Supplemental Materials

Risk and Predictors of Subsequent Cancers of Patients with Newly-Diagnosed

Atrial Fibrillation - A Nationwide Population-Based Study

Yi-Ping Hung, M.D. 1,2, Yu-Wen Hu, M.D.1,3, Chia-Jen Liu, M.D.1,4, Yenn-Jiang Lin, M.D.5,6,

Shih-Lin Chang, M.D.5,6, Li-Wei Lo, M.D.5,6, Yu-Feng Hu, M.D.5,6, Ta-Chuan Tuan, M.D.5,6,

Jo-Nan Liao, M.D.5,6, Fa-Po Chung, M.D.5,6, Tzeng-Ji Chen, M.D.7, Shih-Ann Chen, M.D.5,6

Christine M. Albert, M.D.8*, Tze-Fan Chao, M.D.5,6*

1Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei,

Taiwan. 2Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. 3Division of Radiation Oncology, Department of Oncology, Taipei Veterans General

Hospital, Taiwan. 4Division of Hematology and Oncology, Department of Medicine, Taipei

Veterans General Hospital, Taipei, Taiwan. 5Division of Cardiology, Department of

Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 6Institute of Clinical Medicine,

and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan. 7Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 8Divisions of Cardiovascular and Preventive Medicine, Department of Medicine, Brigham

and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Running title: AF and cancer; Total word count: 4,115

Dr. Yi-Ping Hung and Dr. Yu-Wen Hu contributed equally to this study

*Dr. Christine M. Albert and Dr. Tze-Fan Chao are joint senior authors

Address for correspondence (Tze-Fan Chao, M.D. and Chia-Jen Liu, M.D.)

Tze-Fan Chao, M.D.

Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital,

No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan.

Tel: 886-2-2875-7156; Fax: 886-2-2873-5656 E-Mail: eyckeyck@gmail.com

Chia-Jen Liu, M.D.

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Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General

Hospital. No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan.

Tel: 886-2-2875-7529; Fax: 886-2-2875-7762 E-Mail: chiajenliu@gmail.com

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Supplemental Table 1. Cancer incidence rates among AF patients stratified by different age groups and duration of AF

Characteristics

All Male Female

Incidence of cancer *(95% CI) IRR (95% CI) Incidence of cancer *

(95% CI) IRR (95% CI) Incidence of cancer *(95% CI) IRR (95% CI)

All cancers 1.65 (1.63 – 1.67) 1.92 (1.89 – 1.95) 1.31 (1.29 – 1.34)

Age at diagnosis of AF

20 – 39 years 0.23 (0.18 – 0.27) Reference 0.20 (0.15 – 0.25) Reference 0.27 (0.19 – 0.34) Reference

40 – 59 years 0.88 (0.84 – 0.91) 3.90 (3.23 – 4.74) 0.95 (0.91 – 0.98) 4.72 (3.68 – 6.14) 0.77 (0.72 – 0.82) 2.68 (2.15 – 3.90)

60 – 79 years 1.86 (1.83 – 1.89) 8.27 (6.88 – 10.04) 2.24 (2.21 – 2.27) 6.21 (4.87 – 8.06) 1.39 (1.36 – 1.42) 5.16 (3.90 – 6.99)

≥ 80 years 2.32 (2.25 – 2.38) 10.29 (8.55 – 12.51) 2.90 (2.80 – 3.00) 11.57 (9.06 – 15.01) 1.81 (1.74 – 1.89) 6.74 (5.08 – 9.14)

Durations after AF being diagnosed

0 – 1, years 2.65 (2.59 – 2.71) 10.20 (9.57 – 10.89) 3.05 (2.96 – 3.14) 9.52 (8.81 – 10.31) 2.16 (2.08 – 2.24) 11.36 (10.13 –12.76)

1 – 5, years 1.02 (1.00 – 1.04) 3.91 (3.67 – 4.17) 1.18 (1.15 – 1.21) 3.69 (3.41 – 3.98) 0.81 (0.78 – 0.84) 4.27 (3.82 – 4.79)

