Circulation Journal

Official Journal of the Japanese Circulation Society

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

Low Body Weight Is Associated With the Incidence of

Stroke in Atrial Fibrillation Patients
– Insight From the Fushimi AF Registry –
Yasuhiro Hamatani, MD; Hisashi Ogawa, MD; Ryuji Uozumi, BSc; Moritake Iguchi, MD, PhD;
Yugo Yamashita, MD; Masahiro Esato, MD, PhD; Yeong-Hwa Chun, MD, PhD;
Hikari Tsuji, MD, PhD; Hiromichi Wada, MD, PhD; Koji Hasegawa, MD, PhD;
Mitsuru Abe, MD, PhD; Satoshi Morita, PhD; Masaharu Akao, MD, PhD

Background: Japanese patients with atrial fibrillation (AF) are generally small and lean, but knowledge of the
clinical characteristics of those with low body weight (LBW: ≤50 kg) is limited.

Methods and Results:  The Fushimi AF Registry is a community-based prospective survey of AF patients who visited
the participating medical institutions in Fushmi-ku, Japan. The BW and follow-up data were available for 2,945 patients.
We compared the background and the incidence of clinical events during a median follow-up of 746 days between
a LBW and non-LBW group. Patients in the LBW group accounted for 26.8% (788 patients) of the total. The LBW group
was more often female, older, and had higher CHADS2 score. The incidence of stroke/systemic embolism (SE) during
follow-up was higher in the LBW group (hazard ratio (HR): 2.19, 95% confidence interval (CI): 1.57–3.04; P<0.01),
whereas that of major bleeding was comparable (HR: 1.05, 95% CI: 0.64–1.68; P=0.84). This trend was consistently
observed in the subgroups stratified by age, sex, and oral anticoagulant prescription at baseline. Multivariate analy-
sis as well as propensity-score matching analysis further supported the significance of LBW as a risk of stroke/SE.

Conclusions:  Patients in the LBW group had high risk profiles and showed a higher incidence of stroke/SE, but the
incidence of major bleeding was not particularly high.   (Circ J 2015; 79: 1009 – 1017)

Key Words: Atrial fibrillation; Low body weight; Stroke

A
trial fibrillation (AF) is a common cardiac arrhythmia
among the elderly,1 and its incidence is increasing
significantly (0.6% of the total population in Japan).2
AF increases the risk of thromboembolism, such as stroke or
systemic embolism (SE), 5-fold.3 Oral anticoagulants (OAC)
are highly effective therapy for preventing thromboembolism
in AF patients and for many years, warfarin was the only OAC
for preventing thromboembolism, but novel OACs (NOACs)
have recently become available in clinical practice.4–7
Editorial p 960
There have been several studies investigating the effect of
obesity on stroke/SE in patients with non-valvular AF,8–11 but
that of low body weight (LBW) has not been reported. Large
clinical trials of NOACs demonstrated that bleeding complica-
tions were more often observed in patients with LBW, especially
if ≤50 kg.12 However, those studies were performed mainly in
Western populations, whereas Japanese are generally small
and lean, and data regarding those with LBW are very limited.
The Fushimi AF Registry is a community-based prospective
survey of AF patients in Fushimi-ku, Japan.13,14 We aimed to
enroll all AF patients who visited the participating medical insti-
tutions in Fushimi-ku, a densely populated urban area with a
total population of 283,000. The aim of this study was to evalu-
ate the effect of LBW on AF outcomes, such as stroke, SE, and
major bleeding, in Japanese AF patients, based on the outcomes
recorded in the Fushimi AF Registry.

Received November 14, 2014; revised manuscript received December 22, 2014; accepted December 26, 2014; released online February 13,
2015   Time for primary review: 16 days
Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto (Y.H., H.O., M.I., Y.Y., M. Abe, M. Akao);
Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto (R.U., S.M.); Department
of Arrhythmia, Ijinkai Takeda General Hospital, Kyoto (M.E., Y.-H.C.); Tsuji Clinic, Kyoto (H.T.); and Division of Translational
Research, National Hospital Organization Kyoto Medical Center, Kyoto (H.W., K.H.), Japan
Mailing address: Masaharu Akao, MD, PhD, Department of Cardiology, National Hospital Organization Kyoto Medical Center, 1-1
Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan.   E-mail: akao@kuhp.kyoto-u.ac.jp
ISSN-1346-9843  doi: 10.1253/circj.CJ-14-1245
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.79, May 2015

