Europace (2015) 17, ii31–ii39 SUPPLEMENT: REVIEW

doi:10.1093/europace/euv231

Asian strategy for stroke prevention in atrial

fibrillation
Chern-En Chiang 1*, Kang-Ling Wang 1, and Shing-Jong Lin 2
1
General Clinical Research Center and Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan;

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and 2Department of Medical Research, Cardiovascular Research Center, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan

Received 14 April 2015; accepted after revision 4 June 2015

Atrial fibrillation (AF) has become a major health burden in Asia. It is estimated that in year 2050 Asia will have 72 million AF patients, and 2.9
million among them will suffer from AF-associated stroke. Asian AF patients have similar cardiovascular co-morbidities as westerns, and the
recently developed CHA2DS2-VASc score remains valid in predicting stroke risk in Asians, outperforming other scoring systems. There is little
evidence supporting a role of aspirin in preventing AF-associated stroke in Asians. Warfarin is effective for the prevention of stroke in Asians,
but is very difficult to use. Warfarin-induced bleeding events are more common in Asians. Four major clinical trials have been performed to test
non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin in the stroke prevention in AF. Warfarin produced higher risk of major
bleeding and intra-cranial haemorrhage in Asians compared with those in non-Asians, even though anticoagulation intensity was lower in Asians.
All these trials consistently demonstrated that NOACs were superior or non-inferior to warfarin. The benefits of NOACs were especially
robust in Asians. The relative risk reduction in most of the efficacy endpoints and the safety endpoints was numerically greater in Asians
than in non-Asians. There was no evidence of increased risk of gastro-intestinal bleeding associated with NOACs in Asians. Unless in a few
conditions when NOACs are contraindicated, NOACs are preferred medications in the stroke prevention for AF in Asians.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Atrial fibrillation † Asians † NOACs † Stroke

Burden of atrial fibrillation in Asia
Atrial fibrillation (AF) is the most common sustained cardiac ar-
rhythmia.1 According to the recent report from the Global Burden
of Disease study, both the age-adjusted prevalence rate and the in-
cidence rate increased from 1990 to 2010.2 The disability-adjusted
life-years associated with AF increased by 18.8% in men and 18.9% in
women in the same period of time.2 The prevalence rate of AF in
adult population is 1% in most Asian countries, lower than that
in western countries (2%).3,4 Owing to the rapid growing of eld-
erly population in Asia, the burden of AF should is huge.5 In 2050,
Asia will have 72 million AF patients,5 more than the combined num-
bers of patients from Europe and the USA.6,7 Moreover, 2.9 million
Asian patients will suffer from AF-associated stroke in 2050.8
Patients with non-valvular AF have 4- to 5-fold higher risk of is-
chaemic stroke than those without AF.9 About 20% of all ischaemic
stroke were associated with AF. The risk of AF-associated stroke
can be predicted by several risk factors and some scoring sys-
tems.10,11 The prevalence rates of these risk factors were similar
among Asians and non-Asians (Figure 1).12 – 23 Congestive heart fail-
ure was found in 20 – 30% of patients (Figure 1A). Hypertension
was identified in 60 – 70% of patients (Figure 1B). The mean age
was around 70 years (Figure 1C). Type 2 diabetes was diagnosed
in 20 – 30% of patients (Figure 1D). Asian patients had a higher
prevalence of previous stroke or transient ischaemic attack than
non-Asians (Figure 1E). Coronary heart disease (CHD) was more
commonly found in non-Asian cohorts, except in one cohort study
from China21 (Figure 1F).
Risk scoring system in Asians
The CHADS2 [Congestive heart failure, Hypertension, Age ≥75,
Diabetes, Stroke (doubled)] score has widely been used to predict
the annual risk of stroke for AF until recently.10,11 The newly devel-
oped CHA2DS2-VASc [Congestive heart failure, Hypertension, Age
≥75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age
65 – 74, Sex category (female)] score24 has been used more often
in recent years and has been adopted by most contemporary guide-
lines.24 – 27 The CHA2DS2-VASc score has been validated in several
Asian cohorts,21,23,28,29 and has been shown to be a better scoring
system than others.28 The CHA2DS2-VASc score has been

* Corresponding author. Tel: +886 228757774; fax: +886 228745422. E-mail address: cechiang@vghtpe.gov.tw
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
ii32 C.-E. Chiang et al.

