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1 Supplementary Online Content Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among patients taking non vitamin K antagonist vs vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. doi: /jama etable 1. Missing Values etable 2. Outcome Measures by Anticoagulant Type in Patients Without Preceding Use of Any Antiplatelet Agents etable 3. Outcome Measures by Anticoagulant Type in Patients With NIHSS on Admission etable 4. Baseline Characteristics by Number of Antiplatelet Agents etable 5. Direct Comparison of In-hospital Mortality Between NOACs and Warfarin Stratified by Number of Antiplatelet Agents etable 6. Outcome Measures by INR Levels in ICH Patients With Preceding Use of Warfarin This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Missing Values Characteristics Missing values, % (Total No. of patients = 141,311) Imputation If applicable Age 0% N/A Women 0.03% Men Race 0.16% Insurance 7.39% Non-Hispanic white Private/other insurance Medical History AF or atrial flutter 1.06% No Previous Stroke or TIA 1.06% No CAD or myocardial infarction 1.06% No Carotid Stenosis 1.06% No Diabetes Mellitus 1.06% No PVD 1.06% No Hypertension 1.06% No Smoker 1.06% No Dyslipidemia 1.06% No Heart failure 1.06% No

3 Drugs or Alcohol Abuse 1.06% No Obesity or overweight 1.06% No Renal insufficiency 0.94% No Arrival and admission information EMS arrival and transfer in 1.59% Private transportation Arrived off-hours 0% N/A NIHSS at presentation 36.2% Sensitivity analysis Preadmission medication Antihypertensive 18.08% No Cholesterol reducer 1.52% No Diabetic medications 21.81% No Hospital Characteristics Bed size 1.45% Excluded Academic center 1.14% Excluded Primary Stroke Center 0% Excluded Rural hospital 0.76% Excluded Abbreviations: AF, atrial fibrillation; TIA, transient ischemic attack; CAD, coronary artery disease; PVD, peripheral vascular disease; EMS, emergency medical services; NIHSS, National Institute of Health Stroke Scale.

4 etable 2. Outcome Measures by Anticoagulant Type in Patients Without Preceding Use of Any Antiplatelet Agents a Outcome Measures Warfarin NOACs No OAC Event rates 3101/9777 (31.7) 873/3307 (26.4) 18526/82859 (22.4) Primary outcome: In-hospital Death Adjusted OR b (97.5% CI) Adjusted RD b (97.5% CI), % Adjusted OR b (97.5% CI) Adjusted RD b (97.5% CI), % Reference 0.77 ( ) 0.64 ( ) Reference -5.0 (-6.8, -3.2) -8.1 (-9.5, -6.7) 1.56 ( ) 1.21 ( ) Reference 8.1 (6.7, 9.5) 3.1 (1.2, 5.0) Reference Event rates 4108/9777 (47.0) 1241/3307 (37.5) 24276/82859 (29.3) In-hospital Death or Discharge to Hospice Reference 0.81 ( ) 0.68 ( ) Reference -4.6 (-6.4, -2.8) -7.8 (-9.1, -6.5) 1.46 ( ) 1.18 ( ) Reference 7.8 (6.5, 9.1) 3.2 (1.4, 5.0) Reference Event rates 1720/6087 (28.3) 668/2247 (29.7) 20714/54193 (38.2) Able to Ambulate Independently at Discharge c Reference 1.10 ( ) 1.09 ( ) Reference 1.8 (-0.4, 4.0) 1.7 (0.2, 3.2)

5 0.92 ( ) 1.01 ( ) Reference -1.7 (-3.2, -0.2) 0.1 (-2.0, 2.2) Reference Event rates 1655/9777 (16.9) 658/3307 (19.9) 23486/82859 (28.3) Discharge Home Reference 1.26 ( ) 1.17 ( ) Reference 3.0 (1.6, 4.5) 2.1 (1.1, 3.2) 0.86 ( ) 1.08 ( ) Reference -2.1 (-3.2, -1.1) 0.9 (-0.6, 2.4) Reference Event rates 683/9162 (7.5) 270/2939 (9.2) 8813/67496 (13.1) Modified Rankin Scale 0-1 d Reference 1.18 ( ) 1.27 ( ) Reference 1.2 (-0.2, 2.6) 1.9 (1.0, 2.9) 0.79 ( ) 0.93 ( ) Reference -1.9 (-2.9, -1.0) -0.7 (-2.1, 0.7) Reference Modified Rankin Scale 0-2 d Event rates 684/5916 (11.6) 280/1965 (14.3) 8944/44925 (19.9)

