Circulation Journal

Official Journal of the Japanese Circulation Society

ORIGINAL  ARTICLE
http://www. j-circ.or.jp Epidemiology

One-Year Cardiovascular Event Rates in Japanese Outpatients

With Myocardial Infarction, Stroke, and Atrial Fibrillation
– Results From the Japan Thrombosis Registry for Atrial Fibrillation,
Coronary, or Cerebrovascular Events (J-TRACE) –
Shinya Goto, MD, PhD; Yasuo Ikeda, MD; Kazuyuki Shimada, MD;
Shinichiro Uchiyama, MD; Hideki Origasa, PhD; Hiroyuki Kobayashi, MD
on behalf of the J-TRACE Investigators

Background:  There remains uncertainty about the risk of cardiovascular events in stable outpatients with a history
of myocardial infarction (MI), stroke, and atrial fibrillation in Japan.

Methods and Results:  In the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events
(J-TRACE), a nationwide prospective cohort of stable outpatients with a history of MI (n=2,291), stroke (n=3,554),
and/or atrial fibrillation (n=2,242), 1-year follow-up data were available for 7,513 of 8,087 patients (follow-up rate:
92.9%). The primary endpoint (death/MI/stroke) was reported in 3.53 events per 100 person-years (95% confidence
interval [CI]: 3.11–3.99) within 1 year. The rates of all-cause death, death from stroke, and death from MI within
1 year were 1.35 (95%CI: 1.10–1.65), 0.15 (95%CI: 0.08–0.27), and 0.06 (95%CI: 0.02–0.14) per 100 person-years,
respectively. The rate of non-fatal stroke was 1.85 (95%CI: 1.55–2.19), while that of non-fatal MI was 0.33 (95%CI:
0.21–0.49). The rate of non-fatal stroke was highest among stroke patients (2.95; 95%CI: 2.39–3.60 per 100 person-
years), while that of non-fatal MI was similar across all disease categories. Investigator-decided serious non-fatal
bleeding events occurred in 0.21 events (95%CI: 0.12–0.34) per 100 person-years.

Conclusions:  In this large, nationwide Japanese registry, the highest stroke event rate was seen in patients with
a history of stroke.   (Circ J  2011; 75: 2598 – 2604)

Key Words: Atrial fibrillation; Bleeding; Myocardial infarction; Registry; Stroke

T
he risk of cardiovascular (CV) diseases such as myo-
cardial infarction (MI) and ischemic stroke vary
greatly across the regions of the world.1–9 Although
the higher risk of stroke in patients with atrial fibrillation (AF),
especially those with risk factors,10–13 is recognized in the
medical community, regional heterogeneity in the rates of CV
diseases in AF patients, especially in Asian cohorts,14,15 is still
insufficiently understood. The limited data currently available
in Japan have suggested a higher risk of cerebrovascular dis-
eases (CVD), including stroke, compared with coronary artery
diseases (CAD) such as MI.1,16–21 Most global clinical studies
in the field of CV disease have recruited patients predominantly
from North America and Europe, where CAD is predominant
compared with CVD.16,19,22 Thus a clinical database of patients
with CV diseases in a real-world setting in Japan is necessary
to adjust the global clinical trial results for real-world clinical
practice in Japan. Therefore, the aim of the present study was
to clarify the event rate of high-risk CV diseases in Japanese
patients in real world medical practice using the database of
the Japan Thrombosis Registry for Atrial Fibrillation, Coronary,
or Cerebrovascular Events (J-TRACE).23

Received April 14, 2011; revised manuscript received June 23, 2011; accepted July 5, 2011; released online August 20, 2011   Time for
primary review: 34 days
Department of Medicine (Cardiology) (S.G.), Departments of Clinical Pharmacology and of General Clinical Research Center (H.K.), Tokai
University School of Medicine, Isehara; Department of Life Science and Medical Bioscience, Waseda University School of Advance
Science and Engineering, Tokyo (Y.I.); Department of Neurology, Tokyo Women’s Medical University, Tokyo (S.U.); Department of
Cardiology, Jichi Medical University, Shimotsuke (K.S.); and Biostatistics and Clinical Epidemiology, University of Toyama Graduate
School of Medicine, Toyama (H.O.), Japan
A complete list of the J-TRACE Investigators has been published in H. Origasa et al, Circ J 2008; 72: 991 – 997.
Mailing address:  Shinya Goto, MD, PhD, FACC, Department of Medicine (Cardiology), Tokai University School of Medicine, 143
Shimokasuya, Isehara 259-1143, Japan.   E-mail: shinichi@is.icc.u-tokai.ac.jp
ISSN-1346-9843   doi: 10.1253/circj.CJ-11-0378
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.75,  November  2011

