Risk of Bleeding and Stroke with Oral Anticoagulation and Antiplatelet Therapy in Patients with Atrial Fibrillation in Taiwan: A Nationwide Cohort Study
Risk of Bleeding and Stroke with Oral Anticoagulation and Antiplatelet Therapy in Patients with Atrial Fibrillation in Taiwan: A Nationwide Cohort Study
Pei-Chun Chen 0 1
Gregory Y. H. Lip 0 1
Grace Yeh 0 1
Hung-Ju Lin 0 1
Kuo-Liong Chien 0 1
0 1 Clinical Informatics and Medical Statistics Research Center, Chang Gung University , Tao-Yuan, Taiwan , 2 University of Birmingham Centre for Cardiovascular Sciences, City Hospital , Birmingham , United Kingdom , 3 National Taiwan University Health Data Research Center , Taipei, Taiwan , 4 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University , Taipei, Taiwan , 5 Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan
1 Academic Editor: Yan Gong, University of Florida, UNITED STATES
Data Availability Statement: This study used
National Health Insurance Research Database
managed by the National Health Research Institutes,
Taiwan. The data cannot be made available in the
manuscript, the supplemental files, or a public
repository because of the regulations executed by
Taiwans government. The application and use of the
database follows some access restrictions (http://
nhird.nhri.org.tw/en/Data_Protection.html). For more
information about the party from which we obtained
the database and that readers may contact to request
Data on the use of oral anticoagulation (OAC) and antiplatelet therapy and the risk of
bleeding and stroke amongst Asian patients with atrial fibrillation (AF) are limited. We investigated
the risks of bleeding and stroke with use of oral anticoagulation (OAC) and antiplatelet
therapy as mono- or combination therapy, in patients with AF from a Chinese nationwide
We studied a cohort of 10384 patients (57.2% men, age 67.8 13.2 yrs) between 1999 and
2010 from the National Health Insurance Research Database in Taiwan. Records of
prescriptions were obtained during follow-up. The main outcome was a recurrent stroke during
the follow-up period. Time-dependent Cox proportional hazards models were used for
We documented 1009 events for bleeding, as well as 224 hemorrhagic stroke and 1642
ischemic stroke events during a median 3.2 (interquartile range, 1.05-6.54) years follow-up.
Compared with warfarin users, patients with antiplatelet therapy had a lower risk of bleeding
(adjusted relative risk [RR], 0.59, 95% confidence interval [CI], 0.49-0.71, p<0.001) whilst
combination therapy had a non-statistically significant higher bleeding risk (RR, 1.33, 95%,
0.91-1.94, p = 0.20). Patients on antiplatelet monotherapy had a similar risk for ischemic
stroke compared with OAC (RR 1.05, 95% CI, 0.89-1.25, p = 0.50), whilst those on
combination therapy had a significantly higher risk (RR 1.90, 95% CI, 1.34-2.70, p<0.001).
the data, please refer to: http://nhird.nhri.org.tw/en/
Funding: This study was supported from the
National Science Council, Taiwan (NSC
102-2314-B002 -080 -MY2 and NSC 102-2314-B-002 -075). The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
Competing Interests: Prof. Lip has served as a
consultant for Bayer, Astellas, Merck, Sanofi, BMS/
Pfizer, Daiichi-Sankyo, Biotronik, Portola and
Boehringer Ingelheim and has been on the speakers'
bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim,
and Sanofi Aventis. This does not alter the authors'
adherence to PLOS ONE policies on sharing data
In a national representative cohort, antiplatelet therapy had no significant difference in
ischemic stroke risk to warfarin. For bleeding, aspirin had a lower risk compared to warfarin.
This may reflect poor anticoagulation control, highlighting important missed opportunities
for improved stroke prevention, especially in countries where anticoagulation management
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia, with the prevalence increasing
progressively with age . A national survey based on health insurance data in Taiwan showed
hospitalizations due to AF increased from 91 per 100,000 to 150 per 100,000 between 1997 and
2002 [2,3]. AF is an important risk factor for stroke, which confers a major healthcare burden
on acute or long-term medical care, as well as on patient disability[4,5].
