Introduction
Endoscopic submucosal dissection (ESD) is widely accepted as a minimally invasive
treatment for gastric neoplasms when the risk of lymph node metastasis is minimal
[1]
[2]
[3]
[4]. The rate of complications such as intraoperative bleeding or a perforation caused
by conventional endoscopic mucosal resection (EMR) is less than that of ESD [5]. However, the failure rate of en bloc resection for lesions > 20 mm in diameter,
with or without ulceration, with EMR is significantly higher than that with ESD [5]. An advantage of ESD is that the tumor can be endoscopically resected en bloc regardless
of its size or presence of ulceration. Therefore, ESD is recommended in cases of lesions
≥ 20 mm in diameter with or without ulceration.
Although considerable expertise is required to perform ESD, incidence of perforations
has decreased due to technological advances in various devices, including surgical
knives, hemostatic forceps, and high-frequency devices. Proton pump inhibitors (PPIs)
and post-ESD coagulation therapy for visible vessels after ESD have been reported
to be effective for preventing postoperative bleeding [6]
[7]. However, postoperative bleeding is still controversial because prophylactic therapy
for post-ESD bleeding has not yet been perfectly established.
Anticoagulants are used to prevent cerebrovascular and cardiovascular diseases, such
as atrial fibrillation (AF), valvular heart disease, or deep vein thrombosis. These
drugs must not be discontinued before endoscopic procedures that have a low risk of
bleeding, such as diagnostic endoscopy or endoscopic biopsy [1]. However, endoscopic procedures with a high risk of bleeding, such as EMR or ESD,
require patients to discontinue anticoagulants or replace them with unfractionated
heparin or low-molecular-weight heparin as a bridge therapy based on the European
Society of Gastrointestinal Endoscopy (ESGE) and guidelines of the American Society
for Gastrointestinal Endoscopy (ASGE) and Japan Gastroenterological Endoscopy Society
(JGES) [8]
[9]
[10]. Although patients receiving warfarin usually require heparin bridge therapy (HBT)
to prevent thromboembolic events during ESD, clinical data that confirm its safety
and efficacy are limited [11]
[12].
ESGE, ASGE and JGES guidelines advocate continuous use of warfarin in patients who
undergo endoscopic procedures are associated with a low risk of bleeding, such as
esophagoduodenoscopy (EGD), colonoscopy, or mucosal biopsy [8]
[9]
[10]. Some studies have recently reported that patients who were receiving warfarin underwent
colonic polypectomy [13]
[14]
[15]. However, there are no reports on the clinical outcomes of bleeding after gastric
ESD in patients who were receiving continuous warfarin. Herein, we report clinical
outcomes after gastric ESD in patients with continuous use of low-dose warfarin (LDW).
Patients and methods
This was a prospective observational study and single-center evaluation. From December
2014 to January 2016, 22 patients receiving warfarin who were scheduled to be treated
with gastric ESD were enrolled. The patients were treated with gastric ESD with a
low dose of warfarin (≤ 4 mg). The ethics committee of the New Tokyo Hospital approved
the study protocol (IRB No.NTH 2014-12-11-0069). We also analyzed 23 patients with
HBT who underwent gastric ESD from January 2011 to November 2014 ([Fig. 1]). To evaluate the feasibility of gastric ESD with continuous LDW, we compared outcomes
of gastric ESD between the continuous LDW group and the HBT group. All patients provided
written informed consent before enrollment. The treatment indication for these patients
was based on guidelines proposed by the Japanese Gastric Cancer Association and included
the expanded criteria proposed by Gotoda et al [16].
Fig. 1 Flowchart of inclusions and exclusions criteria for this study. ESD, endoscopic submucosal
dissection; LDW, low-dose warfarin.
Patient clinical records were reviewed after obtaining approval from the institutional
review board of the New Tokyo Hospital.
