Supplementary Appendix

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 CHA 2 DS 2 -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

2 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 8 th revision (ICD8) and from 1994 the 10 th 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 polycystic kidney disease Defined from diagnosis ICD8: 75310, 75319 ICD10: Q612-Q613, Q619 Alcohol abuse Defined from diagnosis and adverse alcohol consumption reported during hospitalization ICD8: 291, 303, N979-N980 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 ICD10: N11-N12, N14, N158-N160, N162-N164, N168 Diabetic nephropathy Defined from diagnosis 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 Defined from treatment Treatment: Glucose-lowering medication Drug consumption Defined from treatment with non-steroidal antiinflammatory drugs (patients treated with antiplatelet drugs was excluded from the study) Treatment: Non-steroidal anti-inflammatory drugs 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 α-antagonist, non-loop-diuretics,

5 two classes of antihypertensive drugs. This definition of hypertension has a positive predictive vasodilators, beta blockers, calcium channel blockers, 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 liver disease, liver surgery, cirrhosis, and hepatitis ICD8: 070, 155, 571-573 ICD10: B15-B19, C22, D684C, I982B, K70-K77, DQ618A, Z944 NCSP: KJJC Nephropathy of unknown etiology Defined from diagnosis ICD8: 581, 584 ICD10: N04, N18-N19, N26 Previous bleeding Defined from diagnoses of gastrointestinal, intracranial, urinary tract, or airway bleedings ICD8: 430-431, N852-N853 ICD10: I60-I62, I690-I692, J942, K250, K254, K260, Previous stroke or systemic thromboembolism Defined from diagnoses of peripheral artery embolism, stroke, and transient ischaemic attack K264, K270, K280, K920-K922, N02, R04, R31, S064- S066 ICD8: 433-438, 444 ICD10: G458-G459, I63-I64, I74

6 Vascular disease Defined from diagnoses of myocardial infarction, peripheral artery disease, and aortic plaque ICD8: 410, 440 ICD10: I21-I22, I700, I702-I709 Outcomes Bleeding Death from or diagnosis of gastrointestinal, intracranial, urinary tract, or airway bleedings ICD10: I60-I62, I690-I692, J942, K250, K254, K260, K264, K270, K280, K920-K922, N02, R04, R31, S064- S066 Myocardial infarction 5 Death from or diagnosis of myocardial infarction ICD10: I21-I22 Stroke or systemic thromboembolism 6 Death from or diagnosis of peripheral artery embolism, stroke, and transient ischaemic attack ICD10: G458-G459, I63-I64, I74 ICD8: ICD10: NCSP: 8 th revision of the International Classification of Diseases system 10 th revision of the International Classification of Diseases system The Nordic Medical Statistics Committees Classification of Surgical Procedures

7 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

8 Table S1. The CHA 2 DS 2 -VASc score 7 Letter Risk factor Points C Congestive heart failure 1 H Hypertension 1 A Age 75 years 2 D Diabetes mellitus 1 S Stroke or transient ischaemic attack or systemic thromboembolism 2 V Vascular disease (myocardial infarction, peripheral artery disease, aortic plaque) 1 A Age 65-74 years 1 Sc Sex category (female sex) 1

9 Table S2. The HAS-BLED score 8 Letter Risk factor Points H Hypertension (i.e. uncontrolled blood pressure) 1 A Abnormal liver or renal function 1 or 2 S Stroke or transient ischaemic attack or systemic thromboembolism 1 B Bleeding tendency or predisposition 1 L Labile international normalized ratio (INR) 1 E Elderly (i.e. >65 years) 1 D 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 No renal disease (n=127,884) Non-end-stage chronic kidney disease (n=3,587) Renal replacement therapy (n=901) p- value Concomitant medication, n (%) Adrenergic α-antagonist 1,689 (1.3) 107 (3.0) 47 (5.2) <0.001 Non-loop-diuretics 42,946 (33.6) 1,444 (40.3) 72 (8.0) <0.001 Vasodilators 3,926 (3.1) 144 (4.0) 44 (4.9) <0.001 Beta blockers 56,090 (43.9) 1,507 (42.0) 514 (57.1) <0.001 Calcium channel blockers 36,160 (28.3) 1,240 (34.6) 441 (49.0) <0.001 RASi 39,217 (30.7) 1,616 (45.1) 384 (42.6) <0.001 Loop-diuretics 47,154 (36.9) 2,375 (66.2) 557 (61.8) <0.001 Statins 15,295 (12.0) 673 (18.8) 187 (20.8) <0.001 Digoxin 61,284 (47.9) 1,592 (44.4) 302 (33.5) <0.001 Amiodarone 4,101 (3.2) 137 (3.8) 34 (3.8) 0.08 RASi: Renin-angiotensin system inhibitors

