Original Contribution

Ischemic Stroke and Intracranial Hemorrhage

With Aspirin, Dabigatran, and Warfarin
Impact of Quality of Anticoagulation Control
Chi-Wai Ho, MBBS*; Mei-Han Ho, MBBS*; Pak-Hei Chan, MBBS; Jo-Jo Hai, MBBS;
Emmanuel Cheung, MBBS; Chun-Yip Yeung, MBBS; Kui-Kai Lau, MBBS; Koon-Ho Chan, MD;
Chu-Pak Lau, MD; Gregory Y.H. Lip, MD; Gilberto Ka-Kit Leung, MS;
Hung-Fat Tse, MD, PhD; Chung-Wah Siu, MD

Background and Purpose—Little is known about the impact of quality of anticoagulation control, as reflected by time in
therapeutic range (TTR), on the effectiveness and safety of warfarin therapy in Chinese patients with atrial fibrillation.
We investigated the risks of ischemic stroke and intracranial hemorrhage (ICH) in relation to warfarin at various TTRs in
a real-world cohort of Chinese patients with atrial fibrillation receiving warfarin and compared with those on dabigatran,
aspirin, and no therapy.
Methods—This is an observational study.
Results—Of 8754 Chinese patients with atrial fibrillation and CHA2DS2-VASc ≥1 (79.5±9.2 years; CHA2DS2-VASc, 4.1±1.5;
and Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International
Normalized Ratio, Elderly (>65 years), Drugs/Alcohol Concomitantly [HAS-BLED], 2.2±0.9), 16.3% received warfarin,
41.1% aspirin, 4.5% dabigatran, and 38.1% received no therapy. The incidence of ischemic stroke was highest in patients
with no therapy (10.38%/y), followed by patients on aspirin (7.95%/y). The incidence of stroke decreased progressively with
increasing TTR quartiles (<17.9%, 17.9%–38.8%, 38.8%–56.2%, and >56.2%) from 7.34%/y (first quartile) to 3.10%/y
(fourth quartile). Patients on dabigatran had the lowest incidence of stroke among all groups (2.24%/y). The incidence of
ICH was lowest in patients on dabigatran (0.32%/y) compared with those on warfarin (0.90%/y), aspirin (0.80%/y), and no
therapy (0.53%/y). ICH incidence decreased with increasing TTR from 1.37%/y (first quartile) to 0.74%/y (fourth quartile).
Conclusions—In Chinese patients with atrial fibrillation, the benefits of warfarin therapy for stroke prevention and ICH risk
are closely dependent on the quality of anticoagulation, as reflected by TTR. Even at the top TTR quartile, warfarin was
associated with a higher stroke and ICH risk than dabigatran.   (Stroke. 2015;46:00-00.)
Key Words: atrial fibrillation ◼ intracranial hemorrhages

A trial fibrillation (AF) confers a 5-fold higher risk of isch-

emic stroke and accounts for >20% of all ischemic strokes.1
Although warfarin therapy with a target international normal-
ized ratio (INR) between 2.0 and 3.0 has been shown effective
in reducing ischemic stroke and mortality among patients with
nonvalvular AF,2–4 its benefit could be offset by the increased
intracranial hemorrhage (ICH) inherent with the therapy. This is
of particular relevance to Asian populations such as the Chinese
given a higher baseline risk of ICH among Chinese,5–7 thus under-
mining the potential benefit of any antithrombotic therapy. This
fear may be reflected in the gross underutilization of warfarin
therapy (15%–20%) and the high prevalence of aspirin therapy
(as a perceived alternative to warfarin) in these populations.8–10
Even among those on warfarin therapy, the quality of antico-
agulation has been poor in Chinese (and other Asian) patients
even in the setting of randomized clinical trials.11,12 The time
in therapeutic range (TTR), reflecting the proportion of time
spent within therapeutic range of 2.0 to 3.0, has emerged as a
marker reflecting the quality of anticoagulation control while
on warfarin therapy. The TTR has been shown to be closely
correlated with ischemic stroke, hemorrhage, and mortality.13–15

Received June 16, 2014; final revision received September 11, 2014; accepted September 15, 2014.
From the Cardiology Division (C.-W.H., M.-H.H., P.-H.C., J.-J.H., E.C., C.-P.L., H.-F.T., C.-W.S.), Endocrinology Division (C.-Y.Y.), and Neurology
Division (K.-K.L., K.-H.C.), Department of Medicine, Queen Mary Hospital and Division of Neurosurgery, Department of Surgery, Li Ka Shing Faculty
of Medicine (G.K.-K.L.), University of Hong Kong, Hong Kong SAR, China; and University of Birmingham Centre for Cardiovascular Sciences, City
Hospital, University Department of Medicine, Birmingham, United Kingdom (G.Y.H.L.).
*C.-W. Ho and M.-H. Ho contributed equally.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.
006476/-/DC1.
Correspondence to Chung-Wah Siu, MD, Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China. E-mail
cwdsiu@hku.hk
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.006476

