Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Olesen JB, Lip GYH, Kamper A-L, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-35. DOI: 10.1056/NEJMoa1105594

Supplementary Appendix
Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

Table of contents
Methods Data sources - The applied Danish registries ................................................................................... 2 Definitions used for the population, comorbidity, and outcomes .................................................... 3 Figures S1. Results from multivariate time-dependent Cox regression analyses for all outcomes .............. 7 Tables S1. The CHA2DS2-VASc score ....................................................................................................... 8 S2. The HAS-BLED score ............................................................................................................... 9 S3. Baseline characteristics - Concomitant medication ................................................................. 10 S4. Distribution of outcome events ................................................................................................ 11 S5. Risk of ischaemic stroke or peripheral artery embolism only ................................................. 13 S6. Risk with level and type of non-end-stage chronic kidney disease ......................................... 14 References ......................................................................................................................................... 16

Data sources - The applied Danish registries

The Central Population Registry holds information on vital status for all citizens.

The National Patient Registry holds information on all patient admissions to Danish hospitals since 1978. At discharge each hospitalization is registered by one primary and, if appropriate, one or more secondary discharge diagnoses according to the International Classification of Diseases; until 1994 according to the 8th revision (ICD8) and from 1994 the 10th revision (ICD10). Since 1996 invasive therapeutical procedures have been coded according to the Nordic Medical Statistics Committees Classification of Surgical Procedures (NCSP).1

The Registry of Medicinal Product Statistics (National Prescription Register) holds information on all prescriptions dispensed from Danish pharmacies since 1995. All dispensed drugs are classified according to the Anatomical Therapeutical Chemical (ATC) classification. The register keeps information about date of dispensing as well as dispensed drug formulation, strength, and quantity. Pharmacies in Denmark are required to register all dispensed prescriptions due to partial reimbursement of drug expenses by the national healthcare system, which ensures a complete and accurate registration.2

The National Registry on Regular Dialysis and Transplantation contains accurate data on all Danish patients actively treated for end-stage renal disease since 1990.3

The National Causes of Death Registry holds information on primary and contributing causes of death.

3 Diagnoses, surgical procedures, and pharmacotherapy used for defining the population, comorbidity, and outcomes

Non-valvular atrial fibrillation Presence of ICD10: I48 Absence of ICD8: 394-396, 4240, 4241 ICD10: I05, I06, I34, I35 NCSP: KFK, KFM, KFP

Comorbidity Adult disease Alcohol abuse polycystic kidney Defined from diagnosis ICD8: 75310, 75319 ICD10: Q612-Q613, Q619 Defined from diagnosis and adverse alcohol ICD8: 291, 303, N979-N980 consumption reported during hospitalization ICD10: E244, E52, F1, G312, G621, G721, I426, K292, K70, K860, L278A, O354, T51, Z714, Z721 Chronic glomerulonephritis Defined from diagnosis ICD8: 582-583 ICD10: N02-N03, N05-N07 Chronic tubulointestinal Defined from diagnosis ICD8: 59009, 59320

4 nephropathy Diabetic nephropathy Defined from diagnosis ICD10: N11-N12, N14, N158-N160, N162-N164, N168 ICD8: 25002 ICD10: E102, E112, E132, E142, N083 Non-end-stage kidney disease chronic Defined from diagnosis ICD8: 25002, 40039, 403-404, 581-584, 59009, 59320, 75310-75311, 75319 ICD10: E102, E112, E132, E 142, I120, M321B, M300, M313, M319, N02-N08, N11-N12, N14, N158-N160, N162-N164, N168, N18-N19, N26, Q612-Q613, Q615, Q619, Diabetes mellitus Drug consumption Defined from treatment Treatment: Glucose-lowering medication

