Journal of Cardiology (2010) 56, 111—117

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jjcc

Original article

Rationale and design of the NAGOYA HEART Study:

Comparison between valsartan and amlodipine
regarding morbidity and mortality in patients with
hypertension and glucose intolerance
Kunihiro Matsushita (MD, PhD), Takashi Muramatsu (MD),
Takahisa Kondo (MD, PhD), Kengo Maeda (MD, PhD),
Satoshi Shintani (MD, PhD), Toyoaki Murohara (MD, PhD) ∗ ,
on behalf of the NAGOYA HEART Study Group

Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan

Received 14 January 2010; received in revised form 15 March 2010; accepted 17 March 2010
Available online 20 April 2010

KEYWORDS Summary
Hypertension; Background: Inhibitors of the renin angiotensin system are recommended as the first-line med-
Diabetes mellitus; ications for diabetic hypertensive patients. However, there is less evidence supporting this
Impaired glucose recommendation especially among East Asians, a population with a unique distribution of
tolerance; cardiovascular disease compared to the Western population.
Angiotensin receptor Methods and results: The NAGOYA HEART Study is a prospective randomized open-label blinded-
blocker; endpoint study to compare an angiotensin II receptor blocker, valsartan, and a calcium channel
Calcium channel blocker, amlodipine, regarding their efficacies on cardiovascular morbidity and mortality in
blocker; Japanese hypertensive patients with glucose intolerance. Of 1168 eligible patients, we enrolled
Cardiovascular 1150 patients from October 2004 to January 2009. The participants will be followed for more
mortality and than a median follow-up period of 3 years. The primary composite endpoint includes myocar-
morbidity dial infarction, stroke, coronary revascularization, and admission due to congestive heart failure
or sudden cardiac death. Any of these events are adjudicated by an independent committee
under blinded information regarding the treatment arm. Secondary endpoints include all-cause
mortality, changes in glucose tolerance status, kidney function, left ventricular structure mea-
sured by echocardiogram, and incident atrial fibrillation/flutter. The study was registered at
ClinicalTrials.gov NCT00129233.

∗ Corresponding author. Tel.: +81 52 744 2149; fax: +81 52 744 2138.
E-mail address: murohara@med.nagoya-u.ac.jp (T. Murohara).

0914-5087/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jjcc.2010.03.004
112
Conclusion: The NAGOYA HEART Study will provide us with a relevant insight for appropriate
treatment of hypertension with glucose intolerance.
© 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction
Hypertensive patients with type 2 diabetes mellitus (T2DM)
have almost 2-fold higher risk for suffering from ischemic
cardiovascular diseases compared to non-diabetic hyperten-
sive patients [1]. Inhibitors of the renin angiotensin system
[i.e. angiotensin-converting enzyme inhibitors (ACEIs) or
angiotensin II receptor-1 blockers (ARBs)] are widely
recommended as the first-line medications for diabetic
hypertensive patients in clinical guidelines issued by most
developed countries [1—4]. This is because many clini-
cal trials [5—8], but not all [9—11], have suggested that
ACEIs and/or ARBs protect more effectively against the
development of macrovascular and microvascular diseases
compared to other types of antihypertensive drugs in this
particular patient population.
Angiotensin II plays pivotal roles in the development of
hypertension and vascular complications by inducing vaso-
constriction, sodium and water retention, smooth muscle
cell proliferation, myocardial fibrosis, superoxide forma-
tion, plasminogen activator inhibitor-1 production, and
activation of the sympathetic nervous system [12—14].
Importantly, angiotensin II also reduces insulin sensitivity
possibly through the inhibition of intracellular insulin sig-
naling [12]. In fact, ACEIs and/or ARBs have been shown to
prevent new onset of T2DM in many clinical trials [6,15].
Therefore, there is a concrete background supporting par-
ticular benefits of ACEIs and/or ARBs for the treatment
of hypertensive patients with glucose intolerance [i.e.
impaired glucose tolerance (IGT) or T2DM].