1
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2  Stroke  January 2015
Nonetheless, data on the impact of TTR of warfarin therapy
on the risk of ischemic stroke or ICH in Chinese patients are
limited. The non–vitamin K oral anticoagulants (NOACs, pre-
viously referred to as new or novel oral anticoagulants, eg,
dabigatran, rivaroxaban, and apixaban) have been shown in ran-
domized trials to have relative efficacy, safety, and convenience
compared with warfarin in patients with AF. Thus, international
guidelines recommend the NOACs in preference to conventional
warfarin therapy for stroke prevention where possible. However,
there are limited published real-world data in Chinese AF popu-
lations comparing the efficacy and safety of dabigatran, warfarin
therapy at different TTRs, and aspirin therapy.
In this analysis, we aimed to investigate the risk of ischemic
stroke and ICH in relation to TTR in a real-world cohort of
Chinese patients with AF receiving warfarin (at different degrees
of anticoagulation control, as reflected by TTR) and compared
outcomes with those on dabigatran, aspirin, and no therapy.
Methods
Study Design
This was an observational study based on a hospital-based AF reg-
istry. The study protocol was approved by the local institutional re-
view board. Informed consents were not obtained from the patients
given the registry nature of the study; however, all patient records
or information was anonymized and deidentified before analysis.
Patients diagnosed to have AF in Queen Mary Hospital, Hong Kong,
from July 1997 to December 2011, were identified via the comput-
erized database of clinical management system.8,9,16 Patients were
excluded if they had significant valvular heart disease and previ-
ous valvular replacement or had incomplete clinical and follow-up
data. In addition, patients with AF diagnosed after the commercial
availability of dabigatran were also identified (Figure I in the on-
line-only Data Supplement).3 All hospital admissions, outpatient
clinic visits, laboratory results, and radiological images have been
recorded in the computer-based clinical management system since
1996. Demographic data, cardiovascular risk factors, and medica-
tions were recorded at baseline. The index date was defined as the
date of the first occurrence of AF. For registration of outcomes during
follow-up, a blanking period of 14 days after the index date was ap-
plied as the occurrence of a stroke or ICH within the first few days
of diagnosis of AF is most likely related to initial presentation rather
than a new event.17 Stroke risk was calculated at baseline using the
CHA2DS2-VASc score (C: congestive heart failure [1 point], H: hy-
pertension [1 point], A2: age 65 to 74 years [1 point] and age ≥75
years [2 points], D: diabetes mellitus [1 point], S: prior stroke or tran-
sient ischemic attack [2 points], VA: vascular disease [1 point], and
Sc: sex category [female; 1 point]) as described in recent guidelines.
Subsequent occurrence of risk factor contributory to CHA2DS2-VASc
score had not been taken into account. The Hypertension, Abnormal
Renal/Liver Function, Stroke, Bleeding History or Predisposition,
Labile International Normalized Ratio, Elderly (>65 years), Drugs/
Alcohol Concomitantly (HAS-BLED) score was likewise calculated
at baseline as a measure of bleeding risk. Uncontrolled hypertension
was defined as systolic blood pressure >160 mm Hg at baseline and
subsequent visit-to-visit changes in systolic blood pressure had not
been taken in account. Similarly, liver disease as determined by the
derangement in liver biochemistry and renal disease as determined
by serum creatinine level were only assessed at baseline, subsequent
changes had not been taken into account. The labile INR criterion was
quantified as 0 in every patient as none of patients were on warfarin
at baseline.
The final analysis included 8754 patients with nonvalvular AF
with CHA2DS2-VASc >1, who were classified according to their
antithrombotic strategies: warfarin, aspirin, and no antithrombotic
therapy. Among patients receiving warfarin therapy, TTR was calcu-
lated for each patient using Rosendaal method,18 in which INR was
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assumed to change in a linear manner between measurements, and
INR values on the days with no measurement were interpolated. The
percentage of time during which a patient had an INR within 2.0 to
3.0 was taken as TTR. Patients were then further classified into 4
groups according to quartiles of TTR.
Outcomes, Variables, and Data Source
The primary outcome was hospital admission for ischemic stroke,
whereas the secondary outcome was admission for ICH. Stroke was de-
fined as a neurological deficit of sudden onset, persisting for >24 hours,
corresponding to a vascular territory and not explained by other causes
(eg, trauma, infection). ICH comprises intracerebral hemorrhage, sub-
arachnoid hemorrhage, and subdural hemorrhage. Neuroimaging evi-
dence, either from computerized tomography or MRI, was required to
confirm the diagnosis of stroke and ICH. Data were retrieved from the
medical records and discharge summaries from the territory-wide infor-
mation network of all public hospitals in Hong Kong.
Statistical Analysis
Continuous and discrete variables are expressed as mean±SD and per-
centages, respectively. Statistical comparison of the baseline clinical
characteristics was performed using Student t test or 1-way ANOVA
as appropriate. Kaplan–Meier survival analyses with the log-rank
test were performed and Cox proportional hazards regression model
was used to calculate hazard ratios (HRs) of some predictive factors
and their 95% confidence interval (CIs) for the incidence of stroke.
Calculations were performed using SPSS software (version 12.0). All
tests were 2-sided, and P values were considered significant if <0.05.
Results
A total of 8754 Chinese patients (79.5±9.2 years; women, 56.7%)
with nonvalvular AF and CHA2DS2-VASc score >1 was included
in the final analysis. Table 1 summarizes the clinical character-
istics of the study population. The mean CHA2DS2-VASc and
HAS-BLED scores were 4.1±1.5 and 2.2±0.9, respectively.
Of this cohort, 1428 patients (16.3%) were on warfarin.
The quartiles of individual TTR were categorized as follows:
<17.9% (first quartile), 17.9% to 38.8% (second quartile),
38.8% to 56.2% (third quartile), and >56.2% (fourth quartile).
Increasing age, diabetes mellitus, renal failure on dialysis, and
higher CHA2DS2-VASc score were associated with low TTRs
(ie, TTRs in the first quartile; Table 1). In multivariate analysis,
only increasing age (HR, 1.03; 95% CI, 1.01–1.04), diabetes
mellitus (HR, 1.40; 95% CI, 1.07–1.82), and renal failure on
dialysis (HR, 2.63; 95% CI, 1.24–5.60) were independent pre-
dictors of poor TTR.
In addition, 3600 patients (41.1%) were on aspirin (80–160
mg daily), 393 patients (4.5%) were on dabigatran, and 3333
patients (38.1%) received neither warfarin nor aspirin (no
antithrombotic therapy).
Ischemic Stroke
After a mean follow-up of 3.0±3.2 years (26 130 patient-
years), there were 2005 patients who developed an ischemic
stroke (23.8%) with an annual incidence of ischemic stroke of
7.74%/y. Table 2 summarizes factors predictive of ischemic
stroke together with the corresponding HRs based on Cox pro-
portional hazard model and 95% CIs. On univariate analysis,
increasing age, female sex, hypertension, diabetes mellitus,
prior ischemic stroke, smoking history, and renal failure on
dialysis were associated with the increasing risk of ischemic
stroke, as was type of antithrombotic strategies.
 Ho et al   Ischemic Stroke and ICH in Chinese Patients With AF   3