One-Year Events in J-TRACE
Table 1.  Baseline Characteristics of Patients With 1-Year Follow-up Data
All
Available for 1-year follow-up (n) 7,513
Age (years), mean ± SD 68.6±10.1
Men (%) 71.5
Hypertension (%) 66.3
Diabetes (%) 24.4
Hypercholesterolemia (%) 38.9
Heart failure (%) 10.3
Body mass index (mean ± SD) 23.9±7.6　 23.6±6.7　 24.0±3.3　 24.1±10.6
Current smoker (%) 22.3
Alcohol consumption (%) 29.1
MI, myocardial infarction; AF, atrial fibrillation.
Editorial p 2537
We have developed a contemporary, nationwide, prospec-
tive cohort of patients with so-called high-risk CV diseases
(stroke and MI, as well as AF) in Japan, namely, J-TRACE.24
Baseline characteristics of the 8,087 recruited patients have
been published.25 In the present study, we focused on the 1-year
events rate of all-cause mortality, stroke, and MI in patients
recruited in the J-TRACE.
Methods
Details of the study design, including rationale, strategy for
selecting participating investigators (physicians), and recruit-
ment of patients to generate a clinical database that represents
real-world clinical practice in Japan, have been published else-
where.24–26 Briefly, we divided Japan into 10 regions. We then
selected region coordinators of cardiologists and stroke special-
ists from all 10 regions. Every region coordinator nominated
the study hospitals and participating clinics as well as study
investigators to represent real-world medical practice in each
region.
Briefly, consecutive outpatients aged 20–90 years with a
history of stroke, MI, and/or AF were enrolled. Definitions of
stroke, MI, and AF were described as previously published.24
Of note, both ischemic and hemorrhagic stroke patients diag-
nosed on computed tomography (CT) or magnetic resonance
imaging (MRI) were included. According to the definition,
patients with chronic, persistent, or paroxysmal AF diagnosed
on electrocardiography can be enrolled.24 Indeed, all the AF
patients enrolled were those with non-valvular AF.23 Any
acute-phase patients, defined as patients requiring hospitaliza-
tion, were excluded because the CV event risk in these acute
phase patients is known to be markedly higher than that of
stable outpatients.19,27–29 Patients were enrolled from 201 sites
to represent real-world medical care in Japan. The study pro-
tocol was approved by the institutional review board at each
participating institute and signed informed consent was ob-
tained from all patients. Data were collected centrally via use
of a Web-based, standardized, electronic case report form
completed by participating physicians. Finally, a total of 8,087
patients were recruited.25
Baseline characteristics of all patients recruited in this reg-
istry have been published elsewhere.23 In spite of repeated
systemic alert, 1-year event information was not entered for
all patients at the time of database lock. Thus, the 1-year fol-
low up rate in the present study is not 100%. Risk factors such
Circulation Journal  Vol.75,  November  2011
2599
Stroke MI AF
3,351 2,106 2,056
68.2±10.1 67.9±10.4 70.0±9.4　
69.1 78.0 68.7
74.5 62.1 57.4
22.3 34.8 17.3
35.4 55.9 27.1
  2.9 10.9 21.7
19.2 33.2 16.3
30.0 21.7 35.1
as hypertension, diabetes mellitus, hypercholesterolemia, were
defined according to practice guidelines as previously pub-
lished.23 We assessed the distribution of the congestive heart
failure, hypertension, aging, diabetes mellitus, and history of
stroke or transient ischemic attack (CHADS2) score in that
group and its relation to outcome.
A 2-year follow-up was planned for recruited patients. The
primary outcome measure was a composite of all-cause death,
non-fatal symptomatic stroke, and non-fatal MI. Non-fatal
stroke was defined as acute onset of focal neurological mani-
festation and the responsible lesion was confirmed on brain
CT or MRI. Non-fatal MI was defined as increased bio-
chemical markers such as creatinine phosphokinase-MB and
troponin, and either prolonged ischemic symptoms (lasting for
>30 min) or newly developed ischemic electrocardiographic
changes, including abnormal Q waves and ST-segment eleva-
tion or depression. Secondary outcomes were all-cause death,
non-fatal MI, non-fatal stroke separately, and any dropouts
from the study, and the incidence of cerebral hemorrhage, any
other bleedings, or serious adverse experiences leading to
admission.24 If the patients died during follow-up, the reason
for death for each patient was described in detail in the case
report form by the investigators. All outcomes were defined
by the investigators and were not adjudicated by a specific
committee. In the present study, all events occurring in each
patient from study entry to 12 months were considered as
‘1-year events’.
Methods of data analysis have already been published.24
Briefly, all relevant data were presented using means and
standard deviations for continuous data, and as counts or per-
centages for categorical data. The event rate was expressed as
number of events per 100 person-years. When multiple events
occurred in the same patients during the follow-up period, those
events were regarded as multiple independent events. Sta-
tistical analysis was conducted with R 2.13.0 (R Foundation
for Statistical Computing, Department of Statistics and
Mathematics, Wirtschafts Universitat, Wien, Austria). The
95% confidence interval (CI) was calculated by the normal
approximation of Poisson distribution that the number of
events per year was assumed to follow. Cumulative incidence
curves were constructed for primary endpoints using the
Kaplan – Meier approach.
Results
Follow-up Rate, Risk-Factor Profile, and Drug Usage
Of the 8,087 patients enrolled from Japan nationwide in
the J-TRACE registry, 1-year event data were available for
2600 GOTO S et al.