Defined from treatment with non-steroidal anti- Treatment: Non-steroidal anti-inflammatory drugs inflammatory drugs (patients treated with

antiplatelet drugs was excluded from the study) Heart failure Defined from diagnosis plus treatment ICD8: 425, 4270-4271 ICD10: I110, I42, I50, J819 Treatment: Loop-diuretics Hypertension Defined from combination treatment with a least Treatment: Adrenergic -antagonist, non-loop-diuretics,

5 two classes of antihypertensive drugs. This vasodilators, beta blockers, calcium channel blockers, definition of hypertension has a positive predictive and renin-angiotensin system inhibitors. value of 80.0% and a specificity 94.7%.4 Hypertensive nephropathy Defined from diagnosis ICD8: 40039, 403-404 ICD10: I120 Liver disease Defined from diagnoses of liver cancer, chronic ICD8: 070, 155, 571-573 liver disease, liver surgery, cirrhosis, and hepatitis ICD10: B15-B19, C22, D684C, I982B, K70-K77, DQ618A, Z944 NCSP: KJJC Nephropathy of unknown Defined from diagnosis etiology Previous bleeding Defined from diagnoses of ICD8: 581, 584 ICD10: N04, N18-N19, N26 gastrointestinal, ICD8: 430-431, N852-N853 ICD10: I60-I62, I690-I692, J942, K250, K254, K260, K264, K270, K280, K920-K922, N02, R04, R31, S064S066 Previous stroke or systemic Defined from diagnoses of peripheral artery ICD8: 433-438, 444 thromboembolism embolism, stroke, and transient ischaemic attack ICD10: G458-G459, I63-I64, I74

intracranial, urinary tract, or airway bleedings

6 Vascular disease Defined from diagnoses of myocardial infarction, ICD8: 410, 440 peripheral artery disease, and aortic plaque ICD10: I21-I22, I700, I702-I709

Outcomes Bleeding Death from or diagnosis of gastrointestinal, ICD10: I60-I62, I690-I692, J942, K250, K254, K260, intracranial, urinary tract, or airway bleedings K264, K270, K280, K920-K922, N02, R04, R31, S064S066 Myocardial infarction5 Stroke or Death from or diagnosis of myocardial infarction ICD10: I21-I22

systemic Death from or diagnosis of peripheral artery ICD10: G458-G459, I63-I64, I74 embolism, stroke, and transient ischaemic attack

thromboembolism6

ICD8: ICD10: NCSP:

8th revision of the International Classification of Diseases system 10th revision of the International Classification of Diseases system The Nordic Medical Statistics Committees Classification of Surgical Procedures

Figure S1

Risk with non-end-stage chronic kidney disease (CKD) and renal replacement therapy (RRT) in patients with non-valvular atrial fibrillation

Stroke or TE Non-end-stage CKD RRT Bleeding Non-end-stage CKD RRT Myocardial infarction Non-end-stage CKD RRT Death from all causes Non-end-stage CKD RRT
0,8 1 1,5 2 2,5 3

Hazard ratio

Results from multivariate (adjusted for all baseline characteristics) time-dependent Cox regression analyses. Results only shown for non-end-stage CKD and RRT, the reference was patients with no renal disease. TE: systemic thromboembolism

Table S1. The CHA2DS2-VASc score7 Letter Risk factor C H A D S V A Sc Congestive heart failure Hypertension Age 75 years Diabetes mellitus Stroke or transient ischaemic attack or systemic thromboembolism Points 1 1 2 1 2

Vascular disease (myocardial infarction, peripheral artery disease, aortic plaque) 1 Age 65-74 years Sex category (female sex) 1 1

Table S2. The HAS-BLED score8 Letter Risk factor H A S B L E D Hypertension (i.e. uncontrolled blood pressure) Abnormal liver or renal function Stroke or transient ischaemic attack or systemic thromboembolism Bleeding tendency or predisposition Labile international normalized ratio (INR) Elderly (i.e. >65 years) Points 1 1 or 2 1 1 1 1

Drugs (antiplatelet agents, non-steroidal anti-inflammatory drugs) or alcohol abuse 1 or 2