5 – 10, years 0.53 (0.51 – 0.54) 2.04 (1.91 – 2.18) 0.63 (0.60 – 0.65) 1.95 (1.80 – 2.12) 0.41 (0.39 – 0.43) 2.15 (1.91 – 2.43)

≥ 10, years 0.26 (0.25 – 0.28) Reference 0.32 (0.30 – 0.35) Reference 0.19 (0.17 – 0.20) Reference

AF = atrial fibrillation; CI = confidence interval; IRR = incidence risk ratio *Per 100 person-years

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Supplemental Table 2. Numbers of mortality and durations to mortality after cancer being diagnosed

Patient number Event number of mortality

Durations (years) between incident cancers to mortality, mean (SD)

All cancers 22,911 12,201 1.23 (1.82)Timing of incident cancers after AF being diagnosed

0 – 1, years 7,413 4,310 1.27 (2.00)1 – 5, years 9,568 5,120 1.36 (1.89)5 – 10, years 4,858 2,366 0.98 (1.33)

≥ 10, years 1,072 405 0.59 (0.73)

AF = atrial fibrillation; SD = standard deviation

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Supplemental Table 3. Clinical characteristics of AF patients with or without cancer

Total With cancer Without cancer P valueNo. of patients 332,555 22,911 309,644Age (years), mean (SD) 70.8 ± 13.1 71.5 ± 10.2 70.78 ± 13.2 < 0.001Age at diagnosis of AF, n(%)20 – 29 years 2,174 (0.7) 22 (0.1) 2,152 (0.7) < 0.001

30 – 39 years 5,709 (1.7) 92 (0.4) 5,617 (1.8) < 0.00140 – 49 years 16,964 (5.1) 612 (2.7) 16,352 (5.3) < 0.00150 – 59 years 36,812 (11.1) 2,086 (9.1) 34,726 (11.2) < 0.00160 – 69 years 67,834 (20.4) 5,743 (25.1) 62,091 (20.1) < 0.00170 – 79 years 112,684 (33.9) 9,451 (41.3) 103,233 (33.3) < 0.001≥ 80 years 90,378 (27.2) 4,905 (21.4) 85,473 (27.6) < 0.001

Comorbidities, n(%) Hypertension 227,956 (68.5) 15,185 (66.3) 212,771 (68.7) < 0.001 Diabetes mellitus 94,515 (28.4) 5,773 (25.2) 88,742 (28.7) < 0.001 Heart failure 136,745 (41.1) 7,959 (34.7) 128,786 (41.6) < 0.001 History of ischemic stroke 116,068 (34.9) 6,422 (28.0) 109,646 (35.4) < 0.001

Peripheral arterial disease 28,067 (8.4) 1,623 (7.1) 26,444 (8.5) < 0.001 Coronary artery disease 8,205 (2.5) 463 (2.0) 7,742 (2.5) < 0.001 Prior MI 25,141 (7.6) 1,362 (5.9) 23,779 (7.7) < 0.001 Aortic aneurysm 1,901 (0.6) 101 (0.4) 1,800 (0.6) < 0.001 Aortic dissection 1,181 (0.4) 55 (0.2) 1,126 (0.4) < 0.001 ESRD 24,751 (7.4) 1,205 (5.3) 23,546 (7.6) < 0.001 COPD 117,248 (35.3) 7,770 (33.9) 109,478 (35.4) < 0.001 Liver cirrhosis 10,236 (3.1) 1,177 (5.1) 9,059 (2.9) < 0.001 Autoimmune diseases 18,305 (5.5) 1,087 (4.7) 17,218 (5.6) < 0.001 Dyslipidemia 83,207 (25.0) 4,754 (20.7) 78,453 (25.3) < 0.001Degree of urbanization, n (%)

