72 Coagulation and Fibrinolysis

Is There a Preferred Stroke Prevention Strategy

for Diabetic Patients with Non-Valvular Atrial
Fibrillation? Comparing Warfarin, Dabigatran
and Rivaroxaban
Chih-Cheng Hsu1,2,3,4 Pai-Feng Hsu5,6 Shih-Hsien Sung6,7 Shih-Te Tu8 Ben-Hui Yu1
Chi-Jung Huang9 Hao-Min Cheng6,9,10

1 Institute of Population Health Sciences, National Health Research Address for correspondence Dr. Hao-Min Cheng, MD, PhD, No. 201,
Institutes, Zhunan, Miaoli County, Taiwan Sec. 2, Shih-Pai Road, Beitou District, Taipei, Taiwan 112, ROC
2 Department of Health Services Administration, China Medical (e-mail: hmcheng@vghtpe.gov.tw).
University, Taichung City, Taiwan
3 Institute of Clinical Medicine, National Yang Ming University,
Taipei, Taiwan
4 Department of Family Medicine, Min-Sheng General Hospital,
Taoyuan, Taiwan
5 Healthcare and Management Center, Taipei Veterans General

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Hospital, Taipei, Taiwan
6 Department of Medicine, National Yang-Ming University, Taipei, Taiwan
7 Division of Cardiology, Department of Internal Medicine, Taipei
Veterans General Hospital, Taipei, Taiwan
8 Department of Endocrinology, Changhua Christian Hospital,
Changhua, Taiwan
9 Center for Evidence-based Medicine, Taipei Veterans General
Hospital, Taipei, Taiwan
10 Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

Thromb Haemost 2018;118:72–81.

Abstract Background The prevalence of diabetes is growing, and diabetes is an independent

Keywords
► cardiovascular events
► diabetes
► atrial fibrillation
► anticoagulation
► stroke prevention
risk factor for both atrial fibrillation (AF) and stroke. However, the relative effectiveness
and safety of different oral anticoagulants for diabetic patients with non-valvular AF
remain unclear. We aimed to compare thromboembolic events, bleeding and mortality
in diabetic AF patients treated with rivaroxaban, dabigatran and warfarin.
Methods and Results Diabetic AF patients taking dabigatran (n ¼ 322), rivaroxaban
(n ¼ 320) or warfarin (n ¼ 1,899) were identified from the nationwide diabetes pay-for-
performance program (n ¼ 814,465) in Taiwan. Outcomes and comorbidities were
evaluated by linking with Taiwan National Health Insurance Research Database. Propensity
score weighting method was used to balance covariates across study groups. Patients were
followed up until the first occurrence of any study outcome or the study end date.
Compared with warfarin, dabigatran significantly decreased the risk of all-cause mortality
(hazard ratio [HR] ¼ 0.348, 95% confidence interval [CI] ¼ 0.157–0.771) and gastroin-
testinal bleeding (HR ¼ 0.558, 95% CI ¼ 0.327–0.955). Relative effectiveness and safety
outcomes between rivaroxaban and warfarin were comparable. Compared with rivarox-
aban, dabigatran significantly decreased the risk of all-cause mortality (HR ¼ 0.310, 95%

received Copyright © 2018 Schattauer DOI https://doi.org/

February 10, 2017 10.1160/TH17-02-0095.
accepted after revision ISSN 0340-6245.
September 28, 2017