Table 1.  Baseline Characteristics

Warfarin TTR
No Aspirin
All or Warfarin Aspirin First Quartile Second Quartile Third Quartile Fourth Quartile Dabigatran
(n=8754) (n=3333) (n=3600) (n=357) (n=357) (n=357) (n=357) (n=393) P Value*
Age, y
 Mean age, y 79.5±9.2 80.6±9.4 80.3±8.8 77.5±8.8 76.7±8.5 75.7±8.5 74.8±8.8 74.5±9.5 <0.0001
 Female, n (%) 4960 (56.7) 1971 (59.1) 2026 (56.3) 202 (56.6) 190 (53.2) 180 (50.4) 178 (49.9) 213 (54.2) 0.001
 HT, n (%) 5379 (61.4) 1802 (54.1) 2361 (65.6) 223 (62.5) 240 (67.2) 219 (61.3) 240 (67.2) 294 (74.8) <0.0001
 DM, n (%) 2180 (24.9) 695 (20.9) 975 (27.1) 115 (32.2) 103 (28.9) 95 (26.6) 74 (20.7) 123 (31.3) <0.0001
 Smoker, n (%) 2903 (33.2) 1123 (33.7) 1242 (34.5) 127 (35.6) 102 (28.6) 123 (34.5) 109 (30.5) 77 (19.6) <0.0001
 Hyperthyroidism, n (%) 503 (5.7) 196 (5.9) 210 (5.8) 25 (7.0) 31 (8.7) 21 (5.9) 20 (5.6) 0 (0) <0.0001
 Dialysis, n (%) 163 (1.9) 54 (1.6) 80 (2.2) 13 (3.6) 13 (3.6) 3 (0.8) 0 (0.0) 0 (0) <0.0001
 Heart failure, n (%) 2191 (25.0) 712 (21.4) 1013 (28.1) 101 (28.3) 92 (25.8) 92 (25.8) 82 (23.0) 99 (25.2) <0.0001
 CAD, n (%) 1733 (19.8) 319 (9.6) 981 (27.3) 102 (28.6) 117 (32.8) 92 (25.8) 96 (26.9) 26 (6.6) <0.0001
 PAD, n (%) 331 (3.8) 51 (1.5) 163 (4.5) 30 (8.4) 24 (6.7) 28 (7.8) 20 (5.6) 15 (3.8) <0.0001
 Stroke/TIA, n (%) 2360 (27.0) 675 (20.3) 1054 (29.3) 108 (30.3) 130 (36.4) 121 (33.9) 137 (38.4) 135 (34.4) <0.0001
 Prior ICH, n (%) 241 (2.8) 110 (3.3) 94 (2.6) 8 (2.2) 9 (2.5) 5 (1.4) 15 (4.2) 0 (0) 0.002
Mean CHA2DS2-VASc 4.1±1.5 3.8±1.4 4.4±1.6 4.3±1.6 4.4±1.7 4.1±1.6 4.0±1.6 4.1±1.5 <0.0001
CHA2DS2-VASc
 2, n (%) 1428 (16.3) 681 (20.4) 458 (12.7) 48 (13.4) 50 (14.0) 66 (18.5) 61 (17.1) 64 (16.3) <0.0001
 3, n (%) 1995 (22.9) 896 (26.9) 711 (19.8) 63 (17.6) 79 (22.1) 73 (20.4) 92 (25.8) 81 (20.6) …
 4, n (%) 2051 (23.4) 806 (24.2) 837 (23.2) 90 (25.2) 70 (19.6) 75 (21.0) 77 (21.6) 96 (24.4) …
 5, n (%) 1652 (18.9) 552 (16.6) 741 (20.6) 79 (22.1) 71 (19.9) 70 (19.6) 61 (17.1) 78 (19.8) …
 6, n (%) 990 (11.3) 276 (8.3) 494 (13.7) 46 (12.9) 44 (12.3) 44 (12.3) 37 (10.4) 49 (12.5) …
 7, n (%) 435 (5.0) 86 (2.6) 243 (6.8) 16 (4.5) 27 (7.6) 24 (6.7) 20 (5.6) 19 (4.8) …
 8, n (%) 170 (1.9) 31 (0.9) 95 (2.6) 12 (3.4) 13 (3.6) 4 (1.1) 9 (2.5) 6 (1.5) …
 9, n (%) 33 (0.4) 5 (0.1) 21 (0.3) 3 (0.8) 3 (0.8) 1 (0.3) 0 (0) 0 (0) …
Mean HAS-BLED 2.2±0.9 2.1±0.8 2.3±0.9 2.3±0.8 2.4±0.9 2.2±0.8 2.3±0.9 2.3±0.9 <0.0001
HAS-BLED
 0, n (%) 51 (0.6) 15 (0.5) 15 (0.4) 5 (1.4) 3 (0.8) 2 (0.6) 4 (1.1) 7 (1.8) <0.0001
 1, n (%) 1561 (17.8) 736 (22.1) 553 (15.4) 48 (13.4) 49 (13.7) 61 (17.1) 45 (12.6) 69 (17.6) …
 2, n (%) 4073 (46.5) 1594 (47.8) 1631 (45.3) 172 (48.2) 160 (44.8) 166 (46.5) 179 (50.1) 171 (43.5) …
 3–6, n (%) 3069 (35.1) 988 (29.6) 1401 (38.9) 132 (37.0) 145 (40.6) 128 (35.9) 129 (36.1) 146 (37.2) …
CAD indicates coronary artery disease; CHA2DS2-VASc, C: congestive heart failure, H: hypertension, A2: age 65 to 74 years and age ≥75 years, D: diabetes mellitus,
and S: prior stroke or transient ischemic attack, VA: vascular disease, Sc: sex category; DM, diabetes mellitus; HAS-BLED, Hypertension, Abnormal Renal/Liver Function,
Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly (>65 years), Drugs/Alcohol Concomitantly; HT, hypertension; ICH, intracranial
hemorrhage; PAD, peripheral arterial disease; TIA, transient ischemic attack; and TTR, time in therapeutic range.
*P value for comparison between all 4 groups.

