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Comparative effectiveness and safety of non-vitamin K antagonists oral anticoagulants
(NOACs) and warfarin in daily clinical practice: A propensity weighted nationwide cohort
study.
Supplementary material
Torben Bjerregaard Larsen, MD, PhD1,2
, Flemming Skjøth, MSc, PhD 2,3
, Peter Brønnum Nielsen,
MSc, PhD 1,2
, Jette Kjældgaard Nordstrøm, MSc2, Gregory Y.H. Lip, MD
2,4
Supplementary Table 1
Definitions on comorbidity and concomitant medication according to ICD-10 codes and ATC-codes.
Conditions marked with † was used in the calculation of the CHA2DS2-VASc score. Conditions
marked with # was used in the calculation of the HAS-BLED score.
International Classification of
Diseases 10th revision (ICD-10)
code
Anatomical Therapeutic Chemical
(ATC) code
Condition
†Congestive heart failure I11.0; I13.0; I13.2; I42.0; I50 CO3C
†Left ventricular dysfunction I50.1; I50.9
†#Hypertension See specified definition*
†Diabetes mellitus E10.0; E10.1; E10·9; E11·0;
E11·1; E11·9
A10
†#Ischemic stroke I63; I64
†Systemic embolism I74
†#Transient ischemic disease G45
†Aortic plaque I70·0
†Peripheral arterial disease I70·2-I70·9; I71; I73·9
†Myocardial infarction I21-I23
#Moderate/severe renal disease I12 I13 N00 N01 N02 N03 N04
N05 N07 N11 N14 N17 N18 N19
Q61
#Moderate/Severe liver disease B150 B160 B162 B190 K704 K72
K766 I85
Cancer C
Chronic pulmonary disorder J44
Mitral stenosis I05
Mechanical heart valve Z952 Z953 Z954
#Haemorrhagic stroke – intercranial
bleeding I60 I61 I62
#Extracranial or unclassified major
bleeding D62 J942 H113 H356 H431 N02
N95 R04 R31 R58
#Gastrointestinal bleeding K250 K260 K270 K280 K290
#Traumatic intercranial bleeding S063C S064 S065 S066
#Alcohol E224 E529A F10 G312 G621
G721 I426 K292 K70 K860
L278A O354 T51 Z714 Z721
Pulmonary embolism I26
Deep venous thromboembolism I801 I802 I803 I808 I809 I819
I636 I676 I822 I823 I829 Atrial fibrillation I48
Medication
Apixaban
Dabigatran
Rivaroxaban
B01AF02
B01AE07
B01AF01
Warfarin B01AA03
Phenprocoumon B01AA04
#Aspirin B01AC06
#Clopidogrel B01AC04
Beta-blockers C07
Statins C10
#Non Steroidal Anti Inflammatory Drugs M01A * We identified subjects with hypertension from combination treatment with at least two of the following classes of
antihypertensive drugs: I· Alpha adrenergic blockers (C02A, C02B, C02C) II· Non-loop diuretics (C02DA, C02L, C03A, C03B, C03D, C03E, C03X, C07C, C07D, C08G, C09BA, C09DA,
C09XA52) III· Vasodilators (C02DB, C02DD, C02DG, C04, C05) IV· Beta blockers (C07) V· Calcium channel blockers (C07F, C08, C09BB, C09DB) VI· Renin-angiotensin system inhibitors (C09)·
Supplementary table 2.
Risk score definitions
Risk score Points
if present
CHA2DS2VASca
Congestive heart failure or Left Ventricular Dysfunction 1
Hypertension 1
Age ≥ 65 years 1
Age ≥ 75 years 1
Diabetes mellitus 1
Stroke (ischemic stroke, transient ischemic disease or systemic embolism) 2
Vascular disease (myocardial infarction, peripheral arterial disease, or aortic plaque)
1
Sex category (female) 1
HAS-BLEDb
Hypertension 1
Abnormal renal function 1
Abnormal hepatic function 1
Stroke (ischemic stroke or transient ischemic attack) 1
Bleeding 1
Labile international normalized ratioc 1
Elderly age (≥ 65 years) 1
Drugs (aspirin, clopidogrel, or non-steroidal anti-inflammatory drugs) 1
Alcohol intake 1 aReflects stroke risk in atrial fibrillation patients not in anticoagulant therapy (Lip GYH, Nieuwlaat R, Pisters R, Lane DA,
Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137(2):263-72) bReflects bleeding risk in atrial fibrillation patients undergoing anticoagulant therapy (Pisters R, Lane DA, Nieuwlaat R,
de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138(5):1093-100) cNot included due to unavailable information
Supplementary Table 3 Odds ratio (OR) for choosing treatment vs any of three alternatives.