CI ¼ 0.121–0.798) and was associated with a borderline reduced risk for composite safety
end points (HR ¼ 0.670, 95% CI ¼ 0.421–1.067).
Conclusion In diabetic AF patients, dabigatran and rivaroxaban showed a superior or
non-inferior effectiveness and safety profile compared with warfarin. Dabigatran was
associated with a significantly lower risk of mortality than rivaroxaban.
Introduction
With the global advent of aging, urbanization and increasing
prevalence of obesity and physical inactivity, the number of
people with diabetes has been growing.1,2 In 2013, 382 mil-
lion people had diabetes, and this number is expected to rise
to 592 million by 2035.2 In Chinese adult population, the
overall prevalence of diabetes was reported to be 11.6% in
2010.3 These data indicate diabetes as a huge global disease
burden, necessitating the development of customized treat-
ment strategies for this population.
Diabetes is an independent risk factor for both atrial fibrilla-
tion (AF)4–6 and stroke,7,8 and AF is commonly accompanied by
multiple comorbidities.9 In the ADVANCE study, 7.6% of dia-
betes patients had AF at baseline, associated with substantially
increased risks of death and cardiovascular events.10 Therefore,
diabetic patients, once they develop AF, should be treated with
prophylactic oral anticoagulation, including vitamin K antago-
nists (VKAs) or non-VKA oral anticoagulants (NOACs), to
reduce the excessive risk of stroke or thromboembolism.11
The approvals of NOACs for stroke prevention in AF (SPAF)
were based on large randomized phase III trials demonstrating
the non-inferiority of dabigatran,12 rivaroxaban,13 apixaban14
or edoxaban15 to warfarin. However, although diabetic
patients with AF represent a large population (around 30 mil-
lion worldwide), to our knowledge, no previous study speci-
fically has compared the anticoagulation strategies for stroke
prevention in this population. Therefore, the present study, by
analysing a pay-for-performance (P4P) diabetes program,
investigated the comparative effectiveness between the antic-
oagulation strategies, including dabigatran, rivaroxaban and
warfarin, for diabetic patients with AF.
Methods
Study Population
The study participants were selected from a research database
derived from a nationwide P4P diabetes care program,16,17
which was implemented by Taiwan’s National Health Insurance
(NHI) Administration at the end of 2001 to improve the quality
of health care for diabetes patients. Diabetic patients in this
program are cared by a qualified physician-led multidisciplin-
ary team according to standardized clinical guidelines.18
Because the P4P diabetes care program is a special NHI
program, information regarding the enrolled patient demo-
graphics, comorbidities, diagnosis, prescriptions and outcomes
can be obtained from the hospital and outpatient reimburse-
ment claims in the National Health Insurance Research data-
base (NHIRD).19 In Taiwan, the National Health Insurance
program is a single-payer health insurance program operating
Anticoagulation for Diabetic Atrial Fibrillation Hsu et al. 73
since 1995 and covering more than 98% of the Taiwanese
population. To protect privacy for research purposes, the
information of all participants in this database has been
managed using a double scrambling protocol. We retrieved
the research data of individuals who were enrolled in the P4P
diabetes care program between January 1, 1999, and Decem-
ber 31, 2015. The study was approved by the ethical committee
of National Health Research Institutes, Zhunan, Taiwan.
Study Design
This is a cohort study enrolling participants with type 2
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diabetes mellitus (T2DM) from the nationwide diabetes P4P
database. We identified a total of 814,465 T2DM patients
enrolled in the P4P database during 1999–2015. As shown
in ►Fig. 1, patients were eligible if they were aged 20 years or
older, had AF on or after their first diagnosis of diabetes, and
were on NOACs or warfarin only at the AF episodes. Diabetic
patients with AF were included on the day they filled a first-
time prescription for warfarin, dabigatran or rivaroxaban
during the study period. Apixaban and edoxaban were not
included in the present study because the expenses of apix-
aban and edoxaban have not been covered by the NHI program
until 2014 and 2016, respectively. The exclusion criteria were
(1) valvular AF, (2) total hip or knee arthroplastics within
5 weeks before the inclusion date, (3) pulmonary embolism or
deep vein thrombosis within 6 months before the inclusion
date, (4) two prescriptions of different oral anticoagulants
claimed at the inclusion date or (5) using aspirin for SPAF.
Concomitant pharmacotherapy was identified from prescrip-
tions dispensed 180 days before the inclusion date. Patients
with comorbidities of coronary heart disease or peripheral
arterial disease who were treated with antiplatelet agent
before the index event were eligible. We used diagnosis codes
recorded within 10 years prior to the inclusion date to define
comorbidities (►Supplementary Table S1, online only). Stroke
risk was estimated with CHA2DS2-VASc (1 point for congestive
heart failure, hypertension, diabetes, vascular disease, age 65–
74 years and female sex, and 2 points for age 75 years).18 Only
few patients on NOACs were prescribed high dosages (11.5% of
patients on dabigatran taking 150 mg twice a day and 12.5% on
rivaroxaban taking 20 mg per day); therefore, all analyses
were based on the anticoagulant classes combining their
corresponding dosages.
Definition of Variables
We defined diabetes as patients with at least three times
outpatient claims with the ICD-9-CM code 250 and AF as those
with the ICD-9-CM code 427.3XX. All confounding variables
and comorbidities were identified according to the diagnosis
Thrombosis and Haemostasis Vol. 118 No. 1/2018
74 Anticoagulation for Diabetic Atrial Fibrillation Hsu et al.
Fig. 1 Data flow illustrating the inclusion and exclusion criteria. NOAC, non–vitamin K antagonist oral anticoagulant.
before the index date in diabetic patients taking NOACs or
warfarin medications, including those for hypertension, dysli-
pidemia, liver disease, congestive heart failure, transient
ischemic attack (TIA), systemic thromboembolism, vascular
diseases and head injury. We defined stroke as those who had
hospitalization claim data by ICD-9-CM codes 430–438 and
coronary heart disease as those who had hospitalization claim
data by ICD-9-CM codes 410–414 (►Supplementary Table S1,
online only).
Outcome
The following outcomes were assessed in this study: all-
cause mortality, ischemic stroke, intracranial haemorrhage,
gastrointestinal (GI) bleeding and genitourinary bleeding.
Patients were followed up from the date of initiation of first-
time oral anticoagulant treatment (the index date) until
death or the end of the study (December 31, 2015), which-
ever occurred first. Stroke or thromboembolism (see
►Supplementary Table S1, online only) was defined as a
hospitalization for cerebral infarction, unspecified cerebral
infarction, arterial embolism and thrombosis, other transi-
ent cerebral ischemic attacks and related syndromes, or
unspecified transient cerebral ischemic attack. Intracranial
bleeding (ICD-9 430–432) included intracerebral haemor-
Thrombosis and Haemostasis Vol. 118 No. 1/2018
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rhage (ICH), non-traumatic/traumatic subarachnoid hae-
morrhage, traumatic subdural haemorrhage and traumatic
epidural haemorrhage. We defined GI haemorrhage as a
bleeding in any site from oesophagus to rectum due to acute
or chronic ulcer, inflammation and lesions (►Supplementary
Table S1, online only). Haematuria was identified according
to ICD-9-CM codes of 599.7, which comprised gross, micro-
scopic and unspecified haematuria.
Statistical Methods
Categorical data were compared across groups using the chi-
square test, and parametric continuous data were compared
across groups using the analysis of variance. Survival times
were calculated from the index date to the onset date of the
cardiovascular event or to the end of the study (December 31,
2015), whichever occurred first. The intention-to-treat study
design was used for study group classification in this study.
The Kaplan–Meier method was used to estimate survival
curves for each group, and log-rank tests were used to assess
the homogeneity between survival curves. The hazard ratio
(HR) and 95% confidence interval (CI) between different
stroke prevention strategies were estimated for cardiovas-
cular events and mortalities using the Cox proportional
hazards models. We conducted a 1:1 matching on the
 Table 1 Baseline characteristics of type 2 diabetes patients by medication at the first atrial fibrillation before and after propensity score match