6 Reference 1.29 ( ) 1.29 ( ) Reference 2.6 (1.0, 4.2) 2.9 (1.7, 4.0) 0.77 ( ) 1.00 ( ) Reference -2.9 (-4.0, -1.7) -0.3 (-1.9, 1.4) Reference Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulants; OAC, oral anticoagulant; OR, odds ratio; CI, confidence interval; RD, risk difference. a After excluding 45,368 patients with the preceding use of antiplatelet therapy, a total of 95,943 patients were analyzed. b Adjusting for patient and hospital characteristics as follows: Demographics (age, sex, race-ethnicity [black, Hispanic, Asian and others vs. white]), insurance (Medicare, Medicaid, private insurance/va/others, vs. no insurance), medical history (atrial fibrillation or flutter, prior coronary artery disease or myocardial infarction, carotid stenosis, diabetes, peripheral vascular disease, hypertension, smoking, dyslipidemia, prior stroke or transient ischemic attack, heart failure, drug or alcohol abuse, obesity or overweight, renal insufficiency), arrival and admission information (emergency medical services arrival and transfer in [vs. private transportation], arrived off-hours), prior to admission medications (antihypertensive, lipid lowering, diabetic agents), hospital characteristics (rural vs. urban setting, number of beds, teaching hospital, regions, certified primary stroke center). c Data were missing for 10,916 patients (11.4%). d Data were missing for 43,137 patients (45.0%).

7 etable 3. Outcome Measures by Anticoagulant Type in Patients With NIHSS on Admission a Outcome Measures Warfarin NOACs No OAC Primary outcome: In-hospital Death In-hospital Death or Discharge to Hospice Able to Ambulate Independently at Discharge c Event rates 2603/9301 (28.0) 755/3308 (22.8) 13876/77614 (17.9) Adjusted OR b (97.5% CI) Reference 0.77 ( ) 0.58 ( ) Adjusted RD b (97.5% CI), % Reference -3.6 (-5.2, -2.0) -7.0 (-8.0, -5.9) Adjusted OR b (97.5% CI) 1.71 ( ) 1.32 ( ) Reference Adjusted RD b (97.5% CI), % 7.0 (5.9, 8.0) 3.4 (1.8, 4.9) Reference Event rates 3539/9301 (38.1) 1099/3308 (33.2) 19721/77614 (25.4) Reference 0.78 ( ) 0.63 ( ) Reference -3.5 (-5.0, -2.0) -6.3 (-7.3, -5.2) 1.59 ( ) 1.24 ( ) Reference 6.3 (5.2, 7.3) 2.8 (1.3, 4.3) Reference Event rates 1806/6213 (29.1) 705/2387 (29.5) 20897/56718 (36.8) Reference 1.06 ( ) 1.20 ( ) Reference 1.0 (-1.0, 3.0) 3.2 (1.9, 4.5) 0.83 ( ) 0.88 ( ) Reference -3.2 (-4.5, -1.9) -2.2 (-3.9, -0.4) Reference