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Figure 1 Prevalence of co-morbidities of AF in non-Asians and Asians in major cohort studies or registries.12 – 23 (A) Congestive heart failure, (B)
hypertension, (C) mean age, (D) type 2 diabetes, (E) stroke and transient ischaemic attack, and (F) coronary heart disease.

recommended by the Asia Pacific Heart Rhythm Society as a basic risk of stroke was generally higher in Asians compared with that
risk assessment tool for selecting better anticoagulation therapy.30 in a Swedish cohort, starting from CHA2DS2-VASc score of 0 – 5
The risk of AF-associated stroke in Asians vs. non-Asians was not (Figure 2).23,28,31 The stroke risk was extremely high in the Hong
very clear in the past. In two recent cohorts from Asia, the annual Kong cohort. 23 It should be mentioned that in this Hong Kong
Asian strategy for stroke prevention ii33

14
12.7
Sweden
12 Taiwan 11.6

Hong Kong

10 9.6

7.8
8 7.2
6.6 6.6
5.8
6

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4.8
4.2
4
3.2 3.2
2.4 2.2
2 1.7
1.1
0.6
0.2
0
% 0 1 2 3 4 5
CHA2DS2-VASc score

Figure 2 The annual stroke risk for corresponding CHA2DS2-VASc score in recent AF cohorts from Sweden, Taiwan, and Hong Kong.23,28,31

cohort the mean age was 77 years and all patients were from a ter-
tiary referred centre.23
Role of aspirin
Aspirin was ineffective in the stroke prevention for AF in Cauca-
sians.32,33 Owing to a general impression that aspirin is safer than
warfarin, aspirin was widely used for stroke prevention in Asia in
the past. In a report from the National Health Insurance Research
database of Taiwan, only 15.4% of patients who had a CHADS2
score ≥2 received warfarin, while 50.6% of them received aspirin.34
Recent Asian data suggested that aspirin was ineffective in the stroke
prevention in AF. In this Japanese trial, aspirin was compared with
placebo in the stroke prevention in low-risk AF patients.35 Notwith-
standing no effect with the use of aspirin in reducing stroke, the risk
of bleeding was increased by aspirin.35 In a recent Hong Kong co-
hort, the use of aspirin was not effective.23 However, the use of as-
pirin continues to be recommended in some country-specific
guidelines in Asia, putting patients at risk of stroke.36
Role of vitamin K antagonists
Vitamin K antagonists (VKAs), such as warfarin, were very effective
in reducing AF-associated stroke. In a meta-analysis of six trials, the
warfarin group had a 64% reduction in stroke compared with the
placebo group.33 There was no large-scaled randomized controlled
trial (RCT) in Asia to compare warfarin vs. placebo or aspirin in the
stroke prevention in AF patients. In a recent AF cohort from Hong
Kong, the use of warfarin significantly reduced the risk of stroke by
53%, compared with placebo.23
The problems of using warfarin in Asia are multiple. First, the op-
timal international normalized ratio (INR) for Asian patients was un-
known.37 Many studies in Asia suggested a lower range of INR (1.6–
2.6), but they were usually small-scaled or retrospective.38 – 40 A tar-
get INR of 1.6 – 2.6 was suggested by a recent report from the
J-RHYTHM registry, but the time in therapeutic range (TTR) was
not provided.41 In fact, there was no large-scaled RCT to test the
optimal range of INR in Asians.
Secondly, Asians are more difficult to keep INR in the therapeutic
range (2.0 –3.0). Poor TTR in Asians may be due to diet, extensive
use of herbal drugs, etc.42 It is uncommon to have structured antic-
oagulation clinic in many Asian countries, adding to more hurdles in
optimal control of INR. In a recent global AF cohort of 15 400 pa-
tients, mean TTRs for China, India, and Southeast Asia were 35.5,
33.7, and 36.0%, respectively,16 lower than those from North
America (50.9%) and West Europe (62.4%).16
Thirdly, Asians had higher bleeding events when treated with
VKA. In a recent analysis of the four large-scaled RCTs of non-VKA
oral anticoagulants (NOACs, previously referred to as new or novel
OACs)43 in the stroke prevention in AF, warfarin-treated Asians had
higher bleeding risk than warfarin-treated non-Asians, despite that
Asians were less intensively anticoagulated, i.e. higher proportions
of Asian patients with an INR ,2 than those in non-Asians.36 The
annual risk of haemorrhagic stroke among warfarin-users in Asians
ranged from 0.75 to 1.33%, compared with 0.32 – 0.41% in non-
Asians.36 Similarly, the annual risk of intra-cranial haemorrhage
(ICH) for Asians ranged from 1.10 to 2.46%, compared with
0.63 –0.74% in non-Asians.36 Because more Asian patients in these
trials had an INR ,2.0, the risk of stroke and systemic embolization
events (SEEs) was higher in Asians than in non-Asians.36 These data
 ii34
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Table 1 Comparisons of four RCTs