Before propensity score match After propensity score match

Dabigatran Rivaroxaban Warfarin p-Value Dabigatran Warfarin χ2 test Rivaroxaban Warfarin p-Value
N % N % N % N % N % p-Value N % N %
Patients number, n 322 320 1,899 305 305 300 301
Sex
Male 182 56.5% 141 44.1% 966 50.9% 0.0066 172 56.4% 150 49.2% 0.0744 134 44.7% 158 52.5% 0.0550
Female 140 43.5% 179 55.9% 933 49.1% 133 43.6% 155 50.8% 166 55.3% 143 47.5%
Age, y
Mean (SD) 75.3 (9.0) 75.4 (8.6) 70.0 (10.3) 75.1 (9.1) 73.9 (8.7) 75.2 (8.7) 74.4 (8.2)
 64 41 12.7% 37 11.6% 582 30.6% <0.0001 41 13.4% 37 12.1% 0.3126 37 12.3% 33 11.0% 0.8408
65–74 102 31.7% 115 35.9% 637 33.5% 99 32.5% 117 38.4% 110 36.7% 109 36.2%
 75 179 55.6% 168 52.5% 680 35.8% 165 54.1% 151 49.5% 153 51.0% 159 52.8%
Hba1c
Mean (SD) 7.56 (1.67) 7.54 (1.66) 7.82 (2.71) 0.0612 7.55 (1.68) 7.36 (1.59) <0.001 7.55 (1.68) 7.58 (1.76) <0.001
> 8.0 89 27.6% 82 25.6% 625 32.9% 0.0106 84 27.5% 70 23.0% 0.1920 78 26.0% 80 26.6% 0.8721
 8.0 233 72.4% 238 74.4% 1274 67.1% 221 72.5% 235 77.0% 222 74.0% 221 73.4%
Drugs
Metformin 171 53.1% 157 49.1% 926 48.8% 0.3517 158 51.8% 149 48.9% 0.4661 145 48.3% 155 51.5% 0.4383
Sulfonylurea 166 51.6% 151 47.2% 1,072 56.5% 0.0042 160 52.5% 159 52.1% 0.9354 147 49.0% 146 48.5% 0.9034
Meglitinide 8 2.5% 10 3.1% 27 1.4% 0.0594 7 2.3% 8 2.6% 0.7938 6 2.0% 4 1.3% 0.5202
Thiazolidinedione 26 8.1% 18 5.6% 187 9.8% 0.0414 24 7.9% 21 6.9% 0.6422 18 6.0% 17 5.6% 0.8538
DPP-4 inhibitor 120 37.3% 126 39.4% 393 20.7% <0.0001 104 34.1% 102 33.4% 0.8640 106 35.3% 102 33.9% 0.7094
Insulin 74 23.0% 70 21.9% 675 35.5% <0.0001 74 24.3% 67 22.0% 0.5014 68 22.7% 79 26.2% 0.3074
Statins 235 73.0% 238 74.4% 1,156 60.9% <0.0001 218 71.5% 214 70.2% 0.7216 219 73.0% 232 77.1% 0.2483
Comorbidity
Congestive heart failure 125 38.8% 126 39.4% 883 46.5% 0.0049 123 40.3% 114 37.4% 0.4547 124 41.3% 128 42.5% 0.7672
Hypertension 297 92.2% 296 92.5% 1,655 87.2% 0.0017 280 91.8% 273 89.5% 0.3302 277 92.3% 288 95.7% 0.0838

Thrombosis and Haemostasis

Stroke/TIA/thromboembolism 109 33.9% 111 34.7% 675 35.5% 0.8219 103 33.8% 95 31.1% 0.4891 107 35.7% 115 38.2% 0.5190
Coronary artery disease 206 64.0% 219 68.4% 1,265 66.6% 0.4791 196 64.3% 190 62.3% 0.6143 205 68.3% 198 65.8% 0.5428
Anticoagulation for Diabetic Atrial Fibrillation

Vol. 118
Peripheral artery disease 232 72.0% 215 67.2% 1,257 66.2% 0.1178 220 72.1% 221 72.5% 0.9279 203 67.7% 208 69.1% 0.7049
Chronic kidney disease 124 38.5% 135 42.2% 732 38.5% 0.4576 117 38.4% 118 38.7% 0.9337 130 43.3% 123 40.9% 0.5628
Liver disease 163 50.6% 148 46.3% 891 46.9% 0.4324 155 50.8% 145 47.5% 0.4180 138 46.0% 152 50.7% 0.2527

No. 1/2018
Hsu et al.

