Hypertension Research (2014) 37, 457–462

& 2014 The Japanese Society of Hypertension All rights reserved 0916-9636/14
www.nature.com/hr

ORIGINAL ARTICLE

Rivaroxaban versus warfarin in Japanese patients

with non-valvular atrial fibrillation in relation to
hypertension: a subgroup analysis of the
J-ROCKET AF trial
Masayasu Matsumoto1, Masatsugu Hori2, Norio Tanahashi3, Shin-ichi Momomura4, Shinichiro Uchiyama5,
Shinya Goto6, Tohru Izumi7, Yukihiro Koretsune8, Mariko Kajikawa9, Masaharu Kato9, Hitoshi Ueda9,
Kazuma Iekushi9, Satoshi Yamanaka9 and Masahiro Tajiri9 on behalf of the J-ROCKET AF Study
Investigators

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF)
trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and
warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with
hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of
patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety
outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with
baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84–1.45) and 16.71% per year and 15.00%
per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66–1.97), indicating no
significant interaction (P ¼ 0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the
warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25;
95% CI: 0.03–2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54;
95% CI: 0.25–1.16), indicating no significant interaction (P ¼ 0.509). In conclusion, the safety and efficacy profile of
rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.
Hypertension Research (2014) 37, 457–462; doi:10.1038/hr.2014.1; published online 30 January 2014

Keywords: anticoagulants; atrial fibrillation; Japanese; stroke prevention

INTRODUCTION approximately 40 million.3 Studies in Europe and the US have also

The prevalence and incidence of atrial fibrillation (AF), one of the
most common diseases worldwide, is steadily increasing as the global
population ages.1 The presence of AF is strongly associated with the
increased risk of stroke and thromboembolism, and in Japan, the
morbidity and mortality associated with stroke are still higher
than those associated with ischemic heart disease or myocardial
infarction.2
Hypertension is an independent risk factor for stroke, myocardial
infarction and chronic kidney disease. The prevalence of hypertension
in Japan, which has increased as the population ages, is now
shown that hypertension causes an approximately 1.5-fold increase in
the risk of developing AF.4 Moreover, because hypertension increases
the risk of thromboembolism in patients with AF, blood pressure (BP)
management is critical in these patients.5,6
For patients with AF, warfarin has traditionally been the only
clinically available oral anticoagulant that allows effective reduction in
the risk of stroke and non-central nervous system (CNS) systemic
embolism. Recently, however, the new anticoagulant rivaroxaban,
which inhibits thrombus formation by direct inhibition of Factor Xa
through a mechanism of action that is different from that of

1Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, Japan; 2Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan;
3Department of Neurology, Saitama Medical University International Medical Center, Saitama, Japan; 4Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical
University, Saitama, Japan; 5Department of Neurology, Tokyo Women’s Medical University, Tokyo, Japan; 6Department of Medicine (Cardiology), Tokai University School of
Medicine, Tokyo, Japan; 7Department of Cardio-Angiology, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan; 8Institute for Clinical Research, Osaka
National Hospital, Osaka, Japan and 9Bayer Yakuhin Limited, Osaka, Japan
Correspondence: Professor M Matsumoto, Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences,
Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan.
E-mail: mack@hiroshima-u.ac.jp
Received 13 August 2013; revised 1 December 2013; accepted 13 December 2013; published online 30 January 2014
 Rivaroxaban and hypertension in J-ROCKET AF
M Matsumoto et al
458