ESD procedure
ESD was performed with either a single-channel endoscope or a 2-channel endoscope
(GIF-Q260 J, GIF-H290Z, and GIF-2TQ260M; Olympus, Tokyo, Japan). We used either a
FlushKnife BT (DK2618JB; Fujifilm, Tokyo, Japan) or a DualKnife (KD-650L; Olympus,
Tokyo, Japan) as the electrosurgical knife, and applied an electrosurgical current
to the knife with an electrosurgical generator (VIO300D; ERBE, Tübingen, Germany).
After detecting the lesion, markings were made around the lesion using the electrosurgical
knife. Sodium hyaluronate was injected into the submucosal layer. The circumferential
mucosal incisions outside the markings were made with the electrosurgical knife and
the submucosa of the lesion was dissected. Prophylactic coagulation was performed
on exposed vessels using hemostatic forceps (FD-230U or FD-410LR; Olympus, Tokyo,
Japan) during the submucosal dissection. Once the lesion was removed, all visible
vessels on the artificial ulcer bed were coagulated with hemostatic forceps.
Management of patients receiving anticoagulation
Patients who were diagnosed as having a high risk for thrombosis were treated with
uninterrupted warfarin. High risk for thrombosis was defined based on ASGE guidelines
and a CHADS2 score as follows: patients with AF associated with valvular heart disease (whether
surgically corrected or not), mechanical valves in the mitral position, mechanical
valves in patients who have had a previous thromboembolic event, and a CHADS2 score > 2 (chronic heart failure, hypertension, aged > 75 years, diabetes mellitus,
or a stroke) [17]
[18]
[19]. We also consulted with the prescribing physician before the procedure to determine
whether warfarin should be stopped or adjusted.
In patients on continuous LDW, we performed ESD with international normalized ratio
(INR) levels at approximately 1.6 – 2.6 using LDW during the periendoscopic period
based on Japanese guidelines [20]
[21]
[22]
[23]. We checked the INR levels a week before ESD. If the INR levels were ≥ 2.6 a week
before ESD, we changed the warfarin dose to a low dose in the outpatient clinic. All
patients were hospitalized a day before ESD, and INR levels were assessed on the day
of ESD. INR levels were also assessed the day after ESD and 3 days after ESD. If INR
levels were ≥ 3.0, vitamin K was used to control the INR levels. If a patient was
bleeding after gastric ESD, warfarin was discontinued temporarily. Once no bleeding
was confirmed the day after EGD, warfarin was restarted.
In HBT patients, heparin was administered continuously while the activated partial
thromboplastin was maintained at approximately twice the preheparinization level after
warfarin was discontinued. Furthermore, the INR was measured on the day of ESD and
the patient was treated after confirming that the effect of warfarin had almost disappeared
(INR ≤ 1.5). Heparin was administered up to 4 – 6 h before ESD and restarted 4 h after
ESD. Once no bleeding was confirmed the day after EGD, warfarin was restarted in patients
with HBT. In patients requiring endoscopic hemostasis for multiple visible vessels
during second-look endoscopy, warfarin was restarted after third-look endoscopy. After
giving warfarin to HBT patients, heparin was continued until therapeutic INR levels
(approximately 1.6 – 2.6) were achieved.
Treatment after ESD
PPIs were administered intravenously for 2 days following the procedure. Second-look
endoscopy was performed on all patients the day after ESD. If vessels in the ulcer
bed were observed, we performed coagulation with hemostatic forceps. Once it was confirmed
that there were no signs of postoperative bleeding, a liquid diet with oral administration
of PPI was started 2 days after ESD. PPIs were administered to all patients for 8
weeks after ESD.
Patients not receiving anticoagulants were usually discharged approximately 5 days
after ESD if they had no complications. Patients receiving continuous LDW who had
no signs of bleeding after ESD were usually discharged within 5 – 7 days. Patients
receiving HBT were discharged after confirming that they had no signs of bleeding
and their therapeutic INR level was checked after recommencement of warfarin was achieved.