Head injury 22 6.8% 13 4.0% 96 5.1% 0.2628 20 6.6% 19 6.2% 0.8685 13 4.3% 17 5.6% 0.4594
75

(Continued)

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76 Anticoagulation for Diabetic Atrial Fibrillation Hsu et al.

propensity score to balance potential confounders for ensur-

p-Value

0.9949
ing comparability between patients who used NOACs and
warfarin. A propensity score was calculated for each study
participant for the likelihood of using dabigatran/rivaroxa-

18.6%
11.6%
14.3%
20.6%
18.3%
16.6%
ban by multivariable logistic regression analysis, conditional
on the baseline covariates listed in ►Table 1, and the nearest-
Warfarin
%
neighbour method was applied to construct matched pairs.20
Given type I error of 0.05, power of 0.8 and our incidence rate
35

56
43
62
55
50
N

in different treatment groups, the sample size for the com-

13.0%

19.0%
14.7%
19.3%
17.7%
16.3%
Rivaroxaban

parison of all-cause mortality between dabigatran and war-

farin were 261 in each group, and the required sample size
%

for the comparison between dabigatran versus rivaroxaban

were 122 in each group, suggesting adequate sample size of
39

57
44
58
53
49
N

our current analysis. Furthermore, we performed stratified

p-Value

analyses based on patients’ underlying status of comorbid-

0.8730
χ2 test

ities to investigate the comparative effectiveness of different

SPAF strategies on all-cause mortality. All statistical analyses
After propensity score match

were performed using the statistical package SAS 9.2 (SAS

13.4%

15.1%
16.4%
20.0%
21.6%
13.4%

Institute, Inc, Cary, NC).

Warfarin
%

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Results
41

46
50
61
66
41
N

Characteristics of the Study Population

12.8%

16.4%
15.7%
22.3%
18.0%
14.8%
Dabigatran

As shown in ►Fig. 1, of the 814,465 patients registered in the

%

diabetes P4P program, 29,969 diabetic patients had AF.

Warfarin was prescribed for 1,899 patients and dabigatran
39

50
48
68
55
45
N

and rivaroxaban were prescribed for 322 and 320 patients,

respectively. We further conducted one-to-one propensity
Abbreviations: DPP4, dipeptidyl peptidase 4; HbA1c, glycated haemoglobin; TIA, transient ischemic attack.
p-Value

0.0008

score matching between NOACs and warfarin users based on

the patients’ baseline characteristics described in ►Table 1.
►Table 1 presents the characteristics of the study popula-
tion before and after propensity score matching. Before
20.6%

13.8%
16.7%
17.2%
16.2%
15.4%

matching, patients on warfarin were younger, with a higher

%
Warfarin

percentage of women, congestive heart failure, and

CHA2DS2-VASc less than 3, but with lower percentage of
392

262
318
326
308
293

hypertension (all p < 0.01; ►Table 1). After propensity score

N
Before propensity score match

matching, all parameters were comparable between patients

12.5%

19.1%
15.0%
20.9%
16.9%
15.6%
Rivaroxaban

on NOACs and those on warfarin.

The characteristics of patients treated with high or low
%

dosage of NOACs are shown in ►Supplementary Table S2

(online only). Patients on low-dose dabigatran were older
40
48
67
54
50
61
N

than those on high-dose dabigatran, and those on low-dose

12.7%
15.5%
22.7%
17.7%
14.3%
17.1%

rivaroxaban had a higher percentage of vascular disease than

Dabigatran

those on high-dose rivaroxaban.

%

Comparative Effectiveness of Different SPAF

41
50
73
57
46
55
N

Strategies
We further evaluated the comparative effectiveness between
different SPAF strategies (►Table 2). The median follow-up
duration was 1.7 years (interquartiles: 0.5–3.7 years). As
CHA2DS2-VASc risk score

shown in ►Table 2a, patients on dabigatran had a significantly

lower rate of all-cause mortality than those on warfarin with
Table 1 (Continued)

an HR in the multivariable model of 0.348 (95% CI ¼ 0.157–

0.771, p ¼ 0.0093). Compared with warfarin users, the risk of
GI bleeding was significantly lower in the dabigatran group
(HR ¼ 0.558, 95% CI ¼ 0.327–0.955, p ¼ 0.0333), while the
3

8
4
5
6
7

risks of ischemic stroke, ICH and haematuria were comparable.