warfarin,7–9 has been approved and now offers a new treatment
option for patients with AF.
The J-ROCKET AF trial compared the safety and efficacy of
rivaroxaban with those of dose-adjusted warfarin among Japanese
patients with AF, in accordance with the Japanese AF guidelines from
The Japanese Circulation Society.10 The J-ROCKET AF trial was
conducted in patients with a moderate or high risk of stroke and who
presented with a CHADS2 score of X2. Hypertension, which affected
approximately 80% patients enrolled in this trial, is a risk factor
contributing to the CHADS2 score. In this subgroup analysis of
J-ROCKET AF, the safety and efficacy of rivaroxaban and of dose-
adjusted warfarin were investigated in the presence or absence of
baseline hypertension.
METHODS
Study design, participants and procedure
The design and results of J-ROCKET AF have been described previously.10 In
brief, J-ROCKET AF was a prospective, randomized, double-blind, double-
dummy, parallel-group, active-controlled, multicenter clinical trial comparing
the safety of rivaroxaban with that of dose-adjusted warfarin used in
accordance with Japanese guidelines in patients with non-valvular AF. The
study was approved by the Institutional Review Boards and all patients gave
informed consent. The trial was conducted in accordance with Japanese Good
Clinical Practice. Japanese patients aged X20 years with non-valvular AF
(documented electrocardiographically p30 days before enrollment) were
randomized at 167 participating facilities in Japan. Patients had a history of
prior ischemic stroke, transient ischemic attack (TIA), or non-CNS systemic
embolism, or had two or more of the following risk factors for
thromboembolism: congestive heart failure and/or left ventricular ejection
fraction of p35%, hypertension (defined as use of antihypertensive
medications within 6 months before the screening visit, persistent systolic
BP 4140 mm Hg or diastolic BP 490 mm Hg), age X75 years, or diabetes
mellitus (that is, a history of type 1 or type 2 diabetes mellitus or the use of
anti-diabetic medications p6 months before screening visit). Enrollment of
patients without prior stroke, TIA or non-CNS systemic embolism and with
only two risk factors for stroke was limited to 10% of the total number of
target patients. Patients with creatinine clearance o30 ml min 1 were
excluded, and patients with sustained, uncontrolled hypertension (systolic
BP X180 mm Hg or diastolic BP X100 mm Hg) were also excluded.
Patients were randomized to receive either 15 mg oral rivaroxaban once daily
(10 mg once daily in patients with creatinine clearance 30–49 ml min 1 at
randomization) or dose-adjusted warfarin, to achieve a target INR of 2.0–3.0
(in patients aged o70 years, or a reduced target INR of 1.6–2.6 in patients
aged X70 years, based on the Japanese guidelines). The pre-specified
maximum exposure period was 30 months. At the end-of-study visit (or at
an early discontinuation visit), patients were transitioned from study
medication to open-label commercial warfarin or other appropriate therapy
by the investigator, according to usual clinical practice. Follow-up assessments
of patients were completed at the follow-up visit (performed 30 days after the
end-of-study visit) or at an early discontinuation visit.
Outcomes
The principal safety outcome was the composite of major bleeding events and
non-major clinically relevant bleeding events.
The primary efficacy endpoint was the composite of stroke and non-CNS
systemic embolism. An independent clinical endpoint committee adjudicated
all the suspected cases of stroke, systemic embolism, myocardial infarction,
death and bleeding events that contributed to the pre-specified endpoints.
Statistical analysis
Although the study was not designed to test efficacy hypotheses, efficacy
endpoints were evaluated in an exploratory manner after treatment in the per-
protocol population (patients in the safety population without any major
protocol violations). The primary objective of the J-ROCKET AF trial was to
test whether rivaroxaban was non-inferior to warfarin, with respect to the
principal safety outcome in the safety population, as evaluated by non-
stratified Cox proportional hazards modeling. Safety outcomes were analyzed
in the safety population, which included all patients who had received
X1 dose of the investigational drug. In this subgroup analysis, the population
for analysis was divided into two groups (based on the presence or absence of
hypertension), and the safety outcomes and rate of the efficacy endpoints were
compared between the groups.
The time to event was assessed using the Kaplan–Meier method and by
determining the hazard ratio (HR) of rivaroxaban vs. warfarin, with its 95%
CIs assessed using the Cox proportional hazard model. For conducting analysis
using the Cox proportional hazards regression model, factors including a
history of hypertension, treatment groups and the interaction of treatment
groups were considered as covariates, to assess the interaction between the
differential effects of rivaroxaban and of warfarin on the events in patients with
and without hypertension.
RESULTS
Patient characteristics
The rate of patients with baseline hypertension was 79.5% (508/639
patients) in the rivaroxaban group, which was equal to that in the
warfarin group (79.5%; 508/639 patients), as shown in Table 1. The
mean baseline BPs in the rivaroxaban and warfarin groups were
130/77 mm Hg and 131/77 mm Hg, respectively, in patients with
baseline hypertension, and 123/74 mm Hg and 124/73 mm Hg, respec-
tively, in patients without baseline hypertension. The mean CHADS2
scores were 3.4 in the group with hypertension and 2.7 in the group
without hypertension. In addition, the rates of prior history of

