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499
Legends for Figures
500
Figure 1. (A) Kaplan-Meier plot of cumulative incidence rate of major and clinically
501
relevant non-major bleeding (n = 27). (B) Kaplan-Meier plot of cumulative incidence
502
rate of major bleeding (n = 27).
503
504
Figure 2. Kaplan-Meier plot for overall survival (n = 27).
32
Table 1. Patient characteristics (n = 27)
Baseline characteristics
Median age (range, years)
n = 27
71 (38-82)
Female
14 (52%)
Eastern Cooperative Oncology Group Performance Status (0/1/2)
9/13/5
Median body weight (range, kg)
51.3 (40.0-90.7)
Median hemoglobin (range, g/dl)
11.4 (7.8-16.2)
Median platelets (range, K/µl)
206 (50-501)
Median prothrombin time-international normalized ratio (range)
1.00 (0.84-1.34)
Median D-dimer (range, µg/dl)
3.4 (0.8-19.4)
Median serum creatinine (range, mg/dl)
0.71 (0.32-1.25)
Primary site (gastrointestinal/lung/breast/genitourinary/pancreas/hematologic malignancy/other)
7/5/4/4/3/2/2
Histology (adenocarcinoma/squamous cell carcinoma/hematologic malignancy/other)
15/7/2/3
Diagnostic procedure (compression ultrasound/spiral computed tomography/both)
17/7/3
Deep venous thrombosis/pulmonary embolism/both,
19/2/6
Symptomatic
15 (56%)
Recurrent, regionally advanced or metastatic solid cancer
20/25 (80%)
Unfractionated heparin prior to registration
2 (7%)
Prior surgery (≤ 6 months)
7 (26%)
On-going or prior radiotherapy (≤ 6 months)
12 (44%)
On-going or prior systemic therapy (≤ 6 months)
21 (78%)
Table 2. Summary of major and clinically relevant non-major (CRNM) bleeding events (n = 7)
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Age, sex
56F
66M
51F
53F
72F
75F
60M
ECOG-PS
BW (kg)
57.7
60.0
69.0
51.3
50.9
46.8
75.0
Hemoglobin
(g/dl)
12.4
10.5
12.3
10.4
7.8
13.2
8.2
Platelet (K/µl)
238
235
206
365
515
139
50
PT-INR
0.84
1.00
0.97
1.09
1.34
0.89
1.09
Serum creatinine
(mg/dl)
0.52
0.52
1.02
0.49
1.07
0.55
0.60
CG-Ccr (ml/min)
110.0
118.6
71.1
107.5
38.2
65.3
138.9
Primary disease
Intraocular
lymphoma
Pancreas
adenocarcinoma
Malignant
peritoneal
mesothelioma
Breast
adenocarcinoma
Clear cell renal
cell carcinoma
Esophageal
squamous cell
carcinoma
Small cell lung
cancer
Stage
IV
IV
(Recurrent)
IV
IV
On-going
treatment
Cytotoxic agent
without
angiogenesis
inhibitor
Cytotoxic agent
without
angiogenesis
inhibitor
Cytotoxic agent
without
angiogenesis
inhibitor
Cytotoxic agent
without
angiogenesis
inhibitor
Immune check
point inhibitors
None
None
Overall survival
(months)
10.9+
6.6
8.8+
7.1+
0.9
3.7+
1.2
Bleeding characteristics
Site
Vitreous
Gastric
Brain
Breast
Duodenum
Airway
Airway
Timing (months)
0.4
3.9
4.8
2.7
0.4
3.7
0.0
Severity
Major (1)
Major (2)
Major (3)
Major (2)
Major (2)
CRNM
CRNM
Cause
Intravitreal
injection
Invasion to
stomach
Reversible
cerebral
vasoconstriction
syndrome*
Major surgery
Invasion to
duodenum
Intact primary
disease (invasion
to trachea)
Intact primary
disease
Classical risks**
None
None
None
None
None
None
None
（category)
* The only vascular risk factor was dyslipidemia. Prior continuous administration of cytotoxic agents with cisplatin plus pemetrexed followed by gemcitabine
over 4 years may be a cause of reversible cerebral vasoconstriction syndrome.
**Intracranial or intraocular bleeding ≤ 6 months, gastro-intestinal bleeding and/or endoscopically verified ulcer disease ≤ 6 months, head trauma or other major
trauma ≤ 1 month, major surgery and/or neurosurgery ≤ 2 weeks, ischemic stroke ≤ 2 weeks, gross hematuria, intracranial neoplasm, prior angiogenesis inhibitor
≤ 6 weeks
ECOG-PS, Eastern Cooperative Oncology Group Performance Status; BW, body weight; CG-Ccr, Cockcroft-Gault Creatinine clearance; PT-INR, prothrombin
time-international normalized ratio
Table S1. Comparison with pivotal phase III trials: study design.
