1) The study aims to determine if the urate-lowering agent febuxostat can improve clinical outcomes in chronic heart failure patients with hyperuricemia compared to conventional treatment. 2) It is a randomized, open-label trial that will enroll 200 Japanese chronic heart failure patients with hyperuricemia and assign them to either febuxostat treatment or conventional treatment. 3) The primary outcome is the difference in plasma BNP levels between baseline and 24 weeks of treatment, as measured in a blinded manner. This will investigate the efficacy and safety of febuxostat.

1. CLINICAL STUDY
Randomized Trial of Effect of Urate-Lowering Agent Febuxostat in
Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF)
Study Design
Takashi Yokota,1
MD, Arata Fukushima,1
MD, Shintaro Kinugawa,1
MD, Takahiro Okumura,2
MD,
Toyoaki Murohara,2
MD and Hiroyuki Tsutsui,3
MD
Summary
Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of
the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may im-
prove the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional
treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period
of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria
include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of
hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic func-
tion (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriu-
retic peptide (BNP) "100 pg/mL or N-terminal pro BNP (NT-proBNP) "400 pg/mL], and hyperuricemia (se-
rum uric acid >7.0 mg/dL and !10 mg/dL) at the screening visit. The primary outcome is the difference in the
plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in
the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in
chronic heart failure patients with hyperuricemia.
(Int Heart J 2018; 59: 976-982)
Key words: BNP, Oxidative stress, Xanthine oxidase inhibitor
H
yperuricemia is a common finding in patients
with chronic heart failure (CHF) and is a known
independent predictor of mortality and rehospi-
talization due to worsening heart failure (HF).1-4)
The Japa-
nese Cardiac Registry of Heart Failure in Cardiology
(JCARE-CARD) reported that 56% of CHF patients had
hyperuricemia with a higher incidence of all-cause and
cardiac death, and rehospitalization due to worsening HF.3)
In addition, hyperuricemia is closely linked to the occur-
rence of atrial fibrillation, which can be a trigger of wors-
ening HF.5)
The mechanism by which hyperuricemia is as-
sociated with worse clinical outcomes in CHF patients
may be explained by the detrimental effects of uric acid
(UA) on the vascular endothelium through the activation
of inflammatory cytokines.6)
In patients with CHF, xan-
thine oxidase (XO) is highly activated, and increased reac-
tive oxygen species (ROS) emission from XO in the vas-
cular endothelium can cause endothelial dysfunction in the
peripheral vessels, leading to increased cardiac afterload.7)
UA is produced via XO and, thus, it can be a useful
marker for systemic oxidative stress in patients with CHF.
Emerging evidence has drawn more attention to the ef-
fects of XO inhibitors on clinical outcomes.
Previous studies have shown that allopurinol, a
widely used XO inhibitor for patients with hyperuricemia,
may be effective in the treatment of cardiovascular dis-
ease.8)
High-dose allopurinol has been reported to reduce
HF-related death in CHF patients.9,10)
In addition, previous
studies have shown that in patients with CHF, allopurinol
decreases B-type natriuretic peptide (BNP) levels,11)
which
is known as a strong predictive biomarker of HF-related
death.12)
However, a randomized trial to investigate the ef-
fect of oxypurinol, a metabolite of allopurinol, in patients
with CHF did not improve clinical outcomes,13)
and a re-
cent clinical trial using allopurinol also failed to improve
clinical status, exercise capacity, quality of life, or cardiac
function in hyperuricemic HF patients.14)
Febuxostat, a novel urate-lowering agent for treat-
ment against gout and hyperuricemia, inhibits XO via a
different pathway from allopurinol. Febuxostat has dem-
onstrated superiority to allopurinol in XO inhibition in vi-
tro studies15,16)
and lowering serum UA in clinical stud-
ies.17)
Since febuxostat is finally eliminated via not only
renal but also via hepatic pathways, it can be safely and
From the 1
Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan,
2
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan and 3
Department Cardiovascular Medicine, Faculty of Medical
Sciences, Kyusyu University, Fukuoka, Japan.