1010
Methods
The detailed study design, patient enrollment, the definition of
the measurements, and subjects’ baseline clinical characteristics
in the Fushimi AF Registry were previously described (UMIN
Clinical Trials Registry: UMIN000005834).13 The inclusion
criterion for the registry is the documentation of AF on 12-lead
ECG or Holter monitoring at any time. There are no exclusion
criteria. A total of 79 institutions, all of which are members of
Fushimi-Ishikai (Fushimi Medical Association), participated in
the registry. The participating institutions comprised 2 cardio-
vascular centers (National Hospital Organization Kyoto Medical
Center and Ijinkai Takeda Hospital), 9 small- and medium-
sized hospitals, and 68 primary care clinics. The enrollment of
patients was started in March 2011. All of the participating
institutions attempted to enroll all consecutive patients with AF
under regular outpatient care or under admission. Clinical data
of the patients were registered in the Internet Database System
(https://edmsweb16.eps.co.jp/edmsweb/002001/FAF/top.
html) by the doctors in charge at each institution. Data were
automatically checked for missing or contradictory entries and
values out of the normal range. Additional editing checks were
performed by clinical research coordinators at the general office
of the registry. The study protocol conformed to the ethical
guidelines of the 1975 Declaration of Helsinki, and was
approved by the ethics committees of the National Hospital
Organization Kyoto Medical Center and Ijinkai Takeda General
Hospital.
BW was recorded to the nearest 100 g and the data were col-
lected at the time of entry into the registry. We defined LBW
as ≤50 kg. We compared the background and the incidence of
clinical events during the follow-up period between the LBW
group and non-LBW group. We excluded registry participants
for whom BW data were missing.
The primary endpoint in the analysis was the incidence of
stroke/SE during the follow-up period. Other clinical endpoints
included the incidence of major bleeding, all-cause death, and
a composite endpoint of ‘stroke, SE, and all-cause death’ dur-
ing the follow-up period. Stroke was defined as the sudden onset
of a focal neurologic deficit in a location consistent with the
territory of a major cerebral artery. SE was defined as an acute
vascular occlusion of an extremity or organ. Major bleeding
was defined as a reduction in the hemoglobin level of ≥2 g/dl,
transfusion of ≥2 units of blood, or symptomatic bleeding in a
critical area or organ. OACs included warfarin, dabigatran, riva-
roxaban, and apixaban. The prothrombin time-international
normalized ratio (PT-INR) data were collected at the time of
enrollment. The therapeutic range of PT-INR was stratified into
3 groups (over, optimal, and under) according to the current
Japanese guidelines.15 The Japanese guidelines set different
target PT-INR ranges for patients taking warfarin: 1.6–2.6 for
elderly patients (≥70 years old) and 2.0–3.0 for younger patients
(<70 years old).
Statistical Analysis
Continuous variables are expressed as mean ± standard devia-
tion (SD), or median and interquartile range. Categorical vari-
ables are presented as numbers and percentages. We compared
categorical variables using the chi-square test when appropri-
ate; otherwise, we used Fisher’s exact test. We compared
continuous variables using Student’s t-test on the basis of the
distribution. Data were analyzed as crude and stratified by OAC
prescription at baseline because this variable was considered
to be a confounder. Data were also stratified by age (≥75 vs.
<75 years) and sex because men and women or the young and
Circulation Journal  Vol.79, May 2015
HAMATANI Y et al.
the old might have differing body composition. The Kaplan-
Meier method was used to estimate the cumulative incidence
of each clinical event. We carried out multivariate analysis
using a Cox proportional hazards model. The covariates cho-
sen to be included in model 1 were LBW, components of the
CHADS2 risk score (congestive heart failure, hypertension,
age ≥75 years, diabetes mellitus, history of stroke),16 and OAC
prescription at baseline. Those in model 2 were the covariates
included in model 1: female sex, vascular disease, and renal
dysfunction (creatinine clearance <60 ml/min) according to
the components of the CHA2DS2-VASc risk score17 and
R2CHADS2 risk score.18 To reduce the effect of potential
confounding in this observational study, we used propensity-
score matching to perform rigorous adjustment for the differ-
ences in the baseline characteristics.19 The covariates entered
into the propensity score were OAC prescription at baseline,
the components of the CHA2DS2-VASc risk score, and clini-
cally relevant factors (paroxysmal AF, chronic kidney disease,
anemia (defined as hemoglobin <11 g/dl), chronic obstructive
pulmonary disease, and smoking history). The propensity score-
matched pairs were created by matching the LBW and non-
LBW groups on the basis of the nearest neighbor pair-matching
algorithm with a 0.3 caliper width using R version 3.1.0 (pack-
age ‘Matching’ version 4.8-3.4, http://cran.r-project.org/web/
packages/Matching/index.html). A matching ratio of 1:1 was
used. The incidences of stroke/SE were compared between the