RE-LY44,48 ROCKET45,49 ARISTOTLE46,50 ENGAGE47,51

.............................................................................................................................................................................................................................................
Total number 18 113 14 264 18 201 21 105
Asian number 2782 932 1993 1943
Inclusion criteria
CHADS2 ≥0 ≥2 ≥1 ≥2
CHA2DS2-VASc ≥1 ≥2 ≥1 ≥2
Proportion Primary efficacy endpoints Proportion Primary efficacy endpoints Proportion Primary efficacy endpoints Proportion Primary efficacy endpoints
Dab 110 vs. war Dab 150 vs. war Riv 20 vs. war Api 5 vs. war Edo 30 vs. war Edo 60 vs. war
Global patients
CHADS2 (mean) 2.1 3.5 2.1 2.8
0 31.9% NS P , 0.05 0% NA 0% NA 0% NA NA
1 0% NS 34.0% NS 0% NA NA
2 35.6% NS P , 0.05 13.0% NS 35.8% NS 77.4% NS NS
3 32.5% NS P , 0.05 43.6% NS 30.2% P , 0.05
4 28.7% NS 22.6% NS NS
5 12.7% NS
6 2.0% Ns
Asian patients
CHADS2 (mean) 2.2 3.2 2.1 2.9
0 30.2% NA NA 0% NA 0% NA 0% NA NA
1 0% NA 39.3% NA 0% NA NA
2 33.0% NA NA 24.0% NS 28.3% NA 76.5% NA NA
3 36.8% NA NA 42.2% NS 32.4% NA
4 24.3% NS 23.5% NA NA
5 8.3% NS
6 1.2% NS

Api, apixaban; Dab, dabigatran; Edo, edoxaban; NA, not available; NS, non-significant; Riv, rivaroxaban; war, warfarin.

C.-E. Chiang et al.

Asian strategy for stroke prevention ii35

suggested that warfarin was very difficult to use in Asians, and there
is an unmet need for stroke prevention in Asians.
Role of non-vitamin K antagonist
oral anticoagulants
Non-vitamin K antagonist oral anticoagulants provide better solutions
for stroke prevention in AF. These drugs have several important
advantages over VKAs, namely, relatively better efficacy, safety, and
convenience.8 There are two major classes of NOACs—the oral dir-
ect thrombin inhibitors (e.g. dabigatran) and the oral Factor Xa inhi-
bitors (e.g. rivaroxaban, apixaban, and edoxaban). These four drugs
have been studied in four large RCTs,44 – 47 and a substantial propor-
tion of patients were recruited from Asian countries (Table 1).48 – 51
There were some differences in the inclusion criteria in these four
trials (Table 1). Of note, the RE-LY trial included some patients with
CHADS2 score ¼ 0 (CHA2DS2-VASc score ¼ 1, e.g. age 65 – 74