The epidemiology of cardiovascular diseases in Japan
is different from that typically observed in Western coun-
tries. In particular, the age-adjusted incidence rate of
ischemic heart disease in Japan is almost 80% lower than
that in the USA [16]. In contrast, mortality rate due to
stroke is 3—4-fold higher in Japan compared to the USA
[16,17]. Given the fact that calcium channel blockers (CCBs)
are useful for the prevention of stroke [18], one may
assume that CCBs are more beneficial for Japanese hyper-
tensive patients with T2DM or IGT. Regarding the incidence
of heart failure, Japanese have a higher mortality rate
due to heart failure compared to the Western population
[17]. Since inhibitors of the renin angiotensin system can
effectively prevent the development of heart failure com-
pared to other antihypertensive drugs [19], ACEIs and/or
ARBs may be beneficial to Japanese patients in this con-
text.
Taken together, it is still unclear whether inhibitors of
the renin angiotensin system can prevent adverse compos-
ite cardiovascular events more effectively than CCBs in
Japanese hypertensive patients with T2DM or IGT. Accord-
ingly, we designed a clinical trial comparing an ARB,
valsartan, and a CCB, amlodipine, with respect to their
efficacies on cardiovascular morbidity and mortality in
K. Matsushita et al.
Japanese hypertensive patients with glucose intolerance
(T2DM or IGT).
Methods
Study design
The NAGOYA HEART Study is a multicenter study apply-
ing a prospective randomized open-label, blinded-endpoint
(PROBE) design [20]. The study consists of two parallel arms
of antihypertensive treatments, i.e. valsartan-based vs.
amlodipine-based. The study was registered at ClinicalTri-
als.gov (http://www.clinicaltrials.gov/) with the identifier
NCT00129233.
Study population
Patients who were between 30 and 75 years old and had
both hypertension and glucose intolerance (IGT or T2DM)
were eligible to be enrolled in the NAGOYA HEART Study.
Patients were considered as hypertensive when they were
already taking antihypertensive drugs or when they had sys-
tolic or diastolic blood pressure equal to or more than 140 or
90 mmHg, respectively, on at least two different occasions
despite education about appropriate lifestyle modification.
Glucose intolerance consists of T2DM or IGT, which were
defined according to the statement from the American Dia-
betes Association [21]. In brief, T2DM was defined when
subjects had already been taking drugs for T2DM, fast-
ing glucose equal to 126 mg/dL or more, or non-fasting
glucose or glucose 2 hr after 75 g oral glucose tolerance
test (OGTT) equal to 200 mg/dL or more. IGT was defined
by glucose between 140 and 199 mg/dL at 2 h after the
OGTT. We included patients with IGT but not those with
impaired fasting glucose (IFG), since individuals with IGT
have a similar risk of cardiovascular disease as diabetic
patients, but the risk of subjects with IFG is approxi-
mately that of individuals with normal glucose tolerance
[22].
Patients with the following conditions at enrollment were
excluded: (1) history of heart failure, myocardial infarction,
coronary revascularization (percutaneous coronary inter-
vention or coronary artery bypass graft surgery), or stroke
in the last 6 months; (2) patients who were taking CCBs for
the purpose of the suppression of angina pectoris includ-
ing coronary spastic angina; (3) impaired left ventricular
ejection fraction less than 40%; (4) second- or third-degree
atrio-ventricular block; (5) severe hypertension (systolic or
diastolic blood pressure greater than 200 or 110 mmHg,
respectively) or secondary hypertension; (6) serum creati-
nine equal to 2.5 mg/dL or more; (7) estimated prognosis
less than 3 years due to other conditions; (8) pregnant
women or women with a potential of childbearing; (9) other
Design of the NAGOYA HEART Study
Figure 1 Titration schedule of the assigned drugs for the NAGOYA HEART Study. Asterisk (*) indicates other antihypertensive drugs
excluding ACEIs, ARBs, and CCBs.
conditions by which physicians in charge judged inappropri-
ate to enroll because of patients’ safety concern.