11 Table S4. Distribution of outcome events Outcome Number of events (%) Overall No renal disease Non-end-stage CKD Renal replacement therapy Stroke or systemic thromboembolism 17,654 (100) 16,648 (100) 842 (100) 164 (100) Non-fatal stroke or thromboembolism 10,682 (60.5) 10,081 (60.6) 496 (58.9) 105 (64.0) Ischaemic stroke 8,015 (45.4) 7,558 (45.4) 385 (45.7) 72 (43.9) Peripheral artery embolism 653 (3.7) 595 (3.6) 39 (4.6) 19 (11.6) Transient ischaemic attack 2,014 (11.4) 1,928 (11.6) 72 (8.6) 14 (8.5) Fatal stroke or thromboembolism 6,972 (39.5) 6,567 (39.4) 346 (41.1) 59 (36.0) Ischaemic stroke 6,682 (37.8) 6,301 (37.8) 326 (38.7) 55 (33.5) Peripheral artery embolism 167 (0.9) 149 (0.9) 14 (1.7) 4 (2.4) Transient ischaemic attack 123 (0.7) 117 (0.7) 6 (0.7) 0 (0.0) Bleeding 17,535 (100) 16,195 (100) 1,097 (100) 243 (100) Non-fatal bleeding 15,003 (85.6) 13,872 (85.7) 923 (84.1) 208 (85.6) Gastrointestinal 4,995 (28.5) 4,555 (28.1) 353 (32.2) 87 (35.8) Intracranial 1,648 (9.4) 1,574 (9.7) 57 (5.2) 17 (7.0)

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

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 13 Total population (n=132,372) No renal disease (n=127,884*) Non-end-stage CKD patients (n=3,587*) Renal replacement therapy patients (n=901*) HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value All participants 1 (reference) 1.52 (1.41-1.63) <0.001 1.89 (1.61-2.23) <0.001 1 (reference) 1 (reference) 1 (reference) 1 (reference) Warfarin 0.57 (0.54-0.59) <0.001 0.56 (0.53-0.58) <0.001 0.85 (0.70-1.04) 0.11 0.43 (0.25-0.74) 0.003 Aspirin 1.11 (1.07-1.15) <0.001 1.10 (1.06-1.15) <0.001 1.22 (1.03-1.44) 0.02 0.91 (0.60-1.38) 0.66 Warfarin+Aspirin 0.67 (0.62-0.72) <0.001 0.65 (0.60-0.71) <0.001 0.80 (0.59-1.07) 0.15 0.76 (0.33-1.78) 0.53 Results from time-dependent Cox regression analyses adjusted for year of inclusion and CHA 2 DS 2 -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.

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) 14 Frequency Stroke or systemic thromboembolism Bleeding N (%) HR (95% CI) P value HR (95% CI) P value Patients with no renal disease 127,884 (96.6)* 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 1,820 (22.4) 1.40 (1.26-1.54) <0.001 1.93 (1.76-2.11) <0.001 Furosemide 40-160 mg/daily 2,760 (34.0) 1.60 (1.43-1.80) <0.001 2.41 (2.17-2.68) <0.001 Furosemide 160 mg/daily 3,545 (43.6) 1.52 (1.30-1.79) <0.001 2.85 (2.51-3.23) <0.001 Non-end-stage CKD by underlying disease Adult polycystic kidney disease 224 (2.8) 1.22 (0.88-1.69) 0.24 1.78 (1.32-2.40) <0.001 Chronic glomerulonephritis 584 (7.2) 1.30 (1.03-1.64) 0.03 2.81 (2.40-3.30) <0.001

15 Diabetic nephropathy 1,526 (18.8) 1.41 (1.21-1.65) <0.001 1.96 (1.70-2.25) <0.001 Chronic tubulointerstitial nephropathy 875 (10.8) 1.18 (0.97-1.44) 0.09 1.32 (1.08-1.62) 0.01 Hypertensive nephropathy 282 (3.5) 1.92 (1.46-2.54) <0.001 1.82 (1.36-2.43) <0.001 Other etiology 184 (2.3) 1.43 (0.96-2.14) 0.08 1.38 (0.91-2.10) 0.13 Nephropathy of unknown etiology 4,625 (56.9) 1.60 (1.45-1.76) <0.001 2.49 (2.29-2.71) <0.001 Results from time-dependent Cox regression analyses adjusted for CHA 2 DS 2 -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).

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