8 Discharge Home Modified Rankin Scale 0-1 d Modified Rankin Scale 0-2 d Event rates 1617/9301 (17.4) 671/3308 (20.3) 21779/77614 (28.1) Reference 1.23 ( ) 1.27 ( ) Reference 1.8 (0.5, 3.2) 2.3 (1.4, 3.2) 0.79 ( ) 0.97 ( ) Reference -2.3 (-3.2, -1.4) -0.5 (-1.7, 0.8) Reference Event rates 502/5832 (8.6) 219/2019 (10.9) 6574/45049 (14.6) Reference 1.26 ( ) 1.28 ( ) Reference 1.2 (-0.3, 2.7) 1.2 (0.2, 2.1) 0.78 ( ) 0.98 ( ) Reference -1.2 (-2.1, -0.2) 0 (-1.4, 1.5) Reference Event rates 756/5832 (13.0) 328/2019 (16.3) 9509/45049 (21.1) Reference 1.30 ( ) 1.38 ( ) Reference 2.0 (0.4, 3.6) 2.1 (1.1, 3.2) 0.72 ( ) 0.94 ( ) Reference -2.1 (-3.2, -1.1) -0.1 (-1.7, 1.4) Reference Abbreviations: NIHSS, National Institutes of Health Stroke Scale; NOAC, non-vitamin K antagonist oral anticoagulants; OAC, oral anticoagulant; OR, odds ratio; CI, confidence interval; RD, risk difference.

9 a A total of 90,223 patients with NIHSS on admission were analyzed. b Adjusting for patient and hospital characteristics as follows: Demographics (age, sex, race-ethnicity [black, Hispanic, Asian and others vs. white]), insurance (Medicare, Medicaid, private insurance/va/others, vs. no insurance), medical history (atrial fibrillation or flutter, prior coronary artery disease or myocardial infarction, carotid stenosis, diabetes, peripheral vascular disease, hypertension, smoking, dyslipidemia, prior stroke or transient ischemic attack, heart failure, drug or alcohol abuse, obesity or overweight, renal insufficiency), arrival and admission information (emergency medical services arrival and transfer in [vs. private transportation], arrived off-hours), prior to admission medications (antihypertensive, lipid lowering, diabetic agents), hospital characteristics (rural vs. urban setting, number of beds, teaching hospital, regions, certified primary stroke center), NIHSS on admission. c Data were missing for 7,671 patients (8.5%). d Data were missing for 37,323 patients (41.4%). Modified Rankin Scale ranges from 0 to 6, and a higher score indicates worse functional outcome and 6 indicates death. Patients with modified Rankin Scale of 0 or 1 were classified as having excellent recovery, and those with modified Rankin Scale of 0 to 2 were classified as having functional independence.

10 10 etable 4. Baseline Characteristics by Number of Antiplatelet Agents Characteristics Single AP Dual AP No AP (N=39,585) (N=5783) (N=95,943) p-value Age, median (IQR), y 75 (65-83) 74 (65-82) 66 (55-79) <.0001 Women, No. (%) (47.6) 2436 (42.1) (48.6) <.0001 Race, No. (%) <.0001 Non-Hispanic white (70.2) 4165 (72.1) (59.1) Non-Hispanic black 5943 (15.0) 779 (13.5) (19.4) Hispanic 2492 (6.3) 391 (6.8) 9576 (10.0) Asian 1567 (4.0) 164 (2.8) 5231 (5.5) Other 1764 (4.5) 277 (4.8) 5749 (6.0) Insurance, No. (%) <.0001 Private (39.0) 2142 (38.3) (38.7) Medicare 3506 (9.2) 567 (10.1) (12.8) Medicaid (49.3) 2791 (50.0) (40.6) Self-Pay 940 (2.5) 87 (1.6) 6870 (7.9) Medical History, No. (%) AF or atrial flutter 8264 (20.9) 837 (14.5) (14.2) <.0001 Previous Stroke or TIA (32.8) 2831 (49.0) (19.4) <.0001 CAD or myocardial infarction (28.3) 3261 (56.4) 9335 (9.9) <.0001