Informed consent
Participating centers included 46 affiliated hospitals led
by cardiology specialists in Nagoya City and its vicinity.
All participants provided their written informed consent
after receiving explanations by a physician in charge about
study objectives, study protocol, possible adverse effects
of the study drugs, measures for privacy protection, and
study withdrawal. The Ethics Review Committee of Nagoya
University School of Medicine and the Committee at each
participating center approved the study protocol.
Study procedures
Randomization was automatically performed by a host com-
puter system using the minimization method. The treatment
protocol of the NAGOYA HEART Study is shown in Fig. 1. The
initial doses are 80 mg/day for valsartan and 5 mg/day for
amlodipine, respectively. Physicians increased doses until
160 mg or 10 mg per day, respectively, as needed. Also,
diuretics, ␤-blockers, or ␣-blockers can be added to achieve
target blood pressure for hypertensive patients with dia-
betes (i.e. 130/80 mmHg). For participants already taking
antihypertensive drugs at the enrollment, ACEIs, ARBs, and
CCBs were discontinued, and the allocated drug was pre-
scribed without a run-in period. Diuretics, ␤-blockers or
␣-blockers could be continued when physicians considered
appropriate. Clinical care for T2DM/IGT was conducted
according to the guidelines of the Japanese Diabetes Society
[23].
Measurements of interest
Demographic variables such as sex, age, smoking status,
co-morbidities including dyslipidemia, T2DM/IGT, and a
113
past history of cardiovascular disease were obtained at
baseline. Also, physiological findings including blood pres-
sure, anthropometry, blood examination, electrocardiogram
(ECG), and echocardiogram were evaluated at baseline. The
above measurements were repeated every 6 months except
for echocardiogram, which was carried out once a year.
The blood examination included the following items: fast-
ing glucose, hemoglobin A1c, low-density and high-density
lipoprotein cholesterols, triglyceride, uric acid, blood urea
nitrogen, serum creatinine, sodium, and potassium. The
follow-up OGTT was conducted every year only for sub-
jects with IGT. During an echocardiogram, the following
variables were measured: dimension of the left ventricle at
both end-diastole and end-systole, thickness of the inter-
ventricular septum and left ventricular posterior wall at
end-diastole, left ventricular ejection fraction, the ratio of
early ventricular filling to atrial contraction velocity (E/A
ratio).
Evaluation of outcomes
The primary endpoint is a composite of cardiovascular
morbidity and mortality. Components of the primary end-
point include the following: (1) myocardial infarction (ECG
change, elevation of cardiac enzymes, and culprit lesion
detected by coronary angiogram); (2) stroke (neurolog-
ical deficit persisting for more than 24 h and relevant
findings in computed tomography or magnetic resonance
imaging); (3) admission due to congestive heart failure (clin-
ical symptoms including dyspnea, shortness of breath, and
peripheral edema, together with pulmonary congestion in
chest roentgenogram); (4) coronary revascularization (per-
cutaneous coronary intervention or coronary bypass graft
surgery unplanned at randomization); or (5) sudden car-
diac death (unexpected death within 24 h after the onset
of symptoms). Any of these events must be strictly adju-
dicated by an independent Endpoint Evaluation Committee
under the blinded circumstance regarding assigned treat-
ment.
114
Figure 2 Organizational structure of the NAGOYA HEART Study.
The followings are classified as the secondary end-
points: (1) all-cause mortality; (2) glucose control and
incident T2DM; (3) incident atrial fibrillation or flutter
detected by ECG; (4) change in kidney function (doubling
of plasma creatinine levels and transition to dialysis); and
(5) change in cardiac function evaluated by echocardio-
gram.
The follow-up will be conducted every month in the
first 3 months and every 1—3 months after then accord-
ing to physicians’ decisions and will be terminated when
the first event among the primary outcomes occurs. Par-
ticipating physicians will obtain information about clinical
outcomes from patients or their families and report those
to the Data Management Group of the NAGOYA HEART
Study.
