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Table 3 Stroke, bleeding and mortality outcomes reported in included studies

From: Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and meta-analysis

Author Year

Adjustment for confounding

Outcome

Outcome definition

Study groups

Number of patients with ESRD and AF

Number of outcome events

Rates per 100 PY (95 % CI)

Adjusted HR (95 % CI)

Chan 2009e [30]

Adjusted for and PS matched on: CHADS2, gender, race, Charlson comorbidity index, entry date, access, body mass index, facility standardized mortality ratio, cardiovascular drugs, dialysis adequacy, baseline lab values, heparin dosage and heparin regimen

Any stroke

Hospitalization and death for stroke and TIAs identified from diagnoses obtained from hospital discharge summaries and cause of death from medical records

W (warfarin)

C (no warfarin)

746

925

NR

NR

7.1 (5.7, 8.7)

2.9 (2.0, 4.4)

1.74 (1.11, 2.72)c

Ischemic stroke

W (warfarin)

C (no warfarin)

746

925

NR

NR

NR

NR

1.81 (1.12, 2.92)

Hemorrhagic stroke

W (warfarin)

C (no warfarin)

746

925

NR

NR

NR

NR

2.22 (1.01, 4.91)

Major bleeding

Hospitalization for bleeding

W (warfarin)

C (no warfarin)

746

925

97

107

0.09 (NR)

0.07 (NR)

1.04 (0.73, 1.46)

All-cause mortality

-

W (warfarin)

C (no warfarin)

746

925

333

425

27.4 (NR)

25.7 (NR)

1.10 (0.93, 1.30)

Lai 2009e [32]

Adjusted for: gender, age, GFR, hemodialysis/transplant, aspirin, stroke history, heart and artery disease, smoking, hypertension, diabetes, dyslipidemia

Ischemic stroke

Thromboembolic stroke

W (warfarin)

HD: 51;

GFR: 78

HD: 5;

GFR: 8

HD: 10 %b

GFR: 10 %

NR

C (no warfarin)

HD: 42;

GFR: 54

HD: 16

GFR: 20

HD: 38 %

GFR: 37 %

Wizemann 2010 [33]

Adjusted for: age category, sex, race, years with ESRD, study phase, history of stroke, comorbid conditions, permanent pacemaker implanted, history of cardiac arrest, left ventricular hypertrophy, valvular heart disease

Any stroke

Hospitalized for stroke or if they died with cause of death listed as ‘cerebrovascular accident (including intracranial hemorrhage)

W (warfarin)

C (no warfarin)

509

2736

NR

NR

NR

NR

age ≤ 65: 1.29 (0.45, 3.68)

age 66–75: 1.35 (0.69, 2.63)

age > 75 years: 2.17 (1.04, 4.53)

Winkelmayer 2011 [22]

PS matched on: age, gender, race, state, dialysis vintage, dialysis type, comorbidity, vascular access surgery, length of stay, number of hospital days in prior year, number of medications used in prior year, H2 blocker or proton pump inhibitor use, prior nursing home stay, hematocrit, erythropoietin

Any stroke

Ischemic and hemorrhagic stroke identified by ICD-9

W (warfarin)

C (no warfarin)

237

948

38

150

9.7

8.7

1.08c (0.76, 1.55)

Ischemic stroke

ICD-9: 433.x1, 434.x1, 436

W (warfarin)

C (no warfarin)

237

948

29

135

7.4

7.8

0.92c (0.61, 1.37)

Hemorrhagic stroke

ICD-9: 430–432

W (warfarin)

C (no warfarin)

237

948

11

121

2.6

7.5

2.38 (1.15, 4.96)

Gastrointestinal bleed

Previously validated claims-based algorithm

W (warfarin)

C (no warfarin)

237

948

48

216

13.4

13.6

0.96c (0.70, 1.31)

All-cause mortality

-

W (warfarin)

C (no warfarin)

237

948

181

750

42.9

40.2

1.06c (0.90, 1.24)

Olesen 2012 [23]

Adjusted for: changes in renal status or antithrombotic treatment during follow up, risk factors in the CHA2DS2-VASc score, antithrombotic treatment, year of inclusion

Any stroke

Hospitalization or death from stroke or systemic thromboembolism (peripheral-artery embolism, ischemic stroke and transient ischemic attack)

W (warfarin)

C (no warfarin)

NR

NR

NR

NR

NR

NR

0.44 (0.26, 0.74)

