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Tables
Table 1. Clinical Characteristics of the Patients at Baseline (Intention-to-treat Population)*
12-month edoxaban 3-month edoxaban
(N=296)
(N=305)
Baseline characteristics
Age, years
71.6±9.4
70.1±10.3
131 (44)
114 (37)
Male sex, No. (%)
94 (32)
73 (24)
Body weight, kg
56.3±12.1
54.8±11.6
199 (67)
222 (73)
Body mass index, kg/m2
22.7±4.0
22.4±4.1
Symptoms at baseline, No. (%)
53 (18)
69 (23)
Bilateral side, No. (%)
118 (40)
105 (34)
Right side, No. (%)
73 (25)
81 (27)
Left side, No. (%)
105 (35)
119 (39)
Standard dose of edoxaban (60 mg per day), No. (%)†
80 (27)
71 (23)
Lower dose of edoxaban (30 mg per day), No. (%) †
216 (73)
234 (77)
Newly diagnosed with cancer within 6 months, No. (%)
184 (62)
205 (67)
Chemotherapy performed within 6 months, No. (%)
142 (48)
141 (46)
Radiotherapy performed within 6 months, No. (%)
20 (6.8)
32 (10)
Recurrent cancer, No. (%)
31 (10)
34 (11)
Metastatic disease, No. (%)
67 (23)
80 (26)
161 (54)
150 (49)
78 (26)
103 (34)
≥2
57 (19)
52 (17)
Hypertension, No. (%)
133 (45)
130 (43)
Diabetes, No. (%)
54 (18)
47 (15)
Heart failure, No. (%)
7 (2.4)
3 (1.0)
History of stroke, No. (%)
14 (4.7)
13 (4.3)
Age ≥75 years, No. (%)
Body weight <60 kg, No. (%)
Site of thrombosis, No. (%)
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Cancer status
ECOG performance status, No. (%)‡
Comorbidities
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History of venous thromboembolism, No. (%)
20 (6.8)
13 (4.3)
History of major bleeding, No. (%)
7 (2.4)
16 (5.3)
Transient risk factors for venous thromboembolism, No.
80 (27)
71 (23)
41 (14)
44 (14)
Creatinine clearance ≤50 ml/min, No. (%)
69 (23)
62 (20)
Anemia, No. (%)||
199 (67)
203 (67)
Platelet count <100,000 per μl, No. (%)
12 (4.1)
19 (6.2)
D-dimer, μg/mL**
5.2 (2.2-10.8)
4.7 (2.3-11.3)
Antiplatelet, No. (%)
27 (9.1)
21 (6.9)
Steroid, No. (%)
34 (11)
43 (14)
Statin, No. (%)
71 (24)
63 (21)
(%)§
Recent surgery within 2 months, No. (%)
Laboratory tests at diagnosis
Concomitant medication
*Plus–minus values are means ±standard deviation.
†Edoxaban was administered at a dose of 30 mg once daily (instead of 60 mg once daily) in patients with a
creatinine clearance of 30 to 50 ml per minute or a body weight of 60 kg or less or in those receiving
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concomitant treatment with potent P-glycoprotein inhibitors.
‡Eastern Cooperative Oncology Group (ECOG) performance status values range from 0 to 4, with higher
values indicating greater disability.
§Transient risk factors for venous thromboembolism included recent surgery, recent immobilization, longdistance travel, central venous catheter use, pregnancy or puerperium, recent leg trauma, fracture or burn,
severe infection, and estrogen use.
||Anemia was diagnosed if the value of hemoglobin was <13 g/dL for men and <12 g/dL for women.
**Data are missing for 19 patients in the 3-month edoxaban group and 15 patients in the 12-month edoxaban
group. Values (continuous variables) are presented as the median and interquartile range.
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Table 2. Clinical Outcomes at 12 Months*
12-month edoxaban 3-month edoxaban
(N=296)
Odds ratio (95%
(N=305)
CI)
Primary endpoint
Symptomatic recurrent venous
thromboembolism or venous
thromboembolism-related death, No.
