Comparative effectiveness and safety of non-vitamin K ... · bleeding I60 I61 I62 ... bReflects...

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


Ischemic stroke/SE

0.0

00

.02

0.0

40.0

60

.08


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


Ischemic stroke

Weighted failure curves

0.0

00

.03

0.0

60

.09

0.1

2


Apixaban Dabigatran


Any bleeding

0.0

00

.020

.040

.060

.080.1

0


Major bleeding

0.0

00

.01

0.0

10

.01

0.0

2


Intracranial bleeding


0.0

00

.03

0.0

60

.09

0.1

2


Any bleeding

0.0

00

.020

.040

.060

.080.1

0


Major bleeding

0.0

00

.01

0.0

10

.01

0.0

2


Intracranial bleeding


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


Apixaban Dabigatran


All-cause death

0.0

00

.05

0.1

00.1

50

.20


Ischemic stroke/SE/All-cause death


0.0

00

.05

0.1

00

.15

0.2

0


All-cause death

0.0

00

.05

0.1

00.1

50

.20


Ischemic stroke/SE/All-cause death


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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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.







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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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)

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

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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●

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●

●

●

●

●

●

●

●

●

0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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


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


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


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


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


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.







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


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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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


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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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.







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


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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0.01 0.05 0.20 1.00 5.00

FavoursAlternative

FavoursWarfarin


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


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.







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


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


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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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.







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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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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0.2 0.5 1.0 2.0

FavoursAlternative

FavoursWarfarin


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


Comparative effectiveness and safety of non-vitamin K ... · bleeding I60 I61 I62 ... bReflects...

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Transcript of Comparative effectiveness and safety of non-vitamin K ... · bleeding I60 I61 I62 ... bReflects...