►Supplementary Figs. S1 and S2 (online only) show the

Thrombosis and Haemostasis Vol. 118 No. 1/2018

 Table 2 Incidences and risks (after propensity score matching) for all-cause mortality, ischemic stroke, myocardial infarction, ICH, GI bleeding, haematuria, composite safety end point
and net clinical outcome

a. Dabigatran vs warfarin after propensity matching

Dabigatran (n ¼ 305) Warfarin (n ¼ 305) Crude Multivariable adjustedc
Outcomes Events Person-year Incidence rate (%) Events Person-year Incidence rate (%) Hazard ratio (95% CI) p-Value Hazard ratio (95% CI) p-Value
All-cause mortality 8 196 4.1 45 506 8.9 0.348 (0.157–0.771) 0.0093 0.271 (0.119–0.617) 0.0019
Ischemic stroke/TE 47 364 12.9 75 749 10.0 0.924 (0.629–1.359) 0.6894 0.904 (0.608–1.346) 0.6204
Myocardial infarction 6 417 1.4 15 988 1.5 0.891 (0.319–2.488) 0.8254 0.669 (0.228–1.966) 0.4648
ICH 7 413 1.7 11 982 1.1 1.328 (0.455–3.879) 0.6040 1.249 (0.406–3.849) 0.6981
GI bleeding 20 392 5.1 52 895 5.8 0.558 (0.327–0.955) 0.0333 0.518 (0.300–0.895) 0.0183
Haematuria 9 413 2.2 18 964 1.9 0.928 (0.393–2.193) 0.8651 0.927 (0.381–2.255) 0.8665
Composite safety end pointa 34 380 8.9 77 807 9.5 0.687 (0.449–1.051) 0.0835 0.665 (0.431–1.024) 0.0641
Net clinical outcomeb 50 152 32.9 93 360 25.8 0.881 (0.610–1.273) 0.5002 0.956 (0.653–1.401) 0.8189
b. Rivaroxaban vs warfarin after propensity matching
Rivaroxaban (n ¼ 300) Warfarin (n ¼ 301) Crude Multivariable adjustedc
Outcomes Events Person-year Incidence rate (%) Events Person-year Incidence rate (%) Hazard ratio (95% CI) p-Value Hazard ratio (95% CI) p-Value
All-cause mortality 11 75 14.7 33 340 9.7 1.158 (0.521–2.573) 0.7195 1.407 (0.597–3.318) 0.4354
Ischemic stroke/TE 32 233 13.7 54 762 7.1 0.877 (0.552–1.392) 0.5769 0.908 (0.565–1.460) 0.6906
Myocardial infarction 8 242 3.3 13 883 1.5 1.323 (0.500–3.495) 0.5729 1.708 (0.610–4.784) 0.3085
ICH 7 245 2.9 19 866 2.2 0.792 (0.306–2.050) 0.6301 0.837 (0.315–2.221) 0.7201
GI bleeding 22 237 9.3 49 772 6.3 1.093 (0.626–1.906) 0.7553 1.126 (0.639–1.984) 0.6810
Haematuria 10 244 4.1 11 851 1.3 1.742 (0.671–4.521) 0.2542 1.855 (0.662–5.200) 0.2400
Composite safety end pointa 37 226 16.4 67 711 9.4 1.174 (0.755–1.824) 0.4768 1.202 (0.766–1.884) 0.4239
b
Net clinical outcome 38 60 63.3 68 207 32.9 0.970 (0.636–1.480) 0.8878 1.002 (0.638–1.574) 0.9922
c. Dabigatran versus rivaroxaban
Dabigatran (n ¼ 322) Rivaroxaban (n ¼ 320) Crude Multivariable adjustedc
Outcomes Events Person-year Incidence rate (%) Events Person-year Incidence rate (%) Hazard ratio (95% CI) p-Value Hazard ratio (95% CI) p-Value
All-cause mortality 8 200 4.0 11 77 14.3 0.310 (0.121–0.798) 0.0152 0.130 (0.037–0.463) 0.0016
Ischemic stroke/TE 50 379 13.2 34 248 13.7 1.271 (0.819–1.973) 0.2852 1.327 (0.841–2.093) 0.2244
Myocardial infarction 6 434 1.38 8 260 3.1 0.549 (0.188–1.599) 0.2714 0.656 (0.187–2.298) 0.5095
ICH 7 430 1.6 7 263 2.7 0.743 (0.255–2.162) 0.5851 0.918 (0.298–2.824) 0.8810
GI bleeding 22 407 5.4 23 253 9.1 0.645 (0.354–1.178) 0.1535 0.637 (0.341–1.189) 0.1570

Thrombosis and Haemostasis

Haematuria 10 429 2.3 10 263 3.8 0.644 (0.257–1.612) 0.3469 0.495 (0.179–1.371) 0.1763
Anticoagulation for Diabetic Atrial Fibrillation

Composite safety end pointa 37 394 9.4 38 243 15.7 0.670 (0.421–1.067) 0.0914 0.663 (0.409–1.073) 0.0945
Net clinical outcomeb 50 156 32.1 39 61 64 0.669 (0.438–1.021) 0.0624 0.770 (0.485–1.223) 0.2683

Vol. 118
Abbreviations: CI, confidence interval; GI, gastrointestinal; ICH, intracranial haemorrhage; TE, thromboembolism.
a
Composite safety end point ¼ ICH þ GI bleeding þ haematuria.
b

No. 1/2018
Hsu et al.