< 0.001 Urban 170,832 (51.4) 12,062 (52.6) 158,770 (51.3) Suburban 110,836 (33.3) 7,475 (32.6) 103,361 (33.4) Rural 50,887 (15.3) 3,374 (14.7) 47,513 (15.3)Income level, n(%) 0.498 Low 177,871 (53.5) 12,323 (53.8) 165,548 (53.5) Median 111,029 (33.4) 7,442 (32.5) 103,587 (33.5) High 43,655 (13.1) 3,146 (13.7) 40,509 (13.1)Person-years at risk 1,385,140 74,875 1,310,275 < 0.001Median follow-up, years (interquartile range)

3.10 (0.97–6.53) 2.34 (0.52 – 5.13) 3.17 (1.00 – 6.63) < 0.001

COPD = chronic obstructive pulmonary disease; ESRD = end-stage renal disease; MI = myocardial infarction; SD = standard deviation

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Supplemental Table 4. Risk factors for cancer development in AF patients (n = 332,555)

Variables Univariate analysis Multivariate analysis*

HR (95% CI) P Value

HR (95% CI) P ValueAge ≥ 65 years 2.04 (1.97–2.10) <0.001 2.04 (1.98–2.11) <0.001

Sex (male) 1.47 (1.43–1.51) <0.001 1.51 (1.47–1.55) <0.001Comorbidities Hypertension 1.19 (1.16–1.22) <0.001 1.03 (1.00–1.06) 0.035 Diabetes mellitus 1.12 (1.09–1.15) <0.001 1.07 (1.03–1.10) <0.001 Heart failure 0.99 (0.96–1.01) 0.291 History of ischemic stroke 1.01 (0.98–1.04) 0.377 Peripheral arterial disease 1.15 (1.09 – 1.21) < 0.001 1.02 (0.97 – 1.08) 0.427

Coronary artery disease 1.09 (1.06 – 1.12) <0.001 0.96 (0.87 – 1.05) 0.328 Prior MI 1.01 (0.95–1.06) 0.855 Aortic aneurysm 1.20 (0.99 – 1.46) 0.066 Aortic dissection 0.92 (0.70 – 1.19) 0.511 ESRD 1.11 (1.05–1.18) 0.001 0.98 (0.92–1.04) 0.499 COPD 1.34 (1.30–1.38) <0.001 1.10 (1.07–1.13) <0.001 Liver cirrhosis 2.37 (2.23–2.51) <0.001 2.28 (2.15–2.42) <0.001 Autoimmune diseases 1.08 (1.02–1.15) 0.013 1.04 (0.98–1.10) 0.246 Dyslipidemia 0.98 (0.95–1.01) 0.132

AF = atrial fibrillation; CI = confidence interval; COPD = chronic obstructive pulmonary disease; ESRD = end-stage renal disease; HR = hazard ratio; MI = myocardial infarction

*Adjusted for factors with p < 0.1 in univariate analyses, degree of urbanization and income level

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Figure Legends of Supplemental Figures

Supplemental Figure 1. SIRs of cancers in the subgroup analyses. The risk of cancers was

consistently higher for AF patients in subgroup analyses based on the comorbidities of

patients. AF = atrial fibrillation; CI = confidence interval; COPD = chronic obstructive

pulmonary disease; ESRD = end-stage renal disease; SIR = standardized incidence ratio

Supplemental Figure 2. The flowchart of patient enrollment and risk of incident cancers

in different timing periods after AF being diagnosed. AF = atrial fibrillation; NHIRD =

national health insurance research database; SIR = standardized incidence ratio

Supplemental Figure 3. SIRs of cancers of different main systems. The observed risk of

cancer for AF patients was consistently higher for all systems, except for the risk of breast

cancer for AF males. AF = atrial fibrillation; CI = confidence interval; SIR = standardized

incidence ratio.

Supplemental Figure 4. Cumulative incidence curves of cancers. With an increase in the

number of risk factors in AF patients, the cumulative event rate correspondingly increased.

AF = atrial fibrillation.

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Supplemental Figure 1.

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Supplemental Figure 2

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Supplemental Figure 3

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Supplemental Figure 4

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