11 Carotid Stenosis 1099 (2.8) 422 (7.3) 756 (0.8) <.0001 Diabetes Mellitus (34.0) 2468 (42.7) (21.7) <.0001 PVD 1755 (4.4) 552 (9.6) 1868 (2.0) <.0001 Hypertension (83.0) 4904 (84.9) (69.0) <.0001 Smoker 4175 (10.6) 732 (12.7) (14.3) <.0001 Dyslipidemia (49.7) 3365 (58.2) (26.2) <.0001 Heart failure 3970 (10.0) 708 (12.3) 4829 (5.1) <.0001 Drugs or Alcohol Abuse 1986 (5.0) 221 (3.8) (10.7) <.0001 Obesity or overweight 7297 (18.5) 1092 (18.9) (16.5) <.0001 Renal insufficiency 5251 (13.3) 899 (15.6) 8430 (8.8) <.0001 Arrival and admission information, No. (%) EMS arrival (48.1) 2809 (48.6) (45.6) <.0001 Transfer in (35.7) 2215 (38.3) (37.2) Arrived off-hours (52.2) 3080 (53.3) (53.2) NIHSS at presentation, No. (%) a Median (IQR) 8 (2-19) 9 (3-22) 9 (2-20) <.0001 > (19.8) 951 (25.2) (21.3) (16.1) 590 (15.6) (16.9) (14.5) 513 (13.6) 8912 (14.9) < (49.7) 1722 (45.6) (47.0)

12 Preadmission medication, No. (%) Antihypertensive (79.0) 4252 (85.8) (46.4) <.0001 Cholesterol reducer (57.4) 4222 (73.2) (23.6) <.0001 Diabetic medications 8685 (27.7) 1673 (35.5) 9896 (13.3) <.0001 Vital signs b Heart rate, median (IQR), bpm 79 (68-91) 78 (67-91) 82 (70-95) <.0001 Systolic blood pressure, median (IQR), mmhg 160 ( ) 160 ( ) 159 ( ) <.0001 Diastolic blood pressure, median (IQR), mmhg 84 (72-99) 82 (70-96) 88 (74-104) <.0001 Hospital Characteristics Bed size, median (IQR), No. 440 ( ) 457 ( ) 440 ( ) Academic center, No. (%) (72.2) 4090 (71.6) (73.1) Primary Stroke Center, No. (%) (34.3) 1912 (33.1) (35.9) <.0001 Rural hospital, No. (%) 1194 (3.0) 179 (3.1) 2383 (2.5) <.0001 Abbreviations: AP, antiplatelet; IQR, interquartile range; AF, atrial fibrillation; TIA, transient ischemic attack; CAD, coronary artery disease; PVD, peripheral vascular disease; EMS, emergency medical services; NIHSS, National Institute of Health Stroke Scale. a NIHSS at presentation was missing for 51,088 (36.2%). NIHSS ranges from 0 to 42 and a higher score indicates greater stroke severity. b Vital signs indicate first values on admission

13 etable 5. Direct Comparison of In-hospital Mortality Between NOACs and Warfarin Stratified by Number of Antiplatelet Agents Number of antiplatelet Warfarin NOACs Interaction p-value In-hospital mortality rates 3101/9777 (31.7) 873/3307 (26.4) No antiplatelet Adjusted OR a (97.5% CI) Reference 0.77 ( ) b Adjusted RD a (97.5% CI) Reference -5.0 (-6.8, -3.2) In-hospital mortality rates 1615/4862 (33.2) 395/1498 (26.4) Single antiplatelet Adjusted OR a (97.5% CI) Reference 0.70 ( ) c Adjusted RD a (97.5% CI) Reference -7.0 (-10.0, -4.1) In-hospital mortality rates 187/397 (47.1) 37/113 (32.7) Dual antiplatelet Adjusted OR a (97.5% CI) Reference 0.50 ( ) NA Adjusted RD a (97.5% CI) Reference (-26.3, -3.8) Abbreviations: NOAC, non-vitamin K antagonist oral anticoagulants; OR, odds ratio; CI, confidence interval; RD, risk difference; NA, not applicable. a Adjusting for patient and hospital characteristics as follows: Demographics (age, sex, race-ethnicity [black, Hispanic, Asian and others vs. white]), insurance (Medicare, Medicaid, private insurance/va/others, vs. no insurance), medical history (atrial fibrillation or flutter, prior coronary artery disease or myocardial infarction, carotid stenosis, diabetes, peripheral vascular disease, hypertension, smoking, dyslipidemia, prior stroke or transient ischemic attack, heart failure, drug or alcohol abuse, obesity or overweight, renal insufficiency), arrival and admission information (emergency medical services arrival and transfer in [vs. private transportation], arrived off-hours), prior to admission medications (antihypertensive, lipid lowering, diabetic agents), hospital characteristics (rural vs. urban setting, number of beds, teaching hospital, regions, certified primary stroke center). b Interaction for NOACs (vs. warfarin)*no antiplatelet (vs. dual antiplatelet) c Interaction for NOACs (vs. warfarin)*single antiplatelet (vs. dual antiplatelet)