As expected, patients received no therapy had the highest
incidence of ischemic stroke (10.38%/y), followed by those
on aspirin (7.95%/y; Figure 1). Among patients receiving
warfarin, the annual incidence of ischemic stroke decreased
progressively with increasing TTRs, from 7.34%/y in the first
quartile, 5.95%/y in the second quartile, and 4.39%/y in the
third quartile to 3.10%/y in the fourth quartile. The annual
incidence of ischemic stroke was the lowest among those
taking dabigatran (2.24%/y; Figure 1). Figure 2 shows a
Kaplan–Meier analysis of ischemic stroke among patients on
dabigatran, warfarin at different quartiles of TTR, aspirin, and
no therapy (log-rank, 199; P<0.0001).
On multivariate analysis, increasing age (age, 65–75 years:
HR, 1.56; 95% CI, 1.22–2.00 and age, >75 years: HR, 1.82;
95% CI, 1.43–2.31), female sex (HR, 1.16; 95% CI, 1.05–
1.29), hypertension (HR, 1.21; 95% CI, 1.10–1.33), diabetes
mellitus (HR, 1.27; 95% CI, 1.14–1.40), prior ischemic stroke
(HR, 1.27; 95% CI, 1.14–1.40), and renal failure on dialy-
sis (HR, 1.43; 95% CI, 1.06–1.93) were associated with the
increasing risk of ischemic stroke (Table 2). Importantly, the
use of aspirin, warfarin, and dabigatran were all associated
with lower risk of ischemic stroke. For those on warfarin, spe-
cifically, increasing TTR was associated with lower incidence
of ischemic stroke (first quartile: adjusted HR, 0.71; 95% CI,
0.58–0.87; second quartile: HR, 0.56; 95% CI, 0.45–0.69;
third quartile: HR, 0.42; 95% CI, 0.33–0.53; and fourth quar-
tile: HR, 0.31; 95% CI, 0.23–0.40).
Patients on aspirin had a comparable HR with those
patients on warfarin at the lowest quartile (HR, 0.73; 95%
CI, 0.67–0.81 versus HR, 0.71; 95% CI, 0.58–0.87; Table 2).
Despite the decreasing risk of ischemic stroke with increas-
ing TTR in patients on warfarin, patients on dabigatran had