Various stroke risk stratification schemes, including the CHADS2 and CHA2DS2-VASc
 scores for stroke risk, and the HAS-BLED score for bleeding risk, have been used to aid risk
prediction in AF although some ethnic and gender differences may be evident .
Stroke prevention in AF requires the use of oral anticoagulation (OAC) with antiplatelet
therapy only having a weak efficacy. Both OAC and antiplatelet drugs confer an increased
risk of bleeding, which is accentuated by its combined use amongst AF patients.
However, the balance between efficacy and safety with OAC also depends on the quality of INR
control, as reflected by the average time in therapeutic range (TTR) [15,16], with the
recommended TTR being >70%. In many countries, the average TTR is poor, and in a
recent randomized trial, the average TTR in Taiwan was only 44%.
One small hospital based study from Beijing, China reported that stroke and bleeding rates
were not different between warfarin, aspirin and untreated patients, reflecting that many
warfarin-treated patients did not have regular access to anticoagulation monitoring and offering
opportunities for improved stroke prevention with the novel OAC drugs. We are unaware of
any large cohorts comparing stroke and bleeding risk in the Far East, where OAC control with
warfarin may be suboptimal. If the findings from the paper by Guo et al were replicated in
a large nationwide cohort, this would have major implications for missed opportunities for
stroke prevention in AF, as well as important healthcare cost and public health implications.
In this study, we investigated stroke and bleeding rates in a national representative
population amongst AF patients treated with OAC (warfarin), antiplatelet drugs as monotherapy and
as combination therapy, compared to no antithrombotic therapy. Second, we assessed event
rates according to antithrombotic therapy use, by stroke and bleeding risk strata, using
established risk scoring systems, that is, CHADS2 and CHA2DS2-VASc for stroke risk, and the
HAS-BLED score for bleeding risk.
This study used a subset of National Health Insurance Research Database (NHIRD), the
Longitudinal Health Insurance Database of 2000, which contains claims data of a randomly sampled
cohort of one million people enrolled in the Taiwan National Health Insurance program
during 19962000. The health insurance program has covered 99% or more of Taiwanese
population and contracted more than 90% of healthcare institutions in Taiwan. We obtained
the original claim data that included inpatient records, ambulatory care records, contracted
pharmacies records and registries for beneficiaries. The Institutional Review Board in National
Taiwan University Hospital approved the study protocol. The patient records/information was
anonymized and de-identified prior to analysis and the informed consent was waived.
Patients had a first diagnosis for AF (the index admission) during 19992010 was
considered as follows: the first diagnosis for AF: the presence of at least one inpatient claim with an
ICD-9-CM code 427.3 in any one of up to 5 diagnostic codes or at least two outpatient claims
with an ICD-9-CM code 427.3 in any one of up to 3 diagnostic codes. The date of diagnosis
was defined as the index date. The accuracy of the ICD-9-CM codes for AF has been validated
by medical chart review ; of patients who had an AF diagnosis by ICD-9-CM codes and
used medications that might be prescribed to AF patients, 98% and 96% with AF recorded by
either electrocardiogram or 24-hour Holter monitoring in a medical center and community
teaching hospital, respectively. The exclusion criteria included the following: age at index date
<18 years, patients who died during the index admission, patients with rheumatic heart disease
(ICD-9-CM codes 393398 in any one of the five positions on at least one inpatient claims or
in any one of the three positions on at least two outpatient claims), and patients who died
during the index admission.
We defined antithrombotic drug exposure into 8 groups based on prescription after the
index date: (i) OAC (essentially warfarin) monotherapy; (ii) aspirin monotherapy; (iii)
clopidogrel monotherapy; (iv) aspirin + clopidogrel; (v) warfarin + aspirin; (vi) warfarin + clopidogrel;
(vii) warfarin + aspirin +clopidogrel; and (viii) no antithrombotic therapy (ie. never users of
warfarin, aspirin, clopidogrel). We calculated the usage according to the prescription history:
monotherapy was defined as group (1) to group (iii); combination therapy was defined as
group (iv) to group (vii). We defined continuous use if the number of discontinued days was
less than 7 days.