10

Table S3. Baseline medications for patients with atrial fibrillation according to renal disease status at baseline Non-end-stage No renal chronic kidney disease disease (n=127,884) (n=3,587) Concomitant medication, n (%) Adrenergic -antagonist Non-loop-diuretics Vasodilators Beta blockers Calcium channel blockers RASi Loop-diuretics Statins Digoxin Amiodarone 1,689 (1.3) 42,946 (33.6) 3,926 (3.1) 56,090 (43.9) 36,160 (28.3) 39,217 (30.7) 47,154 (36.9) 15,295 (12.0) 61,284 (47.9) 4,101 (3.2) 107 (3.0) 1,444 (40.3) 144 (4.0) 1,507 (42.0) 1,240 (34.6) 1,616 (45.1) 2,375 (66.2) 673 (18.8) 1,592 (44.4) 137 (3.8) 47 (5.2) 72 (8.0) 44 (4.9) 514 (57.1) 441 (49.0) 384 (42.6) 557 (61.8) 187 (20.8) 302 (33.5) 34 (3.8) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.08 (n=901) therapy value replacement pRenal

RASi: Renin-angiotensin system inhibitors

11 Table S4. Distribution of outcome events Outcome Overall Stroke or systemic thromboembolism Non-fatal stroke or thromboembolism Ischaemic stroke Peripheral artery embolism Transient ischaemic attack Fatal stroke or thromboembolism Ischaemic stroke Peripheral artery embolism Transient ischaemic attack 17,654 (100) 10,682 (60.5) 8,015 (45.4) 653 (3.7) 2,014 (11.4) 6,972 (39.5) 6,682 (37.8) 167 (0.9) 123 (0.7) Number of events (%) No renal disease Non-end-stage CKD Renal replacement therapy 16,648 (100) 10,081 (60.6) 7,558 (45.4) 595 (3.6) 1,928 (11.6) 6,567 (39.4) 6,301 (37.8) 149 (0.9) 117 (0.7) 842 (100) 496 (58.9) 385 (45.7) 39 (4.6) 72 (8.6) 346 (41.1) 326 (38.7) 14 (1.7) 6 (0.7) 164 (100) 105 (64.0) 72 (43.9) 19 (11.6) 14 (8.5) 59 (36.0) 55 (33.5) 4 (2.4) 0 (0.0)

Bleeding Non-fatal bleeding Gastrointestinal Intracranial

17,535 (100) 15,003 (85.6) 4,995 (28.5) 1,648 (9.4)

16,195 (100) 13,872 (85.7) 4,555 (28.1) 1,574 (9.7)

1,097 (100) 923 (84.1) 353 (32.2) 57 (5.2)

243 (100) 208 (85.6) 87 (35.8) 17 (7.0)

12 Urinary tract Airway Fatal bleeding Gastrointestinal Intracranial Urinary tract Airway CKD: chronic kidney disease 4,123 (23.5) 4,237 (24.2) 2,532 (14.4) 967 (5.5) 1,495 (8.5) 29 (0.2) 41 (0.2) 3,768 (23.3) 3,975 (24.5) 2,323 (14.3) 863 (5.3) 1,401 (8.7) 22 (0.1) 37 (0.2) 301 (27.4) 212 (19.3) 174 (15.9) 89 (8.1) 76 (6.9) 6 (0.5) 3 (0.3) 54 (22.2) 50 (20.6) 35 (14.4) 15 (6.2) 18 (7.4) 1 (0.4) 1 (0.4)

13 Table S5. Hazard ratio (95% confidence interval) of ischaemic stroke or peripheral artery embolism (transient ischaemic attack not included) in patients with non-valvular atrial fibrillation Non-end-stage CKD Total population (n=132,372) No renal disease patients (n=127,884*) (n=3,587*) HR (95% CI) All participants P value HR (95% CI) P value HR (95% CI) 1.52 (1.41-1.63) P value <0.001 (n=901*) HR (95% CI) 1.89 (1.61-2.23) P value <0.001 therapy patients Renal replacement

