J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Original Article

Volume 18, Number 8, August 2026, pages 585-598

Incidence and Predictors of Anticoagulant-Associated Bleeding in Patients With Venous Thromboembolism

↓ Figure 1. Cumulative incidence of clinically relevant bleeding and major bleeding estimated using the Aalen–Johansen method. For CRB, death was treated as a competing event. For MB, CRNMB and death were treated as competing events; therefore, the cumulative incidence represents the probability of experiencing MB as the first bleeding event. Shaded areas represent the 95% confidence intervals. CRB: clinically relevant bleeding; MB: major bleeding; CRNMB: clinically relevant non-major bleeding.

↓ **Table 1.** Baseline Characteristics
Characteristics	Total	Clinically relevant bleeding	No bleeding	P value
^aECOG performance status was available for 270 patients. ^bProcedural bleeding risk was stratified according to ISTH guidance statements. ^cProvoking factors other than cancer-associated thrombosis. ^dHemoglobin levels and platelet counts were available for 366 patients. ^eSerum creatinine was available for 360 patients. BMI: body mass index; NSAID: nonsteroidal anti-inflammatory drug; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; eGFR: estimated glomerular filtration rate; LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; DOAC: direct oral anticoagulant; IQR: interquartile range; ECOG: Eastern Cooperative Oncology Group.
N (%)	395 (100)	60 (15.19)	335 (84.81)
Age, years	60.71 ± 16.22	67.39 ± 15.67	59.52 ± 16.04	0.001
≥ 65, n (%)	159 (40.25)	37 (61.67)	122 (36.42)	< 0.001
Sex, n (%)				1.000
Female	258 (65.32)	39 (65.00)	219 (65.37)
Male	137 (34.68)	21 (35.00)	116 (34.63)
Weight, median (IQR), kg	59.5 (50.1–70.0), n = 353	53 (48–66), n = 51	60 (52–70), n = 302	0.021
Height, median (IQR), cm	160 (155–167), n = 347	160 (155–165.5), n = 52	160 (155–167), n = 295	0.970
BMI, median (IQR), kg/m²	23.44 (20.70–26.16), n = 332	22.21 (19.72–24.80), n = 47	23.61 (20.82–26.35), n = 285	0.021
< 18.5	38 (11.45)	7 (14.89)	31 (10.88)	0.457
< 20	64 (19.28)	15 (31.91)	49 (17.19)	0.027
ECOG^a performance status, n (%)				0.002
0–1	255 (94.44)	32 (82.05)	223 (96.54)
≥ 2	15 (5.56)	7 (17.95)	8 (3.46)
Comorbidity, n (%)
Diabetes mellitus	83 (21.01)	14 (23.33)	69 (20.60)	0.609
Hypertension	140 (35.44)	27 (45.00)	113 (33.73)	0.107
Coronary artery disease	11 (2.78)	4 (6.67)	7 (2.09)	0.069
Cerebrovascular disease	18 (4.56)	7 (11.67)	11 (3.28)	0.011
Chronic liver disease/cirrhosis	9 (2.28)	1 (1.67)	8 (2.39)	1.000
Chronic kidney disease	31 (7.85)	6 (10.00)	25 (7.46)	0.445
Peripheral arterial disease	4 (1.01)	1 (1.67)	3 (0.90)	0.484
Active cancer, n (%)	172 (43.54)	26 (43.33)	146 (43.58)	1.000
Solid malignancy	159 (92.44)	24 (92.31)	135 (92.47)
Hematologic malignancy	13 (7.56)	2 (7.69)	11 (7.53)
Alcohol use, n (%)	5 (1.37)	2 (3.33)	3 (0.90)	0.167
Medication, n (%)
Antiplatelet				0.002
Aspirin (ASA)	21 (5.32)	8 (13.33)	13 (3.88)
Clopidogrel	3 (0.76)	1 (1.67)	2 (0.60)
Dual antiplatelets	7 (1.77)	3 (5.00)	4 (1.19)
NSAIDs	2 (0.51)	1 (1.67)	1 (0.30)	0.281
Oral contraceptives or hormone therapy, n (%)	8 (2.03)	0 (0.00)	8 (2.39)	0.613
Estrogen	1 (0.25)	0 (0.00)	1 (0.30)
Progestin	0 (0.00)	0 (0.00)	0 (0.00)
Estrogen and progestin	5 (1.26)	0 (0.00)	5 (1.49)
Androgen	0 (0.00)	0 (0.00)	0 (0.00)
Unknown	2 (0.51)	0 (0.00)	2 (0.60)
History of surgery within 3 months before initiation of anticoagulation, n (%)	59 (14.94)	8 (13.33)	51 (15.22)	0.845
Bleeding risk of procedure^b, n (%)				0.407
Low to moderate bleeding risk	44 (74.58)	5 (62.50)	39 (76.47)
High bleeding risk	15 (25.42)	3 (37.50)	12 (23.53)
History of bleeding within 3 months before initiation of anticoagulation, n (%)				0.082
Clinically relevant non-major bleeding	8 (2.03)	1 (1.67)	7 (2.09)
Major bleeding	6 (1.52)	3 (5.00)	3 (0.90)
Type of VTE, n (%)				0.106
DVT	146 (36.96)	22 (36.67)	124 (37.01)
PE	191 (48.35)	24 (40.00)	167 (49.85)
Both DVT and PE	58 (14.68)	14 (23.33)	44 (13.13)
VTE classification, n (%)				0.966
Unprovoked	143 (36.20)	21 (35.00)	122 (36.42)
Provoked^c	80 (20.25)	13 (21.67)	67 (20.00)
Cancer-associated thrombosis (CAT)	172 (43.54)	26 (43.33)	146 (43.58)
Thrombophilia workup, n (%)				1.000
Normal/negative	145 (36.71)	22 (36.67)	123 (36.72)
Protein C deficiency	1 (0.25)	0 (0.00)	1 (0.30)
Antithrombin deficiency	1 (0.25)	0 (0.00)	1 (0.30)
Antiphospholipid syndrome (APS)	14 (3.54)	2 (3.33)	12 (3.58)
No workup	234 (59.24)	36 (60.00)	198 (59.10)
Anticoagulants, n (%)
Individual agents				0.071
Warfarin	129 (32.66)	19 (31.67)	110 (32.84)
UFH	13 (3.29)	3 (5.00)	10 (2.99)
LMWH	154 (38.99)	25 (41.67)	129 (38.51)
Apixaban	50 (12.66)	3 (5.00)	47 (14.03)
Rivaroxaban	28 (7.09)	3 (5.00)	25 (7.46)
Edoxaban	17 (4.30)	5 (8.33)	12 (3.58)
Dabigatran	4 (1.01)	2 (3.33)	2 (0.60)
Type of anticoagulant				0.628
DOACs	99 (25.06)	13 (21.67)	86 (25.67)
Non-DOACs	296 (74.94)	47 (78.33)	249 (74.33)
Laboratory at VTE diagnosis
Hb^d, g/dL	11.05 ± 2.18	10.57 ± 2.14	11.14 ± 2.18	0.067
Anemia, n (%)	253 (69.13)	45 (77.59)	208 (67.53)	0.163
< 10, n (%)	117 (31.97)	24 (41.38)	93 (30.19)	0.124
Platelets^d, median (IQR), /µL	250,500 (187,000–334,000)	240,500 (175,000–369,000)	252,500 (189,500–328,000)	0.921
Creatinine^e, median (IQR), mg/dL	0.78 (0.61–1.04)	0.79 (0.6–1.1)	0.77 (0.61–1)	0.396
eGFR^e, median (IQR), mL/min/1.73 m²	92.28 (66.85–105.42)	80.77 (55.10–98.20)	93.56 (71.18–106.08)	0.010
≥ 30, n (%)	341 (94.72)	53 (91.38)	288 (95.36)
≥ 15 to < 30, n (%)	16 (4.44)	4 (6.90)	12 (3.97)
< 15, n (%)	3 (0.83)	1 (1.72)	2 (0.66)