Highly significant predictors, with OR>1.1 or OR<0.9 are boldfaced and discussed in text. Below one indicate favour
for any alternative; above one indicate favour for treatment.
Apixaban Dabigatran Rivaroxaban Warfarin
Age, 5 years increase* 1.04 (1.03-1.05) 0.85 (0.85-0.86) 1.07 (1.06-1.08) 1.08 (1.07-1.08)
Female sex 1.00 (0.95-1.05) 0.73 (0.70-0.76) 1.17 (1.11-1.23) 1.15 (1.11-1.19)
Prior AF diagnose 1.68 (1.59-1.78) 1.91 (1.83-1.99) 1.11 (1.05-1.16) 0.52 (0.50-0.54)
Cancer 1.05 (0.98-1.13) 0.68 (0.64-0.72) 1.06 (0.99-1.13) 1.22 (1.16-1.27)
Ischemic stroke/SE/TIA 1.55 (1.46-1.66) 0.80 (0.76-0.85) 1.13 (1.06-1.21) 0.91 (0.87-0.95)
Heart failure or LVD 0.92 (0.85-1.00) 0.75 (0.70-0.80) 0.73 (0.67-0.79) 1.41 (1.34-1.48)
Vascular disease 0.88 (0.81-0.94) 0.58 (0.54-0.62) 0.74 (0.69-0.80) 1.66 (1.58-1.74)
Renal dysfunction 0.50 (0.43-0.59) 0.20 (0.17-0.24) 0.36 (0.30-0.43) 4.25 (3.83-4.71)
COPD 1.02 (0.93-1.12) 0.64 (0.59-0.69) 1.01 (0.93-1.11) 1.30 (1.22-1.37)
Prior Bleeding 1.25 (1.16-1.35) 0.79 (0.74-0.84) 1.12 (1.04-1.21) 1.01 (0.96-1.06)
Hypertension 0.97 (0.92-1.02) 0.88 (0.85-0.92) 0.96 (0.91-1.01) 1.12 (1.08-1.15)
Diabetes 1.06 (0.99-1.14) 0.88 (0.84-0.93) 0.91 (0.85-0.98) 1.10 (1.05-1.15)
Aspirin 0.89 (0.84-0.94) 0.89 (0.86-0.93) 0.90 (0.86-0.95) 1.18 (1.14-1.22)
Beta Blocker 0.92 (0.87-0.97) 0.99 (0.95-1.03) 0.94 (0.89-0.99) 1.07 (1.03-1.10)
NSAIDs 0.91 (0.86-0.97) 1.04 (1.00-1.09) 0.89 (0.84-0.94) 1.06 (1.02-1.10)
Statins 1.05 (1.00-1.11) 0.92 (0.88-0.96) 0.95 (0.91-1.00) 1.06 (1.02-1.09)
*Linear effect. SE: Systemic embolism; TIA: Transient ischemic attack; COPD: Compulsive obstructive pulmonary
disease; LVD: Left ventricular dysfunction; NSAID's: non-steroidal anti-inflammatory drugs.
Supplementary Figure 1. Flowchart of patients excluded from study material.
Final study population
Patients with first time prescription of apixaban, dabigatran, rivaroxaban or warfarin
in the period August 1, 2011 to November 30, 2015
Apixaban
N
130
425
344
606
Dabigatran
N
209
449
147
2,651
Rivaroxaban
N
149
2,150
1,282
1,299
Warfarin
N
1,421
8,510
5,386
197
Valvular AF
Prior DVT
Prior PE
OAC within 1 year
Apixaban
2.5 mg
N
5,091
Dabigatran
110mg
N
22,102
Rivaroxaban
15 mg
N
7,842
Warfarin
-
N
-Reduced dose
Apixaban
N
12,945
Dabigatran
N
38,259
Rivaroxaban
N
19,914
Warfarin
N
50,950
Apixaban
N
6,349
Dabigatran
N
12,701
Rivaroxaban
N
7,192
Warfarin
N
35,436
Total
N
1,909
11,534
7,159
4,753
Total
N
35,035
Total
N
122,068
Total
N
61,678
Supplementary Figure 2. Time trends of number of treatment naive patients initiated on
anticoagulation, since introduction of dabigatran.