3 (1.0)
22 (7.2)
0.13 (0.03-0.44)
28 (9.5)
22 (7.2)
1.34 (0.75-2.41)
3 (1.0)
22 (7.2)
0.13 (0.03-0.44)
0 (0)
0 (0)
23 (7.8)
46 (15)
0.47 (0.28-0.80)
53 (18)
41 (13)
1.40 (0.90-2.19)
28 (9.5)
22 (7.2)
1.34 (0.75-2.41)
66 (22)
77 (25)
0.85 (0.58-1.24)
(%)
Major secondary endpoint
Major bleeding, No. (%)†
Other secondary endpoints
Symptomatic venous
thromboembolism recurrence events,
No. (%)
Venous thromboembolism-related
deaths, No. (%)‡
New or worsening thrombus images in
any imaging tests during follow up
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without any symptoms, No. (%)§
All clinically relevant bleeding events,
No. (%)||
Clinically relevant non-major bleeding,
No. (%)
Deaths from all causes, No. (%)
*The analyses were performed for the full analysis set based on the intention-to-treat approach, which
included all the patients who had undergone randomization after excluding patients who withdrew consent.
For patients who did not experience an event, the time to the first event was to be censored at day 365, or the
last day the patient had a complete assessment for study outcomes, whichever comes first. We calculated the
odds ratios, computed using the logistic regression model along with the corresponding 95% confidence
intervals for all clinical endpoints, which have not been adjusted for multiple comparisons.
†Major and nonmajor bleeding events were classified according to the criteria of the International Society on
Thrombosis and Hemostasis.
‡Death due to pulmonary embolism diagnosed prior to death or at autopsy, or death unexplained by other than
pulmonary embolism.
§Appearance of new or worsening thrombus images in the pulmonary arteries and deep veins on imaging tests
(ultrasonography of lower limb vein system, computed tomography examination, pulmonary perfusion
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scintigraphy, pulmonary angiography, venography) that do not match the definition of a symptomatic venous
thromboembolism recurrenc and are not associated with new or worsening symptoms.
||For patients who had more than one event, only the first was counted.
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Figure Legends
Figure 1. Enrollment, Randomization, and Follow-up.
Patients were randomly assigned in a 1:1 ratio to receive a 3-month edoxaban treatment or a 12-month
edoxaban treatment. Randomization was performed centrally through the electronic data capture
system with a stochastic minimization algorithm to balance the treatment assignment within the centers.
The intention-to-treat population included all patients who had undergone randomization.
Figure 2. Kaplan–Meier Curves for a Persistent Edoxaban Discontinuation.
The time-to-event curves over 1-year after the diagnosis of persistent edoxaban discontinuation.
Downloaded from http://ahajournals.org by yyamashi@kuhp.kyoto-u.ac.jp on September 30, 2023
Persistent edoxaban discontinuation was defined as discontinuation of edoxaban according to the study
protocol or lasting for more than 14 days for any reason. The analyses were performed for the full
analysis set based on the intention-to-treat approach.
Figure 3. Kaplan–Meier Curves for the Primary Endpoint.
The time-to-event curves over 1-year after the diagnosis of the primary endpoint (symptomatic
recurrent VTE or VTE-related death).
VTE, venous thromboembolism.
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Figure 4. Kaplan–Meier Curves for the Major Secondary Endpoint.
The time-to-event curves over 1-year after the diagnosis of the major secondary endpoint (major
bleeding). Major bleeding was defined according to the definition of the International Society on
Thrombosis and Haemostasis criteria, which consisted of fatal bleeding, symptomatic bleeding in a
critical area or organ, and bleeding causing a reduction in the hemoglobin level by at least 2 g/dL or
leading to a transfusion of at least 2 units of whole blood or red cells.
Figure 5. Subgroup Analyses for the Primary Endpoint.
The ORs for the primary endpoint in the 2 groups are described according to the pre-defined subgroups.
The 95% CIs have not been adjusted for multiple comparisons.