Table 2.  Baseline Use of Drugs in Patients With 1-Year Data

Disease category
Medication
Stroke (n=3,351) MI (n=2,106) AF (n=2,056)
Hypertensive patients (n) 2,495 1,308 1,180
   Calcium antagonists (%) 60.4 44.2 59.6
   ARB (%) 40.6 37.6 47.2
   ACEI (%) 19.4 28.3 20.8
   β-blockers (%)   9.5 28.7 26.1
   Diuretics (%)   8.0 17.8 30.4
   α-blockers (%)   6.0   3.1   4.9
   α/β-blockers (%)   2.5   8.6   5.2
   Others (%)   0.7   1.6   2.0
   No medication (%) 12.7 12.7   3.1
Diabetic patients (n) 747 732 355
   Oral glucose-lowering drugs (%) 56.2 49.3 46.8
   Insulin (%) 10.7 14.2   8.5
   Others (%)   6.0   6.0   6.5
   No medication (%) 31.7 36.5 42.0
Hypercholesterolemic patients (n) 1,187 1,177 557
   Statins (%) 60.7 74.9 57.3
   Other (%)   9.9   6.4   6.8
   No medication (%) 31.8 21.6 38.1
Anti-thrombotics (%)
   Aspirin 46.0 82.6 30.1
   Ticlopidine 19.1 39.4   4.0
   Clopidogrel   0.2 0 0
   Cilostazol   9.8   5.6   1.8
   Dipyridamole   0.7   1.0   0.5
   Warfarin 20.3 10.9 70.0
ARB, angiotensin II receptor blockers; ACEI, angiotensin-converting enzyme inhibitors. Other abbreviations see in
Table 1.

Figure 1.    Kaplan – Meier event curves

as a function of time from enrollment
for the combined endpoint of all-cause
death, non-fatal stroke, or non-fatal
myocardial infarction from enrollment
to 1 year.