Table 1 Baseline demographics of patients with and without hypertension in the J-ROCKET AF trial

Patients without hypertension Patients with hypertension

Rivaroxaban (n ¼ 131) Warfarin (n ¼ 131) Rivaroxaban (n ¼ 508) Warfarin (n ¼ 508)

Female (%) 19.1 16.0 16.5 23.2

Body weight, mean (kg) 60.8 61.4 65.2 64.8
Age, mean (years) 70 70 71 72
Blood pressure, mean ( mm Hg) 123/74 124/73 130/77 131/77
Creatinine clearance o50 ml min 1 (%) 19.1 19.1 22.8 23.2
CHADS2 score, mean 2.7 2.7 3.4 3.4
Congestive heart failure (%) 26.0 29.8 45.3 42.9
Diabetes mellitus (%) 28.2 26.7 41.7 39.8
Baseline stroke/transient ischemic attack/systemic embolism (%) 92.4 89.3 56.5 56.7

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 Rivaroxaban and hypertension in J-ROCKET AF
M Matsumoto et al
459

congestive heart failure and diabetes (which are also risk factors The rate of administration of antihypertensive medication at baseline
contributing to the CHADS2 score) were higher in the group did not differ between the rivaroxaban and the warfarin groups
with hypertension. The rate of prior history of stroke/TIA, (Table 2).
conversely, tended to be higher in patients without hypertension.

Table 2 Anti-hypertensive medications received by patients at Safety outcomes

baseline in the J-ROCKET AF trial The event rates of the principal safety outcomes in the rivaroxaban
and warfarin groups were 18.39% per year and 16.81% per year,
Total Rivaroxaban Warfarin respectively, in patients with baseline hypertension (HR: 1.10; 95% CI:
(n ¼ 1278) (n ¼ 639) (n ¼ 639) 0.84–1.45) and 16.71% per year and 15.00% per year, respectively, in
patients without baseline hypertension (HR: 1.14; 95% CI: 0.66–1.97),
ACE-inhibitors, n (%) 178 (13.93) 84 (13.15) 94 (14.71)
which indicates no significant interaction (P ¼ 0.933). In the rivar-
ARBs, n (%) 604 (47.26) 297 (46.48) 307 (48.04)
oxaban group, patients without hypertension showed a marginally
Calcium antagonists, n (%) 599 (46.87) 301 (47.10) 298 (46.64)
favorable trend of the incidence rates of major bleeding events
Beta-blockers, n (%) 457 (35.76) 231 (36.15) 226 (35.37)
Diuretics, n (%) 506 (39.59) 249 (38.97) 257 (40.22)
compared with patients with hypertension; however, there were no
significant differences in incidence rates between the warfarin and
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker.
rivaroxaban groups (HR 0.25; 95% CI: 0.03–2.23 and HR: 0.93;

Incidence rate (%/year)