Postoperative bleeding
Postoperative bleeding was defined as incidence of hematemesis and melena or decrease
in blood hemoglobin (Hb) levels ≥ 2 mg/dL and simultaneously requiring endoscopic
hemostasis. All patients with hematemesis and melena had emergency EGD and endoscopic
hemostasis was performed. If bleeding and decreased Hb levels were excessive, we performed
blood transfusion. Second-look endoscopy was performed on all patients the day after
the endoscopic hemostasis.
Outcome measurements
The main outcome of this study was to investigate postoperative bleeding after gastric
ESD in patients with continuous LDW. We also investigated postoperative bleeding compared
with HBT.
Statistical analysis
Categorical variables were compared using chi-squared test or Fisher’s exact test,
and continuous variables were compared using Student’s t test. A P value < 0.05 was considered statistically significant. All data analyses were conducted
using SPSS version 22.0 (IBM Corp., Armonk, NY, USA).
Results
Patient demographic data between continuous LDW and HBT are shown in [Table 1]. Twenty-two patients receiving continuous LDW were treated with ESD in the study.
On the other hand, there were 23 patients received HBT. The mean CHADS2 score in the continuous LDW group was higher than that in the HBT group (P < 0.001). The mean INR in the continuous LDW group was also higher than that in the
HBT group (P < 0.001). There were no significant differences between the 2 groups in terms of
age, sex, comorbidities, antiplatelet therapy, and tumor location.
Table 1
Clinical findings of gastric neoplasms resected by ESD between continuous LDW and
heparin bridge therapy: baseline demographic data.
|
Continuous LDW (n = 22)
|
Heparin bridge therapy (n = 23)
|
P value
|
Age, mean (SD), years
|
76.8 (6.0)
|
72.7 (7.9)
|
0.057
|
Male sex, n (%)
|
19 (86.4)
|
21 (91.3)
|
0.665
|
Comorbidities, n (%)[1]
|
22 (100)
|
21 (91.3)
|
0.489
|
Antiplatelet therapy, n (%)
|
11 (50.0)
|
10 (47.6)
|
0.768
|
INR, mean (SD)
|
1.85 (0.4)
|
1.26 (0.1)
|
< 0.001
|
CHADS2 score, mean (SD)[2]
|
2.9 (0.4)
|
1.7 (1.0)
|
< 0.001
|
Tumor location, n (%)
|
|
|
0.779
|
|
5 (22.7)
|
4 (17.4)
|
|
|
6 (27.3)
|
5 (21.7)
|
|
|
11 (50.0)
|
14 (60.9)
|
|
ESD, endoscopic submucosal dissection; LDW, low-dose warfarin; SD, standard deviation;
INR, international normalization ratio.
1 Comorbidities indicate current diseases (hypertension, diabetes mellitus, chronic
renal failure, or liver cirrhosis).
2 CHADS2 score indicates the risk of stroke with regards to atrial fibrillation.
Clinical outcomes between continuous LDW and HBT are shown in [Table 2]. The mean specimen size in the continuous LDW group was smaller than that in the
HBT group; however there was no significant difference between the 2 groups (P = 0.099). The mean operation time in the continuous LDW group was lesser than that
in the HBT group (P = 0.004). Two of the 22 patients (9.1 %) in the continuous LDW group and 5 of the
23 patients (21.7 %) in the HBT group had postoperative bleeding after gastric ESD.
Although the rate of postoperative bleeding in the continuous LDW group was lower
than that in the HBT group, no significant difference was observed between the 2 groups
(P = 0.414). The average length of hospitalization in the continuous warfarin group
(7.5 ± 4.8 days) was almost identical to that in the group that received no anticoagulation
therapy (7.4 ± 2.6 days); the length of hospitalization in the HBT group was 14.2 ± 3.3
days.