Study organization
The study organization is shown in Fig. 2. The Executive
Committee created the protocol of the NAGOYA HEART Study
and observes the progress comprehensively. The Steering
Committee approved the study protocol and makes a deci-
sion about the management of the study. The Data and
Safety Monitoring Board consists of a physician, an epi-
demiologist, an endocrinologist, and a cardiologist and
provides the Steering Committee with advice when there
are any concerns about participants’ safety. The Endpoint
Evaluation Committee comprised a cardiologist, a vascular
surgeon, and a neurologist, and they adjudicated primary
endpoints reported from physicians. The data are collected
through the Internet into a secure server and are centrally
managed by the independent Data Management Group.
The Statistical Analysis Board will perform all statistical
analyses independently from any of the above commit-
tees.
K. Matsushita et al.
Sample size and statistical analysis
In the Hisayama study, incidence rate of coronary heart
disease (myocardial infarction and sudden cardiac death)
and stroke among Japanese patients with T2DM was 5.0
and 6.5 per 1000 person-years [24]. In the Japan Diabetes
Complications Study (JDCS), incidence rate of coronary
heart disease consisting of angina pectoris and myocardial
infarction, and brain infarction were 6.7 and 6.5 per 1000
person-years, respectively [25]. Since myocardial infarction,
unstable/stable angina pectoris requiring revascularization,
congestive heart failure, sudden cardiac death, and stroke
were all included as a primary composite endpoint in the
present study and all participants had hypertension, we
estimated at least 5—8% of participants would have car-
diovascular events each year. Under the assumption that
valsartan can reduce cardiovascular events by 20% and the
median follow-up time would be 3 years, sample size for
each group was estimated to be 1500 with a two-sided ˛
level of 0.05 and statistical power of 80%.
Patients’ enrollment began in October 2004 and was
anticipated to be finished by the end of 2006. Of 1168
patients eligible for the recruitment of the present study,
we had recruited 1150 patients by the end of January
2009, when the Data and Safety Monitoring Board sug-
gested stopping patient recruitment due to relatively longer
recruitment period than anticipated. Consequently, the
Steering Committee decided not to recruit patients after
February 2009 and to follow-up participants until median of
follow-up period reaches more than 3 years.
Analyses will be performed by an independent Statisti-
cal Analysis Board based on the intention-to-treat approach.
All randomized patients (n = 1150) were included in the
analysis. Cox proportional hazard model will be used for
comparing the difference in risk between the two treatment
groups.
Design of the NAGOYA HEART Study
Discussion
The NAGOYA HEART Study (the NHS) is the first large-
scale clinical trial comparing an ARB, valsartan, and a
CCB, amlodipine, specifically among Japanese hypertensive
patients with glucose intolerance (IGT or T2DM). The benefit
of ACEIs/ARBs compared to CCBs with respect to prevention
of major cardiovascular events among diabetic hypertensive
patients was mainly demonstrated in relatively small studies
with participants <500 such as the ABCD or the FACET Trials
[5,8]. However, no superiority of ACEIs/ARBs with respect to
the prevention of macrovascular disease has been shown in
larger clinical studies (e.g. the ALLHAT or the IDNT) [9,26].
More importantly, the Blood Pressure Lowering Treatment
Trialists’ Collaboration (BPLTTC) investigators conducted a
meta-analysis to elucidate this issue, and they found that
ACEIs were equivalent to CCBs regarding protection against
composite cardiovascular events in hypertensive patients
with T2DM [19]. Only few studies had compared ARBs and
CCBs directly at this moment.
This meta-analysis included only one clinical study from
Asia, that was the Japan Multicenter Investigation for Car-
diovascular Diseases-B (JMIC-B) trial [19]. This JMIC-B trial
compared ACEIs and a CCB, long-acting nifedipine, among
1650 Japanese hypertensive patients and could not show
any significant difference in cardiovascular events in the
two treatment arms during 3-year follow-up period [27].