AMPLIFY [20]
(NCT00643201)
AMPLIFY-J [27]
(NCT01780987)
ADAM VTE [23]
(NCT02585713)
CARAVVAGIO [24]
(NCT03045406)
Current study
(UMIN000028447)
No. of patients
5614 (no Japanese)
80 (all Japanese)
287 (no Japanese)
1168 (no Japanese)
27 (all Japanese)
Study treatment
Apixaban
UFH/warfarin
Apixaban vs dalteparin
Apixaban
dalteparin
Study duration
24 weeks
24 weeks
180 days
6 months
24 weeks
Primary endpoint
Recurrent VTE/VTErelated death
Major/CRNM bleeding
Major bleeding
Recurrent VTE
Major/CRNM bleeding
Key secondary endpoints
Recurrent VTE/VTErelated death or major
bleeding
Major/CRNM bleeding
Recurrent VTE/VTErelated death
Thrombotic
burden
deterioration
Recurrent VTE/VTErelated death
Major/CRNM bleeding
Recurrent VTE
major bleeding
Quality of life
Age
≥ 18 years old
≥ 20 years old
≥ 18 years old
Age ≥ 18 years old
Age ≥ 20 years old
VTE
Symptomatic proximal
DVT or PE
Proximal DVT or PE
VTE
or
splanchnic/cerebral
vein thrombosis
Proximal DVT or PE
VTE
Yes
Yes (including cancer
diagnosed within 2
years)
Yes
≥ 60 days
≥ 6 months
≥ 6 months
0-2
0-2
0-2
vs
Apixaban
UFH/warfarin
vs
vs
or
Apixaban (single arm)
Recurrent VTE/VTErelated death
Thrombotic
burden
deterioration
Key eligibility criteria
Active cancer
Life expectancy
ECOG-PS
(no limitation)
≥ 6 months
(no limitation)
(no limitation)
≥ 6 months
(no limitation)
Concomitant thienopyridine
Ineligible
Ineligible
Concomitant dual antiplatelet
therapy
Ineligible
Ineligible
Ineligible
Ineligible
Ineligible
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
Concomitant use of aspirin <
165 mg/day
(no limitation)
(no limitation)
(no limitation)
Concomitant
use
of
cytochrome P-450 3A4/Pglycoprotein
(no limitation)
(no limitation)
Ineligible
(strong
inhibitor of cytochrome
P-450 3A4)
Use of a Factor Xa inhibitor
(no limitation)
(no limitation)
Ineligible (≤ 3 months)
(no limitation)
Ineligible (≤ 3 months)
Ineligible
Ineligible
Uncontrolled hypertension
Ineligible
Ineligible
Clinically significant liver
disease
Ineligible
Ineligible
Ineligible
Intracranial/intraocular
bleeding
Ineligible (≤ 6 months)
Ineligible (≤ 6 months)
Ineligible (≤ 6 months)
(no limitation)
(no limitation)
Gastrointestinal
bleeding
and/or endoscopically proven
ulcer disease
Ineligible (≤ 6 months)
Ineligible (≤ 6 months)
Ineligible (≤ 6 months)
(no limitation)
(no limitation)
Head trauma/other
trauma
Ineligible (≤ 2 months)
Ineligible (≤ 1 month)
Ineligible (≤ 1 month)
(no limitation)
(no limitation)
Ineligible (≤ 2 months)
Ineligible (≤ 1 month)
Ineligible (≤ 1 week)
(no limitation)
(no limitation)
Major surgery
(no limitation)
Ineligible
Ineligible
(HIV
protease
inhibitor,
Azole antifungals, or
Macrolide antibiotics)
Active bleeding/high risk of
bleeding/bleeding tendency
major
Ineligible
Ineligible
Ineligible
Ineligible
Ineligible
(no limitation)
Ineligible
Ischemic stroke
Ineligible (≤ 1 week)
Ineligible (≤ 2 weeks)
Neurosurgery
Ineligible (≤ 1 week)
Ineligible (≤ 2 weeks)
Planned major surgery
Ineligiblemamo
Ineligible
Intracranial neoplasm
Ineligible
Ineligible
Platelet count
≥ 100,000 /μl
≥ 100,000 /μl
Hemoglobin
≥ 9 g/dl
≥ 9 g/dl
CG-Ccr
≥ 25 ml/min
≥ 25 ml/min
≥ 30 ml/min
≥ 30 ml/min
≥ 30 ml/min
AST/ALT
< 3 times the ULN
< 2 times the ULN
< 3 times the ULN
< 3 times the ULN
< 3 times the ULN
Total bilirubin
< 1.5 times the ULN
< 1.5 times the ULN
PT-INR
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
(no limitation)
Ineligible (≤ 2 weeks)
≥ 50,000 /μl
(no limitation)
(no limitation)
< 1.6
≥ 75,000 /μl
≥ 50,000 /μl
≥ 8 g/dl
(no limitation)
< 2 times the ULN
(no limitation)
(no limitation)
< 1.6
UFH, unfractionated heparin; VTE, venous thromboembolism; CRNM, clinically relevant non-major; DVT, deep vein thrombosis; PE, pulmonary embolism;
ECOG-PS, Eastern Cooperative Oncology Group Performance Status; HIV, human immunodeficiency virus; CG-Ccr, Cockcroft-Gault Creatinine clearance; AST,
aspartate aminotransferase; ALT, alanine aminotransferase; PT-INR, prothrombin time-international normalized ratio; ULN, upper limit of normal
Table S2. Definition of major endpoints.