Table 2
Clinical outcomes of gastric neoplasms resected by ESD between continuous LDW and
heparin bridge therapy.
|
Continuous LDW (n = 22)
|
Heparin bridge therapy (n = 23)
|
P value
|
Specimen size, mean (SD), mm
|
30.6 (8.3)
|
36.2 (13.1)
|
0.099
|
Pathological findings, n (%)[1]
|
|
|
0.974
|
|
21 (95.2)
|
22 (95.7)
|
|
|
1 (4.8)
|
1 (4.3)
|
|
Bleeding rate, n (%)
|
2 (9.1)
|
5 (21.7)
|
0.414
|
Operation time, mean (SD), minutes
|
40.4 (18.3)
|
79.3 (57.4)
|
0.004
|
Hospitalization, mean (SD), days
|
7.5 (4.8)
|
14.2 (3.3)
|
< 0.001
|
ESD, endoscopic submucosal dissection; LDW, low-dose warfarin; SD, standard deviation.
1 Differentiated, adenoma/well or moderately differentiated adenocarcinoma/papillary
adenocarcinoma; undifferentiated, signet-ring cell carcinoma/poorly differentiated
adenocarcinoma/mucinous adenocarcinoma.
Clinical and endoscopic characteristics of patients on continuous LDW are shown in
[Table 3]. The average warfarin dose that patients received was 2.3 mg/day (range 0.5 – 4.0).
The INR level averaged 1.87 (range 1.41 – 2.75) on the day of ESD.
Table 3
Clinical and endoscopic features of patients with continuous LDW for gastric ESD.
Case no.
|
Age, Sex (M/F)
|
Postoperative bleeding
|
Tumor location (U/M/L)
|
Specimen size (mm)
|
Operation time (minutes)
|
Dose of warfarin (mg)
|
INR (0POD)
|
INR (1POD)
|
INR (3POD)
|
Antiplatelet drugs
|
Comorbidities
|
CHADS2 score[1]
|
1
|
65, M
|
–
|
U
|
12
|
20
|
3.0
|
1.67
|
1.68
|
1.73
|
+
|
HT
|
2
|
2
|
86, M
|
–
|
U
|
18
|
33
|
2.5
|
2.16
|
1.93
|
1.83
|
+
|
DM
|
3
|
3
|
71, M
|
+
|
M
|
35
|
45
|
0.5
|
1.42
|
1.47
|
1.58
|
+
|
HT, RF
|
4
|
4
|
72, F
|
–
|
M
|
28
|
23
|
1.5
|
1.53
|
1.87
|
2.11
|
–
|
HT, DM
|
2
|
5
|
79, M
|
–
|
U
|
43
|
82
|
3.0
|
1.55
|
1.68
|
1.96
|
–
|
HT, DM
|
3
|
6
|
82, F
|
–
|
M
|
25
|
41
|
2.0
|
1.79
|
1.67
|
1.32
|
–
|
HT
|
2
|
7
|
71, M
|
–
|
L
|
31
|
26
|
2.0
|
1.41
|
1.47
|
1.77
|
+
|
DM
|
3
|
8
|
82, M
|
+
|
L
|
38
|
78
|
2.0
|
2.04
|
1.88
|
2.48
|
+
|
HT, DM
|
3
|
9
|
80, M
|
–
|
M
|
32
|
39
|
2.5
|
2.47
|
2.15
|
1.70
|
+
|
DM
|
3
|
10
|
72, M
|
–
|
L
|
45
|
68
|
2.0
|
1.50
|
1.46
|
2.13
|
+
|
HT, DM
|
3
|
11
|
73, M
|
–
|
M
|
25
|
33
|
3.0
|
1.42
|
1.49
|
1.80
|
+
|
HT
|
3
|
12
|
83, M
|
–
|
L
|
31
|
23
|
4.0
|
1.97
|
2.12
|
2.47
|
+
|
HT, DM
|
3
|
13
|
77, M
|
–
|
L
|
40
|
36
|
2.5
|
1.94
|
2.11
|
1.85
|
–
|
HT
|
2
|
14
|
82, M
|
–
|
M
|
25
|
26
|
2.0
|
1.54
|
1.80
|
3.04
|
–
|
HT, DM
|
3
|
15
|
71, M
|
–
|
L
|
30
|
22
|
1.5
|
2.75
|
3.11
|
2.57
|
–
|
HT, RF
|
2
|
16
|
82, F
|
–
|
L
|
42
|
41
|
2.5
|
1.97
|
1.86
|
2.49
|
–
|
HT
|
3
|
17
|
79, M
|
–
|
L
|
34
|
58
|
2.0
|
1.94
|
2.18
|
1.85
|
–
|
HT, DM
|
3
|
18
|
69, M
|
–
|
L
|
20
|
21
|
2.0
|
1.78
|
2.03
|
2.30
|
–
|
HT, DM
|
2
|
19
|
74, M
|
–
|
U
|
28
|
52
|