Downloaded from http://ahajournals.org by yyamashi@kuhp.kyoto-u.ac.jp on September 30, 2023
OR, odds ratio; CI, confidence interval; VTE, venous thromboembolism
31
Figure 1
605 patients with active cancer who were newly diagnosed
with isolated distal deep vein thrombosis were
assessed for eligibility and signed the consent form
between April 2019 and June 2022 at 60 institutions in Japan
1 withdrew from the study
before the randomization
604 underwent randomization
298 were assigned to the
12-month edoxaban group
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2 withdrew consent
306 were assigned to the
3-month edoxaban group
1 withdrew consent
296 were included in the
intention-to-treat analysis
305 were included in the
intention-to-treat analysis
223 completed 1-year follow-up
73 not complete 1-year follow-up
66 died
7 loss to follow-up (2.4%)
224 completed 1-year follow-up
81 not complete 1-year follow-up
77 died
4 loss to follow-up (1.3%)
Figure 2
Cumulative incidence
Persistent edoxaban discontinuation
3-month edoxaban
12-month edoxaban
Days after diagnosis
0-day
60-day
90-day
120-day
180-day
365-day
37
48
60
76
116
253
240
224
202
151
12.6%
16.4%
20.6%
26.3%
41.3%
46
124
256
271
277
255
173
40
23
15
15.2%
41.4%
86.3%
91.6%
93.9%
12-month edoxaban
N of patients with discontinuation
N of patients on edoxaban
296
Cumulative incidence
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3-month edoxaban
N of patients with discontinuation
N of patients on edoxaban
Cumulative incidence
305
Figure 3
Primary endpoint
(Symptomatic recurrent VTE or VTE-related death)
Cumulative incidence
12-month edoxaban
3-month edoxaban
Log-rank P<0.001
Days after diagnosis
0-day
60-day
90-day
120-day
180-day
365-day
283
274
269
253
222
0.3%
0.7%
0.7%
0.7%
1.2%
22
289
280
275
256
210
0.3%
0.7%
1.8%
3.2%
8.5%
12-month edoxaban
N of patients with event
N of patients at risk
296
Cumulative incidence
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3-month edoxaban
N of patients with event
N of patients at risk
Cumulative incidence
305
Figure 4
Major secondary endpoint
(Major bleeding)
Cumulative incidence
12-month edoxaban
3-month edoxaban
Days after diagnosis
0-day
60-day
90-day
120-day
180-day
365-day
13
15
17
20
28
273
267
261
245
210
4.4%
5.2%
5.9%
7.0%
10.2%
14
16
18
20
22
279
271
264
250
217
4.7%
5.3%
6.1%
6.8%
7.6%
12-month edoxaban
N of patients with event
N of patients at risk
296
Cumulative incidence
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3-month edoxaban
N of patients with event
N of patients at risk
Cumulative incidence
305
Figure 5
12-month
edoxaban (N=296)
3-month
edoxaban (N=305)
OR (95%CI)
P interaction
Age
≥75 years
0/131
(0%)
<75 years
3/165
(1.8%)
7/114
(6.1%)
15/191
(7.9%)
5/73
(6.9%)
0.11
0.22 (0.06-0.76)
Sex
Male
0/94
(0%)
0.16
Female
3/202
(1.5%)
17/232
(7.3%)
0.19 (0.06-0.66)
<60 kg
2/199
(1.0%)
14/222
(6.3%)
0.15 (0.03-0.67)
≥60 kg
1/97
(1.0%)
8/83
(9.6%)
0.10 (0.01-0.80)
Yes
0/20
(0%)
2/13
(15%)
No
3/276
(1.1%)
20/292
(6.9%)
0.15 (0.04-0.51)
≤50 mL/min
1/69
(1.5%)
6/62
(9.7%)
0.14 (0.02-1.17)
>50 mL/min
2/227
(0.9%)
16/243
(6.6%)
0.13 (0.03-0.55)
Weight
0.74
History of VTE
0.35
Creatinine clearance
0.95
Platelet count
<100,000/μl
0/12
1/19
(5.3%)
≥100,000/μl
3/284
(1.1%)
21/286
(7.3%)
0.13 (0.04-0.46)
Yes
3/199
(1.5%)
17/203
(8.4%)
0.17 (0.05-0.58)
No
0/97
(0%)
5/102
(4.9%)
1/80
(1.3%)
7/71
(9.9%)
0.12 (0.01-0.97)
2/216
(0.9%)
15/234
(6.4%)
0.14 (0.03-0.60)
2/16
(13%)
20/289
(6.9%)
0.14 (0.04-0.48)
(0%)
0.68
Anemia
0.24
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Edoxaban dose adjustment
Normal dose (60 mg/day)
0.90
Low dose (30 mg/day)
History of major bleeding
Yes
0/7
(0%)
0.61
No
3/289
(1.0%)
Yes
2/67
(3.0%)
12/80
(15%)
0.17 (0.04-0.81)
No
1/229
(0.4%)
10/225
(4.4%)
0.09 (0.01-0.74)
Overall
3/296
(1.0%)
22/305
(7.2%)
0.13 (0.03-0.44)
Cancer metastasis
0.63
0.0625
0.25
12-month
edoxban better
3-month
edoxban better
...
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