↓ Table 1. Baseline Characteristics

Characteristics

Total

Clinically relevant bleeding

No bleeding

P value

^aECOG performance status was available for 270 patients. ^bProcedural bleeding risk was stratified according to ISTH guidance statements. ^cProvoking factors other than cancer-associated thrombosis. ^dHemoglobin levels and platelet counts were available for 366 patients. ^eSerum creatinine was available for 360 patients. BMI: body mass index; NSAID: nonsteroidal anti-inflammatory drug; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; eGFR: estimated glomerular filtration rate; LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; DOAC: direct oral anticoagulant; IQR: interquartile range; ECOG: Eastern Cooperative Oncology Group.

N (%)

395 (100)

60 (15.19)

335 (84.81)

Age, years

60.71 ± 16.22

67.39 ± 15.67

59.52 ± 16.04

0.001

≥ 65, n (%)

159 (40.25)

37 (61.67)

122 (36.42)

< 0.001

Sex, n (%)

1.000

Female

258 (65.32)

39 (65.00)

219 (65.37)

Male

137 (34.68)

21 (35.00)

116 (34.63)

Weight, median (IQR), kg

59.5 (50.1–70.0), n = 353

53 (48–66), n = 51

60 (52–70), n = 302

0.021

Height, median (IQR), cm

160 (155–167), n = 347

160 (155–165.5), n = 52

160 (155–167), n = 295

0.970

BMI, median (IQR), kg/m²

23.44 (20.70–26.16), n = 332

22.21 (19.72–24.80), n = 47

23.61 (20.82–26.35), n = 285

0.021

< 18.5

38 (11.45)