Rivaroxaban Warfarin
HR (95% CI)
(n=131) (n=131) Without hypertension Rivaroxaban P-value
(n=508) (interaction)
(n=508) With hypertension vs warfarin
16.71 15.00 1.14 (0.66–1.97)
Primary safety endpoints 0.933
18.39 16.81 1.10 (0.84–1.45)
0.54 2.24 0.25 (0.03–2.23)
Major bleeding events 0.249
3.66 3.96 0.93 (0.54–1.62)
Bleeding associated with a 0.54 2.24 0.25 (0.03–2.23)
hemoglobin decrease of 0.280
2 g/dl or more 1.75 1.97 0.89 (0.41–1.95)
Bleeding requiring 0.00 1.12 N/A
transfusion of 2 units or 0.993
0.58 0.60 0.97 (0.24–3.87)
more
0.00 0.56 N/A
Bleeding in important 0.990
organs 1.89 1.81 1.05 (0.48–2.31)
0.00 0.00 N/A
Bleeding causing death 0.999
0.14 0.45 0.32 (0.03–3.13)

Non-major clinically 16.09 12.48 1.32 (0.74–2.36)

0.734
relevant bleeding events 15.24 13.13 1.17 (0.87–1.58)

0.01 0.1 1 10 100

Rivaroxaban is Warfarin is
better better

50

45 With hypertension Rivaroxaban

With hypertension Warfarin

Cumulative incidence rate (%)

40

35

30

25

20

15 Without hypertension Rivaroxaban

10 Without hypertension Warfarin

0
0 100 200 300 400 500 600 700 800 900

Day following randomization

At risk (n):
131 110 105 103 76 59 36 27 6 0
508 438 396 370 291 201 139 98 33 0
131 116 106 98 75 52 40 29 4 0
508 435 398 363 275 189 130 88 31 0

Figure 1 Principal safety outcomes in the safety population in the on-treatment analysis according to hypertensive status. (a) Principal safety outcomes in
patients with and without hypertension. (b) Kaplan–Meier curve of time to first major bleeding event or first non-major clinically relevant bleeding event.
CI, confidence interval; HR, hazard ratio; N/A, not applicable.

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 Rivaroxaban and hypertension in J-ROCKET AF
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460

Table 3 Baseline demographics of patients with intracranial hemorrhage and with or without hypertension in the J-ROCKET AF trial

All Hypertension ( þ ) Hypertension ( )

Rivaroxaban Warfarin Rivaroxaban Warfarin

n ¼ 15 n¼5 n¼9 n¼0 n¼1

Female, n (%) 2 (13.3) 0 (0) 2 (22.2) N/A 0 (0)

Body weight, mean (kg) 67.1±19.8 67.5±22.3 68.6±20.2 N/A 51.9
Age, mean (years) 72.8±8.0 74.8±7.9 72.3±8.6 N/A 67
Systolic blood pressure, mean (mm Hg) 135.4±19.4 138.4±29.4 133.4±14.7 N/A 138
Diastolic blood pressure, mean (mm Hg) 82.7±12.9 82.6±3.8 81.9±3.8 N/A 91
Creatinine clearance o50 ml min 1, n (%) 6 (40.0) 2 (40.0) 3 (33.3) N/A 1 (100)
CHADS2 score, mean 3.7±0.9 3.8±0.4 3.8±1.0 N/A 2
Congestive heart failure, n (%) 3 (20.0) 1 (20.0) 2 (22.2) N/A 0 (0)
Diabetes mellitus, n (%) 6 (40.0) 1 (20.0) 3 (33.3) N/A 0 (0)
Prior stroke/TIA/non-CNS embolism, n (%) 11 (73.3) 3 (60.0) 7 (77.8) N/A 1 (100)

Previous and concurrent medication, n (%)

Prior VKA, n (%) 15 (100) 5 (100.0) 9 (100) N/A 1 (100)
Prior ASA, n (%) 4 (26.7) 2 (40.0) 2 (22.2) N/A 0 (0)
Concurrent single antiplatelet use 0 (0) 0 (0) 0 (0) N/A 0 (0)
Concurrent dual antiplatelet use 0 (0) 0 (0) 0 (0) N/A 0 (0)
ACE-inhibitors, n (%) 4 (26.7) 3 (60.0) 1 (11.1) N/A 0 (0)
ARBs, n (%) 7 (46.7) 1 (20.0) 6 (66.6) N/A 0 (0)
Calcium antagonists, n (%) 8 (53.3) 3 (60.0) 5 (55.5) N/A 0 (0)
Beta-blockers, n (%) 3 (20.0) 0 (0) 3 (33.3) N/A 0 (0)
Diuretics, n (%) 3 (20.0) 0 (0) 3 (33.3) N/A 0 (0)

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; CNS, central nervous system; N/A, not applicable; TIA, transient ischemic attack;
VKA, vitamin K antagonist.