1 (reference)

1 (reference) Warfarin Aspirin Warfarin+Aspirin 0.57 (0.54-0.59) 1.11 (1.07-1.15) 0.67 (0.62-0.72) <0.001 <0.001 <0.001

1 (reference) 0.56 (0.53-0.58) 1.10 (1.06-1.15) 0.65 (0.60-0.71) <0.001 <0.001 <0.001

1 (reference) 0.85 (0.70-1.04) 1.22 (1.03-1.44) 0.80 (0.59-1.07) 0.11 0.02 0.15

1 (reference) 0.43 (0.25-0.74) 0.91 (0.60-1.38) 0.76 (0.33-1.78) 0.003 0.66 0.53

Results from time-dependent Cox regression analyses adjusted for year of inclusion and CHA2DS2-VASc risk factors. CI: confidence interval; CKD: chronic kidney disease; HR: hazard ratio * Numbers at baseline. As the analyses were time-dependent, these numbers changed during follow-up.

14 Table S6. Risk of stroke or systemic thromboembolism and bleeding associated with level and type of non-end-stage chronic kidney disease in patients with non-valvular atrial fibrillation (n=132,372) Stroke or systemic Frequency thromboembolism N (%) Patients with no renal disease 127,884 (96.6)* HR (95% CI) P value HR (95% CI) P value Bleeding

1 (reference)

1 (reference)

Non-end-stage CKD (overall)

3,587 (2.7)*

1.49 (1.38-1.59)

<0.001

2.24 (2.10-2.38)

<0.001

Non-end-stage CKD by loop-diuretics Furosemide 40 mg/daily Furosemide 40-160 mg/daily Furosemide 160 mg/daily 1,820 (22.4) 2,760 (34.0) 3,545 (43.6) 1.40 (1.26-1.54) 1.60 (1.43-1.80) 1.52 (1.30-1.79) <0.001 <0.001 <0.001 1.93 (1.76-2.11) 2.41 (2.17-2.68) 2.85 (2.51-3.23) <0.001 <0.001 <0.001

Non-end-stage CKD by underlying disease Adult polycystic kidney disease Chronic glomerulonephritis 224 (2.8) 584 (7.2) 1.22 (0.88-1.69) 1.30 (1.03-1.64) 0.24 0.03 1.78 (1.32-2.40) 2.81 (2.40-3.30) <0.001 <0.001

15 Diabetic nephropathy Chronic tubulointerstitial nephropathy Hypertensive nephropathy Other etiology Nephropathy of unknown etiology 1,526 (18.8) 875 (10.8) 282 (3.5) 184 (2.3) 4,625 (56.9) 1.41 (1.21-1.65) 1.18 (0.97-1.44) 1.92 (1.46-2.54) 1.43 (0.96-2.14) 1.60 (1.45-1.76) <0.001 0.09 <0.001 0.08 <0.001 1.96 (1.70-2.25) 1.32 (1.08-1.62) 1.82 (1.36-2.43) 1.38 (0.91-2.10) 2.49 (2.29-2.71) <0.001 0.01 <0.001 0.13 <0.001

Results from time-dependent Cox regression analyses adjusted for CHA2DS2-VASc risk factors or HAS-BLED risk factors, respectively, antithrombotic treatment, and year of inclusion. CI: confidence interval; CKD: chronic kidney disease; HR: hazard ratio. * Numbers at baseline. As the analyses were time-dependent, these numbers changed during follow-up. Patients with non-end-stage CKD were time-dependently stratified according to loop-diuretic treatment dose. Number of patients with maximum treatment dose during follow-up 168 patients had minimum two of the specific underlying diseases (i.e. adult polycystic kidney disease, chronic glomerulonephritis, diabetic nephropathy, chronic tubulointerstitial nephropathy, hypertensive nephropathy).

16

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