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4  Stroke  January 2015

Table 2.  Associations Between Baseline Factors and Ischemic Stroke

Univariate Analysis Multivariate Analysis
No. of
Ischemic Strokes HR (95% CI) P Value HR (95% CI) P Value
Age, y
 <65 72 Reference … Reference …
 65–75 509 1.53 (1.19–1.96) 0.0001 1.56 (1.22–2.00) <0.0001*
 >75 1424 1.90 (1.49–2.41) <0.0001* 1.82 (1.43–2.31) <0.0001*
Female 1258 1.22 (1.16–1.34) <0.0001* 1.16 (1.05–1.29) 0.003*
Hypertension 1242 1.21 (1.10–1.32) <0.0001* 1.21 (1.10–1.33) <0.0001*
Diabetes mellitus 535 1.32 (1.19–1.45) <0.0001* 1.27 (1.14–1.40) <0.0001*
Smoker 621 0.90 (0.82–0.99) 0.035 0.96 (0.86–1.06) 0.421
Hyperthyroidism 138 0.92 (0.77–1.09) 0.327 … …
Renal failure on dialysis 45 1.45 (1.08–1.95) 0.014* 1.43 (1.06–1.93) 0.018*
Heart failure 426 0.99 (0.89–1.11) 0.919 … …
Coronary artery disease 425 1.02 (0.91–1.13) 0.758 … …
Peripheral arterial disease 75 1.18 (0.94–1.49) 0.156 … …
Prior ischemic stroke 540 1.14 (1.04–1.26) 0.008 1.27 (1.14–1.40) <0.0001*
Prior intracranial hemorrhage 48 1.05 (0.79–1.40) 0.724 … …
Antithrombotic therapy
 No therapy 760 Reference … Reference …
 Aspirin 893 0.78 (0.71–0.85) <0.0001* 0.73 (0.67–0.81) <0.0001*
 Warfarin
  First quartile TTR 107 0.73 (0.59–089) 0.002* 0.71 (0.58–0.87) <0.0001*
  Second quartile TTR 97 0.59 (0.48–0.73) <0.0001* 0.56 (0.45–0.69) <0.0001*
  Third quartile TTR 77 0.43 (0.35–0.55) <0.0001* 0.42 (0.33–0.53) <0.0001*
  Fourth quartile TTR 57 0.31 (0.24–0.40) <0.0001* 0.31 (0.23–0.40) <0.0001*
 Dabigatran 14 0.21 (0.12–0.35) <0.0001* 0.20 (0.12–0.34) <0.0001*
CI indicates confidence interval; HR, hazard ratio; and TTR, time in therapeutic range.
*P<0.05.

the lowest ischemic stroke risk (HR, 0.20; 95% CI, 0.12–
0.34) among all antithrombotic strategies. Further analysis
comparing patients on warfarin with TTR ≥70% (n=154) and
patients on dabigatran, despite comparable CHA2DS2-VASc
(4.10±1.53 versus 4.12±1.49; P=0.90) and age (73.8±9.2
versus 74.5±9.5 years; P=0.48), the risk of ischemic stroke
in patients on dabigatran remained lower than of patients on
warfarin with TTR ≥70% (HR, 0.31; 95% CI, 0.15–0.66;
Figure II in the online-only Data Supplement). The annual
ischemic stroke free survival (%)
ischemic stroke for patients on warfarin with TTR ≥70%
remained higher than those on dabigatran (3.69%/y versus
2.24%/y).
As the registry including patients diagnosed AF during a
long period of time, during which awareness and guidelines
for treatment had changed, separate analyses of patients
diagnosed AF before and after 2008 were thus performed.
Although the overall trends were qualitatively comparable,
patients with AF diagnosed before 2008 had higher incidences
of ischemic stroke (as well as ICH) in all treatment groups
(Figures III and IV in the online-only Data Supplement). As

a result, the difference in annual incidence of ischemic stroke

Percentage of patients with

Dabigatran
between those on warfarin at the top quartile and those on
4th Quartile TTR dabigatran narrowed.
3rd Quartile TTR
2nd Quartile TTR
Intracranial Hemorrhage
Aspirin
1st Quartile TTR
There were 195 ICHs during the study period (0.75%/y):
No therapy 121 intracerebral hemorrhages (62.1%), 52 subdural hemor-
rhages (26.7%), and 22 subarachnoid hemorrhages (11.2%).
Log Rank: 200.0, P<0.0001*
The factors predictive of ICH based on Cox proportional
hazard models were as follows: age >75 years (adjusted HR,
Months 2.93; 95% CI, 1.28–6.68), prior ICH (HR, 2.49; 95% CI,
1.30–4.77), hypertension (HR, 1.42; 95% CI, 1.04–1.93),
Figure 1. Kaplan–Meier estimates of ischemic stroke-free sur-
vival in Chinese patients with atrial fibrillation receiving different and diabetes mellitus (1.55; 95% CI, 1.12–2.12; Table 3).
antithrombotic therapy. TTR indicates time in therapeutic range. Also, warfarin therapy with the TTR in the lowest quartile