Net clinical outcome ¼ all-cause mortality þ ischemic stroke/TE þ ICH þ GI bleeding þ haematuria.
c
Adjusted for age, sex, congestive heart failure, hypertension, stroke/TIA/thromboembolism, peripheral artery disease, head injury and CHA2DS2-VASc risk score.
77

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78 Anticoagulation for Diabetic Atrial Fibrillation Hsu et al.
subgroup analyses based on baseline characteristics between
dabigatran and warfarin for all-cause mortality and safety
end points, respectively. The lower risk of GI bleeding asso-
ciated with dabigatran versus warfarin was consistent in most
subgroup analysis shown in ►Supplementary Fig. S3 (online
only). All p-values for interaction were not less than 0.05.
As shown in ►Table 2b, comparisons for all outcomes
demonstrated comparable risk between patients on rivarox-
aban and those on warfarin. The subgroup analyses
(►Supplementary Figs. S4 and S5, online only) also revealed
consistent results. The comparable risk of GI bleeding asso-
ciated with rivaroxaban versus warfarin use was consistent in
subgroup analysis, shown in ►Supplementary Fig. S6 (online
only).
The risk of all-cause mortality was significantly lower in
patients on dabigatran than in those on rivaroxaban
(►Table 2c), with an HR of 0.310 (95% CI ¼ 0.121–0.798,
p ¼ 0.0152). Regarding the composite safety end point,
combining ICH, GI bleeding and haematuria, dabigatran
had a borderline superiority over rivaroxaban (HR ¼ 0.670,
95% CI ¼ 0.421–1.067, p ¼ 0.0914).
In our study population, a larger proportion of patients on
warfarin were simultaneously prescribed with antiplatelet
agents on the index date and after the index date
(►Supplementary Table S3, online only). The results were
not changed after further adjustment for use of antiplatelet
agents as a time-dependent variable (►Supplementary
Table S4, online only).
The survival curves between the three different SPAF
strategies for all-cause mortality and composite safety out-
comes are shown in ►Fig. 2. During follow-up, patients on
Fig. 2 Panel A: Adjusted survival curves of all-cause mortality for
diabetic patients with atrial fibrillation on different oral anticoagu-
lants. Panel B: Adjusted survival curves of composite safety outcome
for diabetic patients with atrial fibrillation on different oral anti-
coagulants. Composite safety outcomes include gastrointestinal
bleeding, intracranial bleeding and genitourinary bleeding.
Thrombosis and Haemostasis Vol. 118 No. 1/2018
dabigatran had a lower risk of mortality or any safety out-
comes than patients on rivaroxaban and warfarin. In con-
trast, the incidence rates of mortality and safety outcomes
between rivaroxaban and warfarin users were similar.
Discussion
Among the SPAF strategies for diabetic AF patients, NOACs
appear to have a comparable or even superior effectiveness
and safety profile than warfarin. In addition, compared with
rivaroxaban, patients on dabigatran had a significantly lower
risk of mortality and bleeding.
In the retrospective studies, selection bias is an imperative
bias and should be carefully handled. We used two strategies,
propensity score matching and multivariable adjustment, to
avoid the potential residual confounding. The variables used
for the propensity matching were listed in ►Table 1, which
included baseline characteristics, glycated haemoglobin, anti-
diabetic agents, CHA2DS2-VASc score and common comorbid-
ities. We further adjusted age, sex, congestive heart failure,
Downloaded by: Umea University Library. Copyrighted material.
hypertension, stroke/TIA/thromboembolism, peripheral
artery disease, head injury, CHA2DS2-VASc risk score and
time-variant antiplatelet use (►Supplementary Table S4,
online only) in the multivariable models. The results remained
supportive for the major findings and conclusion of the present
study. Moreover, the main finding that dabigatran was asso-
ciated with a survival benefit over warfarin (p ¼ 0.0019) and
rivaroxaban (p ¼ 0.0016) could not be easily explained by the
differential characteristics and management, given their simi-
lar clinical conditions, especially between dabigatran versus
rivaroxaban.
Previous large-scale, landmark phase III NOAC trials
included certain proportions of diabetic AF patients,12–15
which are as follows: 23.3% in the Randomized Evaluation
of Long-term Anticoagulant Therapy (RE-LY) trial with dabi-
gatran,12 39.9% in the Rivaroxaban Once-daily, Oral, Direct
Factor Xa Inhibition Compared with Vitamin K Antagonism
for Prevention of Stroke and Embolism Trial in Atrial Fibrilla-
tion (ROCKET AF) trial with rivaroxaban,13 25% in the Apix-
aban for Reduction of Stroke and Other Thromboembolic
Events in Atrial Fibrillation (ARISTOTLE) trial with apixa-
ban14 and 36% in the Effective Anticoagulation with Factor Xa
Next Generation in Atrial Fibrillation–Thrombolysis In Myo-
cardial Infarction 48 (ENGAGE AF-TIMI 48) trial with edox-
aban.15 A post hoc analysis on ROCKET AF trial focusing on
diabetic AF patients demonstrated that the relative efficacy
and safety of rivaroxaban versus warfarin were similar in AF
patients with and without diabetes,21 with HRs of 0.82 (95%
CI ¼ 0.63–1.08) for stroke or systemic embolism, 0.98 (95%
CI ¼ 0.36–1.05) for bleeding events and 0.62 (95% CI ¼ 0.88–
1.10) for ICH. In contrast, in the subgroup analysis on diabetic
AF patients, the relative risk of stroke or systemic embolism
in the RE-LY trial was 0.74 (95% CI ¼ 0.51–1.07) for dabiga-
tran 110 mg versus warfarin and 0.61 (95% CI ¼ 0.41–0.91)
for dabigatran 150 mg versus warfarin.22 The results in our
study are consistent with the findings in these subgroup
analyses. More importantly, by directly comparing dabiga-
tran with rivaroxaban, we provide further information in