7 (14.89)

31 (10.88)

0.457

< 20

64 (19.28)

15 (31.91)

49 (17.19)

0.027

ECOG^a performance status, n (%)

0.002

0–1

255 (94.44)

32 (82.05)

223 (96.54)

≥ 2

15 (5.56)

7 (17.95)

8 (3.46)

Comorbidity, n (%)

Diabetes mellitus

83 (21.01)

14 (23.33)

69 (20.60)

0.609

Hypertension

140 (35.44)

27 (45.00)

113 (33.73)

0.107

Coronary artery disease

11 (2.78)

4 (6.67)

7 (2.09)

0.069

Cerebrovascular disease

18 (4.56)

7 (11.67)

11 (3.28)

0.011

Chronic liver disease/cirrhosis

9 (2.28)

1 (1.67)

8 (2.39)

1.000

Chronic kidney disease

31 (7.85)

6 (10.00)

25 (7.46)

0.445

Peripheral arterial disease

4 (1.01)

1 (1.67)

3 (0.90)

0.484

Active cancer, n (%)

172 (43.54)

26 (43.33)

146 (43.58)

1.000

Solid malignancy

159 (92.44)

24 (92.31)

135 (92.47)

Hematologic malignancy

13 (7.56)

2 (7.69)

11 (7.53)

Alcohol use, n (%)

5 (1.37)

2 (3.33)

3 (0.90)

0.167

Medication, n (%)

Antiplatelet

0.002

Aspirin (ASA)

21 (5.32)

8 (13.33)

13 (3.88)

Clopidogrel

3 (0.76)

1 (1.67)

2 (0.60)

Dual antiplatelets

7 (1.77)

3 (5.00)

4 (1.19)

NSAIDs

2 (0.51)

1 (1.67)

1 (0.30)

0.281

Oral contraceptives or hormone therapy, n (%)

8 (2.03)

0 (0.00)

8 (2.39)

0.613

Estrogen

1 (0.25)

0 (0.00)

1 (0.30)

Progestin

0 (0.00)

Estrogen and progestin

5 (1.26)

0 (0.00)

5 (1.49)

Androgen

0 (0.00)

Unknown

2 (0.51)

0 (0.00)

2 (0.60)

History of surgery within 3 months before initiation of anticoagulation, n (%)

59 (14.94)

8 (13.33)

51 (15.22)

0.845

Bleeding risk of procedure^b, n (%)

0.407

Low to moderate bleeding risk

44 (74.58)

5 (62.50)

39 (76.47)

High bleeding risk

15 (25.42)

3 (37.50)

12 (23.53)

History of bleeding within 3 months before initiation of anticoagulation, n (%)

0.082

Clinically relevant non-major bleeding

8 (2.03)

1 (1.67)

7 (2.09)

Major bleeding

6 (1.52)

3 (5.00)

3 (0.90)

Type of VTE, n (%)

0.106

DVT

146 (36.96)

22 (36.67)

124 (37.01)

191 (48.35)

24 (40.00)

167 (49.85)

Both DVT and PE

58 (14.68)

14 (23.33)

44 (13.13)

VTE classification, n (%)

0.966

Unprovoked

143 (36.20)

21 (35.00)

122 (36.42)

Provoked^c

80 (20.25)

13 (21.67)

67 (20.00)

Cancer-associated thrombosis (CAT)

172 (43.54)

26 (43.33)

146 (43.58)

Thrombophilia workup, n (%)

1.000

Normal/negative

145 (36.71)

22 (36.67)

123 (36.72)

Protein C deficiency

1 (0.25)

0 (0.00)

1 (0.30)

Antithrombin deficiency

1 (0.25)

0 (0.00)

1 (0.30)

Antiphospholipid syndrome (APS)

14 (3.54)

2 (3.33)

12 (3.58)

No workup

234 (59.24)

36 (60.00)

198 (59.10)

Anticoagulants, n (%)

Individual agents

0.071

Warfarin

129 (32.66)

19 (31.67)

110 (32.84)

UFH

13 (3.29)

3 (5.00)

10 (2.99)

LMWH

154 (38.99)

25 (41.67)

129 (38.51)

Apixaban

50 (12.66)

3 (5.00)

47 (14.03)

Rivaroxaban

28 (7.09)

3 (5.00)

25 (7.46)

Edoxaban

17 (4.30)

5 (8.33)

12 (3.58)

Dabigatran

4 (1.01)

2 (3.33)

2 (0.60)

Type of anticoagulant

0.628

DOACs

99 (25.06)

13 (21.67)

86 (25.67)

Non-DOACs

296 (74.94)

47 (78.33)

249 (74.33)

Laboratory at VTE diagnosis

Hb^d, g/dL

11.05 ± 2.18

10.57 ± 2.14

11.14 ± 2.18

0.067

Anemia, n (%)