0200
40
0600
800
10
00
Num
be
r of ne
w s
tart
ers
pr
mo
nth
01jul2011 01jul2012 01jul2013 01jul2014 01jul2015month
Apixaban Dabigatran
Rivaroxaban Warfarin
Supplementary Figure 3a. Crude cumulative incidence curves of stroke endpoints according
to current treatment.
Supplementary Figure 3b. Crude cumulative incidence curves of bleeding endpoints
according to current treatment.
0.0
00
.02
0.0
40
.06
0.0
8
0 .5 1 1.5 2 2.5Years since treatment initiation
Apixaban Dabigatran
Rivaroxaban Warfarin
Ischemic stroke/SE
0.0
00
.02
0.0
40.0
60
.08
0 .5 1 1.5 2 2.5Years since treatment initiation
Ischemic stroke
Crude failure curves
0.0
00
.02
0.0
40
.06
0.0
80 .5 1 1.5 2 2.5
Years since treatment initiation
Ischemic stroke/SE
0.0
00
.02
0.0
40.0
60
.08
0 .5 1 1.5 2 2.5Years since treatment initiation
Ischemic stroke
Weighted failure curves
0.0
00
.03
0.0
60
.09
0.1
2
0 .5 1 1.5 2 2.5Years since treatment initiation
Apixaban Dabigatran
Rivaroxaban Warfarin
Any bleeding
0.0
00
.020
.040
.060
.080.1
0
0 .5 1 1.5 2 2.5Years since treatment initiation
Major bleeding
0.0
00
.01
0.0
10
.01
0.0
2
0 .5 1 1.5 2 2.5Years since treatment initiation
Intracranial bleeding
Crude failure curves
0.0
00
.03
0.0
60
.09
0.1
2
0 .5 1 1.5 2 2.5Years since treatment initiation
Any bleeding
0.0
00
.020
.040
.060
.080.1
0
0 .5 1 1.5 2 2.5Years since treatment initiation
Major bleeding
0.0
00
.01
0.0
10
.01
0.0
2
0 .5 1 1.5 2 2.5Years since treatment initiation
Intracranial bleeding
Weighted failure curves
Supplementary Figure 3c. Crude cumulative incidence curves of all-cause death and
combined endpoint ischemic stroke/SE or all-cause death according to current treatment.
0.0
00
.05
0.1
00
.15
0.2
0
0 .5 1 1.5 2 2.5Years since treatment initiation
Apixaban Dabigatran
Rivaroxaban Warfarin
All-cause death
0.0
00
.05
0.1
00.1
50
.20
0 .5 1 1.5 2 2.5Years since treatment initiation
Ischemic stroke/SE/All-cause death
Crude failure curves
0.0
00
.05
0.1
00
.15
0.2
0
0 .5 1 1.5 2 2.5Years since treatment initiation
All-cause death
0.0
00
.05
0.1
00.1
50
.20
0 .5 1 1.5 2 2.5Years since treatment initiation
Ischemic stroke/SE/All-cause death
Weighted failure curves
9
10
Supplementary Figure 4a. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (intension to treat) for NOACs compared to
warfarin for stroke and death endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
1.01 (0.86−1.18)
1.01 (0.81−1.27)
0.80 (0.69−0.94)
0.96 (0.80−1.16)
0.89 (0.68−1.15)
0.85 (0.71−1.03)
1.04 (0.70−1.55)
0.94 (0.76−1.17)
0.84 (0.59−1.20)
1.00 (0.84−1.19)
1.02 (0.78−1.35)
0.78 (0.66−0.93)
0.93 (0.71−1.22)
1.00 (0.67−1.50)
0.79 (0.63−1.00)
1.02 (0.85−1.23)
0.95 (0.76−1.18)
0.79 (0.64−0.97)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SEHazard ratio (95% CI)
1.03 (0.88−1.21)
1.06 (0.84−1.34)
0.84 (0.72−0.99)
0.99 (0.83−1.19)
0.90 (0.69−1.18)
0.87 (0.72−1.05)
1.00 (0.66−1.49)
1.02 (0.81−1.27)
0.93 (0.64−1.33)
1.04 (0.88−1.24)
1.07 (0.81−1.41)
0.81 (0.68−0.97)
1.00 (0.75−1.31)
1.05 (0.69−1.59)
0.83 (0.66−1.06)
1.04 (0.86−1.26)