14 14 etable 6. Outcome Measures by INR Levels in ICH Patients With Preceding Use of Warfarin a Sub-therapeutic Therapeutic Supra-therapeutic Event rates 700/2797 (25.0) 860/2657 (32.4) 635/1675 (37.9) In-hospital Death Adjusted OR b (97.5% CI) 0.75 ( ) Reference 1.34 ( ) Adjusted RD b (97.5% CI), % -5.5 (-8.2, -2.8) Reference 6.2 (2.8, 9.6) Event rates 959/2797 (34.3) 1148/2657 (43.2) 833/1675 (49.7) In-hospital Death or Discharge to Hospice 0.78 ( ) Reference 1.41 ( ) -5.3 (-7.7, -2.9) Reference 7.6 (4.6, 10.6) Event rates 583/1978 (29.5) 438/1710 (25.6) 249/964 (25.8) Able to Ambulate Independently at Discharge c 1.19 ( ) Reference 0.94 ( ) 3.2 (0.5, 6.0) Reference -1.2 (-4.3, 2.0) Event rates 513/2797 (18.3) 393/2657 (14.8) 258/1675 (15.4) Discharge Home 1.15 ( ) Reference 0.94 ( ) 1.8 (-0.2, 3.8) Reference -0.7 (-2.7, 1.3) Event rates 167/1770 (9.4) 136/1746 (7.8) 61/1114 (5.8) Modified Rankin Scale 0-1 d 1.07 ( ) Reference 0.65 ( ) Adjusted RD b (95% CI),% 0.7 (-1.3, 2.6) Reference -2.3 (-4.1, -0.5) Modified Rankin Scale 0-2 d Event rates 243/1770 (13.7) 200/1746 (11.5) 102/1114 (9.2)

15 1.10 ( ) Reference 0.69 ( ) 1.2 (-1.2, 3.5) Reference -2.9 (-5.1, -0.7) Abbreviations: INR, international normalized ratio; ICH, intracerebral hemorrhage; OR, odds ratio; CI, confidence interval; RD, risk difference. a Among 9,777 patients with the preceding use of warfarin who didn t have antiplatelet agents, after excluding 2,648 patients who have missingness for INR, a total of 7,129 patients were analyzed. b Adjusting for patient and hospital characteristics as follows: Demographics (age, sex, race-ethnicity [black, Hispanic, Asian and others vs. white]), insurance (Medicare, Medicaid, private insurance/va/others, vs. no insurance), medical history (atrial fibrillation or flutter, prior coronary artery disease or myocardial infarction, carotid stenosis, diabetes, peripheral vascular disease, hypertension, smoking, dyslipidemia, prior stroke or transient ischemic attack, heart failure, drug or alcohol abuse, obesity or overweight, renal insufficiency), arrival and admission information (emergency medical services arrival and transfer in [vs. private transportation], arrived off-hours), prior to admission medications (antihypertensive, lipid lowering, diabetic agents), hospital characteristics (rural vs. urban setting, number of beds, teaching hospital, regions, certified primary stroke center). c Data were missing for 282 patients (5.7%). d Data were missing for 2499 patients (35.1%). Modified Rankin Scale ranges from 0 to 6, and a higher score indicates worse functional outcome and 6 indicates death. Patients with modified Rankin Scale of 0 or 1 were classified as having excellent recovery, and those with modified Rankin Scale of 0 to 2 were classified as having functional independence. e Sub-therapeutic INR was defined as INR <2, therapeutic INR was defined as INR ranging from 2 to 3, and supra-therapeutic INR was defined as INR >3.