addition to the comparisons between NOACs and warfarin,
which may be helpful for clinicians to make informed
decisions in the care of diabetic AF patients and generate
hypothesis for future randomized controlled trials.
To date, there have also been several “real-world” studies on
the effectiveness and safety of NOACs therapy in AF
patients.23–27 A comprehensive meta-analysis of observational
studies comparing dabigatran with VKAs in AF patients
showed that the risks of ischemic stroke, ICH and mortality
were significantly lower in the dabigatran group, with HRs of
0.86 (95% CI ¼ 0.74–0.99), 0.45 (95% CI ¼ 0.38–0.52) and 0.73
(95% CI ¼ 0.61–0.87), respectively, whereas the risk of GI
bleeding in the dabigatran was higher (HR ¼ 1.13, 95% CI
¼ 1.00–1.28).28 In another meta-analysis of observational
studies on AF patients with oral anticoagulants, rivaroxaban
was associated with a lower risk of stroke/systematic throm-
boembolism (HR ¼ 0.75, 95% CI ¼ 0.64–0.85) and ICH (HR
¼ 0.54, 95% CI ¼ 0.43–0.64), but a higher risk of GI bleeding
(HR ¼ 1.20, 95% CI ¼ 1.07–1.33) when compared with war-
farin.29 Different from the aforementioned studies, our study
specifically focused on diabetic AF patients; our findings can
provide useful information for selecting appropriate antic-
oagulation strategies for this high-risk population.
The necessity of a focused interest in the relative efficacy
and safety of anticoagulation strategies for diabetic AF
population is debatable. It should be emphasized that dia-
betic patients with stroke have higher rates of mortality than
nondiabetic patients,22,30,31 which may be related to the
excessive activation of the coagulation system, reduced
fibrinolytic activity, platelet and endothelial dysfunction,
and increased peripheral tissue plasminogen activator anti-
gen and factor VIII activity.32 In the era of precision medicine,
the higher risk features of diabetic AF patients and the large
population size suggest the need for a relatively more
patient-specific management strategy.
The relative efficacy and safety between dabigatran and
rivaroxaban have been evaluated in a meta-analysis of
randomized controlled trials using indirect comparison,33
in an Asian claims-based database34 and in a retrospective
new-user cohort study of elderly AF patients (aged  65
years).35 These studies reported inconsistent results but, in
general, a trend of a relatively better safety profile of dabiga-
tran than that of rivaroxaban. Our study also demonstrated
an HR of 0.663 (95% CI ¼ 0.409–1.073) for the composite
safety end points when comparing dabigatran with rivarox-
aban. Moreover, the risk of all-cause mortality was signifi-
cantly lower in diabetic AF patients on dabigatran than in
those on rivaroxaban. This finding was similar to the result
from meta-analysing observational studies.29
The comparative safety profile between dabigatran and
rivaroxaban can be attributed to certain factors. Although
plasma half-lives of dabigatran and rivaroxaban are each about
12 hours, dabigatran is dosed twice daily and rivaroxaban only
once daily.11,36 Compared with twice-daily dosing of the same
total daily dose, once-daily dosing is expected to achieve
higher peak and lower trough serum concentrations. This
may help explain the better safety profile of dabigatran and
apixaban used as SPAF strategies.33 As to the increased safety
Anticoagulation for Diabetic Atrial Fibrillation Hsu et al. 79
of dabigatran versus warfarin for GI bleeding, distinct mechan-
isms involved in anticoagulation process could be the reason
for this. Unlike warfarin that inhibits several coagulation
proteins, dabigatran directly inhibits only thrombin, resulting
in a significant antithrombotic effect and preserving some
other haemostasis in the coagulation system. In this way, it
might mitigate the risk of bleeding.12
Medication adherence, a pivotal issue in the management
of oral anticoagulants for diabetic AF patients in whom
polypharmacy often occurs, is associated with quality of
anticoagulation control and clinical outcomes.37 Compared
with warfarin users, AF patients on NOACs are expected to
have better adherence because of the use of fixed-dose
regimen and fewer concerns about drug–drug and drug–
food interactions.38 A greater adherence was found in
patients at a high risk of stroke and patients with more
comorbidities;39,40 however, persistence of anticoagulants
treatment would generally decrease over time.40 It is needed
to develop strategies for improving patient adherence and
therapy persistence to anticoagulants, even NOACs, to ensure
Downloaded by: Umea University Library. Copyrighted material.
effective and safe treatment in AF patients.
Interpretation of the findings of this study should be done
with the acknowledgment of our study limitations. First, as a
retrospective cohort study, although we have conducted
propensity score matching to avoid selection bias, the inher-