253 (69.13)

45 (77.59)

208 (67.53)

0.163

< 10, n (%)

117 (31.97)

24 (41.38)

93 (30.19)

0.124

Platelets^d, median (IQR), /µL

250,500 (187,000–334,000)

240,500 (175,000–369,000)

252,500 (189,500–328,000)

0.921

Creatinine^e, median (IQR), mg/dL

0.78 (0.61–1.04)

0.79 (0.6–1.1)

0.77 (0.61–1)

0.396

eGFR^e, median (IQR), mL/min/1.73 m²

92.28 (66.85–105.42)

80.77 (55.10–98.20)

93.56 (71.18–106.08)

0.010

≥ 30, n (%)

341 (94.72)

53 (91.38)

288 (95.36)

≥ 15 to < 30, n (%)

16 (4.44)

4 (6.90)

12 (3.97)

< 15, n (%)

3 (0.83)

1 (1.72)

2 (0.66)

↓ **Table 2.** Doses of Anticoagulants Used in the Study Population
Anticoagulants	Total	Clinically relevant bleeding	No bleeding	P value
^aTTR (%) was calculated using the traditional (direct) method based on the proportion of INR values within the therapeutic range for up to 1 year after warfarin initiation. LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; DOAC: direct oral anticoagulant; TTR: time in therapeutic range.
N (%)	395 (100)	60 (15.19)	335 (84.81)
Warfarin, n (%)	129 (32.66)	19 (31.67)	110 (32.84)
TTR^a, median (IQR), %	30.0 (16.8–50.0), n = 100	36.8 (5.0–60.0), n = 15	28.0 (19.0–50.0), n = 85	0.831
UFH, n (%)	13 (3.29)	3 (5.00)	10 (2.99)
LMWH, n (%)	154 (38.99)	25 (41.67)	129 (38.51)
Therapeutic dose	150 (37.97)	25 (41.67)	125 (37.31)
Intermediate dose	2 (0.51)	0 (0.00)	2 (0.6)
Prophylaxis dose (e.g., enoxaparin 40 mg daily)	2 (0.51)	0 (0.00)	2 (0.6)
DOACs, n (%)	99 (25.06)	13 (21.67)	86 (25.67)
Dabigatran 110 mg twice daily	2 (0.51)	1 (1.67)	1 (0.30)
Dabigatran 150 mg twice daily	2 (0.51)	1 (1.67)	1 (0.30)
Apixaban 2.5 mg twice daily	15 (3.80)	0 (0.00)	15 (4.48)
Apixaban 5 mg twice daily	34 (8.61)	3 (5.00)	31 (9.25)
Apixaban 10 mg twice daily	1 (0.25)	0 (0.00)	1 (0.30)
Rivaroxaban 20 mg once daily	19 (4.81)	1 (1.67)	18 (5.37)
Rivaroxaban 15 mg twice daily	3 (0.76)	1 (1.67)	2 (0.60)
Rivaroxaban 10 mg once daily	6 (1.52)	1 (1.67)	5 (1.49)
Edoxaban 60 mg once daily	12 (3.04)	3 (5.00)	9 (2.69)
Edoxaban 30 mg once daily	5 (1.27)	2 (3.33)	3 (0.90)

↓ Table 2. Doses of Anticoagulants Used in the Study Population

Anticoagulants

Total

Clinically relevant bleeding

No bleeding

P value

^aTTR (%) was calculated using the traditional (direct) method based on the proportion of INR values within the therapeutic range for up to 1 year after warfarin initiation. LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; DOAC: direct oral anticoagulant; TTR: time in therapeutic range.

N (%)

395 (100)

60 (15.19)

335 (84.81)

Warfarin, n (%)

129 (32.66)

19 (31.67)

110 (32.84)

TTR^a, median (IQR), %

30.0 (16.8–50.0), n = 100

36.8 (5.0–60.0), n = 15

28.0 (19.0–50.0), n = 85

0.831

UFH, n (%)

13 (3.29)

3 (5.00)

10 (2.99)

LMWH, n (%)

154 (38.99)

25 (41.67)

129 (38.51)

Therapeutic dose

150 (37.97)

25 (41.67)

125 (37.31)

Intermediate dose

2 (0.51)

0 (0.00)

2 (0.6)

Prophylaxis dose (e.g., enoxaparin 40 mg daily)

2 (0.51)

0 (0.00)

2 (0.6)

DOACs, n (%)

99 (25.06)

13 (21.67)

86 (25.67)

Dabigatran 110 mg twice daily

2 (0.51)

1 (1.67)

1 (0.30)

Dabigatran 150 mg twice daily

2 (0.51)

1 (1.67)

1 (0.30)

Apixaban 2.5 mg twice daily

15 (3.80)

0 (0.00)

15 (4.48)