We defined the comorbidity histories, drug usage codes according to ICD-9-CM codes as
the S1 Table. The definitions for the CHADS2, CHA2DS2-VASc and HAS-BLED scores were
listed according to the clinical status within 2 years of the index date (S2 Table).
The follow-up duration began on the index date (or discharge date of index admission) and
lasted until the outcome diagnosis, withdrawal from National Health Insurance, or
December 31, 2010, whichever came first. We defined the following outcomes: (i) bleeding was
defined as hospital admission for bleeding, including gastrointestinal, intracranial, urinary tract
and airway bleeding episodes in the follow-up duration; (ii) hemorrhagic stroke: admission for
hemorrhagic stroke (ICD9CM codes 431432) in the follow-up duration; and (iii) ischemic
stroke defined as admission for ischemic stroke (ICD9CM codes 433437) in the
Demographic and clinical characteristics of the study participants were listed according to
various therapy groups and were compared by ANOVA for continuous variables and by the
chisquare test for categorical data. We calculated the incidence rate (per 1000 person-years) by
dividing numbers of events of bleeding and stroke events with person-years of exposure to each
group. Due to time varying nature of drug exposure, we defined the duration of specific drug
exposure as days of use for each prescription from database at ambulatory care, and contracted
pharmacies, but not at inpatient records because data of days of use of each prescription were
We used multivariable models to estimate the relative risk (RR) and 95% confidence interval
(CI) by Cox proportional hazards model with drug exposure as a time-varying covariate to
assess the association between various groups and bleeding as well as stroke events. We used the
single anticoagulant group (warfarin monotherapy) as the reference group and adjusted
for age, gender and comorbidity status, including history of ischemic heart, hypertension,
ischemic stroke, heart failure, diabetes, liver disease, renal failure, malignancy, bleeding, and
drug history of aspirin, warfarin and clopidogrel usage which were defined before index atrial
fibrillation date. Moreover, we calculated the numbers and crude incidence rates of ischemic
stroke and bleeding events according to the categories of CHADS2, CHA2DS2-VASc and
HAS-BLED scores among various drug exposure groups to evaluate potential effects of drug
treatment on the impact of risk stratification. All data analyses were performed using SAS
version 9.3 (SAS Institute Inc., Carey, NC).
We included 10384 patients (57.2% male; mean age 67.8 years) with first-time AF diagnosis
and live at discharge between 1999 and 2010 [Table 1]. Compared with those treated with
warfarin therapy, patients taking aspirin and clopidogrel were older and more likely to be male,
and to have a history of ischemic heart disease, heart failure, hypertension, ischemic stroke,
diabetes, renal failure, and history of bleeding, including gastrointestinal, intracranial and urinary
track bleeding, and amiodarone use.
Trends over time of the various antithrombotic drug used between 1999 and 2010 are
shown in Fig 1. As time progressed, warfarin usage increased significantly, from 13.5% in 2000
to 27.6% in 2010. Aspirin usage decreased between 2000 (65.4%) and 2010 (48.5%). Dual and
triple therapy use remained relatively stable across the time period.
During a median 3.2 (interquartile range, 1.056.54) years follow-up period, 1009 cases
experienced bleeding events, whilst 224 hemorrhagic stroke and 1642 ischemic stroke events
were recorded. The diagnostic image study has been performed by computed tomography
(89%) and magnetic resonance image (26%). The incidence rates and associated risk estimates
were listed in Table 2 and shown in Fig 2.
Relation to risk of bleeding and hemorrhagic stroke and therapy
Compared with those treated with warfarin (reference treatment), patients on antiplatelet
drugs had a lower risk of bleeding (adjusted RR, 0.59, 95% CI, 0.490.71, p<0.001) and
hemorrhagic stroke (RR, 0.52, 95% CI, 0.360.75, p<0.001) [Table 2]. Patients with combination
therapy had a non-statistically significant higher risk of bleeding (RR, 1.33, 95%, 0.911.94,
p = 0.20) and an appreciably elevated risk of hemorrhagic stroke (RR, 2.03, 95% CI, 1.083.83,
p = 0.011). Patients taking no antithrombotic treatment had a higher risk of bleeding (RR, 1.45,
95% CI, 1.171.80, p<0.001), whereas no difference in incidence of hemorrhagic stroke was
seen between warfarin group and no antithrombotic therapy group.