A B

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20 100
14
Non-Asians Non-Asians
8 77
Asians Asians
0
50
–7 38*
–11 –12
–20 17 17
–19 –19*
–22
–26 1 1
–28* –29 0
–40 –6 –6
–18 –14

–36
–60 –55* –50 –45*
% Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban % Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban
150 mg 110 mg 20 mg 5 mg 60 mg 30 mg 150 mg 110 mg 20 mg 5 mg 60 mg 30 mg

C D
0 50

33
26
22
17

–38*
–41* –43* 0
–50 0

–6
–60 –60* –12
–63* –64* –13 –15
–68* –19 –17
–72*
–75* Non-Asians –26
–78* Non-Asians
–85* Asians
Asians
–100 –50
% Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban % Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban
150 mg 110 mg 20 mg 5 mg 60 mg 30 mg 150 mg 110 mg 20 mg 5 mg 60 mg 30 mg

E
50
Non-Asians

Asians

0
–2
–7
–10 –11 –12* –12*
–15
–22
–27
–34
–37*
–50
% Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban
150 mg 110 mg 20 mg 5 mg 60 mg 30 mg

Figure 3 Relative risk reduction in five major efficacy endpoints in Asians and non-Asians in four major clinical trials.48 – 51 (A) Stroke/systemic
embolization events, (B) ischaemic stroke, (C) haemorrhagic stroke, (D) myocardial infarction, and (E) all-cause mortality. *P , 0.05.
ii36 C.-E. Chiang et al.

year and a history of CHD).44 All other trials enrolled patients with a
CHADS2 score of at least 1. The ROCKET trial enrolled patients
with higher risk (CHADS2 score ≥ 2), and the mean CHADS2 score
was 3.5.45 The ENGAGE trial also recruited patients with higher risk
(CHADS2 score ≥ 2), and the mean CHADS2 score was 2.8.47 Pa-
tients with a CHADS2 score ¼ 0 or 1 were not included in the
ROCKET trial,45 nor in the ENGAGE trial.47 When the primary ef-
ficacy endpoints (stroke and SEE) were examined in the subgroup
analyses of patients with different CHADS2 score, dabigatran
150 mg b.d. dosing was the only regimen to show consistent bene-
fits in all subgroups.52 Rivaroxaban and edoxaban failed to show ef-
ficacy in any subgroup.45,47 Apixaban was effective in patients with a
dabigatran 150 mg was the only one that significantly reduced is-
chaemic stroke in Asians (Figure 3B). Most NOACs, except rivarox-
aban, significantly reduced haemorrhagic stroke in Asians
(Figure 3C ). None of NOACs increased myocardial infarction in
Asians (Figure 3D). Except dabigatran 110 mg and apixaban, the
RRR for most NOACs in reducing all-cause mortality was numeric-
ally greater in Asians than that in non-Asians, and edoxaban 60 mg
was the only one showing statistically significance (Figure 3E).
The RRR in four safety endpoints (major bleeding, ICH, gastro-
intestinal bleeding, and bleeding of any cause) in Asians and non-
Asians is shown in Figure 4.48 – 51 Most NOACs, except rivaroxaban,
significantly reduced major bleeding in Asians (Figure 4A). All