0.99 (0.80−1.24)
0.82 (0.66−1.02)
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●
●
●
●
●
●
●
●
●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic strokeHazard ratio (95% CI)
0.67 (0.58−0.77)
0.65 (0.54−0.79)
0.96 (0.87−1.06)
0.69 (0.59−0.80)
0.68 (0.54−0.87)
0.92 (0.82−1.03)
0.53 (0.27−1.03)
0.64 (0.51−0.79)
1.01 (0.74−1.38)
0.67 (0.58−0.77)
0.64 (0.52−0.79)
0.93 (0.84−1.03)
0.64 (0.54−0.75)
0.65 (0.54−0.79)
0.90 (0.80−1.00)
0.73 (0.58−0.91)
0.55 (0.39−0.79)
1.12 (0.93−1.34)
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●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
DeathHazard ratio (95% CI)
0.78 (0.70−0.86)
0.76 (0.65−0.88)
0.90 (0.83−0.98)
0.78 (0.69−0.88)
0.74 (0.61−0.89)
0.89 (0.80−0.98)
0.77 (0.54−1.10)
0.77 (0.66−0.90)
0.93 (0.73−1.18)
0.77 (0.68−0.86)
0.74 (0.62−0.87)
0.87 (0.80−0.95)
0.70 (0.60−0.81)
0.71 (0.59−0.84)
0.88 (0.80−0.98)
0.90 (0.77−1.04)
0.78 (0.64−0.95)
0.90 (0.78−1.04)
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●
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●
●
●
●
●
●
●
●
●
●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SE/DeathHazard ratio (95% CI)
11
Supplementary Figure 4b. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (intension to treat) for NOACs compared
to warfarin for bleeding endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
0.64 (0.54−0.76)
0.68 (0.59−0.79)
0.98 (0.87−1.10)
0.68 (0.56−0.82)
0.69 (0.58−0.83)
0.96 (0.83−1.10)
0.39 (0.23−0.66)
0.64 (0.52−0.79)
0.77 (0.54−1.08)
0.69 (0.58−0.83)
0.68 (0.57−0.81)
1.01 (0.89−1.14)
0.61 (0.50−0.74)
0.69 (0.59−0.81)
0.98 (0.86−1.11)
0.74 (0.54−1.00)
0.69 (0.46−1.03)
0.97 (0.75−1.25)
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●
●
●
●
●
●
●
●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Any bleedingHazard ratio (95% CI)
0.63 (0.52−0.76)
0.68 (0.58−0.80)
1.03 (0.90−1.17)
0.66 (0.53−0.81)
0.70 (0.58−0.83)
0.99 (0.85−1.16)
0.36 (0.20−0.65)
0.57 (0.45−0.71)
0.73 (0.50−1.08)
0.69 (0.56−0.84)
0.69 (0.57−0.82)
1.09 (0.95−1.25)
0.59 (0.48−0.74)
0.67 (0.57−0.79)
1.03 (0.89−1.19)
0.77 (0.54−1.10)
0.63 (0.46−0.88)
1.06 (0.79−1.41)
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●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Major bleedingHazard ratio (95% CI)
0.83 (0.52−1.34)
0.39 (0.27−0.56)
0.66 (0.45−0.98)
0.87 (0.51−1.51)
0.38 (0.26−0.57)
0.71 (0.45−1.11)
0.71 (0.17−3.09)
0.89 (0.44−1.82)
0.43 (0.08−2.15)
0.85 (0.51−1.41)
0.31 (0.21−0.48)
0.69 (0.46−1.02)
0.78 (0.43−1.42)
0.43 (0.29−0.63)
0.58 (0.36−0.93)
0.62 (0.28−1.36)
0.28 (0.13−0.62)
0.77 (0.39−1.52)
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●
●
●
●
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●
●
●
●
0.01 0.05 0.20 1.00 5.00
FavoursAlternative
FavoursWarfarin
Intracranial bleedingHazard ratio (95% CI)
12
Supplementary Figure 5a. Sensitivity analyses. Cox hazard ratios for 1 year follow-up (intension to treat) for NOACs compared to warfarin
for main stroke, bleeding and death endpoints. Four analysis methods and 2 cohort definitions are contrasted.