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 Ho et al   Ischemic Stroke and ICH in Chinese Patients With AF   5

12
Annual Incidence of ischemic

10.38
10

7.95 7.74
8 7.34
stroke(%)

Figure 2. Relationship between different antithrom-

5.95
6 botic therapies and the annual risk of ischemic
4.39
stroke in Chinese patients with atrial fibrillation. Q1:
Time in therapeutic range (TTR) at first quartile; Q2:
4
3.10 TTR at second quartile; Q3: TTR at third quartile;
2.24 and Q4: TTR at fourth quartile.
2

0
No therapy Aspirin Q1 Q2 Q3 Q4 Dabigatran Overall

Warfarin

was associated with increased risk of ICH (HR, 2.40; 95% (0.74%/y–0.86%/y) were comparable with that on aspirin
CI, 1.39–4.14). (0.80%/y). Patients on dabigatran had the lowest incidence of
The annual incidence of ICH varied according to the types
ICH (0.32%/y), which was lower than that of patients with no
of antithrombotic strategies (Figure 3). Among patients on
warfarin, the incidence of ICH decreased with increasing therapy (Figure 3). Furthermore, after excluding patients with
quartiles of TTR. The incidences of ICH among patients prior ICH (because of the difference in proportion of patients
on warfarin from the second quartile to the fourth quartile with history of prior ICH among various treatment groups), the

Table 3.  Associations Between Baseline Factors and Intracranial Hemorrhage

Univariate Analysis Multivariate Analysis
No. of Intracranial
Hemorrhage HR (95% CI) P Value HR (95% CI) P Value
Age, y
 <65 6 Reference … Reference …
 65–75 54 1.90 (0.82–4.42) 0.137 2.21 (0.94–5.16) 0.066
 >75 135 2.10 (0.92–4.75) 0.077 2.93 (1.28–6.68) 0.011*
Female 117 1.10 (0.83–1.47) 0.512 … …
Hypertension 131 1.48 (1.09–2.00) 0.011* 1.42 (1.04–1.93) 0.029*
Diabetes mellitus 60 1.62 (1.19–2.20) 0.002* 1.55 (1.12–2.12) 0.007*
Smoker 63 1.04 (0.77–1.40) 0.822 … …
Hyperthyroidism 13 0.91 (0.52–1.59) 0.732 … …
Renal failure on dialysis 2 0.64 (1.60–2.59) 0.535 … …
Heart failure 38 0.87 (0.61–1.24) 0.433 … …
Coronary artery disease 52 1.34 (0.97–1.84) 0.076 1.19 (0.86–1.64) 0.309
Peripheral arterial disease 8 1.26 (0.62–2.55) 0.526 … …
Prior ischemic stroke 51 1.13 (0.82–1.55) 0.462 … …
Prior intracranial hemorrhage 10 2.41 (1.27–4.55) 0.007* 2.49 (1.30–4.77) 0.006*
Antithrombotic therapy
 No therapy 39 Reference … Reference …
 Aspirin 91 1.54 (1.06–2.24) 0.025* 1.43 (0.97–2.09) 0.071
 Warfarin
  First quartile TTR 20 2.39 (1.39–4.10) 0.002* 2.40 (1.39–4.14) 0.002*
  Second quartile TTR 14 1.54 (0.84–2.84) 0.166 1.49 (0.80–2.77) 0.209
  Third quartile TTR 15 1.35 (0.74–2.45) 0.328 1.40 (0.77–2.57) 0.271
  Fourth quartile TTR 14 1.20 (0.65–2.21) 0.560 1.29 (0.69–2.41) 0.423
 Dabigatran 2 0.76 (0.18–3.16) 0.700 0.79 (0.19–3.31) 0.744
CI indicates confidence interval; HR, hazard ratio; and TTR, time in therapeutic range.
*P<0.05.