Address for correspondence: Shintaro Kinugawa, MD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine,
Hokkaido University, Kita-15 Nishi-7, Kita-Ku, Sapporo 060-8638. E-mail: tuckahoe@med.hokudai.ac.jp
Received for publication September 30, 2017. Revised and accepted December 15, 2017.
Released in advance online on J-STAGE August 11, 2018.
doi: 10.1536/ihj.17-560
All rights reserved by the International Heart Journal Association.
976

2. Int Heart J
September 2018 977EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Table. Inclusion and Exclusion Criteria in the LEAF-CHF Study
Criteria
Inclusion criteria 1 Male and female ambulatory patients aged ≥20 years at the time of enrollment with heart failure, or inpatients with sta-
ble heart failure when informed consent is obtained.
2 Patients with hyperuricemia, as indicated by a serum uric acid level between > 7.0 mg/dL and ≤ 10.0 mg/dL at the time
of enrollment.
3 Chronic heart failure patients with stable NYHA functional class II to III with no change in the dose of the baseline
therapies, including ACE-Is, ARBs, and β-blockers, within 4 weeks prior to enrollment.
4 Patients with plasma BNP concentration ≥ 100 pg/mL or NT-proBNP concentration ≥ 400 pg/mL at the time of enroll-
ment.
5 LVEF < 40%, as measured by echocardiography within 8 weeks before enrollment.
6 Eligible patients with a history of admission due to worsening heart failure before enrollment.
7 Patients who provide written informed consent prior to participation.
Exclusion criteria 1 Patients who receive treatment with anti-hyperuricemic agents, including allopurinol, benzbromarone, probenecid, bu-
colome, topiroxostat, and febuxostat within 2 weeks prior to enrollment.
2 Patients receiving mercaptopurine hydrate, azathioprine, vidarabine, and didanosine at the time of enrollment.
3 Patients with a history of acute coronary syndrome or coronary revascularization within the last 3 months.
4 Patients with valvular disease or congenital heart disease as the cause of heart failure.
5 Patients with active gouty tophus or those who have symptoms of acute gouty arthritis within 1 year prior to enroll-
ment.
6 Patients who have serious liver disease, renal impairment (eGFR < 30 mL/minute or on dialysis), or malignancy.
7 Patients with a history of hypersensitivity to febuxostat.
8 Patients who are not appropriate for participation in this study as determined by the investigators.
ACE-I indicates angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; eGFR, estimated
glomerular filtration rate; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association.
efficiently used even in patients with mild to moderate re-
nal dysfunction. A randomized trial reported that fe-
buxostat demonstrated superiority to allopurinol in reduc-
ing oxidative stress and in improving cardiac and renal
function in patients with hyperuricemia who underwent
cardiac surgery.18)
Accordingly, febuxostat is expected to
have a stronger inhibitory effect than allopurinol on XO.
The aim of the randomized LEAF-CHF (Effect of
urate-LowEring Agent Febuxostat in Chronic Heart Fail-
ure patients with hyperuricemia) study is to determine
whether febuxostat may improve morbidity and mortality
in patients with HF with reduced ejection fraction
(HFrEF) and hyperuricemia. BNP levels are evaluated as a
primary endpoint of this study, with a follow-up period of
24 weeks to assess the efficacy of febuxostat in CHF pa-
tients. All the subjects receive the general lifestyle guid-
ance for hyperuricemia recommended by the Japanese So-
ciety of Gout and Nucleic Acid Metabolism19)
throughout
the study period.
Methods
Study design: LEAF-CHF is a multicenter, prospective,
randomized, open-label, blinded endpoint (PROBE) study
that investigates whether the urate-lowering agent, fe-
buxostat, reduces plasma BNP levels in CHF patients with
hyperuricemia. This study is approved by the institutional
ethics committee at each participating site and is con-
ducted in accordance with the ethical principles described
in the Declaration of Helsinki (2013 revised version).