Crude, entire AF cohort
Adjusted, entire AF cohort
IPTW, entire AF cohort (Main analysis)
SMR, entire AF cohort
Crude, AF hospitalised cohort
Adjusted, AF hospitalised cohort
IPTW, AF hospitalised cohort
SMR, AF hospitalised cohort
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Approach / Treatment
1.33 (1.15−1.55)
0.87 (0.77−0.98)
0.87 (0.73−1.02)
1.10 (0.94−1.28)
1.01 (0.88−1.15)
0.79 (0.67−0.94)
1.08 (0.91−1.27)
1.17 (0.89−1.54)
0.83 (0.69−0.99)
1.11 (0.92−1.34)
1.07 (0.91−1.26)
0.88 (0.72−1.09)
1.17 (0.98−1.39)
0.78 (0.67−0.90)
0.84 (0.69−1.02)
1.02 (0.85−1.21)
0.97 (0.83−1.14)
0.76 (0.63−0.93)
1.03 (0.86−1.25)
1.00 (0.72−1.38)
0.86 (0.70−1.07)
1.01 (0.81−1.27)
0.99 (0.83−1.18)
0.92 (0.68−1.24)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SEHazard ratio (95% CI)
0.65 (0.55−0.77)
0.54 (0.48−0.61)
0.97 (0.85−1.11)
0.66 (0.56−0.79)
0.67 (0.59−0.76)
1.02 (0.89−1.16)
0.63 (0.53−0.76)
0.61 (0.51−0.74)
0.99 (0.86−1.14)
0.69 (0.56−0.85)
0.70 (0.59−0.82)
1.00 (0.85−1.17)
0.65 (0.54−0.79)
0.51 (0.44−0.58)
0.97 (0.83−1.14)
0.72 (0.59−0.87)
0.69 (0.60−0.80)
1.06 (0.90−1.24)
0.68 (0.55−0.83)
0.61 (0.49−0.76)
1.01 (0.86−1.19)
0.81 (0.63−1.04)
0.73 (0.61−0.89)
1.07 (0.88−1.32)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Any bleedingHazard ratio (95% CI)
0.59 (0.51−0.67)
0.32 (0.28−0.35)
0.88 (0.79−0.97)
0.67 (0.59−0.77)
0.55 (0.49−0.62)
0.94 (0.85−1.05)
0.65 (0.56−0.75)
0.63 (0.48−0.82)
0.92 (0.82−1.03)
0.68 (0.58−0.80)
0.59 (0.51−0.69)
0.94 (0.83−1.07)
0.58 (0.49−0.67)
0.27 (0.24−0.31)
0.82 (0.73−0.94)
0.74 (0.63−0.86)
0.58 (0.50−0.67)
0.94 (0.83−1.07)
0.67 (0.57−0.79)
0.69 (0.48−0.98)
0.88 (0.77−1.01)
0.70 (0.58−0.85)
0.61 (0.51−0.74)
0.93 (0.79−1.09)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
DeathHazard ratio (95% CI)
13
Supplementary Figure 5b. Sensitivity analyses. Cox hazard ratios for 2.5 years follow-up (intension to treat) for NOACs compared to
warfarin for main stroke, bleeding and death endpoints. Four analysis methods and 2 cohort definitions are contrasted.