Major bleeding

Bleeding (gastrointestinal, intracranial, urinary tract and airway bleeding)

W (warfarin)

C (no warfarin)

NR

NR

NR

NR

NR

NR

1.27 (0.91, 1.77)

Khalid 2013 [34]

PS adjusted for: age, gender, race, fresh frozen plasma, vitamin K, Charlson comorbidity index, cancer, INR, TTR, heart failure, aspirin, NSAIDs and clopidogrel use, ICU stay, blood transfusions

Ischemic stroke

thromboembolism

W (restarted warfarin)

C (did not restart warfarin)

34

62

NR

NR

NR

NR

0.44 (0.27, 0.73)

Gastrointestinal bleed

NR

W (restarted warfarin)

C (did not restart warfarin)

34

62

NR

NR

NR

NR

1.72 (1.29, 2.30)

All-cause mortality

-

W (restarted warfarin)

C (did not restart warfarin)

34

62

NR

NR

NR

NR

0.22 (0.13, 0.40)

Wakasugi 2014 [29]

Adjusted for: CHADS2 score; PS matched on: age, gender, BMI, duration of dialysis, cause of ESRD, vascular access, medical history, medication, comorbidity, blood pressure, lab data, mobility

Ischemic stroke

New ischemic stroke (fatal or nonfatal) not including TIA

W (warfarin)

C (no warfarin)

28

32

8

5

14.8 (6.4, 29.2)

8.9 (2.9, 20.8)

3.36c (0.67, 16.66)

Major bleeding

fatal bleeding or bleeding that required hospitalization

W (warfarin)

C (no warfarin)

28

32

3

4

5.3 (1.1, 15.5)

6.6 (1.8, 17.0)

0.85d (0.19, 3.64)

All-cause mortality

-

W (warfarin)

C (no warfarin)

28

32

9

9

14.2 (6.5, 26.9)

14.2 (6.5, 26.9)

1.00d (0.40, 2.52)

Bonde 2014 [24]

Adjusted for: aspirin treatment, stroke/TE comorbidity, concomitant medication, CHA2DS2-VASc score, bleeding comorbidity, HAS-BLED score

Any stroke

Hospitalization/death from stroke/TE (i.e., peripheral arterial embolism, ischemic stroke and transient ischemic attack)

W (warfarin)

C (no warfarin)

260

882

41a,f

186a,f

NR

NR

NR

All-cause mortality

-

W (warfarin)

C (no warfarin)

NR

NR

NR

NR

NR

NR

Low/intermediate risk: 1.36 (0.96, 1.94)

High risk: 0.85 (0.72, 0.99)

Carrero 2014 [25]

Adjusted for and PS matched on: age, sex, eGFR, comorbidities, patient presentation characteristics at admission, hospital course, discharge medication, center effect, left ventricular ejection fraction

Ischemic stroke

Hospitalizations due to ischemic stroke identified from claims

W (warfarin)

C (no warfarin)

66

412

0

16

NR

NR

MF

Major bleeding

Readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia identified from claims

W (warfarin)

C (no warfarin)

66

412

4

34

9.1

13.5

0.46c (0.11, 1.89)

All-cause mortality

-

W (warfarin)

C (no warfarin)

66

412

32

222

NR

NR

0.72 (0.46, 1.14)

Chen 2014 [26]

Adjusted for and PS matched on: age, gender, dialysis method, diabetes, risk factors, comorbidities, concomitant medication

Any stroke

Ischemic stroke, transient ischemic accident or hemorrhagic stroke identified by ICD9 codes

W (warfarin)

C (no warfarin)

294 (250 analyzed)

2983 (250 analyzed)

NR

NR

5.1%b

6.6 %

1.017c (0.673, 1.537)

Friberg 2014e [13]

Adjusted for: renal failure, age, sex, year of inclusion, duration since first AF diagnosis, previous thrombo-embolism, venous thrombo-embolism, intracranial bleeding, anaemia, coagulopathy or platelet defect, vascular disease, heart failure, pericarditis, other valvular disease, pacemaker, comorbidity, baseline use of medication

Ischemic stroke

Principal or first secondary diagnosis code for ischemic stroke

W (warfarin)

C (no warfarin)

3766

9669

NR

NR

2.7 (2.3, 3.1)

4.6 (4.2, 4.9)