Table 3 shows results of analyses stratified by the HAS-BLED score. As expected, the
bleeding risk increased with increasing HAS-BLED score. Patients on antiplatelet drugs were at a
consistently lower risk for bleeding compared to the warfarin group irrespective of HAS-BLED
strata (p values in each strata, 0.002 for low risk; <0.001 for intermediate risk; 0.004 for high
risk). RRs of bleeding was 0.37 (95% CI, 0.190.69, p = 0.002) for the low risk stratum, and 0.70
(95% CI, 0.550.89, p = 0.004) for the high risk stratum. Compared to the warfarin group,
patients in the intermediate and high bleeding risk strata who were taking no antithrombotic
Fig 1. Trends of various antiplatelet and anticoagulant agent usages during the study period, 1999
Warfarin and antiplatelet Warfarin [reference]
1.63(1.322.02), 0.001 0.86(0.711.31),0.15
1.45(1.171.80), <0.001 0.59(0.490.71), <0.001
Bleeding: Model 1 was adjusted for age, sex, comorbidities (Ischemic heart, Hypertension, Ischemic stroke, Heart Failure, Diabetes, Liver disease, Renal
failure, Malignancy, Bleeding, Aspirin, Warfarin and Clopidogrel) were defined before index AF (including index admission date).
Hemorrhagic stroke: Model 1 was adjusted for sex, comorbidities (Ischemic heart, Hypertension, Ischemic stroke, Liver disease, Renal failure, Bleeding,
Aspirin, Warfarin and Clopidogrel) were defined before index AF (including index admission date).
Ischemic stroke: Model 1 was adjusted for sex, comorbidities (Ischemic heart, Hypertension, Ischemic stroke, Heart Failure, Diabetes, Liver disease,
Renal failure, Malignancy, Aspirin, Warfarin and Clopidogrel) were defined before index AF (including index admission date).
Comorbidity was defined as presence if the disease was diagnosed two years before the index date.
drugs were at higher risk for bleeding (RR, 2.44, 95% CI, 1.843.23, p<0.001 for HAS-BLED
Relation to risk of ischemic stroke and therapy
When compared with patients on warfarin, those patients on antiplatelet drugs had a similar
risk (RR 1.05, 95% CI, 0.891.25, p = 0.50), whilst the no antithrombotic therapy (RR 1.33,
95%CI, 1.091.61, p = 0.003) and combination therapy had a significantly higher risk (RR 1.90,
95% CI, 1.342.70, p<0.001) [Table 2].
As expected, there was increasing stroke risk with increasing risk strata of the CHADS2 and
CHA2DS2-VASc scores [Table 3]. For the low risk strata based on the CHA2DS2-VASc score,
patients taking no antithrombotic therapy or antiplatelet drugs were at similar risk for ischemic
stroke, when compared to those on warfarin as the reference treatment (RR, 0.75, 95% CI,
0.401.40, p = 0.28 for antiplatelet drugs, RR, 0.72, 95% CI, 0.351.50, p = 0.30 for no therapy).
For the high risk strata, patients taking no antithrombotic therapy and on combination therapy
had a higher risk for ischemic stroke, compared with those on warfarin (RR, 1.62, 95% CI,
1.302.02, p<0.001 for no therapy; RR, 1.69, 95% CI, 1.142.52, p<0.001 for combination
Fig 2. Relative risks for the risk of bleeding (A), hemorrhagic stroke (B), and ischemic stroke (C),
associated with the use of warfarin, aspirin, clopidogrel, and combinations of these drugs in the
study patients. CI indicates confidence interval.
therapy); however, patients taking antiplatelet drugs had a similar risk for ischemic stroke (RR,
1.07, 95% CI, 0.881.31, p = 0.63). A similar pattern was evident when analyzed by the
CHADS2 score (classical or revised).