7,513 patients (92.9%) at the time of the database lock on 13
February 2009. The numbers of patients in each disease sub-
category (stroke, MI, or AF) with 1-year event-rate data are
given in Table 1, along with baseline demographic character-
istics and risk factor profiles. Of note, only 69 of 3,351 patients
categorized as stroke patients were those with hemorrhagic
stroke. Thus, the majority of stroke patients recruited in this
registry were patients with ischemic stroke. Of the 574 patients
lost to follow-up, withdrawal consent was the reason for
39 patients with stroke, 8 in the MI category, and 12 in AF
patients. Follow-up rates were similar across the disease sub-
categories, ranging from 94.3% in stroke patients to 91.7% in
AF patients.
Baseline use of drugs among patients with 1-year follow-up

Circulation Journal  Vol.75,  November  2011

One-Year Events in J-TRACE 2601

Table 3.  Rate of Death due to Various Causes in 1 Year in J-TRACE

No. events per 100 person-years (95%CI)
Events
All (n=7,513) Stroke (n=3,351) MI (n=2,106) AF (n=2,056)
Total death 1.35 (1.10–1.65) 1.29 (0.93–1.74) 0.98 (0.60–1.52) 1.83 (1.28–2.54)
Death due to stroke 0.15 (0.08–0.27) 0.22 (0.09–0.44)   0.05 (0.001–0.27) 0.15 (0.03–0.45)
Death due to MI 0.06 (0.02–0.14)   0.03 (0.001–0.17) 0.10 (0.01–0.35)   0.05 (0.001–0.28)
Death due to serious bleeding 0.05 (0.01–0.14) 0.06 (0.01–0.22) 0 (0–0.18) 0.10 (0.01–0.37)
Others 1.09 (0.86–1.36) 0.98 (0.67–1.39) 0.83 (0.49–1.34) 1.53 (1.03–2.18)
CI, confidence interval. Other abbreviations see in Table 1.

Table 4.  Non-Fatal Stroke, MI, Serious Bleeding and Others in 1 Year in J-TRACE
No. events per 100 person-years (95%CI)
Events
All Stroke MI AF
Total events 3.80 (3.36–4.28) 5.19 (4.43–6.04) 1.86 (1.32–2.56) 3.51 (2.73–4.45)
Non-fatal stroke 1.85 (1.55–2.19) 2.95 (2.39–3.60) 0.49 (0.24–0.90) 1.43 (0.96–2.06)
Non-fatal MI 0.33 (0.21–0.49) 0.40 (0.21–0.68) 0.39 (0.17–0.77) 0.15 (0.03–0.45)
Non-fatal bleeding 0.15 (0.08–0.27) 0.09 (0.02–0.27)   0.05 (0.001–0.27) 0.36 (0.14–0.73)
Others 1.47 (1.21–1.78) 1.75 (1.33–2.27) 0.931 (0.56–1.46)　 1.58 (1.07–2.24)
Abbreviations see in Tables 1,3.

Figure 2.    Rates of all-cause death (red),

non-fatal stroke (blue), and non-fatal
myocardial infarction (MI; green) in all
recruited patients and in each subcate-
gory of disease. Results are shown as
number of events per 100 person-years.
AF, atrial fibrillation.

data is summarized in Table 2. Calcium-channel blockers
(calcium antagonists) were the most frequently used anti-hyper-
tensive drugs in all disease categories. Approximately half of
the patients with diabetes were treated with oral glucose-low-
ering agents. Statins were most frequently used in MI patients
with hypercholesterolemia (74.9%), while their use in patients
with stroke or AF patients was lower (60.7% and 57.3%,
respectively). Aspirin use was 82.6% in MI patients and 46.0%
in stroke patients. Use of warfarin was 70.0% in AF patients
and was less frequent in stroke or MI patients.
Primary Endpoint
The cumulative event rate of the combined endpoint of all-
cause mortality, non-fatal MI, or non-fatal stroke is shown as
a Kaplan – Meier curve (Figure 1). Indeed, 3.53 per 100 per-
son-years (95%CI: 3.11–3.99 per 100 person-years) of patients
experienced the primary endpoint within 1 year. Details of
secondary endpoints are summarized in Tables 3,4, respec-
tively. Rates of death from stroke and from MI are also shown
in Table 3. Most frequent cause of death within 1 year (1.35
per 100 person-years; 95%CI: 1.10–1.65) in the J-TRACE was
neither death from stroke, MI, nor major bleeding events.
Indeed, the rates of death from stroke and MI were only 0.15
per 100 person-years (95%CI: 0.08–0.27) and 0.06 per 100
person-years (95%CI: 0.02–0.14), respectively. The rate of
death from serious bleeding was 0.05 per 100 person-years