Crude, entire AF cohort
Adjusted, entire AF cohort
IPTW, entire AF cohort (Main analysis)
SMR, entire AF cohort
Crude, AF hospitalised cohort
Adjusted, AF hospitalised cohort
IPTW, AF hospitalised cohort
SMR, AF hospitalised cohort
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Approach / Treatment
1.27 (1.10−1.46)
0.79 (0.71−0.88)
0.85 (0.73−0.99)
1.07 (0.92−1.23)
0.94 (0.84−1.05)
0.78 (0.67−0.91)
1.01 (0.86−1.18)
1.01 (0.81−1.27)
0.80 (0.69−0.94)
1.05 (0.88−1.25)
0.97 (0.85−1.11)
0.86 (0.71−1.03)
1.11 (0.94−1.31)
0.72 (0.64−0.82)
0.85 (0.71−1.01)
0.99 (0.83−1.17)
0.93 (0.81−1.06)
0.77 (0.65−0.92)
0.96 (0.80−1.16)
0.89 (0.68−1.15)
0.85 (0.71−1.03)
0.97 (0.79−1.20)
0.93 (0.80−1.08)
0.90 (0.70−1.17)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SEHazard ratio (95% CI)
0.66 (0.57−0.77)
0.59 (0.54−0.65)
0.97 (0.87−1.09)
0.66 (0.57−0.77)
0.71 (0.65−0.78)
0.99 (0.89−1.11)
0.64 (0.54−0.76)
0.68 (0.59−0.79)
0.98 (0.87−1.10)
0.66 (0.55−0.80)
0.72 (0.64−0.81)
1.01 (0.88−1.15)
0.66 (0.55−0.78)
0.55 (0.49−0.61)
0.94 (0.82−1.07)
0.70 (0.59−0.84)
0.72 (0.64−0.80)
0.99 (0.86−1.13)
0.68 (0.56−0.82)
0.69 (0.58−0.83)
0.96 (0.83−1.10)
0.76 (0.60−0.95)
0.76 (0.66−0.87)
1.03 (0.87−1.22)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Any bleedingHazard ratio (95% CI)
0.59 (0.52−0.66)
0.34 (0.31−0.37)
0.88 (0.81−0.96)
0.67 (0.59−0.76)
0.60 (0.55−0.65)
0.94 (0.87−1.03)
0.67 (0.58−0.77)
0.65 (0.54−0.79)
0.96 (0.87−1.06)
0.68 (0.59−0.79)
0.62 (0.55−0.70)
0.95 (0.85−1.05)
0.58 (0.51−0.67)
0.30 (0.27−0.33)
0.83 (0.75−0.92)
0.73 (0.64−0.84)
0.63 (0.57−0.70)
0.94 (0.84−1.04)
0.69 (0.59−0.80)
0.68 (0.54−0.87)
0.92 (0.82−1.03)
0.71 (0.59−0.84)
0.65 (0.57−0.75)
0.91 (0.80−1.03)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
DeathHazard ratio (95% CI)
14
Supplementary Figure 6a. Propensity weighted (IPTW) Cox hazard ratios for 1 years follow-up (continuous treatment) for NOACs compared
to warfarin for stroke and death endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
1.08 (0.92−1.28)
1.14 (0.85−1.53)
0.78 (0.65−0.95)
1.03 (0.85−1.24)
1.00 (0.71−1.41)
0.83 (0.66−1.03)
1.05 (0.69−1.61)
1.02 (0.79−1.33)
0.77 (0.51−1.17)
1.09 (0.91−1.31)
1.17 (0.82−1.66)
0.77 (0.62−0.95)
1.03 (0.77−1.39)
1.25 (0.70−2.24)
0.81 (0.61−1.08)
1.07 (0.88−1.30)
1.00 (0.78−1.27)
0.76 (0.60−0.96)
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●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SEHazard ratio (95% CI)
1.11 (0.94−1.31)
1.22 (0.91−1.64)
0.82 (0.68−1.00)
1.06 (0.87−1.28)
1.02 (0.72−1.45)
0.84 (0.67−1.06)
1.01 (0.66−1.55)
1.17 (0.90−1.52)
0.87 (0.56−1.33)
1.14 (0.95−1.37)
1.23 (0.86−1.75)
0.80 (0.64−0.99)
1.12 (0.83−1.51)
1.35 (0.74−2.45)
0.85 (0.63−1.14)
1.10 (0.90−1.33)
1.06 (0.83−1.35)
0.79 (0.62−1.01)
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●
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●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic strokeHazard ratio (95% CI)
0.67 (0.58−0.79)
0.59 (0.45−0.77)
0.96 (0.85−1.08)
0.71 (0.60−0.83)
0.65 (0.45−0.94)
0.91 (0.79−1.05)
0.46 (0.21−1.02)
0.59 (0.43−0.81)
0.82 (0.54−1.24)
0.69 (0.59−0.81)
0.58 (0.42−0.78)
0.96 (0.85−1.08)