The detailed breakdown by actual therapy shown in Fig 2 shows that compared to warfarin
(reference treatment), the use of aspirin and aspirin+clopidogrel had similar risk of ischemic
stroke, whilst stroke risk was increased with warfarin+aspirin, with a trend for warfarin
Table 3. Incidence rate and relative risks, 95% confidence intervals of events associated with anticoagulant and antiplatelet within different risk
Warfarin and antiplatelet
Categorization of Bleeding
risk by HAS-BLED
High (> = 3)
Categorization of risk of
High (> = 2)
Abbreviations: CI, confidence interval; RR, relative risk.
*Incidence rate/1000 person-years
The detailed breakdown by actual therapy shown in Fig 2 shows that compared to warfarin (reference), aspirin was associated with less bleeding.
However, bleeding risk was not significantly different for other categories of drug exposures.
In this study of a large national representative cohort of AF patients from Taiwan, we show for
the first time that antiplatelet therapy had no significant difference in ischemic stroke risk to
warfarin, whilst combination therapy was associated with higher risks. For hemorrhagic stroke
and bleeding, aspirin had a lower risk compared to warfarin, whilst combination therapy
conferred a higher risk. These data are consistent with the poor efficacy and safety of warfarin in
Asian patients, and offers important opportunities for improved stroke prevention with novel
A metaanalysis of clinical trial data has shown that adjusted dose anticoagulant therapy
compared to control reduces stroke in AF by 64% and all cause mortality by 26%, and that
warfarin was more protective than aspirin. However, uncertain factors, such as genetics,
dietary and drug factors make the adjustment of warfarin dosage unpredictable. Our study
clearly demonstrates antiplatelet usage had a lower risk for bleeding and hemorrhagic stroke,
compared with warfarin, consistent with older trial data in Western population.
Interestingly we found that patients without any antithrombotic therapy in the high risk
strata had a higher risk for bleeding, as well as ischemic stroke, compared to warfarin use. This
is inconsistent with large observational data in USA and Swedish cohorts where compared
with no warfarin use, patients treated with warfarin had a lower risk for ischemic stroke and
hemorrhage. Residual confounding may explain this, representing associated
comorbidities, or risk factors for bleeding leading to non-prescription of OAC.
A population-based elderly cohort based on 125195 elderly patients (> = 66 years old) with
AF in Ontario showed the warfarin therapy was associated an overall rate of 3.8 per 100
person-year for bleeding, and the rates of bleeding increased from 1.8 in the low stratum of
CHADS2 to 6.7 per 100 person-year in the CHADS2 scores of 4 or greater. Our results
showed similar bleeding event rates by HAS-BLED scores, which has recently been shown to
be a better predictor for serious bleeding compared to the CHADS2 and CHA2DS2-VASc
Importantly, racial difference for drug susceptibility may be evident, especially for warfarin.
Indeed, non-white patients had a higher risk for warfarin-related hemorrhagic stroke risk, and
Asian population in particular have a higher risk for warfarin-related intracranial hemorrhage
(relative risk,4.06, 95% CI, 2.476.65). Also, Asian patients with AF may do badly on
warfarin compared to non-Asian patients, with higher rates of stroke, hemorrhagic stroke, major
bleeding and intracranial bleeding. Our data are also consistent with a small study by Guo
et al, which showed antiplatelet drugs and warfarin had a similar risk of stroke/
Nonetheless, efficacy and safety whilst on warfarin is highly dependent upon the quality of
anticoagulation control, as reflected by average time in therapeutic range (TTR)[15,16,30]. For
warfarin, this is established as an INR of 2.03.0, and an average TTR of >70% is
recommended in guidelines. Unfortunately, our dataset does not have detailed TTR data, but we
know from other published studies that the average TTR for warfarin is low, for example, being
only 44% in the RE-LY trial. Also, there is the perception that an INR 1.62.6 is best for
older patients, and this may contribute to the stroke rates seen on warfarin, which appears no
different to those on aspirin. Herbal medicines are commonly used in our population
which may also influence TTR status. Nonetheless, our study shows a progressive increase
in use of warfarin among the Taiwanese patients over time, although usage rates are still low
when compared with Danish cohort (36.6%).