95% CI: 0.54–1.62, respectively; P-value for interaction: 0.249)
(Figures 1a and b).
With regards to intracranial hemorrhage (ICH), which is one of the
most serious of all bleeding events, 14/15 patients in the overall
population presented with baseline hypertension (5/5 in the rivarox-
aban group, 9/10 in the warfarin group). The mean baseline BP of
patients with ICH was 139/82 mm Hg in the rivaroxaban group and
134/83 mm Hg in the warfarin group. The mean CHADS2 scores of
patients with ICH was 3.8 in both the rivaroxaban and the warfarin
groups. The rate of ICH was higher in patients with a history of prior
stroke/TIA than in those with baseline hypertension (with or without
ICH), as shown in Table 3.
Efficacy outcomes
The incidence rates of the primary efficacy endpoints in the
rivaroxaban and warfarin groups were 0.54% per year and 2.24%
per year, respectively, in patients without baseline hypertension (HR:
0.25; 95% CI: 0.03–2.25), and 1.45% per year and 2.71% per year,
respectively, in patients with baseline hypertension (HR: 0.54; 95% CI:
0.25–1.16); this indicates no significant interaction (P ¼ 0.509).
The incidence of the primary efficacy endpoint (stroke or non-CNS
systemic embolism) was consistent with rivaroxaban, independent of
the patient’s baseline hypertensive status.
DISCUSSION
Our results confirmed that the efficacy and safety of rivaroxaban, as
evaluated in the J-ROCKET AF study, is consistent in the subgroup of
patients with AF and baseline hypertension and in the overall study
population. In addition, in both the rivaroxaban and warfarin groups,
the rates of the principal safety outcome (major or non-major
bleeding) and the primary efficacy endpoint (stroke/non-CNS sys-
temic embolism) were higher in patients with hypertension than in
those without hypertension.
Stroke and blood pressure management
As discussed above, rivaroxaban reduces the rate of the primary
efficacy endpoint (stroke or non-CNS systemic embolism), indepen-
dent of baseline hypertensive status. However, in the rivaroxaban
group, patients with hypertension had three times higher incidence of
primary endpoints than those without. In addition, in the rivarox-
aban group, patients without hypertension showed a marginally
favorable trend of the frequency of major bleeding events compared
with those with hypertension. Moreover, all patients with ICH had
baseline hypertension, except for one patient in the warfarin group.
The patients with ICH had higher baseline BP and higher CHADS2
scores, and were therefore at higher risk of stroke (Table 3).
Hypertensive status is also an important component of the
HAS-BLED score,11 a bleeding risk score that has recently been
recommended by international guidelines (from the European Society
of Cardiology12 and the Canadian Cardiovascular Society13) to assess
bleeding risk. These factors suggest that stringent BP management is
required for administering anticoagulant therapy.
Development of AF and the control of blood pressure
Hypertension is the risk factor most closely associated with the onset
of AF.4 In particular, left ventricular hypertrophy and left atrial
enlargement are independent risk factors for new-onset AF, and the
reduction of left ventricular hypertrophy by anti-hypertensive therapy
has been shown to decrease the incidence of new-onset AF.14 These
pathologies are associated with the renin-angiotensin system (RAS)