LBW and non-LBW groups after matching. Thereafter, we
performed similar tests for the composite endpoint of ‘stroke,
SE, and all-cause death’. We used JMP version 9 (SAS Insti-
tute, Cary, NC, USA) to perform all of these analyses except
propensity-score matching. Two-sided P-values less than 0.05
were considered statistically significant.
Results
A total of 4,115 patients had been enrolled by the end of July
2014. Of 3,666 patients who were enrolled 1 year prior (by the
end of July 2013), follow-up data (collected every year) were
available for 3,304 patients (follow-up rate: 90.1%). Among
these 3,304 patients, BW data were available for 2,945 patients,
and 359 patients’ BW data were missing. Patients without BW
data were younger, had lower CHADS2 score (patients without
BW data vs. those with BW data; mean age 72.0 vs. 73.8 years;
P<0.01, and mean CHADS2 score 1.54 vs. 2.09; P<0.01), and
lower cumulative incidence of stroke during the follow-up
period (1.7% (6/359 patients) vs. 5.0% (148/2,945 patients);
P<0.01).
A total of 2,945 patients were included in the analysis.
Median follow-up period was 746 days (interquartile range:
404–1,109 days). The distributions of BW in the entire cohort,
in male patients, and in female patients are shown in Figure 1.
The mean (±SD) body weight was 59.1 (±13.3) kg in the
entire cohort. Patients in the LBW group accounted for 26.8%
(788 patients) of all of the patients, and 47.0% (433 patients)
of patients ≥80 years of age. Those with BW ≤60 kg accounted
for 55.1% (1,623 patients) of all of the patients. The mean
(±SD) BW was 64.6 (±11.9) kg in males and 50.9 (±11.0) kg
in females.
Baseline characteristics, comorbidities, and OAC prescrip-
tion at baseline are shown in Table 1. The LBW group was
more often female (LBW group 78% vs. non-LBW group 26%;
P<0.01) and older (79.6±9.8 vs. 71.8±10.2 years; P<0.01).
The mean CHADS2 score was higher in the LBW group
(2.31±1.33 vs. 2.00±1.32; P<0.01), and histories of stroke and
heart failure were more common in the LBW group (22% vs.
AF Patients With Low Body Weight
17%, P<0.01; and 39% vs. 25%, P<0.01, respectively), whereas
hypertension and diabetes mellitus were less common (57%
vs. 65%, P<0.01; and 15% vs. 28%, P<0.01, respectively,
LBW vs. non-LBW). The LBW group tended to experience
more episodes of major bleeding (4% vs. 2%, P=0.04). The
LBW group received a prescription of OAC less often at base-
line (46% vs. 56%, P<0.01). The details of the prescribed OACs
are as follows: warfarin: 44% vs. 51% (P<0.01), dabigatran:
2% vs. 4% (P<0.01), rivaroxaban: 0.4% vs. 0.8% (P=0.20), and
apixaban: 0.1% vs. 0.1% (P=0.80), respectively. The intensity
of warfarin control was comparable between the LBW and
non-LBW groups.
The incidences of major clinical events in the entire cohort
during follow-up period were as follows: stroke/SE in 148 (2.5
per 100 person-years), ischemic stroke in 111 (1.9 per 100
person-years), hemorrhagic stroke in 34 (0.6 per 100 person-
years), SE in 3, major bleeding in 89 (1.5 per 100 person-years),
all-cause death in 414 (6.8 per 100 person-years), cardiac death
in 68 (1.1 per 100 person-years), non-cardiac death in 346 (5.7
per 100 person-years), and stroke/SE/all-cause death in 516 (8.7
per 100 person-years). Annual incidence of stroke/SE, major
bleeding, all-cause death, and stroke/SE/all-cause death in the
LBW group were 4.3 per 100 person-years, 1.6 per 100 person-
years, 13.5 per 100 person-years, and 16.1 per 100 person-years,
respectively (Table 2).
Kaplan-Meier curves for the incidences of stroke/SE, major
bleeding, all-cause death, and stroke/SE/all-cause death are
Circulation Journal  Vol.79, May 2015
1011
Figure 1.  Distribution of body
weight in (A) the entire cohort, (B)
male patients and (C) female
patients.
shown in Figure 2. LBW was significantly associated with a
higher incidence of stroke/SE (hazard ratio (HR): 2.19, 95%
confidence interval (CI): 1.57–3.04; P<0.01), worse mortality
rate (HR: 2.74, 95% CI: 2.25–3.32, P<0.01), and higher inci-
dence of stroke/SE/all-cause death (HR: 2.45, 95% CI: 2.06–
2.92, P<0.01), compared with non-LBW. The incidence of major
bleeding was comparable between the groups (HR: 1.05, 95%
CI: 0.64–1.68, P=0.84).
A higher risk of stroke/SE during follow-up period in the
LBW group was consistently observed in patients stratified by
OAC prescription at baseline (with OAC: HR: 1.94, 95% CI:
1.23–2.98, P<0.01; without OAC: HR: 2.65, 95% CI: 1.59–
4.40, P<0.01), by sex (male: HR: 2.79, 95% CI: 1.56–4.68,
P<0.01; female: HR: 2.46, 95% CI: 1.46–4.32, P<0.01), or by
age (≥75 years: HR: 1.80, 95% CI: 1.23–2.65, P<0.01; <75
years: HR: 1.86, 95% CI: 0.87–3.63, P=0.08) (Figure 3). Sta-
tistical test for interaction was not significant for all subgroups
(P=0.28 for interaction with OAC prescription, P=0.78 for that
with sex, and P=0.93 for that with age). The incidence of major
bleeding during the follow-up period was consistently compa-
rable between the groups stratified by OAC prescription at base-
line (with OAC: HR: 0.68, 95% CI: 0.30–1.37, P=0.30; without
OAC: HR: 1.67, 95% CI: 0.81–3.07, P=0.17), by sex (male:
HR: 1.49, 95% CI: 0.62–3.06, P=0.34; female: HR: 1.67, 95%
CI: 0.74–3.97, P=0.22) or by age (≥75 years: HR: 1.07, 95%
CI: 0.60–1.84, P=0.83; <75 years: HR: 0.59, 95% CI: 0.14–
1.64, P=0.34).
1012 HAMATANI Y et al.