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CHADS2 score of 3– 6, but not effective in patients with a CHADS2
score of 1–2.46 The effects of NOACs in Asian patients with differ-
ent CHADS2 score have not been reported, except in one study.49
The relative risk reduction (RRR) in five efficacy endpoints
(stroke/SEE, ischaemic stroke, haemorrhagic stroke, myocardial in-
farction, and all-cause mortality) in Asians and non-Asians is shown
in Figure 3.48 – 51 For stroke/SEE, RRR was numerically greater in
Asians than in non-Asians for most NOACs, except edoxaban
30 mg (Figure 3A). Dabigatran 150 mg was the only regimen showing
statistically significance in reducing stroke/SEE in Asians. Similarly,
NOACs significantly reduced ICH in Asians (Figure 4B). For gastro-
intestinal bleeding, data were not available for rivaroxaban and apix-
aban in Asians (Figure 4C ). For the remaining NOACs, none of them
increased gastro-intestinal bleeding in Asians (Figure 4C ). Most
NOACs, except rivaroxaban, significantly reduced bleeding of any
cause in Asians (Figure 4D).
Table 2 summarizes the effects of NOACs on five efficacy end-
points and four safety endpoints in the four RCTs.36 In general,
the effect of NOACs in Asians was comparable with non-Asians.
The major difference was in the risk of gastro-intestinal bleeding.

A 20 B 20 Non-Asians
4
0 Asians
0 0

–20 –15 –17* –20

–28*
–40 –33 –40 –33*
–39*
–43* –43*
–47*
–51* –49*
–60 –60 –56*
–59*–60*
–66* –64*
–68* –69* –68*
–80 Non-Asians
–80 –76* –76*
Asians –80*

–100 –100
% Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban
%
150 mg 110 mg 20 mg 5 mg 60 mg 30 mg 150 mg 110 mg 20 mg 5 mg 60 mg 30 mg

C 100 D 20
Non-Asians Non-Asians
Asians Asians
67* 3
1
0
50 46 –2

27* –12*
–20 –15
13
–23*
0 –28*
–32* –33*
–9 –40
–11 –40*
–18 –42*

–32 –33*–33 –52*

–50 –60
% Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban % Dabigatran Dabigatran Rivaroxaban Apixaban Edoxaban Edoxaban
150 mg 110 mg 20 mg 5 mg 60 mg 30 mg 150 mg 110 mg 20 mg 5 mg 60 mg 30 mg

Figure 4 Relative risk reduction in four major safety endpoints in Asians and non-Asians in four major clinical trials.48 – 51 (A) Major bleeding, (B)
intra-cranial haemorrhage, (C) gastro-intestinal bleeding, and (D) bleeding of any cause. *P , 0.05.
 Asian strategy for stroke prevention
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Table 2 Efficacy and safety endpoints of different NOACs in non-Asians and Asians

Stroke/ Ischaemic Haemorrhagic Myocardial All-cause Major Intra-cranial GI Bleeding of any

SEE stroke stroke infarction mortality bleeding haemorrhage bleeding cause
.............................................................................................................................................................................................................................................
Non-Asians
Dabigatran V V V X
150 mg
Dabigatran V V V V
110 mg
Rivaroxaban V V X
Apixaban V V V V V V
Edoxaban 60 mg V V V X V
Edoxaban 30 mg X V V V V V
Asians
Dabigatrana V V V V V V
150 mg
Dabigatrana V V V V
110 mg
Rivaroxabanb V NR
Apixabanc V V V NR V
Edoxaband 60 mg V V V V V
Edoxaband 30 mg V V V V

Modified from Lip et al. 36 with permission.

GI, gastrointestinal; NOACs, non-vitamin K antagonist oral anticoagulants; NR, not reported; SEE, systemic embolization event.
a
China, Japan, South Korea, Taiwan, Hong Kong, Philippines, Singapore, Malaysia, Thailand, and India.
b
China, South Korea, Taiwan, and Hong Kong.
c
China, Japan, South Korea, Taiwan, Hong Kong, Philippines, Singapore, and Malaysia.
d
China, Japan, South Korea, and Taiwan.