0.64 (0.53−0.77)
0.56 (0.42−0.74)
0.86 (0.75−0.99)
0.75 (0.58−0.97)
0.61 (0.37−1.01)
1.26 (1.01−1.58)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
DeathHazard ratio (95% CI)
0.81 (0.72−0.91)
0.75 (0.62−0.92)
0.88 (0.79−0.97)
0.82 (0.72−0.93)
0.73 (0.56−0.93)
0.87 (0.76−0.98)
0.74 (0.50−1.09)
0.80 (0.65−0.97)
0.75 (0.56−1.02)
0.81 (0.72−0.92)
0.73 (0.58−0.92)
0.89 (0.79−0.99)
0.71 (0.60−0.83)
0.65 (0.50−0.85)
0.85 (0.75−0.97)
0.96 (0.82−1.13)
0.86 (0.68−1.09)
0.91 (0.77−1.08)
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●
●
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●
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SE/DeathHazard ratio (95% CI)
15
Supplementary Figure 6b. Propensity weighted (IPTW) Cox hazard ratios for 1 years follow-up (continuous treatment) for NOACs compared
to warfarin for bleeding endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
0.62 (0.51−0.74)
0.56 (0.45−0.69)
1.02 (0.89−1.18)
0.64 (0.52−0.79)
0.56 (0.44−0.71)
1.07 (0.91−1.27)
0.42 (0.24−0.74)
0.51 (0.36−0.71)
0.72 (0.45−1.14)
0.66 (0.54−0.80)
0.56 (0.44−0.70)
1.07 (0.93−1.25)
0.59 (0.47−0.73)
0.58 (0.45−0.74)
1.06 (0.91−1.24)
0.72 (0.51−1.01)
0.66 (0.34−1.27)
0.95 (0.69−1.31)
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0.01 0.05 0.20 1.00 5.00
FavoursAlternative
FavoursWarfarin
Any bleedingHazard ratio (95% CI)
0.60 (0.48−0.74)
0.52 (0.42−0.64)
1.09 (0.93−1.28)
0.62 (0.49−0.80)
0.55 (0.42−0.72)
1.14 (0.94−1.38)
0.37 (0.19−0.70)
0.41 (0.29−0.58)
0.67 (0.40−1.14)
0.65 (0.52−0.81)
0.52 (0.40−0.66)
1.19 (1.01−1.40)
0.56 (0.44−0.73)
0.52 (0.41−0.66)
1.13 (0.95−1.35)
0.74 (0.50−1.11)
0.50 (0.32−0.77)
1.04 (0.72−1.50)
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●
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0.01 0.05 0.20 1.00 5.00
FavoursAlternative
FavoursWarfarin
Major bleedingHazard ratio (95% CI)
0.71 (0.40−1.24)
0.30 (0.16−0.53)
0.56 (0.34−0.92)
0.75 (0.40−1.39)
0.30 (0.16−0.57)
0.61 (0.35−1.08)
0.73 (0.17−3.22)
0.60 (0.18−2.04)
0.16 (0.02−1.25)
0.70 (0.38−1.29)
0.24 (0.12−0.47)
0.59 (0.35−0.99)
0.69 (0.34−1.40)
0.30 (0.15−0.58)
0.55 (0.31−0.99)
0.50 (0.21−1.22)
0.27 (0.09−0.84)
0.52 (0.20−1.33)
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0.01 0.05 0.20 1.00 5.00
FavoursAlternative
FavoursWarfarin
Intracranial bleedingHazard ratio (95% CI)
16
Supplementary Figure 7a. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (continuous treatment) for NOACs
compared to warfarin for stroke and death endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
1.03 (0.88−1.22)
1.04 (0.82−1.32)
0.77 (0.65−0.91)
0.99 (0.82−1.19)
0.93 (0.71−1.24)
0.83 (0.67−1.01)
1.06 (0.70−1.60)
0.99 (0.79−1.24)
0.84 (0.58−1.22)
1.03 (0.87−1.23)
1.04 (0.78−1.40)
0.74 (0.61−0.89)
0.94 (0.71−1.25)
1.05 (0.67−1.63)
0.76 (0.59−0.98)
1.05 (0.87−1.27)
0.98 (0.78−1.23)
0.75 (0.60−0.94)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SEHazard ratio (95% CI)
1.06 (0.90−1.25)
1.10 (0.86−1.41)
0.81 (0.68−0.96)
1.02 (0.84−1.23)
0.95 (0.71−1.27)
0.85 (0.69−1.04)
1.01 (0.67−1.53)
1.09 (0.86−1.37)
0.93 (0.64−1.37)
1.08 (0.90−1.28)
1.09 (0.81−1.47)
0.76 (0.63−0.93)
1.01 (0.76−1.35)