Table 1.  Baseline Characteristics and Comorbidities of AF Patients From the Fushimi AF Registry
LBW (n=788) Non-LBW (n=2,157) P value
Baseline characteristics
  Female (%) 614 (78%) 564 (26%) <0.01
   Age (years), mean ± SD 79.6±9.8　　 71.8±10.2 <0.01
   Age ≥75 years 584 (74%) 949 (44%) <0.01
   Body mass index (kg/m2), mean ± SD 19.2±2.3　　 24.4±3.6　　 <0.01
   Systolic BP (mmHg), mean ± SD 123.0±20.2　　 125.2±18.3　　 <0.01
   Diastolic BP (mmHg), mean ± SD 68.2±13.4 71.1±12.4 <0.01
   Heart rate (beats/min), mean ± SD 79.0±17.1 77.4±15.1 　0.01
  Smoking history 148 (19%) 889 (41%) <0.01
  Paroxysmal AF 392 (50%) 1,005 (46%)　　　 　0.13
Comorbidities
  CHADS2 score, mean ± SD 2.31±1.33 2.00±1.32 <0.01
   History of stroke 173 (22%) 373 (17%) <0.01
  Heart failure 309 (39%) 538 (25%) <0.01
  Hypertension 453 (57%) 1,395 (65%)　　　 <0.01
  Diabetes mellitus 118 (15%) 613 (28%) <0.01
  Vascular disease 90 (11%) 211 (10%) 　0.19
   Chronic kidney disease 334 (42%) 737 (34%) <0.01
   Anemia (hemoglobin <11 g/dl) 245 (32%) 236 (12%) <0.01
   Chronic obstructive pulmonary disease 58 (7%) 102 (5%)　　 <0.01
   History of major bleeding 28 (4%) 48 (2%) 　0.04
OAC prescription at baseline 364 (46%) 1,206 (56%)　　　 <0.01
  Warfarin 348 (44%) 1,102 (51%)　　　 <0.01
  Dabigatran 12 (2%) 84 (4%) <0.01
  Rivaroxaban 3 (0.4%) 18 (0.8%) 　0.20
  Apixaban 1 (0.1%) 2 (0.1%) 　0.80
Warfarin control at baseline
  PT-INR value 1.82±0.46 1.83±0.47 　0.78
Therapeutic range of PT-INR
  Under 37.2% 42.8%
  Optimal 57.5% 53.5% 　0.18
  Over 5.4% 3.8%
Categorical data are presented as number (%). Continuous data are presented as mean ± standard deviation (SD).
AF, atrial fibrillation; BP, blood pressure; LBW, low body weight; OAC, oral anticoagulant; PT-INR, prothrombin time-
international normalized ratio. Vascular disease included old myocardial infarction and peripheral artery disease.