ii37
ii38
It was increased by dabigatran 150 mg, rivaroxaban, and edoxaban
60 mg in non-Asians, but not in Asians. While these data were ob-
tained from subgroup analyses, and the case number in Asians was
much less than that in non-Asians, these data provided clear evi-
dence that NOACs outperformed warfarin in Asians for the stroke
prevention in AF. Certain NOACs might be preferred over the
others when different endpoints are of interest.
Conclusions
There is a tremendous burden of AF in Asians. Non-vitamin K antag-
onist oral anticoagulants are preferentially indicated for stroke pre-
vention in Asians, while aspirin and warfarin should be abandoned in
most cases.
Funding
This work was supported, in part, by grants from the Taiwan Ministry of
Health and Welfare (MOHW103-TDU-B-211-113-003) and intramural
grants from the Taipei Veterans General Hospital (V103B-024;
V103C-051).
Conflict of interest: C.-E.C. has been on the speakers bureau for As-
trazeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, GSK,
MSD, Novartis, Pfizer, Roche, Sanofi-aventis, Servier, Tanabe, Takeda,
and TTY. K.-L.W. has been on the speakers bureau for Astrazeneca
and Bayer. S.-J.L. has nothing to disclose.
References
1. Chiang CE, Zhang S, Tse HF, Teo WS, Omar R, Sriratanasathavorn C. Atrial fibril-
lation management in Asia: from the Asian expert forum on atrial fibrillation. Int J
Cardiol 2013;164:21 –32.
2. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ et al.
Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010
Study. Circulation 2014;129:837 –47.
3. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV et al. Prevalence of
diagnosed atrial fibrillation in adults: national implications for rhythm management
and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation
(ATRIA) Study. JAMA 2001;285:2370 – 5.
4. Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a
systematic review of the epidemiology of atrial fibrillation in regions outside North
America and Europe. Chest 2012;142:1489 – 98.
5. Tse HF, Wang YJ, Ahmed Ai-Abdullah M, Pizarro-Borromeo AB, Chiang CE,
Krittayaphong R et al. Stroke prevention in atrial fibrillation—an Asian stroke per-
spective. Heart Rhythm 2013;10:1082 –8.
6. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP et al. Secular
trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to
2000, and implications on the projections for future prevalence. Circulation 2006;
114:119–25.
7. Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A et al. Projections
on the number of individuals with atrial fibrillation in the European Union, from
2000 to 2060. Eur Heart J 2013;34:2746 – 51.
8. Chiang CE, Wang KL, Lip GY. Stroke prevention in atrial fibrillation: an Asian per-
spective. Thromb Haemost 2014;111:789 –97.
9. Chien KL, Su TC, Hsu HC, Chang WT, Chen PC, Chen MF et al. Atrial fibrillation
prevalence, incidence and risk of stroke and all-cause death among Chinese. Int J
Cardiol 2010;139:173 –80.
10. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Valid-
ation of clinical classification schemes for predicting stroke: results from the Na-
tional Registry of Atrial Fibrillation. JAMA 2001;285:2864 –70.
11. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and
why? Eur Heart J 2013;34:1041 –9.
12. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW et al. Atrial
fibrillation management: a prospective survey in ESC Member Countries. Eur Heart
J 2005;26:2422 –34.
13. Le Heuzey JY, Breithardt G, Camm J, Crijns H, Dorian P, Kowey PR et al. The Re-
cordAF study: design, baseline data, and profile of patients according to chosen
treatment strategy for atrial fibrillation. Am J Cardiol 2010;105:687 –93.
C.-E. Chiang et al.
14. Steinberg BA, Holmes DN, Ezekowitz MD, Fonarow GC, Kowey PR, Mahaffey KW
et al. Rate versus rhythm control for management of atrial fibrillation in clinical
practice: results from the Outcomes Registry for Better Informed Treatment of At-
rial Fibrillation (ORBIT-AF) registry. Am Heart J 2013;165:622–9.
15. Gamra H, Murin J, Chiang CE, Naditch-Brule L, Brette S, Steg PG. Use of antithrom-
botics in atrial fibrillation in Africa, Europe, Asia and South America: insights from