3.0
|
2.35
|
2.78
|
2.52
|
+
|
HT, DM
|
3
|
20
|
79, M
|
–
|
L
|
31
|
44
|
2.0
|
1.95
|
2.10
|
2.28
|
–
|
HT
|
3
|
21
|
88, M
|
–
|
L
|
35
|
26
|
3.5
|
1.80
|
1.80
|
1.82
|
–
|
HT, DM
|
3
|
22
|
73, M
|
–
|
U
|
26
|
52
|
2.0
|
2.08
|
2.11
|
2.25
|
+
|
HT, DM
|
3
|
LDW, low-dose warfarin; ESD, endoscopic submucosal dissection; INR, international
normalization ratio; POD, postoperative day; HT, hypertension; DM, diabetes mellitus;
RF, renal failure.
1 CHADS2 score indicates the risk of stroke with regards to atrial fibrillation.
Postoperative bleeding
Postoperative bleeding started later in the HBT group compared with the continuous
LDW group. Postoperative bleeding was observed on Days 2 and 4 in the continuous LDW
group, and on days 4, 5, and 7 in the HBT group. Postoperative bleeding was sparse
in patients not taking any anticoagulant and was observed between days 0 and 12. All
bleeding events were successfully managed with endoscopic hemostasis.
Discussion
This study investigated postoperative outcomes after gastric ESD in patients receiving
continuous LDW. Although the results showed that the rate of postoperative bleeding
in the continuous LDW group was lower than that in the HBT group, there was no significant
difference between the 2 groups (P = 0.414). The average length of hospitalization in the continuous LDW group was almost
half that in the HBT group because continuous heparin was given IV during hospitalization
3 – 5 days before ESD, and HBT patients were discharged after confirmation that their
therapeutic INR level had been achieved after recommencement of warfarin.
A recent retrospective study reported on HBT in high-risk patients who underwent ESD
[11]. The authors showed that there was a higher frequency of delayed bleeding after
ESD in the HBT group compared with the control group (no anticoagulant therapy). The
delayed bleeding rate was 37.5 % in the HBT group and only 4.8 % in the control group. Moreover,
the study showed that the average period of postoperative bleeding in the HBT group
was 8.0 ± 5.7 days versus 3.8 ± 4.1 days for the control group [11]. Our study showed that postoperative bleeding started later in the HBT group compared
with that in the continuous LDW group. Postoperative bleeding was observed on Days
2 and 4 in the continuous LDW group and on Days 4, 5, and 7 in the HBT group. Why
did this discrepancy occur between the 2 groups? Presumably, the double effect of
heparin and warfarin after recommencement of warfarin caused delayed bleeding after
ESD in the previous study. Our study shows that delayed bleeding of HBT occurred approximately
5 – 7 days after ESD, simultaneous with the action of warfarin. The discrepancy in
the previous study likely was for the same reason.