Written informed consent is provided by all the enrolled
patients prior to any study-related procedures. The study
has been registered at the University Hospital Medical In-
formation Network (UMIN ID: 000013330).
Patient population: The inclusion and exclusion criteria
are listed in the Table. We enroll a total of 200 ambula-
tory or admitted HF patients with hyperuricemia, who do
not meet any exclusion criteria. Briefly, eligible patients
have New York Heart Association (NYHA) functional
class II or III and left ventricular ejection fraction (LVEF)
< 40% with elevated plasma BNP and hyperuricemia (se-
rum UA levels > 7.0 mg/dL and !10.0 mg/dL). The
LVEF is calculated from the apical four- and two-chamber
views based on the modified Simpson’s method by echo-
cardiography.
Randomization: After providing written informed con-
sent, eligible patients are randomly assigned to the fe-
buxostat group or the control group in a 1:1 ratio through
a Web-based randomization system. Patient allocation is
performed by the minimization method according to the
following baseline variables: age, serum UA, plasma BNP
or NT-proBNP, and LVEF. Since eligible participants have
asymptomatic hyperuricemia as shown by the serum UA
levels > 7.0 mg/dL and !10.0 mg/dL, all the subjects are
provided lifestyle guidance aimed at decreasing the UA
levels.
In the febuxostat group, the investigators prescribe
the febuxostat preparation (FeburicⓇ
Tablets, Teijin
Pharma, Tokyo, Japan) per the dosage schedule listed in
the protocol (Figure 1), and the control group is also fol-
lowed. The data on the dosing condition in the febuxostat
group and concomitant therapies in both groups are fol-
lowed from the time of enrollment until the completion of
the study or withdrawal from the study.
Study protocol: Figure 1 and Figure 2 summarize the
study schema and the visit schedule. The duration of the
study is 24 weeks, which includes a 12-week titration
phase of stepwise dose increases and a 12-week dose-
maintenance phase, defined by the previous finding of the
BNP-lowering effect of allopurinol at 12 weeks.11)
Prelimi-

3. Int Heart J
September 2018978 Yokota, ET AL
Figure 1. Intervention schedule. After randomization to the febuxostat or the control group, patients are followed up for 24 weeks. In the fe-
buxostat group, patients receive 10 mg/day febuxostat at the baseline (Day 0), and the dose is increased every 4 weeks until it reaches the target
dose (60 mg/day), unless serum uric acid is < 2.0 mg/dL. The target dose of febuxostat is typically administered for 12 weeks during the last
study period. In both the febuxostat and control groups, the patient receives lifestyle modification to decrease serum UA throughout the study
period.
nary screening for trial eligibility is based on clinical in-
formation from a review of medical records by investiga-
tors at or before the baseline visit. The initial dose of fe-
buxostat is 10 mg/day.
The dose is up-titrated to 20 mg/day at the 4-week
visit, then, increased to 40 mg/day at the 8-week visit to
reach the target dose of 60 mg/day at 12 weeks, unless
the serum UA< 2.0 mg/dL. The target dose of 60 mg/day
is maintained until the end of the study (24 weeks) after
randomization. If the serum UA is < 2.0 mg/dL, the dos-
age is reduced by 20 mg from the previous dose. The tar-
get dose of 60 mg was determined to exert the maximum
inhibitory effect of febuxostat on UA levels and ROS
emission via the potent suppression of XO.
Patient demographic data such as age, gender, height
and body weight, etiology of HF, and medical history are
recorded at the baseline in all the patients. Signs and
symptoms of HF, NYHA functional class, systolic and
diastolic blood pressure, and heart rate are monitored at
the baseline and every 4 weeks. Chest X-ray and echocar-
diography are performed at the baseline and at 24 weeks.