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centering on angiotensin II as an accelerating factor. Several clinical
studies have reported previously that inhibition of the RAS
suppressed at least the new onset of AF.15,16 On the basis of these
results, inhibition of the RAS was expected to be developed into a
novel AF therapy; however, multiple clinical studies17–20 and their
meta-analyses produced varied results. First, inhibitors of the RAS did
not suppress new-onset AF in patients with hypertension but without
left ventricular hypertrophy or cardiac failure. Second, efficacy was
not demonstrated in patients who had already been diagnosed with
AF in a study investigating the preventative effect of angiotensin
receptor blockers on the recurrence of AF; this indicated that the
efficacy of RAS inhibition against AF was not as high as initially
expected. Although there is at present no anti-hypertensive drug that
specifically inhibits new-onset AF, the current consensus is that the BP
itself should be reduced (regardless of the concomitant use of anti-
hypertensive drugs) in all patients with hypertension, including those
with existing AF.
Limitations
First, as noted above (‘Method’), hypertension was defined as use of
antihypertensive medications p6 months before the screening visit,
persistent systolic BP 4140 mm Hg or diastolic BP 490 mm Hg. This
means that, in this study, some patients with hypertension were
already taking anti-hypertensive medications at baseline (Table 2). In
addition, patients with sustained uncontrolled hypertension (systolic
BP X180 mm Hg or diastolic BP X100 mm Hg) were excluded,
which could have influenced the results, because this fact suggests
that the patients with hypertension who were included in this trial are
fairy well controlled.
The second factor that could have influenced the results of this
trial is the timing of BP assessment. In the BAT (Bleeding with
Antithrombotic Therapy) trial,21 which was also conducted in Japan,
BP—when measured during the administration of anticoagulant
therapy—was independently associated with development of ICH,
after adjustment for established ICH predictors. Several large-scale
clinical studies have reported that baseline BP could not be considered
a predictor of major bleeding events.6,22,23 Nevertheless, only baseline
BP could be assessed in this trial. At present, in Japan, a post-
marketing surveillance of rivaroxaban is being conducted, with the
planned number of enrolled patients set at 10 000. We expect this
surveillance to produce further data showing the significance of the
use of anti-hypertensive therapy in conjunction with the use of
rivaroxaban in clinical practice, by assessing the BP not only at the
time of patient enrollment but also during the course of treatment
and, in addition, before the onset of major bleeding events.
In conclusion, the safety and efficacy of rivaroxaban vs. dose-
adjusted warfarin were consistent, regardless of the baseline BP.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
The rivaroxaban clinical development program is co-sponsored by Janssen
Pharmaceuticals (Raritan, NJ, USA) and Bayer HealthCare Pharmaceuticals
AG (Leverkusen, Germany). The trial was funded by Bayer HealthCare
Pharmaceuticals AG’s Japanese subsidiary, Bayer Yakuhin. Dr Hori has received
consultancy fees from Bayer, Boehringer Ingelheim, Bristol Myers-Squibb and
Pfizer. Dr Matsumoto and Dr Momomura have received consultancy fees from
Bayer. Dr Tanahashi has received consultancy fees from Bayer and Mitsubishi
Tanabe, and honoraria from Mitsubishi Tanabe and Sanofi-Aventis.
Dr Uchiyama has received consultancy fees from Bayer and Boehringer
Rivaroxaban and hypertension in J-ROCKET AF
M Matsumoto et al
461
Ingelheim and research grants from Bayer, Boehringer Ingelheim and Daiichi-
Sankyo. Dr Goto has received research grants from Astellas, AstraZeneca,
Daiichi, Eisai, Kowa, Ono, Otsuka, Pfizer, Sanofi-Aventis, and Takeda, and
honoraria from Daiichi-Sankyo, Eisai, Otsuka, Sanofi-Aventis and Schering-
Plough. Dr. Izumi has received consultancy fees from Bayer and Pfizer.
Dr Koretsune has received honoraria from Bayer, Boehringer Ingelheim,
Daiichi-Sankyo and Bristol Myers-Squibb. Drs Iekushi, Yamanaka, Kajikawa
and Ueda, and Mr Tajiri and Mr Kato report employment by Bayer Yakuhin.
No other conflicts of interest are reported.
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