0.687 (0.584, 0.807)h

Any stroke

Codes related to arterial or venous thromboembolism regardless of coding position

W (warfarin)

C (no warfarin)

3766

9669

NR

NR

6.2 (5.6, 6.8)

9.2 (8.7, 9.8)

0.779 (0.697, 0.870)h

Intracranial bleeding

Principal or first secondary diagnosis codes for haemorrhage

W (warfarin)

C (no warfarin)

3766

9669

NR

NR

1.0 (0.8, 1.2)

0.7 (0.6, 0.9)

1.557 (1.149, 2.110)h

Any bleeding

Codes related to intracranial, gastrointestinal and other bleeding

W (warfarin)

C (no warfarin)

3766

9669

NR

NR

9.6 (8.9, 10.4)

9.8 (9.3, 10.4)

1.096 (0.995, 1.206)h

All-cause mortality

-

W (warfarin)

C (no warfarin)

3766

9669

NR

NR

24.7 (23.5, 25.8)

41.7 (40.7, 42.8)

0.747 (0.708, 0.788)h

Shah 2014 [27]

PS adjusted for: age, sex, specific components of CHADS2 or HAS-BLED score

Ischemic stroke

ischemic cerebrovascular disease including transient ischemic attack (TIA) and retinal infarct

W (warfarin)

C (no warfarin)

756

870

52

55

3.37 (NR)

2.91 (NR)

1.17c (0.79, 1.75)

Any bleeding

intracerebral bleeding, gastrointestinal bleeding, intraocular bleeding, hematuria and unspecified location of bleeding

W (warfarin)

C (no warfarin)

756

870

149

126

10.88 (NR)

7.31 (NR)

1.41c (1.09, 1.81)

Genovesi 2015 [31]

Adjusted for: age and dialytic age, gender, antiplatelet therapy and hypertension status at recruitment, permanent AF and bleedings/haemorrhagic strokes, diabetes, ischaemic stroke, ischaemic heart disease and heart failure as time-dependent covariates

Any stroke

cerebrovascular event defined as ischemic or hemorrhagic by computed tomographic scan or nuclear magnetic resonance

W (warfarin)

C (no warfarin)

134

156

8

9

3.7 (NR)

3.7 (NR)

0.12 (0.00, 3.59)

Major bleeding

hemorrhagic episode requiring hospitalization or blood transfusion, or causing a hemoglobin plasma level reduction >2 g/dl

W (warfarin)

C (no warfarin)

134

156

38

29

17.6 (NR)

11.8 (NR)

3.96 (1.15, 13.68)

All-cause mortality

-

W (warfarin)

C (no warfarin)

134

156

51

64

NR

NR

0.96 (0.59, 1.56)

Chan KE 2015e [20]

Adjusted for: age, sex, race, diabetes, vintage, catheter vascular access, blood pressure, albumin, hemoglobin, thrombocytopenia, erythropoietin dose, heparin dose, antiplatelet use, Charlson comorbidity score, bleeding index score, recent minor or major bleeding event

Ischemic stroke

embolic stroke or arterial embolism, within 2 years of medication initiation

W (warfarin)

A (aspirin)

D (dabigatran)

R (rivaroxaban)

8064

6018

281

244

244

168

13

8

6.2 (NR)

5.0 (NR)

10.6 (NR)

11.2 (NR)

W vs. A: 1.23g (1.01, 1.52)

W vs. D: 1.71g (0.97, 2.99)

W vs R: 0.55g (0.27, 1.12)

Major bleeding

a hemorrhagic event resulting in hospitalization or death

W (warfarin)

A (aspirin)

D (dabigatran)

R (rivaroxaban)

8064

6018

281

244

NR

NR

NR

NR

47.1 (NR)

35.9 (NR)

83.1 (NR)

68.4 (NR)

W vs. A: 1.28g (1.19, 1.39)

W vs. D: 0.68g (0.55, 0.83)

W vs. R: 0.72g (0.55, 0.97)

Chan PH 2015 [21]

Adjusted for: age, gender, hypertension, diabetes, smoker, heart failure, coronary artery disease, prior stroke/TIA, prior ICH, CHA2DS2-VASc, HAS-BLED

Ischemic stroke

a neurological deficit of sudden onset that persisted for more than 24 h in the absence of primary hemorrhage or other cause and confirmed by CT or MRI

W (warfarin)

A (aspirin)

C (no antithrombotic therapy)