In this study, we performed gastric ESD with low-dose warfarin to maintain the INR
level at approximately 1.6 – 2.6. Relevant studies have shown that an INR level between
1.6 and 1.9 is sufficiently effective for anticoagulation in Japanese patients with
nonvalvular AF (NVAF) [20]. Moreover, this study has shown that bleeding complications associated with warfarin
were increased to levels > 2.6 in older Japanese patients with NVAF [20]. INR levels in older Japanese patients who had AF associated with valvular diseases
were appropriately maintained at approximately 1.6 – 2.2, and those who had AF after
an artificial heart valve replacement were appropriately maintained at approximately
2.0 – 2.5, based on Japanese guidelines [21]
[22]. Therefore, the target INR during the periendoscopic period was within 1.6 – 2.6
in this study. Effective INR levels in Japanese patients have been reported to differ
from those in patients in Western countries [23]. In Western countries, maintenance of INR levels between 2.0 and 3.0 is recommended,
irrespective of diagnosis [24]. Therefore, our target INR range may not necessarily apply to all ethnic groups.
The INR level in the continuous LDW group averaged 1.87 (range 1.41 – 2.75) on the
day of ESD and was successfully controlled. The average INR level the day after ESD
was 1.94 (range 1.47 – 3.11) and was 2.08 (range 1.32 – 3.04) 3 days after ESD. The
INR levels of 2 patients who suffered postoperative bleeding in the continuous LDW
group ranged from 1.6 to 2.6 during the periendoscopic period. One patient was on
antiplatelet therapy (discontinuation of ticlopidine for 5 days before ESD) and had
a longer operation time whereas the other had renal failure, was on antiplatelet therapy
(discontinuation of clopidogrel for 5 days before ESD), and had a high CHADS2 score (4 points). It appeared that the risk of postoperative bleeding in these two
patients was higher than that in other patients.
In addition to anticoagulation therapy, previous studies present antiplatelet therapy
as one of the independent risk factors for postoperative bleeding after gastric ESD.
Current guidelines recommend continuation of low-dose aspirin in patients with high-risk
of thrombosis who undergo ESD [8]
[9]
[10]. In particular, continuing low-dose aspirin or thienopyridine is mandatory to prevent
thrombosis in patients receiving dual antiplatelet therapy (aspirin plus thienopyridine)
who undergo ESD [8]. At our hospital, thienopyridine was usually discontinued in patients who underwent
ESD. Because data are lacking on continuous use of thienopyridine, further study will
be needed in the future.
It is our opinion that continuous LDW is better than HBT for controlling hemorrhage
during ESD. While there was no excessive bleeding associated with continuous LDW during
ESD, there were 2 HBT patients in whom it was difficult to control bleeding during
ESD. These 2 patients needed frequent endoscopic hemostasis with hemostatic forceps
during ESD; the bleeding was eventually controlled. We have not had any cases of thromboembolic
events in patients who were receiving warfarin during the periendoscopic period. Even
though 1 patient on continuous LDW had a cerebral infarction 3 months after ESD, it
was found to be caused by the patient not receiving warfarin properly after discharge
from the hospital.
This study has several limitations. First,it was a single-center analysis and not
randomized. Second, the comparison with continuous LDW and HBT could have been influenced
by a selection bias. The mean CHADS2 score in the continuous LDW group was higher than that in the HBT group. Furthermore,
the mean operation time in the continuous LDW group was less than that in the HBT
group, and the mean specimen size in the continuous LDW group was smaller than that
in the HBT group. In this study, the comparison with continuous LDW and HBT may not
be adequate because of confounding variables. Therefore, it remains unclear whether
continuous LDW causes less bleeding than HBT.
Conclusion
In conclusion, gastric ESD with continuous LDW as a substitute for HBT was feasible
and may be acceptable. A further prospective, randomized study will be needed in the
future.