To ensure objectivity, the plasma BNP levels are measured
at a central laboratory under blind conditions at the base-
line and every 4 weeks thereafter. Plasma oxidized low-
density lipoprotein cholesterol (ox-LDL), serum high-
sensitivity C-reactive protein (hs-CRP), and urinary 8-
isoprostanes and 8-hydroxydeoxyguanosine (8-OHdG) are
all measured in a central laboratory at the baseline and at
24 weeks. In addition, the following blood examinations
are measured at the baseline and every 4 weeks: hemoglo-
bin (Hb), serum UA, and serum creatinine. The estimated
glomerular filtration rate (eGFR) is calculated from serum
creatinine value and age using the Japanese equation20)
as
follows: eGFR=194 × (serum creatinine in mg/dL) - 1.094
× (age in years) - 0.287 × (0.739 if female).
Study endpoints: The primary endpoint is the change in
plasma BNP concentration from the baseline to 24 weeks.
Plasma BNP is an established surrogate marker that
strongly predicts death and cardiovascular events in HF
patients,21)
and previous studies have shown the reducing
effect of allopurinol on plasma BNP concentration.11,22)
For
between-group comparison of the change in log-
transformed BNP levels, the analysis of covariance will be
performed using the baseline BNP levels as the covariate.
The secondary endpoints include: (1) LVEF and E/e’, the
ratio of peak early transmitral ventricular filling velocity
to early diastolic tissue Doppler velocity, measured at the
baseline and at 24 weeks; (2) NYHA functional class,
eGFR, serum UA, Hb, and the plasma BNP concentration
during the study period; and (3) all-cause mortality or ma-
jor cardiovascular events.
The independent Endpoint Evaluation Committee will
centrally review the events reported by the investigators
per the event adjudication criteria in a blinded manner.
The exploratory endpoint is to determine the effect of fe-
buxostat on the following: (1) markers of inflammatory
activation (hs-CRP), (2) oxidative stress (ox-LDL, 8 iso-
prostanes, and 8-OHdG), and (3) renal function (ratio of
urine albumin and creatinine).
Sample size calculation: The sample size of the present
study is assumed on the basis of a previous study by Ga-
vin, et al.11)
In that randomized, double-blinded, placebo-
controlled trial, 50 patients with CHF were randomly as-
signed to 3 months of treatment with allopurinol (300 mg/

4. Int Heart J
September 2018 979EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Figure 2. Visit schedule for enrollment, assessments, and central measurements. BNP indicates B-type natriuretic peptide; eGFR, estimated
glomerular filtration rate; NYHA, New York Heart Association: and UA, uric acid.
day) or placebo. The BNP levels in the allopurinol group
were 14.5 pmol/L (51 pg/mL) before treatment and 11.9
pmol/L (42 pg/mL) after treatment, whereas those in the
placebo group were unaltered. Based on those results, it is
presumed that the difference in the change in log-
transformed BNP levels is 0.2 and that the standard devia-
tion is twice as large as the change in log-transformed
BNP levels.
To detect the between-group difference by analyzing
covariance under conditions of two-sided α = 0.05, β =
0.9, and allocation ratio = 1.0, the sample sizes of the
needed patient populations were calculated to be 86 for
HF and 86 for controls. Estimating a 15% loss due to
withdrawals and dropouts, we set the target population
size as 100 patients in each group (total 200 patients).
Statistical analysis: Efficacy endpoints will be analyzed
primarily by using the full analysis set (FAS), which in-
cludes all the enrolled and randomized subjects, and
eliminating subjects who do not respond to treatment after
enrollment. The per-protocol set (PPS) of patients meeting
all the inclusion and exclusion criteria will be also ana-
lyzed for reference. Safety endpoints will be evaluated us-
ing the safety analysis population, which comprises all the
enrolled and randomized patients.