In the multivariate analysis, after adjustment for congestive
heart failure, hypertension, age ≥75 years, diabetes mellitus,
history of stroke, and OAC prescription at baseline (model 1),
LBW was an independent risk factor of the incidence of
stroke/SE during the follow-up period (HR: 1.84, 95% CI: 1.29–
2.60, P<0.01). Even after adjustment by the covariates included
in model 1 plus vascular disease, female sex, and renal dysfunc-
tion (model 2), LBW remained an independent risk factor of
stroke/SE (HR: 2.13, 95% CI: 1.39–3.27, P<0.01) (Table 3).
Propensity score-matching for the entire cohort yielded 538
matched pairs of patients. In the matched cohort, there were
no longer any significant differences between the LBW and
non-LBW groups for any covariate. The cumulative events and
incidence of stroke/SE in the propensity score-matched cohort
during the follow-up period was 59 (2.8 per 100 person-years).
Annual incidence of stroke/SE in LBW group was 3.9 per 100
person-years (Table 4). For the 538 propensity score-matched
pairs, LBW was significantly associated with a higher inci-
dence of stroke/SE (HR: 2.13, 95% CI: 1.26–3.73; P<0.01)
(Figure 4).
In addition, LBW was significantly associated with a higher
incidence of the composite endpoint of ‘stroke, SE, and all-
cause death’. It was also the case in the subgroups stratified by
age, sex, and OAC prescription at baseline, or in the propensity
score-matched cohort. This excludes the possibility that undi-
agnosed stroke was much more frequent in the non-LBW group.
We also investigated the possibility of a J-curve or U-shaped
relationship between BW and thromboembolism. Patients with
high BW (>60 kg, >70 kg, >80 kg, and >90 kg) were not high
risk for thromboembolism in either the univariate or multi-
variate analysis.
Discussion
BW and the Risk of Stroke
To the best of our knowledge, the effect of LBW on AF out-
comes has not been reported. Japanese patients are generally
small and lean, and their mean BW is much lower than that of
Western populations. The Fushimi AF Registry represents the
current status of “real-world” AF patients in Japan, and con-
tains many frail elderly patients with LBW.
A previous study concluded that overweight patients with

