pharmaceutical Co., Ltd., Merck Sharp and Dohme, Sanofi K.K.,
and Bayer Yakuhin, Ltd. and lecture fees from Daiichi Sankyo
Co., Ltd. and Bayer Yakuhin, Ltd. T.Y. has received research
fund and/or lecture fees from Bayer Yakuhin, Ltd., Daiichi
Sankyo Co., Ltd., Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Eisai Co., Ltd., Mitsubishi Tanabe Pharma
Corporation, Ono Pharmaceutical and Toa Eiyo. W.S. has
received research fund and/or lecture fees from Bayer, Daiichi
Sankyo Co., Ltd., Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim and Eisai Co., Ltd. M.K. has received lecture
fees from Bayer. K.K. has received research fund and/or lecture
fees from Bayer, Daiichi Sankyo Co., Ltd., Novartis Pharma,
and SBI Pharma. K.F. has received no research fund or lecture
fees from any companies. H.O. has received no research fund or
lecture fees from any companies. I.S. has received lecture fees
from Takeda Pharmaceutical Co., Ltd. K.S. has an Endowed
Department of Molecular Cardiovascular Therapeutics, Fukuoka
University, supported by MSD Co., Ltd., and an Endowed
Department of Advanced Therapeutics for Cardiovascular
Disease Fukuoka University, which is supported by Boston
Scientific Japan Co., Ltd., Japan Medtronic Co., Ltd., Japan
Lifeline Co., Ltd., Biotronik Japan, Co., Ltd., and St Jude
The EXPAND Study
267
Table 5. Comparison with the Previous Observational Studies on Non-valvular AF in Japan (Comorbidity and Medical History).
J-RHYTHM
Registry
Fushimi AF
Registry
EXPAND
Study
(n = 7,937)
(n = 3,183)
(n = 7,164)
Any complication or medical history
NA
NA
93.9
Hypertension
59.1
60.6
70.9
Congestive heart failure
NA
27.9
25.9
Diabetes mellitus
18.2
23.2
24.3
Peripheral arterial disease
NA
4.3
2.6
History of myocardial infarction
NA
6.4
4.2
Angina pectoris
NA
NA
11.6
Deep venous thrombosis
NA
NA
0.5
Pulmonary embolism
NA
NA
0.3
Aortic aneurysm
NA
NA
1.3
Dyslipidemia
NA
42.4
41.8
Liver dysfunction
NA
NA
5.8
NA
21.9
24.2
History of stroke
NA
19.4
22.1
History of ischemic stroke
NA
17.8
20.2
History of hemorrhagic stroke
NA
1.8
1.9
History of TIA
NA
2.4
3.1
History of systemic embolism
NA
1.3
0.8
Pharmacotherapy
NA
NA
60.0
Non-pharmacotherapy
NA
NA
6.1
Comorbidity/medical history
History of stroke/TIA/systemic embolism
Therapy of AF
AF, atrial fibrillation; TIA, transient ischemic attack; NA, not available.
Fig. 2. Patient distribution by HAS-BLED score.
Adapted from J-RHYTHM Registry (Okumura et al. 2014) with permission. HAS-BLED data were not available for
the Fushimi registry.
T. Ikeda et al.
268
Medical Japan Co., Ltd., and an Endowed Department of Future
Medicine for Cardiovascular Disease, Fukuoka University,
which is supported by Nihon Kohden Co., Ltd., Japan. Y.O. has
accepted remuneration from Daiichi Sankyo Co., Ltd.. Y.N. has
received no research fund or lecture fees from any companies.
H.M. has received no research fund or lecture fees from any
companies. N.M. has received research fund and/or lecture fees
from Bayer Yakuhin Ltd., Daiichi Sankyo Co., Ltd., Pfizer and
Bristol-Myers Squibb. A.T. has received no research fund or
lecture fees from any companies. J.A. has received research
fund and lecture fees from Bayer Yakuhin Ltd. N.S. has received
research fund from Bayer Yakuhin Ltd.. S.S. declare no conflict
of interest. H.S. has received lecture fees from Bayer Yakuhin,
Ltd, (Osaka, Japan) and Daiichi Sankyo Co., Ltd.
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