67

86

118

0

9

11

NR

NR

NR

T vs. A: 0.16 (0.04, 0.66)

T vs. C: 0.19 (0.06, 0.65)

Shen 2015 [28]

Included in inverse-probability treatment weighting analysis: age, sex, race, ethnicity, dialysis vintage, geographic location, comorbid conditions, indicators of health services use, baseline medication use, AF diagnosis characteristics

Any stroke

Any stroke or stroke death identified from claims-based algorithms

W (warfarin)

C (no warfarin)

1838

10446

116

765

4.4 (NR)

5.3 (NR)

0.83c (0.61, 1.12)

Ischemic stroke

Identified from claims-based algorithms

W (warfarin)

C (no warfarin)

1838

10446

63

503

2.3 (NR)

3.4 (NR)

0.68c (0.47, 0.99)

Gastrointestinal bleeding

events requiring hospitalization or with gastrointestinal bleeding as reported cause of death

W (warfarin)

C (no warfarin)

1838

10446

153

833

5.9 (NR)

5.9 (NR)

1.00c (0.69, 1.44)

All-cause mortality

-

W (warfarin)

C (no warfarin)

1838

10446

832

4595

33.0 (NR)

32.5 (NR)

1.01c (0.92, 1.11)

Wang 2015 [14]

Adjusted for: cerebrovascular disease, congestive heart failure, body mass index, age, warfarin and aspirin, beta-blocker, ischaemic heart disease, peripheral vascular disease

Any stroke

Ischemic stroke and other arterial embolism

W (warfarin)

C (no warfarin)

59

82

8

11

13.6%b

13.4 %

1.01 (0.380, 2.70)h

Ischemic stroke

focal neurological deficit lasting >24 h with radiological evidence on computed tomography or MRI

W (warfarin)

C (no warfarin)

59

82

5

10

8.5%b

12.2 %

0.667 (0.215, 2.06)h

Any bleed

Intracranial bleed required radiological confirmation, while gastrointestinal, dialysis site and other bleeds required having a blood transfusion to be counted

W (warfarin)

C (no warfarin)

59

82

22

24

37.3 %b

29.3 %

1.44 (0.706, 2.92)h

All-cause mortality

-

W (warfarin)

C (no warfarin)

59

82

44

64

74.6%b

78.0 %

0.825 (0.376, 1.81)h

Yodogawa 2015 [35]

Adjusted for: CHADS2 score

Any stroke

First hospital admission for stroke

W (warfarin)

C (no warfarin)

30

54

2

5

NR

NR

1.07 (0.20, 5.74)

Findlay 2016 [15]

No adjustment

Any stroke

Clinical diagnosis of stroke, presence of ischemic or hemorrhagic stroke on brain imaging, any stroke-related death

W (warfarin)

C (no warfarin)

118

175

17

20

14.4 %b

11.4 %

1.024h (0.536, 1.959)h

All-cause mortality

-

W (warfarin)

C (no warfarin)

118

175

NR

NR

NR

NR

0.671h (0.505, 0.891)h

Tanaka 2016 [16]

Adjusted for: age, sex, ACE/ARB, diabetes, history of CAD, heart failure, AD, eGFR, β-blocker, hemoglobin, calcium levels, phosphate levels and history of cerebral infarction and ICH

All-cause mortality

-

W (warfarin)

C (no warfarin)

46

47

11

10

23.9%b

21.3 %

0.7117h (0.2475, 2.0463)h

  1. AF atrial fibrillation, HD hemodialysis, PD peritoneal dialysis, CKD chronic kidney disease, ESRD end stage renal disease, RRT renal replacement therapy, CI confidence interval, NR not reported, MF model failed to converge, CAD coronary artery disease, ICH intracranial hemorrhage, GFR glomerular filtration rate, AD aortic disease
  2. aData were abstracted from online supplement
  3. bReference paper reported cumulative proportion instead of rates
  4. cEffect measures listed in the table were from the ITT analysis or propensity score adjusted/matched analysis
  5. dReference table reported unadjusted HR
  6. eQuality of warfarin treatment (i.e. INR or TTR) information provided
  7. fNumbers were combined from CHA2DS2-VASc score = 0, = 1, and > = 2 subgroups
  8. g Reference paper reported RR instead of HR. Effect measure and 95 % CI was calculated by taking the reciprocal of the reported RR
  9. h Effect measure and/or 95 % CIs were obtained from personal communication with the study author