The strengths of our study included a large population-based follow-up study and the
integrated details of prescription records such as the drug used, dosages, days of supply dispensed
from database. The health insurance program in Taiwan covers more than 99% of the adult
population, and the cohort was a representative sample of population of Taiwan. Several
studies based on the cohort showed that the score systems of CHADS2 and CHA2DS2-VASc were
applicable in Taiwan[8,35], and the results were compatible with a community based cohort
First, the history of AF prior to 1996 was unknown, but patients with any record of AF before
1999 were excluded to reduce the possibility of including prevalent cases. Second, the validity
of diagnosis of bleeding and stroke events may influence on our results, even though the
accuracy of recording stroke diagnoses and prescriptions in NHIRD was high. Third, we lacked
data for lifestyle information such as weight, drinking, or smoking status in this cohort. Finally,
no data of adherence to the drug usage was obtained, nor TTR data, even we used time
dependent covariate model to handle the exposure status. Poor adherence with various drug
treatments may confound the estimation of bleeding and stroke risk.
In conclusion, in this study of a large national representative cohort from Taiwan, we show
for the first time that antiplatelet therapy had no significant difference in ischemic stroke risk
to warfarin, whilst for bleeding, aspirin had a lower risk compared to warfarin. This may reflect
poor anticoagulation control, highlighting opportunities for improved stroke prevention with
alternative strategies, such as the novel OACs.
S3 Table. Number and crude Incidence rate of bleeding by the HAS-BLED score as well as
ischemic stroke by the CHADS2 and CHA2DS2-VASc score among patients in the
The authors appreciate the staff in the Health Added Value Center, National Taiwan
University and the Department of Health for their support this study.
Conceived and designed the experiments: PCC GL KLC. Performed the experiments: PCC GY
HJL KLC. Analyzed the data: PCC GY HJL. Contributed reagents/materials/analysis tools:
PCC KLC. Wrote the paper: PCC GL HJL KLC.
g te e n 1. Friberg L , Rosenqvist M , Lip GY . Evaluation of risk stratification schemes for ischaemic stroke and
bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study . Eur Heart
J. 2012 ; 33 : 1500 - 1510 . doi: 10.1093/eurheartj/ehr488 PMID: 22246443 2. Lee CH , Liu PY , Tsai LM , Tsai WC , Ho MT , Chen JH , et al. Characteristics of hospitalized patients with
atrial fibrillation in Taiwan: a nationwide observation . Am J Med . 2007 ; 120 : 819 e811- 817 . PMID:
17765055 3. Potpara TS , Lip GYH . Ischemic Stroke and Atrial Fibrillation-A DeadlySerious Combination . Cerebro-
vascular Diseases . 2011 ; 32 : 461 - 462 . doi: 10.1159/000332030 PMID: 22005454 4. Chien KL , Su TC , Hsu HC , Chang WT , Chen PC , Sung FC , et al. Constructing the prediction model for
the risk of stroke in a Chinese population: report from a cohort study in Taiwan . Stroke. 2010 ; 41 :
1858 - 1864 . doi: 10.1161/STROKEAHA.110.586222 PMID: 20671251 5. 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 - 180 . doi: 10.1016/