the International RealiseAF Survey. Arch Cardiovasc Dis 2014;107:77 –87.
16. Oldgren J, Healey JS, Ezekowitz M, Commerford P, Avezum A, Pais P et al. Varia-
tions in cause and management of atrial fibrillation in a prospective registry of
15,400 emergency department patients in 46 countries: the RE-LY Atrial Fibrilla-
tion Registry. Circulation 2014;129:1568 –76.
17. Lip GY, Laroche C, Dan GA, Santini M, Kalarus Z, Rasmussen LH et al.
A prospective survey in European Society of Cardiology member countries of
atrial fibrillation management: baseline results of EURObservational Research
Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace
2014;16:308 – 19.
Downloaded from https://academic.oup.com/europace/article/17/suppl_2/ii31/2802577 by guest on 26 July 2021
18. Kirchhof P, Ammentorp B, Darius H, De Caterina R, Le Heuzey JY, Schilling RJ et al.
Management of atrial fibrillation in seven European countries after the publication
of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention
oF thromboemolic events--European Registry in Atrial Fibrillation (PREFER in AF).
Europace 2014;16:6– 14.
19. J-Rhythm Registry investigators. Determinants of warfarin use and international
normalized ratio levels in atrial fibrillation patients in Japan. Subanalysis of the
J-RHYTHM Registry. Circ J 2011;75:2357 –62.
20. Amerena J, Chen SA, Sriratanasathavorn C, Cho JG, Huang D, Omar R et al. Insights
into management of atrial fibrillation in Asia Pacific gained from baseline data from
REgistry on cardiac rhythm disORDers (RecordAF-Asia Pacific [AP]) registry. Am J
Cardiol 2012;109:378 –82.
21. Guo Y, Apostolakis S, Blann AD, Wang H, Zhao X, Zhang Y et al. Validation of con-
temporary stroke and bleeding risk stratification scores in non-anticoagulated
Chinese patients with atrial fibrillation. Int J Cardiol 2013;168:904 – 9.
22. Wang KL, Wu CH, Huang CC, Wu TC, Naditch-Brule L, Steg PG et al. Complex-
ity of atrial fibrillation patients and management in Chinese ethnicity in routine
daily practice: insights from the RealiseAF Taiwanese cohort. J Cardiol 2014;64:
211 – 7.
23. Siu CW, Lip GY, Lam KF, Tse HF. Risk of stroke and intracranial hemorrhage in
9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;11:
1401 – 8.
24. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratifica-
tion for predicting stroke and thromboembolism in atrial fibrillation using a novel
risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;
137:263 – 72.
25. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al. 2012 fo-
cused update of the ESC Guidelines for the management of atrial fibrillation: an up-
date of the 2010 ESC Guidelines for the management of atrial fibrillation.
Developed with the special contribution of the European Heart Rhythm Associ-
ation. Eur Heart J 2012;33:2719 – 47.
26. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS et al. Focused
2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: re-
commendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;
28:125 – 36.
27. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr.et al. 2014
AHA/ACC/HRS guideline for the management of patients with atrial fibrillation:
executive summary: a report of the American College of Cardiology/American
Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
Circulation 2014;130:2071 –104.
28. Chao TF, Liu CJ, Wang KL, Lin YJ, Chang SL, Lo LW et al. Using the CHA2DS2-VASc
score for refining stroke risk stratification in ‘Low-Risk’ Asian patients with atrial
fibrillation. J Am Coll Cardiol 2014;64:1658 – 65.
29. Senoo K, Lane DA, Lip GY. Stroke risk reduction with oral anticoagulation using
CHA2DS2-VASc in a Japanese AF population: a modeling analysis. Int J Cardiol
2015;181:247 – 54.
30. Ogawa S, Aonuma K, Tse HF, Huang D, Huang JL, Kalman J et al. The APHRS’s 2013
statement on antithrombotic therapy of patients with nonvalvular atrial fibrillation.
J Arrhythmia 2013;29:190–200.
31. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischae-
mic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish At-
rial Fibrillation cohort study. Eur Heart J 2012;33:1500 –10.
32. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY et al. Warfarin versus
aspirin for stroke prevention in an elderly community population with atrial fibril-
lation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a
randomised controlled trial. Lancet 2007;370:493 –503.
33. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent
stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:
857 –67.
Asian strategy for stroke prevention
34. Lin LJ, Cheng MH, Lee CH, Wung DC, Cheng CL, Kao Yang YH. Compliance with
antithrombotic prescribing guidelines for patients with atrial fibrillation—a nation-
wide descriptive study in Taiwan. Clinical Therapeutics 2008;30:1726 – 36.
35. Sato H, Ishikawa K, Kitabatake A, Ogawa S, Maruyama Y, Yokota Y et al. Low-dose
aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan At-
rial Fibrillation Stroke Trial. Stroke 2006;37:447 –51.
36. Lip GY, Wang KL, Chiang CE. Non-vitamin K antagonist oral anticoagulants
(NOACs) for stroke prevention in Asian patients with atrial fibrillation: time for
a reappraisal. Int J Cardiol 2015;180C:246 –54.
37. Wang KL, Chiang CE. Optimal international normalized ratio for atrial fibrillation in
Asians and Japanese. Circ J 2013;77:2242 –3.
38. Yamaguchi T. Group fJNAFESPCS. Optimal intensity of warfarin therapy for sec-
ondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multi-
center, prospective, randomized trial. Stroke 2000;31:817 – 21.
39. You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and 3.0 the optimal level
for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br
J Clin Pharmacol 2005;59:582 – 7.
40. Suzuki S, Yamashita T, Kato T, Fujino T, Sagara K, Sawada H et al. Incidence of major
bleeding complication of warfarin therapy in Japanese patients with atrial fibrilla-
tion. Circ J 2007;71:761 – 5.
41. Inoue H, Okumura K, Atarashi H, Yamashita T, Origasa H, Kumagai N et al. Target
international normalized ratio values for preventing thromboembolic and hemor-
rhagic events in Japanese patients with non-valvular atrial fibrillation: results of the
J-RHYTHM Registry. Circ J 2013;77:2264 –70.
42. Wong RS, Cheng G, Chan TY. Use of herbal medicines by patients receiving war-
farin. Drug Saf 2003;26:585 –8.
43. Husted S, De Caterina R, Andreotti F, Arnesen H, Bachmann F, Huber K et al. Non-
vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel. Thromb
Haemost 2014;111:781–2.
ii39
44. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabiga-
tran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:
1139 –51.
45. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban ver-
sus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883 –91.
46. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al. Apix-
aban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:
981 –92.
47. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al.
Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;
369:2093 –104.
48. Hori M, Connolly SJ, Zhu J, Liu LS, Lau CP, Pais P et al. Dabigatran versus warfarin:
effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians
with atrial fibrillation. Stroke 2013;44:1891 –6.
49. Wong KS, Hu DY, Oomman A, Tan RS, Patel MR, Singer DE et al. Rivaroxaban for
stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014;45:
Downloaded from https://academic.oup.com/europace/article/17/suppl_2/ii31/2802577 by guest on 26 July 2021
1739 –47.
50. Goto S, Zhu J, Liu L, Oh BH, Wojdyla DM, Aylward P et al. Efficacy and safety of
apixaban compared with warfarin for stroke prevention in patients with atrial fib-
rillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and
Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J
2014;168:303 –9.
51. Koretsune Y, Yamashita T, Yang Y, Chen SA, Chung N, Giugliano RP et al. Edoxaban
versus warfarin in East-Asian (including Japanese) patients with atrial fibrillation—
an ENGAGE AF-TIMI 48 sub-analysis. Circ J 2014;78:I – 484.
52. Oldgren J, Alings M, Darius H, Diener HC, Eikelboom J, Ezekowitz MD et al. Risks
for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran
or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial.
Ann Intern Med 2011;155:660 – 7.