Since the JMIC-B included only 372 patients with T2DM,
Asian population with both hypertension and T2DM has
been understudied. Therefore, although we could not enroll
a priori planned number of patients, we anticipate that
the NAGOYA HEART Study will provide us with clinically
relevant information regarding appropriate treatment of
hypertension with glucose intolerance among an East Asian
population.
ACEIs and ARBs are considered particularly effective to
protect renal function [1,4]. Indeed, a number of studies
have reported that these two types of drugs can prevent
deterioration of glomerular filtration rate and deterioration
of proteinuria [28]. However, a meta-analysis conducted by
Casas and colleagues demonstrated that the effectiveness
of ACEIs and ARBs is clearly shown in small studies with par-
ticipants <500 but is less evident in larger clinical studies
[28]. Typically, the ALLHAT including ≈13,000 patients with
T2DM of more than 30,000 hypertensive patients did not
show a superior benefit of an ACEI, lisinopril, compared to
amlodipine or a thiazide-type diuretic with respect to renal
protection [26,28]. Interestingly, when four clinical stud-
ies comprising only diabetic patients were combined, the
occurrence of end-stage renal disease was not statistically
different between ACEIs/ARBs and other antihypertensive
drugs [28]. Thus, renal protective effects of ACEIs/ARBs
beyond lowering blood pressure remain to be proved [28].
This is particularly the case for Japanese. The Japan Mul-
ticenter Investigation of Antihypertensive Treatment for
Nephropathy in Diabetics (J-MIND) Study reported that a
CCB, nifedipine, was similarly protective against deteri-
oration of albuminuria compared to an ACEI, enalapril,
among 438 Japanese diabetic hypertensive patients. Thus,
the NAGOYA HEART study will provide us relevant informa-
tion regarding renal protection by antihypertensive drugs
among Japanese.
115
After the NAGOYA HEART Study was initiated, a few
studies investigated whether an ARB is superior to a
CCB regarding risk reduction of cardiovascular diseases.
The VALUE trial compared the effects of valsartan- and
amlodipine-based regimens among 15,245 hypertensive
patients aged 50 years or older and reported that there
was no statistical difference in the two treatment groups
for the prevention of cardiovascular events [29]. The risk
of myocardial infarction and stroke tended to be lower
in the amlodipine-based treatment group compared to
the valsartan group. The authors raised a possibility that
significantly lower blood pressure levels achieved in the
amlodipine group might contribute to the lower cardio-
vascular incidences. Similarly, Ogihara and colleagues have
recently reported that there was no statistical differ-
ence in the risk of cardiovascular morbidity and mortality
between ARB candesartan-based and amlodipine-based reg-
imens among 4728 Japanese hypertensive patients enrolled
in the Candesartan Antihypertensive Survival Evaluation in
Japan (CASE-J) Trial [30,31]. Although the CASE-J trial has
shown that an ARB-based regimen may be beneficial particu-
larly in obese patients, results specific to T2DM participants,
43% of the entire study population, have not been reported
[30,31].
In contrast, Mochizuki and colleagues reported 40%
reduction of the risk for their primary composite endpoint
(i.e. composite of cardiovascular mortality and morbidity)
with valsartan compared to non-ARB treatment group in the
JIKEI HEART Study including 3081 Japanese patients with
hypertension, coronary heart disease, or heart failure [32].
Similarly, the KYOTO HEART Study reported 45% reduction
of incident cardiovascular disease by valsartan as compared
with non-ARB treatment in Japanese patients with hyper-
tension [33]. The precise reasons of the inconsistent results
observed among these studies are under debate [34,35].
The fact that there was no evident control drug in the JIKEI
HEART Study might explain the results. In fact, participants
in the non-ARB group in the JIKEI HEART Study tended to
take less antihypertensive drugs than those in the valsar-
tan group in the first 2-year follow-up [32]. Furthermore,
since the JIKEI HEART Study recruited not only patients with
hypertension but also those with heart failure and coronary
heart disease, a part of patients with certain characteristics
(e.g. prevalent heart failure) might receive specific benefits
of an ARB-based regimen.
