ICD-9) Used in This Study

Home , Apricoxib, Cortivazol, Famotidine, Lafutidine, Lavoltidine, Meprednisone

Supplementary Table 1

Diagnosis codes of International Classification of Diseases, Ninth Revision (ICD-9) used in this study

Diagnoses † ICD-9 codes GIB UGIB 531.0, 531.2, 531.4, 531.6, 532.0, 532.2, 532.4, 532.6, 533.0, 533.2, 533.4, 533.6, 534.0, 534.2, 534.4, 534.6, 535.01, 535.11, 535.21, 535.31, 535.41, 535.51, 535.61, 535.71 LGIB 562.02, 562.03, 562.12, 562.13, 569.3, 569.85, 569.86 Unspecified GIB 578 (578.0, 578.1, 578.9) GIB or peptic ulcer 531, 532, 533, 534, and other codes of GIB Ischemic heart disease 410, 411, 412, 413, 414 Ischemic stroke, transient ischemic attack 433.x1, 434, 435, 436, 437.0, 437.1, 444, or systemic embolism 445 Hypertension 401, 402, 403, 404, 405 Diabetes 250 Renal disease 403, 404, 580, 581, 582, 583, 584, 585, 586, 590.0, 753.1 Intracranial hemorrhage 430, 431, 432 Cirrhosis 571.2, 571.5, 571.6 Gastrointestinal cancer 150, 151, 152, 153, 154 Inflammatory bowel disease 555, 556 Coagulant deficiency 286 Gastroenteritis or colitis due to radiation 558.1 Excision of gastrointestinal tract segment‡ V15.2, V45.89 † For GIB, the primary outcome, only inpatient records are included. For baseline medical condition, it is considered positive when the code is identified once in primary hospitalization diagnosis records or more than three times in outpatient records before the start date of the follow-up period;

‡ Also includes other diagnoses with description that mentioned gastrectomy, esophagectomy, enterotomy or colectomy.

1 Supplementary Table 2

Drug names used when extracting covariates of concurrent medications

Medication Drug name Gastro-protective agents PPI Omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole H2RA Famotidine, ranitidine, cimetidine, lafutidine, lavoltidine, loxtidine, niperotidine, nizatidine, roxatidine Other antiplatelet drugs Clopidogrel, dipyridamole, cilostazol, ticagrelor, ticlopidine, prasugrel, ticlopidine, aggrenox NSAIDs Naproxen, diclofenac, piroxicam, diclofenac, sulindac, ibuprofen, indomethacin, mefenamic, arcoxia, celecoxib, etoricoxib, apricoxib, lumiracoxib, rofecoxib, valdecoxib, parecoxib Anticoagulants Warfarin, dabigatran, rivaroxaban, apixaban, argatroban, efegatran, edoxaban, betrixaban, darexaban, darexaban, eribaxaban Corticosteroids Betamethasone, dexamethasone, fluocortolone, methylprednisolone, paramethasone, prednisolone, prednisone, triamcinolone, hydrocortisone, cortisone, prednylidene, rimexolone, intraarticular, deflazacort, cloprednol, meprednisone, cortivazol SSRI Zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram Bisphosphonate Alendronate, alendronic acid, ibandronate, ibandronic acid, risedronate, risedronic acid, tidronate, etidronic acid, clodronate, clodronic acid, pamidronate, pamidronic acid, tiludronate, tiludronic acid, zoledronate, zoledronic acid PPI, proton pump inhibitors; H2RA, histamine type-2 receptor antagonists; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRI, selective serotonin reuptake inhibitors.

2 Supplementary Table 3

Causes of gastrointestinal bleeding after H. pylori eradication in each group of aspirin users

New users Chronic users Non-users Causes of GIB (ICD-9 codes) (%) (%) (%)

UGIB Gastric ulcer (531.0, 531.2, 531.4, 531.6) 32 (12.3) 43 (14.2) 85 (6.6) Duodenal ulcer (532.0, 532.2, 532.4, 532.6) 23 (8.8) 22 (7.3) 127 (9.8)

Peptic ulcer site unspecified (533.0, 533.2, 2 (0.8) 7 (2.3) 25 (19.3) 533.4, 533.6)

Gastritis and duodenitis (535.01, 535.11,

535.21, 535.31, 535.41, 535.51, 535.61, 9 (3.4) 6 (1.9) 33 (2.5) 535.71)

Other unspecified UGIB (578.0, 578.1, 30 (11.5) 36 (11.9) 166 (12.8) 578.9) † LGIB Diverticula of intestine (562.02, 562.03, 5 (1.9) 4 (1.4) 5 (0.4) 562.12, 562.13) Other disorders of intestine (569.3, 569.85, 27 (10.3) 10 (3.3) 115 (8.9) 569.86)

Other unspecified intestinal bleeding 76 (29.1) 108 (35.6) 492 (38.0) (578.9) †

Unspecified GIB Other unspecified (578.9) 57 (21.8) 67 (22.1) 247 (19.1)

† Determined using diagnosis description and keywords recorded in the database.

3 Supplementary Table 4 The effects of gastroprotective agents on risk of GIB and UGIB in different subgroups

Subgroups HR (95% CI) for all GIB HR (95% CI) for UGIB All aspirin users 0.34 (0.25-0.46) 0.27 (0.19-0.37) New users 0.31 (0.23-0.42) 0.22 (0.14-0.34) Chronic users 0.53 (0.40-0.70) 0.32 (0.21-0.48) Age  60 0.39 (0.31-0.48) 0.28 (0.20-0.38) Age < 60 0.84 (0.43-1.66) 0.25 (0.09-0.72) Male 0.42 (0.32-0.55) 0.36 (0.24-0.53) Female 0.41 (0.30-0.57) 0.17 (0.10-0.28) NSAIDs users 0.28 (0.17-0.47) 0.14 (0.06-0.35) Other antiplatelet drugs 0.51 (0.30-0.87) 0.27 (0.14-0.55) users Anticoagulants users 0.50 (0.09-2.83) 0.27 (0.03-2.58) Corticosteroids 0.50 (0.19-1.30) 0.28 (0.05-1.61) All patients 0.74 (0.65-0.85) 0.51 (0.40-0.65) Non-users 0.93 (0.80-1.07) 0.71 (0.54-0.92)

4 Supplementary Figure 1 The schematic diagram of the study design.

5 Supplementary Figure 2 Flow chart of patient’s selection. (HP, Helicobacter pylori; GI, gastrointestinal; IBD, inflammatory bowel disease)

6 Supplementary Figure 3 Absolute standardized differences for baseline covariates comparing new aspirin users and chronic aspirin users in the original, the matched and weighted sample. IPTW, inverse probability of treatment weighting.

7 Supplementary Figure 4 The individual Schoenfeld test of new aspirin users with chronic aspirin users as the control in multivariate Cox regression mode for GIB. According to the proportional hazards assumption tests, the coefficients of the aspirin status (new users vs. chronic users) were time-dependent in all models of GIB, and in weighting and multivariate models of UGIB. Therefore, the interaction of aspirin usage status and time was introduced into the time-dependent regression models.