As a primary analysis, the summary statistics of the
BNP levels at the baseline and at 24 weeks, as well as the
ratio of the BNP levels at the baseline to the levels at 24
weeks, will be calculated for each treatment group. For
the between-group comparison of the change in the log-
transformed BNP levels from the baseline to 24 weeks,
analysis of covariance will be performed using dummy
variables that represent the treatment groups, as well as
the log-transformed BNP levels at the baseline as the co-
variates. If the study is terminated before 24 weeks, the
BNP levels at the termination of the study will be used
instead of those at 24 weeks in the primary analysis. In
addition, the paired t-test will be conducted to compare
the change in the log-transformed BNP levels from the
baseline to 24 weeks in each treatment group.
As a secondary analysis, the paired t-test will be per-
formed to compare the LVEF, E/E’, serum UA, eGFR, he-
moglobin, and each exploratory endpoint from the base-
line to 24 weeks or study termination. The analysis of co-
variance will be performed for the comparison of the
between-group change in those variables from the baseline
to 24 weeks. The changes of the NYHA class from the
baseline to 24 weeks will be analyzed within groups by
the Wilcoxon signed-rank test and are compared among
groups by the Wilcoxon rank-sum test. Furthermore, the
Kaplan-Meier method will be used to estimate the event
rate throughout 24 weeks for each treatment group, and
the log-rank test will be used to compare those event
rates.
The differences are considered statistically significant
when P< 0.05. The same analysis will be performed using
PPS to confirm the robustness of the results. An interim
analysis is not scheduled during the study.
Role of the sponsor and the authors: The LEAF-CHF
study is being supported by the sponsor (Teijin Pharma
Ltd., Tokyo, Japan), which will not participate in the data
collection, the event evaluation, and the data analysis. The
study was designed by the authors in collaboration with
the sponsor and the contract research organization (CRO;
Hubitgenomix Co., Tokyo, Japan). The study is conducted
by the LEAF-CHF investigators with the assistance with
the CRO. The first draft of the manuscript was written by
Go Ichien (Hubitgenomix Co.), and was fully reviewed
and revised by all the authors. The authors had final re-

5. Int Heart J
September 2018980 Yokota, ET AL
sponsibility for the decision to submit for publication.
Discussion
The LEAF-CHF study is designed to test the hy-
pothesis that the inhibition of XO by febuxostat, when
added to optimal HF therapy, may be beneficial clinically
in patients with HFrEF. It will not compare the efficacy of
febuxostat with that of allopurinol, although febuxostat is
expected to exert a stronger effect of XO inhibition than
allopurinol, based on the previous studies.15-18)
It compares
the changes in the plasma BNP levels as well as clinical
outcomes between the febuxostat group and the control
group in patients with HFrEF.
The total study period for the LEAF-CHF is 24
weeks; the patients assigned to the active treatment group
will receive febuxostat 60 mg/day as a target dose for 12
weeks after titration, with stepwise dose increases for 12
weeks. A previous study revealed a significant decrease in
the BNP levels after allopurinol treatment for 12 weeks in
patients with CHF.11)
In addition, the administration of 60
mg/day of febuxostat for 6 months, including the dose-
escalation period, has been reported to lower serum UA
significantly more than allopurinol 300 mg/day and to
have a superior inhibitory effect on oxidative stress in pa-
tients with hyperuricemia who underwent cardiac sur-
gery.18)
Taken together, the study period and the target
dose in the present trial appears to be sufficient to evalu-
ate the efficacy of febuxostat in CHF patients.
For this study, the range of serum UA in the inclu-
sion criteria is > 7.0 mg/dL to !10 mg/dL. Although no
universally accepted definition of hyperuricemia exists, we
employed the definition of hyperuricemia as serum UA >
7.0 mg/dL based on the Guideline for the Management of
Hyperuricemia and Gout 2010 of the Japanese Society of
Gout and Nucleic Acid Metabolism.19)
While the guideline
recommends the initiation of pharmacotherapy at a serum
concentration of UA "9.0 mg/dL in patients with asymp-
tomatic hyperuricemia,19)
and in particular, the risk of gout
increases at a serum concentration of UA "10.0 mg/dL.