Major endpoint
Definition
Major bleeding
[30, 32]
Clinically
relevant
nonmajor bleeding
[30]
Acute clinically overt bleeding accompanied by one or more of the following:
A decrease in hemoglobin of 2 g/dl or more
A transfusion of 2 or more units of packed red blood cells
Bleeding that occurs in at least one of the following critical sites:
intracranial
intraspinal
intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed)
pericardial
intraarticular
intramuscular with compartment syndrome
retroperitoneal
• Bleeding that is fatal
The severity of major bleeding at clinical presentation was adjudicated by an independent clinical events committee [3] according
to the following prespecified categories:
• category 1 included bleeding events that were not considered to be a clinical emergency
• category 2 included bleeding events that could not be classified in any of the other categories because they led to some treatment
but were not considered to be a clinical emergency
• category 3 included bleeding events that were considered to be a clinical emergency, such as bleeding with hemodynamic instability
or intracranial bleeding with neurologic symptoms
• category 4 included bleeding events that led to death before or almost immediately after the patient entered the hospital
Acute clinically overt bleeding that consists of:
Any bleeding compromising hemodynamics
Any bleeding leading to hospitalization
Subcutaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause
Intramuscular hematoma documented by ultrasonography, epistaxis that lasted for more than 5 minutes, was repetitive (i.e., two or
Minor
[30]
more
Episodes of bleeding more extensive than spots on a handkerchief within 24 hours), or led to an intervention (e.g., packing or
electrocoagulation)
Gingival bleeding occurring spontaneously (i.e., unrelated to eating or tooth brushing) or lasting for more than 5 minutes
Hematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after instrumentation (e.g., catheter
placement or surgery) of the urogenital tract
Macroscopic gastrointestinal hemorrhage, including at least one episode of rectal
Blood loss, if more than a few spots on toilet paper
Hemoptysis, if more than a few speckles in the sputum and not occurring within the context of pulmonary embolism
Any other bleeding type considered to have clinical consequences for a patient such as medical intervention, the need for
unscheduled contact (visit or telephone call) with a physician, or temporary cessation of a study drug; or associated with pain or
impairment of activities of daily life
bleeding
All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant nonmajor bleeding
were classified as minor bleeding.
Recurrent
pulmonary
embolism (PE)
[17]
Symptoms of PE with one of the following findings:
• A new intraluminal filling defect in (sub)segmental or more proximal branches on spiral computed tomography (CT) of the chest.
• A new intraluminal filling defect, or an extension of an existing defect, or a new sudden cutoff of vessels more than 2.5 mm in
diameter on the pulmonary angiogram.
• A new perfusion defect of at least 75% of a segment with a local normal ventilation result (high probability) on ventilation/perfusion
lung scintigraphy (VQ scan).
• Inconclusive spiral CT, pulmonary angiography, or VQ scan evidence of a new or recurrent PE with demonstration of a new or
recurrent DVT in the lower extremities by compression ultrasound (CUS) or venography
Recurrent deep
vein thrombosis
(DVT) [17]
Symptoms of DVT with one of the following findings:
• For a NEW DVT:
abnormal CUS, including grey-scale or color-coded Doppler
an intraluminal filling defect on venography
• For a RECURRENT DVT:
abnormal CUS where compression had been normal or, if noncompressible during screening, a substantial increase (4 mm
or more) in diameter of the thrombus during full compression
an extension of an intraluminal filling defect, or a new intraluminal filling defect, or an extension of nonvisualization of
veins in the presence of a sudden cutoff on venography
Death [17]
For all patients who died during the study, the cause of death was adjudicated to one of the following categories:
• Venous thromboembolism (VTE)-related death
• PE (based on objective diagnostic testing, autopsy)
• Unexplained death (and VTE cannot be ruled out)
• Sudden death (and VTE cannot be ruled out)
• Cardiovascular-related death
• Cancer
• Bleeding
• Infectious disease
• Other known cause (to be specified)
...
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