j.ijcard. 2008 .10.045 PMID: 19046608 6. Gage BF , Waterman AD , Shannon W , Boechler M , Rich MW , Radford MJ . Validation of clinical classifi-
2001 ; 285 : 2864 - 2870 . PMID: 11401607 7. Lip GY , Nieuwlaat R , Pisters R , Lane DA , Crijns HJ . Refining clinical risk stratification for predicting
heart survey on atrial fibrillation . Chest . 2010 ; 137 : 263 - 272 . doi: 10.1378/chest.09-1584 PMID:
19762550 8. Lin LY , Lee CH , Yu CC , Tsai CT , Lai LP , Hwang JJ , et al. Risk factors and incidence of ischemic stroke
2011 ; 217 : 292 - 295 . doi: 10.1016/j.atherosclerosis. 2011 .03.033 PMID: 21513938 9. Friberg L , Benson L , Rosenqvist M , Lip GY . Assessment of female sex as a risk factor in atrial fibrillation
in Sweden: nationwide retrospective cohort study . BMJ . 2012 ; 344 : e3522. doi: 10.1136/bmj.e3522
PMID: 22653980 10. Olesen JB , Torp-Pedersen C , Hansen ML , Lip GY . The value of the CHA2DS2-VASc score for refining
stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort
study. Thromb Haemost 2012 ; 107 : 1172 - 1179 . doi: 10.1160/TH12- 03 -0175 PMID: 22473219 11. Hart RG , Benavente O , McBride R , Pearce LA . Antithrombotic therapy to prevent stroke in patients with
atrial fibrillation: a meta-analysis . Ann Intern Med . 1999 ; 131 : 492 - 501 . PMID: 10507957 12. Lip GY , Andreotti F , Fauchier L , Huber K , Hylek E , Knight E. Executive Summary of a Position Docu-
diology [ESC] Working Group on Thrombosis. Thromb Haemost . 2011 ; 106 : 997 - 1011 . doi: 10.1160/
TH11- 10 -0690 PMID: 22048796 13. Hansen ML , Srensen R , Clausen MT , Fog-Petersen ML , Rauns J , Gadsbll N , et al. Risk of bleeding
Arch Intern Med . 2010 ; 170 : 1433 - 1441 . doi: 10.1001/archinternmed.2010.271 PMID: 20837828 14. Rther J , Crijns H. Prevention of Stroke in Patients with Atrial Fibrillation: The Role of New Antiarrhyth-
mic and Antithrombotic Drugs . Cerebrovascular Diseases . 2010 ; 30 : 314 - 322 . doi: 10.1159/
000319608 PMID : 20664267 15. Gallagher AM , Setakis E , Plumb JM , Clemens A , van Staa TP . Risks of stroke and mortality associated
with suboptimal anticoagulation in atrial fibrillation patients . Thromb Haemost . 2011 ; 106 : 968 - 977 .
doi: 10.1160/TH11- 05 -0353 PMID: 21901239 16. Wan Y , Heneghan C , Perera R , Roberts N , Hollowell J , Glasziou P , et al. Anticoagulation control and
Outcomes 2008 ; 1 : 84 - 91 . doi: 10.1161/CIRCOUTCOMES.108.796185 PMID: 20031794 17. De Caterina R , Husted S , Wallentin L , Andreotti F , Arnesen H , Bachmann F , et al. New oral anticoagu-
Force on Anticoagulants in Heart Disease position paper . J Am Coll Cardiol . 2012 ; 59 : 1413 - 1425 . doi:
10.1016/j.jacc. 2012 .02.008 PMID: 22497820 18. Wallentin L , Yusuf S , Ezekowitz MD , Alings M , Flather M , Franzosi MG , et al. Efficacy and safety of
prevention in atrial fibrillation: an analysis of the RE-LY trial . Lancet . 2010 ; 376 : 975 - 983 . doi: 10.1016/
S0140-6736(10)61194-4 PMID: 20801496 19 . Guo Y , Pisters R , Apostolakis S , Blann AD , Wang H , Zhao X , et al. Stroke risk and suboptimal thrombo-
pact? Int J Cardiol . 2013 ; 168 : 515 - 522 . doi: 10.1016/j.ijcard. 2012 .09.187 PMID: 23103146 20. Tsai WC , Chen CY , Kuo HF , Wu MT , Tang WH , Chu CS , et al. Areca nut chewing and risk of atrial fibril-
lation in Taiwanese men: a nationwide ecological study . Int J Med Sci . 2013 ; 10 : 804 - 811 . doi: 10.