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AF Patients With Low Body Weight 1013

Table 2.  Incidence of Clinical Events During Follow-up (per 100 Person-Years) of AF Patients From the
Fushimi AF Registry
Total LBW Non-LBW
P value*
(n=2,945) (n=788) (n=2,157)
Stroke/SE 2.5 4.3 1.9 <0.01
  Ischemic stroke 1.9 3.4 1.4 <0.01
  Hemorrhagic stroke 0.6 0.7 0.5 　0.52
Major bleeding 1.5 1.6 1.5 　0.84
All-cause death 6.8 13.5 4.8 <0.01
  Cardiac death 1.1 2.3 0.8 <0.01
  Non-cardiac death 5.7 11.2 4.0 <0.01
Stroke/SE/All-cause death 8.7 16.1 6.4 <0.01
*P value for comparison between LBW and non-LBW from log-rank test. SE, systemic embolism. Other abbreviations
as in Table 1.

Figure 2.   Kaplan-Meier curves for the incidences of stroke or systemic embolism (SE), major bleeding, all-cause death, and
stroke/SE/all-cause death in the entire cohort during the follow-up period. CI, confidence interval; HR, hazard ratio; LBW, low body
weight.

AF were associated with a significantly higher composite end-
point of ischemic stroke, thromboembolism, and death.8 Other
studies found that being overweight was associated with a sig-
nificantly lower risk of all-cause mortality, and concluded that
there might be an obesity paradox among AF patients.9–11 These
studies excluded underweight patients with a body mass index
<18.5, and the characteristics of underweight patients with AF
are unknown. There have been a couple of studies showing a
relationship between underweight and stroke in non-AF patients:
low body mass index in older patients with hypertension was
associated with increased risk of death and stroke,20 and under-
weight patients with acute stroke had a higher risk of stroke
recurrence.21
The mechanisms by which LBW is associated with a higher
risk of stroke/SE are unknown, but there are various possible
explanations. First, LBW may be simply the consequence of
poor nutritional status, or illness-related weight loss because of
malignancy, chronic obstructive pulmonary disease, etc. Second,

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1014 HAMATANI Y et al.