Thus, patients allocated to the control group will be with-
drawn from the study and subsequently receive appropri-
ate therapy if their serum UA levels increase and exceed
10.0 mg/dL during the study period.
We determined the primary endpoint of this study as
the difference in plasma BNP levels between the baseline
and 24 weeks of treatment, since the absolute value of
plasma BNP is influenced by the left ventricular hypertro-
phy and renal dysfunction. BNP is widely used as a clini-
cally relevant diagnostic and predictive marker for HF and
is a powerful predictor of short- and long-term prognosis
and rehospitalization due to worsening HF in CHF pa-
tients.12,23)
A meta-analysis of studies in patients with CHF
has shown that each 100 pg/mL rise in BNP levels is as-
sociated with a 35% increase in the relative risk of
death.21)
To ensure objectivity, the BNP levels will be
measured in a central laboratory in a blinded manner.
Secondary endpoints include all-cause death, cardio-
vascular events, including cardiovascular death, rehospi-
talization due to worsening HF, NYHA class, LVEF, E/e’,
absolute values of plasma BNP, eGFR, hemoglobin (Hb),
and serum UA. As a parameter of left ventricular (LV)
function, E/e’ will be measured to assess LV diastolic
function and LVEF will be used to assess LV systolic
function. Previous studies have shown that elevated serum
UA inversely correlates with the LV diastolic function.24)
In the LEAF-CHF study, we will evaluate eGFR and Hb
because the JCARE-CARD has reported that chronic kid-
ney disease and anemia are powerful and independent
prognostic factors in CHF patients.25,26)
Plasma ox-LDL, and urinary 8-isoprostanes and 8-
OHdG will be measured at the baseline and at 24 weeks
of treatment to assess the inhibitory effect of febuxostat
on systemic oxidative stress in CHF patients. Growing
evidence suggests that oxidative stress is a key to the
pathogenesis and development of HF.27)
In addition, serum
UA levels are not necessarily associated with the cardiac
function and the severity of HF.28)
Our hypothesis is that
febuxostat treatment may improve clinical outcomes via
reduced ROS emission originating from XO rather than
lowered serum UA. In accordance with this hypothesis,
the dosage of febuxostat is increased stepwise up to 60
mg/day even after serum UA level reaches 7.0 mg/dL or
less (except for < 2.0 mg/dL). In previous studies, fe-
buxostat was administered targeting serum UA !6.0 mg/
dL.17,18)
Until now, there is no report of the harmful effect
of febuxostat in a concentration-dependent manner.
LEAF-CHF Study has already begun enrollment in
August 2014. The enrollment of patients will be com-
pleted in December 2017 and the follow-up of the en-
rolled patients will be finished in June 2018. This study
may provide evidence for a novel therapeutic approach to
CHF patients targeting the reduction of not only the se-
rum UA levels but also XO-induced ROS emission.
Acknowledgments
The authors thank all the enrolled patients, participat-
ing cardiologists and other medical professionals who
contributed substantially to this cooperative study.
Disclosures
Conflicts of interest: T.Y., A.F., and S.K. have no conflict
of interest that should be declared. T.O has received re-
search grants from Ono Pharmaceutical, Bayer Yakuhin,
and Daiichi-Sankyo; scholarship funds from Mitsubishi
Tanabe Pharma. T.M. has received speakers’ bureau/hono-
rarium from Teijin Pharma and Pfizer Japan; scholarship
funds from Teijin Pharma and Pfizer Japan. H.T. has re-
ceived speakers’ bureau/honorarium from Astellas Pharma,
Otsuka Pharmaceutical, Takeda Pharmaceutical, Daiichi-
Sankyo, Mitsubishi Tanabe Pharma, Teijin Pharma, Nip-
pon Boehringer Ingelheim, Novartis Pharma K.K, Bayer
Yakuhin, and Bristol- Myers Squibb; honorarium for writ-
ing promotional material for Medical Review; research
grants from Actelion Pharmaceuticals Japan; scholarship
funds from Astellas Pharma and Daiichi-Sankyo.