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6  Stroke  January 2015
1.6
Annual Incidence of Intracranial
1.4
1.2
hemorrhage (%)
1.0
0.80
0.8
0.6 0.53
0.4
0.2
0.0
No therapy Aspirin
incidence of ICH among different treatment groups remained
similar (Figure V in the online-only Data Supplement).
Mortality
In addition to ischemic stroke and ICH, 5019 patients died
during the study period (18.3%/y). The overall high mortality
indicated a high-risk population. Among these, patients on no
therapy and on aspirin had the highest mortality rate: 17.0%/y
and 37.1%/y, respectively. Although patients on warfarin had
a lower overall mortality, there was a progressive decrease in
mortality with decreasing TTR (first quartile, 11.4%/y; second
quartile, 8.9%/y; third quartile, 5.4%/y; and fourth quartile,
4.6%/y). The annual mortality of patients on dabigatran was
1.8%/y (Figure VI in the online-only Data Supplement).
Discussion
To our knowledge, this is the first study to investigate the
impact of TTR on the risk of stroke and ICH in Chinese
patients with nonvalvular AF in a real-world clinical setting. In
the present analysis, we first show that TTRs (median, 38.8%)
were generally poor among Chinese AF patients. Second, the
incidence of ischemic stroke decreased progressively with
increasing TTR quartiles, ranging from 7.34%/y (first quar-
tile) to 3.10%/y (fourth quartile), even on multivariate analy-
sis. Indeed, patients on aspirin had a comparable incidence of
ischemic stroke as those on warfarin in the lowest quartile of
TTR (7.95%/y versus 7.34%/y), whereas the incidence of isch-
emic stroke in those on dabigatran was the lowest across all
groups (2.24%/y). Third, the incidence of ICH decreased with
increasing TTR quartiles among patients on warfarin, rang-
ing from 1.37%/y (first quartile) to 0.74%/y (fourth quartile).
Fourth, patients on dabigatran had the lowest incidence of ICH
(0.32%/y), which was lower than that of patients on warfarin
at the fourth quartile of TTR (ie, good quality anticoagulation
control) or patients not receiving any antithrombotic therapy.
Despite a lower prevalence of AF in Chinese population
(0.7%) in comparison with whites (1%–2%), the Chinese have
a much higher overall disease burden because of its propor-
tionally larger aged population.19–21 Stroke prevention in AF
in Chinese population remains challenging because of the
lack of epidemiological data. Until recently, there has been a
prevailing belief that Chinese patients with AF are at a much
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1.37
0.86
0.82 Figure 3. Relationship between different antithrom-
0.74 0.75 botic therapies and the annual risk of intracranial
hemorrhage in Chinese patients with atrial fibril-
lation. Q1: Time in therapeutic range (TTR) at first
quartile; Q2: TTR at second quartile; Q3: TTR at
0.32 third quartile; and Q4: TTR at fourth quartile.
Q1 Q2 Q3 Q4 Dabigatran Overall
Warfarin
lower risk of ischemic stroke than their white counterparts.22,23
As the same time, the baseline risk of ICH, the greatest bar-
rier to anticoagulation therapy, was reportedly higher among
Chinese,5–7 as well as in other Asian populations. Thereby,
the use of long-term anticoagulation for stroke prevention in
Chinese has been low.8,10
Recent registry data of Chinese populations from Hong
Kong8 and Beijing,24 as well as subanalyses of data from the
different NOAC trials focusing on Asian populations,25–27 have
demonstrated consistently that the risk of ischemic stroke in
Chinese patients with AF was comparable with or even higher
than that of whites. These findings are in accordance with the
fact that globally, China is among the countries with the high-
est stroke rates.28 Although Chinese patients with AF receiv-
ing warfarin therapy have a higher risk of ICH compared with
white counterparts, net clinical benefit analyses favor warfarin
therapy over aspirin and no therapy in almost all combinations
of CHA2DS2-VASc and HAS-BLED scores.8 Indeed, the net
benefit of warfarin therapy is greatest among those at high risk
of both stroke and ICH.
Another major stumbling block to stroke prevention in
AF in Chinese population is the poor quality of anticoagula-
tion control, as well as access to structured anticoagulation
monitoring. In contemporary randomized trials,11,12 TTR var-
ied greatly by country, but Asian populations (particularly
Chinese) were among those with lowest TTRs.11,12 Outside
trial settings, quality of anticoagulation would be expected
to be even worse, as in the present cohort with the median
TTR among Chinese patients with AF being as low as 38.8%.
As the poor TTR could well be the result of poor standard of
clinical practices, there are other plausible explanations. For
instance, the optimal INR range of 2.0 to 3.0 is well estab-
lished in white populations29; however, given the higher base-
line ICH risk among Asian particularly Chinese,5–7 there is a
widespread perception that Asian/Chinese might need a lower
target INR (eg, INR, 1.6–2.6) to avoid this deadliest complica-
tion, albeit the lack of good clinical evidence.30,31 Nonetheless,
the so-called optimal INR in Asian/Chinese would not be
available unless there is a large randomized controlled tri-
als in Chinese to compare the efficacy and safety of warfa-
rin in different ranges of INR. In addition, it is well known
that many traditional Chinese medicines have been shown to
 Ho et al   Ischemic Stroke and ICH in Chinese Patients With AF   7
affect the human cytochrome P450 system.32 For instance,
ginkgo, hypericum, and cranberry have been reported to aug-
ment the anticoagulation effect of warfarin, whereas ginseng
and green tea inhibit its anticoagulation effect and have a sig-
nificant interaction with warfarin.32 Although patients on war-
farin are advised to avoid traditional Chinese medicine, we
have shown previously that ≤50% of Chinese patients with
AF on warfarin reported consumption of herbal ingredients
which may potentially interact with warfarin.32 Interestingly,
frequent herb users were more likely to have a poor TTR than