Apixaban 5 mg twice daily

34 (8.61)

3 (5.00)

31 (9.25)

Apixaban 10 mg twice daily

1 (0.25)

0 (0.00)

1 (0.30)

Rivaroxaban 20 mg once daily

19 (4.81)

1 (1.67)

18 (5.37)

Rivaroxaban 15 mg twice daily

3 (0.76)

1 (1.67)

2 (0.60)

Rivaroxaban 10 mg once daily

6 (1.52)

1 (1.67)

5 (1.49)

Edoxaban 60 mg once daily

12 (3.04)

3 (5.00)

9 (2.69)

Edoxaban 30 mg once daily

5 (1.27)

2 (3.33)

3 (0.90)

↓ **Table 3.** Baseline Characteristics of Patients With Active Cancer According to Clinically Relevant Bleeding Status
Primary cancer site	Total (N = 172)	Clinically relevant bleeding (N = 26)	No bleeding (N = 146)
^aBladder, renal cell carcinoma, and prostate cancer. ^bDiffuse large B-cell lymphoma, follicular lymphoma, extranodal marginal zone lymphoma, primary mediastinal B-cell lymphoma, and small lymphocytic lymphoma. ^cPrimary brain tumors and central nervous system germinoma. ^dSynchronous cecal and ovarian cancers.
Gynecological	47 (27.33)	11 (42.31)	36 (24.66)
Lung	34 (19.77)	4 (15.38)	30 (20.55)
Urological^a	17 (9.88)	2 (7.69)	15 (10.27)
Colorectal	14 (8.14)	1 (3.85)	13 (8.90)
Breast	11 (6.40)	2 (7.69)	9 (6.16)
Lymphoma^b	11 (6.40)	1 (3.85)	10 (6.85)
Cholangiocarcinoma	6 (3.49)	1 (3.85)	5 (3.42)
Pancreatic	6 (3.49)	0 (0.00)	6 (4.11)
Central nervous system^c	4 (2.33)	1 (3.85)	3 (2.05)
Gastric	3 (1.74)	0 (0.00)	3 (2.05)
Head and neck	3 (1.74)	2 (7.69)	1 (0.68)
Thyroid	3 (1.74)	0 (0.00)	3 (2.05)
Hepatocellular	3 (1.74)	0 (0.00)	3 (2.05)
Multiple myeloma	2 (1.16)	1 (3.85)	1 (0.68)
Bone and soft tissue sarcoma	2 (1.16)	0 (0.00)	2 (1.37)
Esophageal	1 (0.58)	0 (0.00)	1 (0.68)
Germ cell	1 (0.58)	0 (0.00)	1 (0.68)
Gallbladder	1 (0.58)	0 (0.00)	1 (0.68)
Two primary cancers^d	1 (0.58)	0 (0.00)	1 (0.68)
Primary peritoneal cancer	1 (0.58)	0 (0.00)	1 (0.68)
Unknown primary	1 (0.58)	0 (0.00)	1 (0.68)

↓ Table 3. Baseline Characteristics of Patients With Active Cancer According to Clinically Relevant Bleeding Status

Primary cancer site

Total (N = 172)

Clinically relevant bleeding (N = 26)

No bleeding (N = 146)

^aBladder, renal cell carcinoma, and prostate cancer. ^bDiffuse large B-cell lymphoma, follicular lymphoma, extranodal marginal zone lymphoma, primary mediastinal B-cell lymphoma, and small lymphocytic lymphoma. ^cPrimary brain tumors and central nervous system germinoma. ^dSynchronous cecal and ovarian cancers.

Gynecological

47 (27.33)

11 (42.31)

36 (24.66)

Lung

34 (19.77)

4 (15.38)

30 (20.55)

Urological^a

17 (9.88)

2 (7.69)

15 (10.27)

Colorectal

14 (8.14)

1 (3.85)

13 (8.90)

Breast

11 (6.40)

2 (7.69)

9 (6.16)

Lymphoma^b

11 (6.40)

1 (3.85)

10 (6.85)

Cholangiocarcinoma

6 (3.49)

1 (3.85)

5 (3.42)

Pancreatic

6 (3.49)

0 (0.00)

6 (4.11)

Central nervous system^c

4 (2.33)

1 (3.85)

3 (2.05)

Gastric

3 (1.74)

0 (0.00)

3 (2.05)

Head and neck

3 (1.74)

2 (7.69)

1 (0.68)

Thyroid

3 (1.74)

0 (0.00)

3 (2.05)

Hepatocellular

3 (1.74)

0 (0.00)

3 (2.05)

Multiple myeloma

2 (1.16)

1 (3.85)

1 (0.68)

Bone and soft tissue sarcoma

2 (1.16)

0 (0.00)

2 (1.37)

Esophageal

1 (0.58)

0 (0.00)

1 (0.68)