Circulation Journal  Vol.75,  November  2011

2602
(95%CI: 0.01–0.14). The most frequent cause of death in the
J-TRACE was classified as ‘others’.
As shown in Table 4, the most frequent non-fatal events
in J-TRACE were stroke. Indeed, 1.85 events per 100 person-
years (95%CI: 1.55–2.19) recruited in J-TRACE experienced
non-fatal stroke within 1 year. The stroke rate was the highest
among the stroke patients (2.95 per 100 person-years; 95%CI:
2.39–3.60) followed by the AF patients (1.43 per 100 person-
years; 95%CI: 0.97–2.06), and then the MI patients (0.49 per
100 person-years; 95%CI: 0.24–0.90). The rate of non-fatal MI
was low (0.33 per 100 person-years; 95%CI: 0.21–0.49), even
in the patients with a history of MI (0.39 per 100 person-years;
95%CI: 0.17–0.77).
Circulation Journal  Vol.75,  November  2011
GOTO S et al.
Figure 3.    Rates of the primary end-
point of all-cause death/myocardial
infarction/stroke within 1 year in each
CHADS2 score category in all pa-
tients (red), and in the subcategories
of stroke (blue), myocardial infarc-
tion (MI; green), and atrial fibrillation
(AF; dark yellow). Results are shown
as number of events per 100 per-
son-years. CHADS2, congestive heart
failure, hypertension, aging, diabetes
mellitus, and history of stroke or tran-
sient ischemic attack.
Figure 4.    Rates of all-cause death
(red), non-fatal stroke (blue), and
non-fatal myocardial infarction (MI;
green) within 1 year in each CHADS2
score category. Results are shown
as number of events per 100 per-
son-years. CHADS2, congestive heart
failure, hypertension, aging, diabetes
mellitus, and history of stroke or tran-
sient ischemic attack.
As shown in Figure 2, the stroke patients experienced the
highest rates of the primary endpoint and of non-fatal stroke,
followed by the AF and MI patients. In general, the rate of
non-fatal stroke was higher in the stroke patients than in the
AF patients.
As shown in Figure 3, the CHADS2 score is a useful pre-
dictor of the primary endpoint, not only in AF patients, but
also in stroke or MI patients. Although all-cause mortality and
stroke rates were well-associated with the CHADS2 score, the
rate of non-fatal MI was not (Figure 4) in all patients recruited
in the J-TRACE.
One-Year Events in J-TRACE
Discussion
J-TRACE is a registry of stable outpatients, whose data have
been used to generate the likelihood of high-risk CV events in
real-world medical practice, who have a history of MI, stroke
or who have AF, recruited nationwide from Japan. Approxi-
mately 3.5 patients per 100 person-years experienced the pre-
defined primary endpoint of death, MI, or stroke within 1 year
even though they are apparently stable outpatients with no
limitation of treatment. This value is relatively lower than that
reported in a similar global registry,19 but is equivalent to the
value reported in a Japanese sub-study of that global registry.30
As shown in the previous studies, most primary endpoint events
were stroke rather than MI.30 The rate of symptomatic MI was
<0.5 per 100 person-years, even in patients with a history of
MI.
The present J-TRACE study confirmed the higher rate of
CVD events (stroke) compared with CAD events (CV death
and MI) in Japanese patients. It is important to note that the
rate of stroke was higher than that of MI even among patients
initially recruited with a history of MI. Although the recurrence
rate for stroke was high, stroke patients were not so frequently
treated with antiplatelet agents or statins compared to MI
patients. The markedly lower use of clopidogrel in this registry
reflects the fact that most of the patients were recruited before
and soon after registration of clopidogrel. Instead, the use of
ticlopidine was relatively common both in the stroke and MI
patients. Non-use of anti-hypertensive agents in patients with
hypertension was also frequent among the stroke patients com-
pared with the MI patients. Thus, we have to conclude that
stroke patients were undertreated compared with MI patients,
despite the recurrence rate for stroke being higher in Japan.
Unlike North America and Europe, the most common cause
of death in Japan is not CV disease, but cancer.31,32 The present
J-TRACE results support the great impact of cancer in Japan
even in stroke, MI, and AF patients, because at least 34 of
the total 98 death events within 1 year were reported as being
caused by newly detected cancer according to the investiga-
tors’ comments. It is also important to note that the rate of
serious bleeding events was only <0.2 per 100 person-years in
Japan, despite the high incidence of cancer and similar use of