Taken together, since it is still unclear whether an ARB
is superior to a CCB with respect to the prevention of car-
diovascular events among Japanese diabetic hypertensive
patients, the results of the NAGOYA HEART Study will be
quite valuable.
Funding and conflict of interest
The study is funded by Nagoya University Graduate School
of Medicine. The Department of Cardiology, Nagoya Uni-
versity Graduate School of Medicine has received donation
grants from various pharmaceutical companies. However,
the research topics of these donation grants are not
restricted. The Executive Committee has full access to all
the data at the end of the study, and has final responsibility
for the decision to submit for publication.
116
Acknowledgments
The authors wish to express their sincere appreciation to
all the patients, collaborating physicians, and other medical
staffs for their important contribution to the NAGOYA HEART
Study. The authors also thank Dr Hiroshi Yatsuya from the
Department of Public Health, Nagoya University Graduate
School of Medicine for his variable advice.
Appendix A.
Toyoaki Murohara supervises the NAGOYA HEART Study as the
principal investigator.
Organization (* indicates Chairman of the Committee)
The Executive Committee
Toyoaki Murohara*, Takahisa Kondo, Satoshi Shintani,
Kengo Maeda, Kunihiro Matsushita and Takashi Muramatsu
all from the Department of Cardiology, Nagoya University
Graduate School of Medicine, Nagoya, Japan.
The Steering Committee
The lead investigators as above, Masato Watarai, Anjo
Kosei Hospital; Nobuyuki Marui, Chubu Rosai Hospital; Chiei
Takanaka, Hamamatsu Medical Center; Miyoshi Ohno,
Japanese Red Cross Nagoya Daiichi Hospital; Toshihiro
Obayashi, Kariya Toyota General Hospital; Taizo Kondo,
Komaki City Hospital; Yasunobu Takada, Konan Kosei
Hospital; Yoshio Iwama, Meijyo Hospital; Makoto Akahoshi,
Meitetsu Hospital; Masato Iida, Mitsubishi Nagoya Hospital;
Haruo Hirayama, Nagoya Daini Red Cross Hospital; Takahito
Sone, Ogaki Municipal Hospital; Toshiyuki Osaka, Shizuoka
Saiseikai General Hospital; Osamu Ohno, Toyohashi
Municipal Hospital; Shinji Kaneko, Toyota Kosei Hospital;
and Satoshi Ichimiya, Yokkaichi Municipal Hospital.
The Endpoints Evaluation Committee
Tatsuaki Matsubara*, Department of Internal Medicine,
Aichi Gakuin University School of Dentistry, Nagoya, Japan;
Kimihiro Komori, Department of Vascular Surgery, Nagoya
University Graduate School of Medicine, Nagoya, Japan;
and Manabu Doyu, Department of Neurology, Aichi Medical
University, School of Medicine, Aichi, Japan.
The Data and Safety Monitoring Board (DSMB)
Hideaki Toyoshima*, Health Care Center of Anjo Kosei
Hospital, Anjo, Japan; Yutaka Oiso, Department of
Endocrinology and Diabetes, Nagoya University Graduate
School of Medicine, Nagoya, Japan; and Makoto Hirai,
Department of Nursing, Nagoya University School of Health
Sciences, Nagoya, Japan.
The Writing and Sub-analysis Study Committee
Toyoaki Murohara*, Takahisa Kondo, Satoshi Shintani,
Kengo Maeda, Kunihiro Matsushita and Takashi Muramatsu
all from the Department of Cardiology, Nagoya University
Graduate School of Medicine, Nagoya Japan.
The Clinical Research Coordinator (CRC) and Data
Management Group
Kumi Sasaki, Emiko Watanabe, and Yoko Inoue all from
Nagoya University, Nagoya, Japan.
K. Matsushita et al.
The Statistical Analysis Board
Nobuo Shirahashi, Department of Preventive Medicine
and Environmental Health, Osaka City University Medical
School, Osaka, Japan.
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