1.11 (0.70−1.76)
0.80 (0.62−1.04)
1.07 (0.88−1.30)
1.03 (0.82−1.30)
0.79 (0.63−0.99)
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic strokeHazard ratio (95% CI)
0.69 (0.60−0.80)
0.58 (0.48−0.70)
0.98 (0.88−1.08)
0.72 (0.61−0.84)
0.61 (0.47−0.80)
0.95 (0.84−1.07)
0.56 (0.28−1.12)
0.62 (0.49−0.79)
0.97 (0.69−1.37)
0.69 (0.59−0.79)
0.55 (0.45−0.69)
0.95 (0.86−1.06)
0.65 (0.55−0.78)
0.59 (0.48−0.73)
0.90 (0.80−1.01)
0.73 (0.58−0.93)
0.51 (0.35−0.75)
1.17 (0.97−1.41)
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●
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
DeathHazard ratio (95% CI)
0.80 (0.72−0.89)
0.71 (0.61−0.82)
0.90 (0.82−0.98)
0.81 (0.72−0.91)
0.69 (0.57−0.83)
0.89 (0.80−0.99)
0.79 (0.55−1.15)
0.79 (0.67−0.93)
0.89 (0.69−1.16)
0.79 (0.70−0.88)
0.68 (0.57−0.81)
0.87 (0.79−0.96)
0.71 (0.61−0.83)
0.66 (0.55−0.80)
0.88 (0.79−0.98)
0.92 (0.79−1.07)
0.78 (0.63−0.96)
0.89 (0.76−1.04)
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●
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●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Ischemic stroke/SE/DeathHazard ratio (95% CI)
17
Supplementary Figure 7b. Propensity weighted (IPTW) Cox hazard ratios for 2.5 years follow-up (continuous treatment) for NOACs
compared to warfarin for bleeding endpoints.
Entire AF cohort (Main analysis)
AF hospitalised cohort (Sensitivity analysis)
Age<65yr (Supplementary analysis)
Age>=65yr (Supplementary analysis)
Primary stroke protection (Supplementary analysis)
Secondary stroke protection (Supplementary analysis)
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Dabigatran
Rivaroxaban
Strata / Treatment
0.61 (0.51−0.73)
0.58 (0.49−0.67)
1.00 (0.89−1.13)
0.62 (0.51−0.76)
0.56 (0.47−0.67)
1.00 (0.87−1.16)
0.40 (0.23−0.69)
0.52 (0.40−0.67)
0.81 (0.57−1.16)
0.65 (0.54−0.78)
0.57 (0.48−0.68)
1.03 (0.91−1.17)
0.58 (0.47−0.71)
0.59 (0.49−0.71)
1.01 (0.88−1.15)
0.70 (0.51−0.96)
0.63 (0.40−0.99)
1.00 (0.77−1.31)
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●
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0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Any bleedingHazard ratio (95% CI)
0.60 (0.49−0.73)
0.58 (0.49−0.68)
1.06 (0.92−1.21)
0.62 (0.50−0.77)
0.58 (0.48−0.71)
1.05 (0.89−1.23)
0.36 (0.20−0.67)
0.46 (0.35−0.60)
0.77 (0.51−1.14)
0.65 (0.53−0.80)
0.58 (0.48−0.69)
1.12 (0.97−1.29)
0.58 (0.46−0.73)
0.58 (0.48−0.71)
1.07 (0.92−1.24)
0.73 (0.51−1.06)
0.54 (0.40−0.74)
1.08 (0.80−1.46)
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●
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●
●
●
●
0.2 0.5 1.0 2.0
FavoursAlternative
FavoursWarfarin
Major bleedingHazard ratio (95% CI)
0.81 (0.49−1.34)
0.28 (0.18−0.44)
0.67 (0.44−1.00)
0.79 (0.44−1.41)
0.29 (0.18−0.48)
0.70 (0.44−1.12)
0.74 (0.17−3.24)
0.58 (0.21−1.56)
0.45 (0.09−2.39)
0.81 (0.47−1.39)
0.24 (0.15−0.40)
0.68 (0.45−1.04)
0.74 (0.39−1.39)
0.27 (0.16−0.45)
0.57 (0.35−0.94)
0.67 (0.30−1.49)
0.29 (0.12−0.68)
0.85 (0.42−1.72)
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●
●
●
●
●
●
●
●
●
0.01 0.05 0.20 1.00 5.00
FavoursAlternative
FavoursWarfarin
Intracranial bleedingHazard ratio (95% CI)
18