anti-thrombotic agents compared with other countries.16
The present J-TRACE results support the usefulness of risk
stratification based upon the CHADS2 score for predicting
primary outcome events within 1 year, not only in AF patients
but also in non-AF stroke and MI patients.10 The predictive
value of the CHADS2 score, however, is limited in all-cause
mortality and stroke. The rate of MI did not correlate with
the CHADS2 score, although the total number of events was
not high.10 Because the total number of CV and serious bleed-
ing events was not large enough, we could not estimate the
validity of the recently developed, detailed, risk-stratification
methods of cardiac failure, hypertension, age ≥75 (doubled),
diabetes, stroke (doubled) – vascular disease, age at 65–74 years
and sex category (female) (CHA2DS2-VASc)12 or the hyper-
tension, abnormal renal/liver function (1 point each), stroke,
bleeding history or predisposition, labile international nor-
malized ratio, elderly (>65 years), drugs/alcohol concomitantly
(1 point each) (HAS-BLED)33 in this registry. Longer fol-
low-up of this registry might be necessary in order to provide
this level of detail.
Although J-TRACE is a nationwide registry, representing
real-world practice in Japan, it might be argued that the loss
to follow-up of approximately 7% of patients could have
influenced the present results. In general, a follow-up rate of
Circulation Journal  Vol.75,  November  2011
2603
93% is sufficiently high, particularly in the case of J-TRACE,
where the registry is large and homogenous (Japanese patients
living in Japan). We cannot exclude a small margin of error,
however, in the estimation of event rates due to the possible
influence of the loss of patients to follow-up. The similarity in
risk-factor profiles and drug usage between all recruited
patients25 and in those with 1-year data reported in the present
study may suggest the absence of systematic bias. Neverthe-
less, the J-TRACE inclusion criteria for MI and stroke have a
restriction only to exclude acute phase inhospital patients, thus
there might be a potential heterogeneity among these patient
groups. Outcome events were not determined by specific adju-
dication committees, thus, there might be a redundancy based
upon the experience and subspecialty of investigators. There
might be redundancy in the rate of death from MI and stroke
because, unlike the WHO-MONICA study,6,7 J-TRACE did
not include the specific criteria for the precise definition of
death caused by MI and stroke. As previously published, the
majority of patients were recruited from hospital by specialists
of cardiology and neurology.23 Thus, J-TRACE might repre-
sent the real-world practice in a hospital setting in Japan with
a relatively small contribution from clinics and GPs.
We recruited patients with a history of MI, stroke and who
had AF (categorized as high-risk CV diseases), even in the
outpatient setting. Although they are considered as high-risk
CV diseases in clinical practice in the real world,10 there is
substantial heterogeneity in pathophysiology among them.
It is interesting to note, however, that the rate of primary end-
points such as stroke are similarly influenced by CHADS2
score in all subcategories of disease at baseline. In the previous
studies we demonstrated the heterogeneity and overlap among
CAD including MI, CVD including stroke, and peripheral
artery diseases.16,19,21,34,35 In addition to providing information
on the impact of AF on these diseases,10 we demonstrated
the heterogeneity and overlap among these vascular diseases
and AF in the present study.
In conclusion, with the use of the large, contemporary,
nationwide J-TRACE database, we have found a low annual
CV event rate in Japanese patients with a history of stroke,
MI, or patients with AF. The rate of stroke was highest among
patients with a history of stroke. The rates of all-cause mortal-
ity and non-fatal stroke, but not non-fatal MI, were higher in
patients with a higher CHADS2 score, in both AF and non-AF
patients.
Acknowledgment
A complete list of the J-TRACE Investigators has been published previ-
ously.24
Disclosure
Funding: The J-TRACE is sponsored by the Japan Heart Foundation. S.G.
received research grants from Grant-in-Aid for Scientific Research in
Japan (19590871), a grant for the Next-Generation Supercomputer Re-
search and Development Program supported by RIKEN, and a grant for
Regulatory Medicine supported by the Ministry of Health, Labor and
Welfare in Japan.
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