ent limitation makes our study a hypothesis-generating
work, which should be further tested in randomized con-
trolled trials on the anticoagulation strategies focusing on
diabetic AF patients. Second, the diagnosis of AF, comorbid-
ities and outcomes are based on ICD coding, which may
become a source of error. However, the all-cause mortality is
a robust parameter confirmed by the absence of medical
claims for at least 1 year and the linkage with the national
death registry. Third, the study population primarily com-
prised Taiwanese of Chinese decent, which restricts the
generalizability of our study findings. Fourth, the percentage
of high-dose NOACs is small; therefore, stratified analysis
based on different dosages of NOACs is not powered enough
to provide precise information. Nevertheless, according to
pharmacokinetic modelling data and clinical practice, a low-
dose of rivaroxaban is commonly administered to Asian
patients with AF for stroke prevention.41 These results
from the study in Japanese patients are consistent with those
of the global ROCKET AF trial, in which rivaroxaban was non-
inferior to warfarin for the safety outcomes. Finally, informa-
tion about quality indicator of VKAs management, time in
therapeutic range (TTR), was not available from our P4P
database. In our population, an international normalized
ratio (INR) of 2.0 to 3.0 is recommended as the optimal
therapeutic range for warfarin users.42 The post hoc analysis
of the RE-LY trial indicated mean TTR in the warfarin users
was only 44% in Taiwan,43 and a poorer INR control for
warfarin use was associated with a greater benefit of dabi-
gatran in total mortality, vascular events and safety
end points.43,44 Therefore, it is possible that the investigation
of the relative efficacy and safety of NOACs versus warfarin
would be affected by quality of warfarin treatment in the
present study. However, the pattern of warfarin prescription
Thrombosis and Haemostasis Vol. 118 No. 1/2018
80 Anticoagulation for Diabetic Atrial Fibrillation Hsu et al.
shown in our study just reflects a real-world routine clinical
practice in most East Asian countries, in which patients seem
to be more susceptible to the pro-haemorrhagic complica-
tions of warfarin, and some “Chinese medicines” use may
also incur harmful interactions, so warfarin is usually pre-
scribed in a lower therapeutic range. The above real-world
conditions make NOACs the preferred SPAF strategies com-
pared with warfarin. Our study provides three comparisons
between dabigatran, rivaroxaban and warfarin. Since most
guidelines now recommended NOACs over VKAs as the SPAF
strategy, the important aspect of our study is the comparison
between NOACs and their relative effectiveness and safety
profiles in the particularly high-risk diabetic AF population.
In this regard, for the comparison between NOACs, the INR
level should be of less concern.
Conclusion
For patients with diabetic AF in a diabetic P4P program,
NOACs showed a superior or non-inferior effectiveness and
safety profile than warfarin. Dabigatran was associated with
a significantly lower risk of mortality than rivaroxaban.
What is known about this topic?
• Prevalence and incidence of diabetes are growing.
• Diabetes is associated with increased risk of atrial
fibrillation and stroke.
• Novel anticoagulants have been demonstrated to have
superior efficacy and safety as compared with vitamin
K antagonist for stroke prevention in atrial fibrillation.
• However, few studies investigated the comparative
efficacy and safety between stroke prevention strate-
gies for the diabetic atrial fibrillation population.
What does this paper add?
• We utilized the database derived from a pay-for-per-
formance program for diabetic patients in Taiwan to
compare thromboembolic events, bleeding and mor-
tality in patients with diabetic AF treated with rivar-
oxaban, dabigatran and warfarin.
• Among the anticoagulants for patients with diabetic
AF, dabigatran and rivaroxaban appear to have a
comparable or even superior effectiveness and safety
profile than warfarin.
• In addition, compared with rivaroxaban, patients on
dabigatran had a significantly lower risk of mortality.
Funding
The study was supported by Ministry of Health and Welfare,
Taiwan grant (MOHW-104-TDU-B-211–113003, MOHW-
105-TDU-B-211–133017, 05D9-PHBHP01, and MOHW-
106-TDU-B-211-113001).
Disclosures
None.
Thrombosis and Haemostasis Vol. 118 No. 1/2018
Authors’ Contributions
C.-C. H. and H.-M. C. conducted study design, wrote the
manuscript and interpreted data. P.-F. H. and S.-H. S.
reviewed/edited the manuscript. S.-T. T. and B.-H. Y.
analysed data and revised the manuscript. All authors
read and approved the final manuscript.
Acknowledgments
C.-C. H. and H.-M. C. take full responsibility for the work as
a whole including the study design, access to data and the
decision to submit and publish the manuscript.
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