Germ cell

1 (0.58)

0 (0.00)

1 (0.68)

Gallbladder

1 (0.58)

0 (0.00)

1 (0.68)

Two primary cancers^d

1 (0.58)

0 (0.00)

1 (0.68)

Primary peritoneal cancer

1 (0.58)

0 (0.00)

1 (0.68)

Unknown primary

1 (0.58)

0 (0.00)

1 (0.68)

↓ **Table 4.** Clinical Characteristics of Patients With Clinically Relevant Bleeding
Characteristics	Total bleeding (N = 60)	Major bleeding (N = 32)	Clinically relevant non-major bleeding (N = 28)	P value
^aPatients may have experienced bleeding at multiple sites. Percentages are calculated based on the total number of patients in each group, and the sum of patients by site may exceed the total N in each category. ^bPercentages were calculated using the number of patients in each column as the denominator. INR: international normalized ratio; IQR: interquartile range.
Time to first bleeding event, median (IQR), months	1.95 (0.33–10.46)	0.59 (0.16–4.88)	5.98 (1.20–13.32)	0.018
INR at bleeding event in warfarin users, median (IQR)	2.66 (1.97–5.31), n = 17	3.45 (2.11–5.31), n = 9	2.33 (1.57–4.30), n = 8	0.370
Site of bleeding^a, n (%)
Upper gastrointestinal	16 (26.67)	10 (31.25)	6 (21.43)	0.559
Lower gastrointestinal	9 (15.00)	5 (15.63)	4 (14.29)	1.000
Central nervous system	6 (10.00)	6 (18.75)	0 (0.00)	0.026
Musculoskeletal/skin	16 (26.67)	7 (21.88)	9 (32.14)	0.397
Respiratory	2 (3.33)	1 (3.13)	1 (3.57)	1.000
Genitourinary	7 (11.67)	3 (9.38)	4 (14.29)	0.695
Other	5 (8.33)	1 (3.13)	4 (14.29)	0.175
Outpatient bleeding, n (%)	40 (66.67)	19 (59.38)	21 (75.00)	0.274
Bleeding requiring hospital admission, n (%)	24 (60.00)	18 (94.74)	6 (28.57)	< 0.001
All-cause mortality, n (%)	18 (30.00)	12 (37.50)	6 (21.43)	0.259
Bleeding-related mortality^b, n (%)	1 (5.56)	1 (8.33)	0 (0.00)

↓ Table 4. Clinical Characteristics of Patients With Clinically Relevant Bleeding

Characteristics

Total bleeding (N = 60)

Major bleeding (N = 32)

Clinically relevant non-major bleeding (N = 28)

P value

^aPatients may have experienced bleeding at multiple sites. Percentages are calculated based on the total number of patients in each group, and the sum of patients by site may exceed the total N in each category. ^bPercentages were calculated using the number of patients in each column as the denominator. INR: international normalized ratio; IQR: interquartile range.

Time to first bleeding event, median (IQR), months

1.95 (0.33–10.46)

0.59 (0.16–4.88)

5.98 (1.20–13.32)

0.018

INR at bleeding event in warfarin users, median (IQR)

2.66 (1.97–5.31), n = 17

3.45 (2.11–5.31), n = 9

2.33 (1.57–4.30), n = 8

0.370

Site of bleeding^a, n (%)

Upper gastrointestinal

16 (26.67)

10 (31.25)

6 (21.43)

0.559

Lower gastrointestinal

9 (15.00)

5 (15.63)

4 (14.29)

1.000

Central nervous system

6 (10.00)

6 (18.75)

0 (0.00)

0.026

Musculoskeletal/skin

16 (26.67)

7 (21.88)

9 (32.14)

0.397

Respiratory

2 (3.33)

1 (3.13)

1 (3.57)

1.000

Genitourinary

7 (11.67)

3 (9.38)

4 (14.29)

0.695

Other

5 (8.33)

1 (3.13)

4 (14.29)

0.175

Outpatient bleeding, n (%)

40 (66.67)

19 (59.38)

21 (75.00)

0.274

Bleeding requiring hospital admission, n (%)

24 (60.00)

18 (94.74)

6 (28.57)

< 0.001

All-cause mortality, n (%)

18 (30.00)

12 (37.50)

6 (21.43)

0.259

Bleeding-related mortality^b, n (%)

1 (5.56)

1 (8.33)

0 (0.00)