7150/ijms.5998 PMID: 23794944 21. 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 - 867 . PMID: 17577005 22. Friberg L , Rosenqvist M , Lip GY . Net clinical benefit of warfarin in patients with atrial fibrillation: a report
from the Swedish atrial fibrillation cohort study . Circulation . 2012 ; 125 : 2298 - 2307 . doi: 10.1161/
CIRCULATIONAHA.111.055079 PMID: 22514252 23. Olesen JB , Lip GY , Lindhardsen J , Lane DA , Ahlehoff O , Hansen ML , et al. Risks of thromboembolism
using a 'real world' nationwide cohort study . Thromb Haemost . 2011 ; 106 : 739 - 749 . doi: 10.1160/
TH11- 05 -0364 PMID: 21789337 24. Singer DE , Chang Y , Fang MC , Borowsky LH , Pomernacki NK , Udaltsova N , et al. The net clinical ben-
efit of warfarin anticoagulation in atrial fibrillation . Ann Intern Med . 2009 ; 151 : 297 - 305 . PMID:
19721017 25. Gomes T , Mamdani MM , Holbrook AM , Paterson JM , Hellings C , Juurlink DN . Rates of hemorrhage
during warfarin therapy for atrial fibrillation . CMAJ . 2013 ; 185 : E121 - 127 . doi: 10.1503/cmaj.121218
PMID: 23184840 26. Roldn V , Marn F , Manzano-Fernndez S , Gallego P , Vlchez JA , Valds M. The HAS-BLED score
gulated patients with atrial fibrillation . J Am Coll Cardiol . 2013 ; 62 : 2199 - 204 . doi: 10.1016/j.jacc. 2013 .
08.1623 PMID: 24055744 27. Apostolakis S , Lane DA , Buller H , Lip GY. Comparison of the CHADS2, CHA2DS2-VASc and HAS-
lation: The AMADEUS trial . Thromb Haemost . 2013 ; 110 : 1074 - 1075 . doi: 10.1160/TH13- 07 - 0552
PMID: 24048467 28. Shen AY , Yao JF , Brar SS , Jorgensen MB , Chen W. Racial /ethnic differences in the risk of intracranial
hemorrhage among patients with atrial fibrillation . J Am Coll Cardiol . 2007 ; 50 : 309 - 315 . PMID:
17659197 29. Hori M , Connolly SJ , Zhu J , Liu LS , Lau CP , Pais P , et al. Dabigatran versus warfarin: effects on ische-
2013 ; 44 : 1891 - 1896 . doi: 10.1161/STROKEAHA.113.000990 PMID: 23743976 30. Morgan CL , McEwan P , Tukiendorf A , Robinson PA , Clemens A , Plumb JM . Warfarin treatment in pa-
Res. 2009 ; 124 : 37 - 41 . doi: 10.1016/j.thromres. 2008 .09.016 PMID: 19062079 31. Camm AJ , Lip GY , De Caterina R , Savelieva I , Atar D , Hohnloser SH . 2012 focused update of the ESC
Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the man-
sociation. Eur Heart J . 2012 ; 33 : 2719 - 2747 . doi: 10.1093/eurheartj/ehs253 PMID: 22922413 32. Wallentin L , Becker RC , James SK , Harrington RA . The PLATO trial reveals further opportunities to im-
doxical excess mortality in the PLATO trial should be independently verified" (Thromb Haemost 2011 ;
105.5). Thromb Haemost . 2011 ; 105 : 760 - 762 . doi: 10.1160/TH11- 03 -0162 PMID: 21394383 33. Ogawa S , Aonuma K , Tse H-F , Huang D , Huang J-L , Kalman J , et al. The APHRS's 2013 statement on
antithrombotic therapy of patients with nonvalvular atrial fibrillation . Journal of Arrhythmia . 2013 ; 29 :
190- 200 . 34. Wong RS , Cheng G , Chan TY . Use of herbal medicines by patients receiving warfarin . Drug Saf . 2003 ;
26 : 585 - 588 . PMID: 12825970 35. Chao TF , Liu CJ , Chen SJ , Wang KL , Lin YJ , Chang SL , et al. Atrial Fibrillation and the Risk of Ischemic
Stroke. Stroke. 2012 ; 43 : 2551 - 2555 . PMID: 22871677 36. Lip GY , Rasmussen LH , Skjoth F , Overvad K , Larsen TB . Stroke and mortality in patients with incident
heart failure: the Diet, Cancer and Health (DCH) cohort study . BMJ Open . 2012 ; 2.