infrequent users. In a recent clinical scoring scheme (SAMe-
TT2R2 [Sex, Age (<60 years), Medical History (at least 2 of
the following: hypertension, diabetes, coronary artery disease/
myocardial infarction, peripheral arterial disease, congestive
heart failure, previous stroke, pulmonary disease, hepatic or
renal disease), Treatment (interacting drugs eg amiodarone for
rhythm control) (all 1 point), as well as current Tobacco use (2
points) and Race (non-Caucasian; 2 points)]) designed to pre-
dict TTRs after initiation of warfarin, non-white race was been
identified as one of the important contributors to poor TTR.33
Why is TTR important? Patients on warfarin at low range
of TTR have higher risk of adverse events including isch-
emic stroke, major bleeding, and mortality compared with
than those with high TTR, as thus, when warfarin is use, a
recent European position article recommended that TTRs
should be >70% for optimal efficacy and safety.14,34,35 Indeed,
warfarin therapy may not confer any stroke prevention when
the TTR is low.35,36 In a subanalysis of the Atrial Fibrillation
Clopidogrel Trial With Irbesartan for Prevention of Vascular
Events (ACTIVE-W) trial, warfarin therapy was only superior
to aspirin–clopidogrel combination therapy only among indi-
viduals with TTR ≥58%.13
Despite the poor overall TTR in the present cohort, warfa-
rin therapy was still associated with lower annual incidence
of ischemic stroke. With an average individual TTR >56.2%,
patients on warfarin therapy still had 69% lower risk of isch-
emic stroke but without significant increase in ICH risk. As
the reduction in ischemic stroke risk diminished with decreas-
ing TTR, the risk of ICH increased progressively. Indeed,
among patients at the first quartile (TTR <17.9%, ie, poor
quality anticoagulation control), the risk of ischemic stroke
was basically similar to those on aspirin therapy, but with the
highest ICH risk among all group.
In contrast, patients on dabigatran not only had the lowest
annual ischemic stroke risk among all groups but also had the
lowest ICH risk. These findings concur with the subanalyses
of the NOAC trials,26,27,37 where Asian patients treated with
warfarin were at higher risk of ischemic stroke, major bleed-
ing and ICH compared with their non-Asian counterparts.25
Our study has several important clinical implications. First,
as the efficacy and safety of warfarin therapy depend heavily
on quality of anticoagulation, the decision and choice of anti-
coagulation should consider the anticipated TTR in Chinese
patients, in addition to the risk of ischemic stroke (CHA2DS2-
VASc score) and risk of ICH. Second, Chinese AF patients
tend to attain a poor TTR when put on warfarin, a marker of
reduced efficacy and added risks. For them, NOAC may be a
safer alternative. Third, among Chinese patients with AF with
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poor TTR (ie, <17.9%), warfarin therapy may be associated
with more risk than benefit.
Limitations
This study is limited by its registry-based and single-center obser-
vational design in primarily hospital-based patients. Because of the
observational nature, the selection of antithrombotic strategies was
not in a randomized fashion, and it is possible that residual con-
founding may be evident such that patients receiving different anti-
thrombotic strategies, as well as patients on warfarin with different
TTR, were in some ways different from each other. For instance, as
indicated in Table 1, there were significant differences in baseline
characteristics between patients on no therapy, aspirin, warfarin,
and dabigatran. Despite statistical adjustments, potential impacts of
residual confounding effects cannot be excluded. Nonetheless, the
differences in mean CHA2DS2-VASc among these groups ranged
only from 0.3 to 0.6. In addition, socioeconomic status might
affect the choice of antithrombotic strategies and lead to potential
selection bias. This is particularly important for dabigatran, which
is currently a self-financing item in Hong Kong. Furthermore,
although our data have demonstrated that dabigatran therapy and
warfarin therapy with good TTR were associated with lower risks
of ischemic stroke and ICH, given the observational nature, it could
not be possible to ascertain causation. Nonetheless, although the
gold standard to demonstrate treatment effects is a randomized
placebo-control trial, which is not ethically possible at this point
in time, a large real-world registry data serve as a good alternative.
Although we carefully ascertained all strokes and ICH by careful
examination of hospitalization records, laboratory and imaging
results, patients with a milder form of stroke and ICH who were
not hospitalized were not included.
In conclusion, the benefits of warfarin therapy for stroke
prevention and ICH risk in Chinese patients with AF are
closely dependent on the quality of anticoagulation control, as
reflected by the TTR. Even at the top TTR quartile, warfarin
therapy was associated with a higher stroke and ICH risk than
dabigatran therapy.
Disclosures
Dr Lip has served as a consultant for Bayer, Astellas, Merck,
AstraZeneca, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Medtronic,
Biotronik, Portola, and Boehringer Ingelheim and has been on the
speakers’ bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim,
Medtronic, Daiichi-Sankyo, and Sanofi Aventis. Dr Tse has served as
a consultant and advisory board member for Boehringer Ingelheim,
Bayer, BMS/Pfizer, and Daiichi-Sankyo and has been on the speak-
ers’ bureau for Boehringer Ingelheim, Bayer, and BMS/Pfizer. The
other authors report no conflicts.
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Ischemic Stroke and Intracranial Hemorrhage With Aspirin, Dabigatran, and Warfarin:
Impact of Quality of Anticoagulation Control
Chi-Wai Ho, Mei-Han Ho, Pak-Hei Chan, Jo-Jo Hai, Emmanuel Cheung, Chun-Yip Yeung,
Kui-Kai Lau, Koon-Ho Chan, Chu-Pak Lau, Gregory Y.H. Lip, Gilberto Ka-Kit Leung,
Hung-Fat Tse and Chung-Wah Siu

Stroke. published online November 18, 2014;

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