↓ **Table 5.** Univariable and Multivariable Competing Risk Regression Analysis of Clinically Relevant Bleeding
Predictor	Univariable model	Multivariable model^c
^aMissing data were handled via MICE; pooled estimates were calculated using Rubin’s rules. ^bPrior clinically relevant bleeding within 3 months before anticoagulation initiation. ^cMultivariable Fine–Gray subdistribution hazard model adjusted for age ≥ 65 years, BMI < 20 kg/m², ECOG performance status ≥ 2, antiplatelet use, and non-DOAC therapy. BMI: body mass index; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; DOAC: direct oral anticoagulant; ECOG: Eastern Cooperative Oncology Group; SHR: sub-distribution hazard ratio; CI: confidence interval.
Age ≥ 65 years	2.51 (1.50–4.20)	< 0.001	1.97 (1.12–3.45)	0.018
Male	1.03 (0.60–1.74)	0.926
BMI^a < 20 kg/m²	2.20 (1.25–3.88)	0.007	2.50 (1.36–4.61)	0.003
ECOG^a ≥ 2	3.86 (1.80–8.28)	0.001	3.05 (1.34–6.94)	0.008
Diabetes mellitus	1.11 (0.61–2.00)	0.738
Hypertension	1.50 (0.90–2.49)	0.116
Coronary artery disease	2.92 (0.99–8.63)	0.052
Cerebrovascular disease	2.92 (1.44–5.92)	0.003
Chronic liver disease/cirrhosis	0.76 (0.11–5.07)	0.778
Chronic kidney disease	1.30 (0.59–2.88)	0.513
Peripheral arterial disease	1.25 (0.19–8.26)	0.817
Active cancer	1.15 (0.69–1.92)	0.589
Antiplatelet use	3.54 (1.95–6.43)	< 0.001	3.48 (1.76–6.90)	< 0.001
History of previous bleeding^b	1.58 (0.61–4.08)	0.347
Non-DOAC therapy	1.54 (0.84–2.82)	0.163	1.79 (0.98–3.26)	0.057
Hb^a < 10 g/dL	1.71 (1.03–2.87)	0.040
Type of VTE
DVT	Reference	-
PE	0.90 (0.51–1.58)	0.709
Both DVT and PE	1.76 (0.90–3.44)	0.099

↓ Table 5. Univariable and Multivariable Competing Risk Regression Analysis of Clinically Relevant Bleeding

Predictor

Univariable model

Multivariable model^c

Crude SHR (95% CI)

P value

Adjusted SHR (95% CI)

P value

^aMissing data were handled via MICE; pooled estimates were calculated using Rubin’s rules. ^bPrior clinically relevant bleeding within 3 months before anticoagulation initiation. ^cMultivariable Fine–Gray subdistribution hazard model adjusted for age ≥ 65 years, BMI < 20 kg/m², ECOG performance status ≥ 2, antiplatelet use, and non-DOAC therapy. BMI: body mass index; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; DOAC: direct oral anticoagulant; ECOG: Eastern Cooperative Oncology Group; SHR: sub-distribution hazard ratio; CI: confidence interval.

Age ≥ 65 years

2.51 (1.50–4.20)

< 0.001

1.97 (1.12–3.45)

0.018

Male

1.03 (0.60–1.74)

0.926

BMI^a < 20 kg/m²

2.20 (1.25–3.88)

0.007

2.50 (1.36–4.61)

0.003

ECOG^a ≥ 2

3.86 (1.80–8.28)

0.001

3.05 (1.34–6.94)

0.008

Diabetes mellitus

1.11 (0.61–2.00)

0.738

Hypertension

1.50 (0.90–2.49)

0.116

Coronary artery disease

2.92 (0.99–8.63)

0.052

Cerebrovascular disease

2.92 (1.44–5.92)

0.003

Chronic liver disease/cirrhosis

0.76 (0.11–5.07)

0.778

Chronic kidney disease

1.30 (0.59–2.88)

0.513

Peripheral arterial disease

1.25 (0.19–8.26)

0.817

Active cancer

1.15 (0.69–1.92)

0.589

Antiplatelet use

3.54 (1.95–6.43)

< 0.001

3.48 (1.76–6.90)

< 0.001

History of previous bleeding^b

1.58 (0.61–4.08)

0.347

Non-DOAC therapy

1.54 (0.84–2.82)

0.163

1.79 (0.98–3.26)

0.057

Hb^a < 10 g/dL

1.71 (1.03–2.87)

0.040

Type of VTE

DVT

Reference

0.90 (0.51–1.58)

0.709

Both DVT and PE

1.76 (0.90–3.44)