6. Int Heart J
September 2018 981EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Appendix
Study organization: The study is managed by the princi-
pal investigator (Hiroyuki Tsutsui) and the Steering Com-
mittee as an investigator-initiated clinical study. The Inde-
pendent Data Monitoring Committee and the Event Evalu-
ation Committee are organized independently from the
study group. A study statistician (Koji Oba, Tokyo Univer-
sity) contributes to ensure statistical accuracy.
Steering committee: Hiroyuki Tsutsui (chair, Kyusyu
University), Toyoaki Murohara (vice chair, Nagoya Uni-
versity Graduate School of Medicine), Mitsuaki Isobe
(Sakakibara Heart Institute), Hiroshi Ito (Okayama Uni-
versity), Takayuki Inomata (Kitasato University Kitasato
Institute Hospital), Koichiro Kinugawa (Internal Medicine,
University of Toyama), Issei Komuro (The University of
Tokyo Hospital), Yoshihiko Saito (Nara Medical Univer-
sity), Yasushi Sakata (Osaka University Graduate School
of Medicine), Yasuhiko Sakata (Tohoku University Gradu-
ate School of Medicine), Hiroaki Shimokawa (Tohoku
University Graduate School of Medicine), Ichiro Hisatome
(Graduate School of Medical Science, Tottori University),
Satoru Masuyama (Hyogo College of Medicine), Shinichi
Momomura (Jichi Medical University Saitama Medical
Center), Masafumi Yano (Yamaguchi University Graduate
School of Medicine), Kazuhiro Yamamoto (Tottori Univer-
sity Faculty of Medicine), and Michihiro Yoshimura (The
Jikei University School of Medicine)
Independent data monitoring committee: Hitonobu To-
moike (chair, Sakakibara Heart Institute), Yutaka Kiyohara
(Hisayama LIFE Institute), and Hideki Orikasa (University
of Toyama)
Event evaluation committee: Masafumi Kitakaze (chair,
National Cerebral and Cardiovascular Center), Hisashi Kai
(Kurume University Medical Center), and Naoyuki
Hasebe (Asahikawa Medical University)
Research institute: Kyusyu University Hospital, Hok-
kaido University Hospital, Nagoya University Hospital,
Tokyo Medical and Dental University, Okayama Univer-
sity Hospital, Kitasato University Hospital, The University
of Tokyo Hospital, Nara Medical University Hospital,
Osaka University Hospital, Tohoku University Hospital,
Hyogo College of Medicine, Jichi Medical University Sai-
tama Medical Center, Yamaguchi University Hospital, Tot-
tori University Hospital, The Jikei University School of
Medicine, Sapporo Medical University Hospital, Heart-
sounds Mori Clinic, Tosei General Hospital, Nishio Mu-
nicipal Hospital, Osaka General Medical Center, Sakura-
bashi Watanabe Hospital, National Cerebral and Cardio-
vascular Center, Sakakibara Heart Institute, Toranomon
Hospital, St. Marianna University School of Medicine,
Nagoya City University Hospital, Hiroshima University,
Osaka Medical College Hospital, Medical Corporation JR
Hiroshima Hospital, Masao Fujii Memorial Hospital, Hi-
roshima Prefectural Hospital, Otaru Kyokai Hospital,
Showa University Hospital, Sapporo City General Hospi-
tal, Tokuyama Central Hospital, Graduate School of Medi-
cine and Faculty of Medicine Kyoto University, Saiseikai
Yamaguchi hospital, and Yamaguchi Prefectural Grand
Medical Center.
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