Figure 3.   Kaplan-Meier curves for the incidence of stroke or systemic embolism (SE) in various subgroups during follow-up period.
We stratified the entire cohort by oral anticoagulant (OAC) prescription at baseline (with OAC vs. without OAC), by sex (male vs.
female), and by baseline age (≥75 vs. <75 years). CI, confidence interval; HR, hazard ratio; LBW, low body weight.

overweight patients have a higher prevalence of coexisting
conditions such as hypertension, dyslipidemia, and diabetes
mellitus, and they may be more likely to receive treatment for
such comorbidities than LBW patients.22 However, the higher
risk of stroke/SE in the present LBW group from the Fushimi
AF Registry patients persisted after adjustment for sex, age,
CHADS2 score, and OAC prescription, and also persisted after
adjustment for antihypertensive agents, lipid-lowering agents,
oral hypoglycemic agents, and insulin. Third, underweight
patients may have advanced atrial fibrosis and remodeling
through activation of the renin-angiotensin system.23 Lean
patients have shown greater increases in plasma renin levels
than obese patients during stress testing.24 Fourth, low body
mass index is reportedly associated with impaired endothelial
dysfunction, leading to reduced bioavailability of nitric oxide,
which plays a role in the regulation of vascular tone and inhi-

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AF Patients With Low Body Weight 1015

Table 3.  Indicators of the Incidence of Stroke or Systemic Embolism During Follow-up of AF Patients From
the Fushimi AF Registry – Multivariate Analysis
Model 1 Model 2
Variable
HR (95% CI) P value HR ratio (95% CI) P value
LBW 1.84 (1.29–2.60) <0.01　 2.13 (1.39–3.27) <0.01　
OAC prescription at baseline 1.08 (0.77–1.52) 0.65 1.05 (0.75–1.49) 0.76
Heart failure 1.14 (0.80–1.61) 0.46 1.07 (0.74–1.53) 0.70
Hypertension 1.03 (0.74–1.46) 0.86 1.06 (0.75–1.51) 0.76
Age (≥75 years) 1.96 (1.36–2.85) <0.01　 1.77 (1.18–2.67) <0.01　
Diabetes mellitus 1.25 (0.85–1.79) 0.25 1.20 (0.82–1.74) 0.34
History of stroke 1.90 (1.32–2.68) <0.01　 1.87 (1.30–2.67) <0.01　
Female sex – – 0.73 (0.49–1.09) 0.12
Vascular disease – – 1.09 (0.75–1.49) 0.76
Renal dysfunction – – 1.26 (0.84–1.89) 0.27
Vascular disease included old myocardial infarction and peripheral artery disease. Renal dysfunction was defined as
creatinine clearance (calculated with Cockcroft-Gault formula) <60 ml/min. CI, confidence interval; HR, hazard ratio.
Other abbreviations as in Table 1.

Table 4.  Propensity Score-Matched Cohort of AF Patients From the Fushimi AF Registry, Baseline
Characteristics and Incidence of Clinical Events During Follow-up
LBW (n=538) Non-LBW (n=538) P value
Baseline characteristics
  Female (%) 368 (68%) 373 (69%) 　0.74　
   Age ≥75 years 350 (65%) 353 (66%) 　0.85　
  Paroxysmal AF 277 (51%) 267 (50%) 　0.54　
  Smoking history 129 (24%) 113 (21%) 　0.38　
   History of stroke 120 (22%) 114 (21%) 　0.66　
  Heart failure 171 (32%) 171 (32%) 　1.00　
  Hypertension 324 (60%) 325 (60%) 　0.95　
  Diabetes mellitus 99 (18%) 91 (17%) 　0.52　
  Vascular disease 57 (11%) 57 (11%) 　1.00　
   Chronic kidney disease 216 (40%) 212 (39%) 　0.80　
   Anemia (hemoglobin <11 g/dl) 139 (26%) 114 (21%) 　0.07　
   Chronic obstructive pulmonary disease 38 (7%) 37 (7%) 　0.90　
   OAC prescription at baseline 264 (49%) 259 (48%) 　0.76　
Incidence of clinical events during follow-up
(/100 person-years)
  Stroke/SE 3.9 1.8 <0.01*
    Ischemic stroke 3.0 1.3 <0.01*
    Hemorrhagic stroke 0.9 0.5 　0.37*
  Major bleeding 1.7 1.7 　0.98*
  All-cause death 12.5 6.1 <0.01*
    Cardiac death 1.8 1.5 　0.72*
    Non-cardiac death 10.7 4.6 <0.01*
  Stroke/SE/all-cause death 15.0 7.5 <0.01*
*P value for comparison between LBW and non-LBW from log-rank test. Categorical data are presented as number
(%). Abbreviations as in Tables 1,2. Vascular disease included old myocardial infarction and peripheral artery
disease.