0.099

↓ **Table 6.** Univariable and Multivariable Time-Dependent Cox Regression Analysis of All-Cause Mortality
Variable	Univariable model	Multivariable model^c
^aMissing data were handled via MICE; pooled estimates were calculated using Rubin’s rules. ^bPrior clinically relevant bleeding within 3 months before anticoagulation initiation. ^cMultivariable time-dependent Cox proportional hazards model adjusted for time-dependent bleeding status (CRNMB and major bleeding), age ≥ 65 years, chronic kidney disease, active cancer, non-DOAC therapy, and type of VTE. CRNMB: clinically relevant non-major bleeding; BMI: body mass index; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; DOAC: direct oral anticoagulant; ECOG: Eastern Cooperative Oncology Group; CI: confidence interval.
Bleeding status (time-dependent)
No bleeding	1.00 (Reference)	-	1.00 (Reference)	-
After CRNMB	4.38 (1.86–10.30)	0.001	3.72 (1.55–8.92)	0.003
After major bleeding	5.87 (3.13–11.00)	< 0.001	5.62 (2.91–10.85)	< 0.001
Age ≥ 65 years	1.50 (0.97–2.33)	0.066	1.52 (0.96–2.43)	0.075
Male	0.92 (0.58–1.46)	0.723
BMI^a < 20 kg/m²	1.58 (0.91–2.74)	0.107
ECOG^a ≥ 2	1.51 (0.58–3.95)	0.402
Diabetes mellitus	1.15 (0.69–1.91)	0.588
Hypertension	1.16 (0.74–1.81)	0.515
Coronary artery disease	1.80 (0.66–4.91)	0.254
Cerebrovascular disease	1.69 (0.74–3.88)	0.216
Chronic liver disease/cirrhosis	1.78 (0.56–5.65)	0.327
Chronic kidney disease	1.74 (0.90–3.37)	0.102	1.71 (0.85–3.42)	0.131
Peripheral arterial disease	1.02 (0.14–7.31)	0.987
Active cancer	3.06 (1.93–4.86)	< 0.001	2.93 (1.83–4.68)	< 0.001
Antiplatelet use	1.21 (0.58–2.52)	0.605
History of previous bleeding^b	1.03 (0.33–3.28)	0.954
Non-DOAC therapy	3.10 (1.60–6.03)	0.001	2.76 (1.41–5.38)	0.003
Hb^a < 10 g/dL	1.87 (1.20–2.93)	0.006
Type of VTE
DVT	1.00 (Reference)	-	1.00 (Reference)	-
PE	2.48 (1.48–4.16)	0.001	2.16 (1.28–3.66)	0.004
Both DVT and PE	1.38 (0.65–2.96)	0.403	1.08 (0.49–2.37)	0.844

↓ Table 6. Univariable and Multivariable Time-Dependent Cox Regression Analysis of All-Cause Mortality

Variable

Univariable model

Multivariable model^c

Hazard ratio (95% CI)

P value

Adjusted hazard ratio (95% CI)

P value

^aMissing data were handled via MICE; pooled estimates were calculated using Rubin’s rules. ^bPrior clinically relevant bleeding within 3 months before anticoagulation initiation. ^cMultivariable time-dependent Cox proportional hazards model adjusted for time-dependent bleeding status (CRNMB and major bleeding), age ≥ 65 years, chronic kidney disease, active cancer, non-DOAC therapy, and type of VTE. CRNMB: clinically relevant non-major bleeding; BMI: body mass index; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; Hb: hemoglobin; DOAC: direct oral anticoagulant; ECOG: Eastern Cooperative Oncology Group; CI: confidence interval.

Bleeding status (time-dependent)

No bleeding

1.00 (Reference)

After CRNMB

4.38 (1.86–10.30)

0.001

3.72 (1.55–8.92)

0.003

After major bleeding

5.87 (3.13–11.00)

< 0.001

5.62 (2.91–10.85)

< 0.001

Age ≥ 65 years

1.50 (0.97–2.33)

0.066

1.52 (0.96–2.43)

0.075

Male

0.92 (0.58–1.46)

0.723

BMI^a < 20 kg/m²

1.58 (0.91–2.74)

0.107

ECOG^a ≥ 2

1.51 (0.58–3.95)

0.402

Diabetes mellitus

1.15 (0.69–1.91)

0.588

Hypertension

1.16 (0.74–1.81)

0.515

Coronary artery disease

1.80 (0.66–4.91)

0.254

Cerebrovascular disease

1.69 (0.74–3.88)

0.216

Chronic liver disease/cirrhosis

1.78 (0.56–5.65)

0.327

Chronic kidney disease

1.74 (0.90–3.37)

0.102

1.71 (0.85–3.42)

0.131

Peripheral arterial disease

1.02 (0.14–7.31)

0.987

Active cancer

3.06 (1.93–4.86)

< 0.001

2.93 (1.83–4.68)

< 0.001

Antiplatelet use

1.21 (0.58–2.52)

0.605

History of previous bleeding^b

1.03 (0.33–3.28)

0.954

Non-DOAC therapy

3.10 (1.60–6.03)

0.001

2.76 (1.41–5.38)

0.003

Hb^a < 10 g/dL

1.87 (1.20–2.93)

0.006

Type of VTE

DVT

1.00 (Reference)

2.48 (1.48–4.16)

0.001

2.16 (1.28–3.66)

0.004

Both DVT and PE

1.38 (0.65–2.96)

0.403

1.08 (0.49–2.37)

0.844