bition of platelet aggregation and adhesion.25,26 Fifth, LBW may
be associated with systemic inflammation.27 Inflammation is
linked to systemic activation of coagulation,28 and is report-
edly related to indexes of prothrombotic state in AF patients.29
However, each of these mechanisms remains speculative and
does not fully explain the relationship between LBW and
thromboembolism.
BW and the Risk of Bleeding
Bleeding complications with NOACs in LBW patients have
been reported. In the RE-LY trial of dabigatran, bleeding com-
plications were more often observed in those with a LBW
(≤50 kg).12 In the J-ROCKET trial, which compared rivaroxa-
ban with warfarin for the prevention of stroke in Japanese AF
patients, the rate of bleeding complications was also higher in
those with a LBW (≤50 kg).30 Increased bleeding complications
among the present LBW patients were consistent with results

Circulation Journal  Vol.79, May 2015

1016
Figure 4.   Kaplan-Meier curves for the incidence of stroke or
systemic embolism (SE) in the propensity score-matched
cohort. CI, confidence interval; HR, hazard ratio; LBW, low
body weight.
from studies on fibrinolytic therapy31 and also on antiplatelet
therapy for those undergoing percutaneous coronary interven-
tion.32,33 However, the incidence of major bleeding was com-
parable between the LBW and non-LBW groups in the Fushimi
AF Registry AF cohort. This was also the case even after adjust-
ment by OAC prescription. As shown in Table 1, the main
prescribed OAC was warfarin, and the PT-INR levels were
comparable between the LBW and non-LBW groups. The rea-
son why the incidence of major bleeding was equivalent remains
elusive. The use of warfarin may be safe in LBW patients under
careful monitoring of PT-INR, but longer follow-up would be
needed.
Study Limitations
First, the results come from an observational study and pro-
vide only associative evidence, not causative. We cannot rule
out the possibility of unmeasured or residual confounding,
especially with age, even after multivariate analysis and pro-
pensity score-matching, as well as the negative P value for
interaction, because advanced age and LBW were strongly asso-
ciated. Although we demonstrated LBW as an independent
risk factor for stroke/SE in the Fushimi AF Registry, the results
need to be validated in other independent datasets. Second,
among 3,304 patients, 359 patients’ (10.9%) were missing BW
data. We believed that the missing data were unlikely to change
the conclusion of our study given the lower incidence of
stroke/SE among those 359 patients during the follow-up period
(1.7%, namely 6 patients), although the possibility cannot be
completely excluded. Third, BW data were collected only at
the time of entry into the study, so we were unable to explore
the relationship between changes in BW and clinical events.
Fourth, antithrombotic drugs and the doses were selected at
the discretion of the attending physician. Despite these limita-
tions, our study is the first to demonstrate a positive associa-
tion between LBW and the risk of stroke/SE in Japanese AF
patients. Only the median follow-up data for 2 years are avail-
able at present, so we would like to continue to follow our cohort
for a longer period.
Circulation Journal  Vol.79, May 2015
HAMATANI Y et al.
Conclusions
In a community-based, large prospective cohort, we demon-
strated that many Japanese AF patients have LBW and they
had a higher risk profile for stroke/SE, and indeed had a higher
incidence of stroke/SE during the follow-up period. However,
the incidence of major bleeding was not particularly high in
the LBW group.
Acknowledgments
We sincerely appreciate the help of all the institutions participating in the
registry and the clinical research coordinators (Shinagawa T, Mitamura
M, Fukahori M, Kimura M, Fukuyama M, Kamata C).
Disclosures
The Fushimi AF Registry is supported by research funding from Boehringer
Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas
Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-
Aventis and Takeda Pharmaceutical. Dr Akao received lecture fees from
Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare.
All authors report no other relationships relevant to the content of this
paper.
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Appendix
The following is a list of the institutions participating in the registry.
Circulation Journal  Vol.79, May 2015
1017
Chief Investigator
Akao M (National Hospital Organization Kyoto Medical Center).
Vice-chief Investigator
Chun YH (Ijinkai Takeda General Hospital).
Steering Committee
Esato M (Ijinkai Takeda General Hospital), Abe M (National Hospital
Organization Kyoto Medical Center), Tsuji H (Tsuji Clinic), Furuke K
(Furuke Clinic).
Statistical Analysis
Wada H (National Hospital Organization Kyoto Medical Center).
Coordinator
Ogawa T (Ogawa Medical Office); Tasato H (Tasato Clinic); Taniguchi
Y (Taniguchi Clinic); Nishikawa M (Nishikawa Clinic); Furukawa K
Takeda General Hospital); Tsukahara T, Fukuda S, Nakamura M, Ito T,
Hasegawa K (National Hospital Organization Kyoto Medical Center).
Clinical Event Committee
Kawabata Y, Yasuda K, Kameyama K (National Hospital Organization
Kyoto Medical Center).
Participating Institutions
Department of Cardiology, National Hospital Organization Kyoto Medical
Center (Akao M, Abe M, Ogawa H, Masunaga N, Iguchi M, Ishii M,
Unoki T, Takabayashi K, Hamatani Y, Yamashita Y, Takagi D, Niki S,
Osakada G, Nakashima Y, Kanasaki M, Nakano T, Funatsu J, Nishio M,
Takenaka Y); Department of Arrhythmia, Ijinkai Takeda General Hospital
(Chun YH, Esato M, Kida Y, Nishina N); Koujinkai Oshima Hospital
(Terada K); Divison of Translational Research, National Hospital
Organization Kyoto Medical Center (Hasegawa K, Wada H); Kanai
Hospital (Nishio M, Kamiya Y, Abe M, Ishii M); Tsuji clinic (Tsuji H);
Furukawa Medical Clinic (Furukawa K); Nishikawa Clinic (Nishikawa
M); Taniguchi Clinic (Taniguchi Y); Gushiken Clinic (Gushiken T);
Fushimi Shimizu Hospital (Hirata Y); Yoda Clinic (Yoda J); Tasato
Clinic (Tasato H); Ogawa Medical Office (Ogawa T); Saiwai Hospital
(Wakatsuki Y, Yahata M, Higashitani N); Itoh Hemodialysis Clinic (Itoh
H); Itoh Clinic (Itoh H, Ohmori Y); Ryokuhoukai Tsuji Clinic (Tsuji K);
Kitamura Clinic (Kitamura S); Izumikawa Clinic (Izumikawa F); Hirota
Clinic (Hirota N); Kyomachi-Oota Clinic (Oota K); Kouseikai Rehabilitation
Clinic (Kou K); Inariyama Hospital (Tanaka T, Iguchi M); Matsushita
Clinic (Matsushita N); Kitani Clinic (Kitani K); Kimura Clinic (Kimura
F); Hayashi Clinic (Hayashi S); Handa Clinic (Handa S); Soseikai General
Hospital (Hasegawa S, Kono T, Otsuka K, Soyama A, Okamoto J, Nakai
Y); Asamoto Clinic (Asamoto H); Sugano Clinic (Tanaka H, Murata T);
Kyoto Ohashi General Hospital (Kayawake S, Kinoshita Y); Furuke
Clinic (Furuke K); Kanehisa Clinic (Asano N); Tahara Clinic (Tahara K);
Matsumoto Medical Office (Matsumoto K); Kuroda Clinic (Kuroda O);
Ochiai Clinic (Ochiai K, Ochiai J); Fujii Clinic (Fujii M); Kurihara Clinic
(Kurihara M); Kuzuyama Clinic (Ito A); Kenkokai Fushimi Clinic
(Totsuzaki S); Nakayama Orthopedic Clinic (Nakayama H); Department
of Cardiovascular Medicine, Ijinkai Takeda General Hospital (Kawai C,
Hashimoto T, Kakio T, Watanabe C, Takeda S, Sasaki Y, Shirasawa K,
Beppu K, Inoue T, Shirasaka A, Doi T); Tatsumi Clinic (Ueda T); Oishi
Clinic (Oishi M); Koizumi Clinic (Kasahara A); Kishida Clinic (Kishida
Su, Kishida Sa); Shibata Clinic (Shibata M); Shimizu Clinic (Shimizu J);
Shirasu Clinic (Shirasu M); Fujinokai Clinic (Tateishi S); Tsukuda Clinic
(Tsukuda N); Shinseikai Tsuji Clinic (Tsuji K); Nishi Clinic (Nishi T);
Nishimura Clinic (Nishimura S); Haba Clinic (Haba T); Higashimae
T); Matsui Clinic (Matsui H, Matsui H); Shadan Matsumoto Clinic
(Matsumoto H); Maruo Clinic (Maruo N); Misu Clinic (Mikami M); Mekata
Clinic (Mekata H); Mori Pediatric Clinic (Mori H); Wakabayashi Clinic
(Wakabayashi M); Nakatsugawa Clinic (Sasaki Z); Shiseikai Nishimura
Clinic (Nishimura S); Yuge Eye Clinic (Yuge K); Gokita Hospital (Haruta
M); Soseikai Clinic (Tsuda E); Toujinkai Hospital (Nishimura M); Kouno
Clinic (Kouno T); Matsumura Clinic (Matsumura S); Fujita Clinic (Fujita
A); Takayasu Clinic (Takayasu F, Takayasu S); Yano Clinic (Yano Y); Niki
Clinic (Niki S); Hasegawa Meiando Clinic (Hasegawa S); Watanabe Medical
Clinic (Watanabe T).