Introduction
The most common cause of acute lower gastrointestinal bleeding is colonic diverticular
hemorrhage (CDH) [1 ]. Given that CDH with stigmata of recent hemorrhage (SRH) treated conservatively
has a high 30-day rebleeding rate (65.8 %) [2 ], endoscopic treatment is indicated for definitive CDH with SRH [1 ]. Several endoscopic treatment techniques for CDH have been reported, including epinephrine
injection, contact thermal therapy, endoscopic clipping, endoscopic band ligation
(EBL), endoscopic detachable snare ligation, and over-the-scope clipping [1 ]
[3 ]. Among these, endoscopic clipping is the most common because of its simplicity and
low invasiveness [1 ]
[4 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ], and is the most frequently performed technique in Japan [11 ].
EBL is, however, becoming more widely performed because it allows for occlusion of
SRH and any underlying arteries [4 ]
[5 ]
[6 ]
[12 ]
[13 ]
[14 ]. Although a recent meta-analysis reported lower early and late rebleeding rates
with EBL compared with clipping [10 ], the number of cases in each study included in the analysis was small, with at most
101 cases per treatment method and only 790 cases analyzed in total. In addition,
these were all single-center studies, so their results may suffer from bias in relation
to the treatment strategies and techniques used in each study setting. Importantly,
relatively few of the studies investigated the long-term effectiveness of the various
endoscopic treatments for CDH [1 ], and the rates of diverticulitis and perforation, which have been reported as adverse
events (AE) of endoscopic treatment for CDH, could not be confirmed by the systematic
review because of the small number of cases analyzed.
To address these issues, we conducted a multicenter long-term cohort study in Japan
and report here the short- and long-term effectiveness of clipping versus EBL for
CDH, as well as the AEs associated with them.
Methods
Patients and study design
The dataset analyzed in this study is from the CODE BLUE-J study (COlonic DivErticular
Bleeding Leaders Update Evidence from multicenter Japanese study), a retrospective
multicenter cohort study that was conducted at 49 hospitals across Japan [15 ]
[16 ]. From among patients emergently hospitalized for acute hematochezia between January
2010 and December 2019, a total of 10 342 patients were enrolled. The ethics committees
and institutional review boards of all 49 participating hospitals approved this study
being conducted with the opt-out method (Table 1 s , see online-only Supplementary material). Of these 10 342 patients, 2020 were diagnosed
with definitive CDH based on the presence of SRH ([Fig. 1a, b ]), with the source of the bleeding being identified as active bleeding, a non-bleeding
visible vessel, or an adherent clot [1 ]. Among these patients, the 1041 patients who were treated with clipping ([Fig. 1c ]) and the 638 who were treated with EBL ([Fig. 1d ]) were analyzed in this study ([Fig. 2 ]).
Fig. 1 Example endoscopic appearances of: a the stigmata of recent hemorrhage as evidenced by active bleeding; b the stigmata of recent hemorrhage as evidenced by adherent clot; c endoscopic clipping (indirect placement of endoclips) for colonic diverticular hemorrhage;
d endoscopic band ligation for colonic diverticular hemorrhage.
Fig. 2 Flow chart of patients in this study. *The high identification rate of stigmata of
recent hemorrhage, about one-third of the 6501 patients diagnosed with colonic diverticular
hemorrhage, may be associated with the high early colonoscopy rate (64.4 % underwent
early colonoscopy [within 24 hours of admission]), high preparation rate (81.4 % received
polyethylene glycol or glycerin enema), and high levels of endoscopic device use (distal
attachment used in 77.1 %; water-jet device used in 79.3 %).
Variables and clinical outcomes
A total of 72 items were collected for evaluation from the electronic medical records
and endoscopy database [15 ]
[16 ]. Data on baseline characteristics included age, sex, presenting symptoms, vital
signs, laboratory data, past history, co-morbidities, medications, computed tomography
(CT) and endoscopic findings, and endoscopic factors. Co-morbidities were assessed
using the modified Charlson co-morbidity index (CCI), consisting of 19 items from
the original CCI [17 ] and two additional items (hypertension and hyperlipidemia). The presence of extravasation
was evaluated using contrast-enhanced CT. The detailed endoscopic factors evaluated
included timing of colonoscopy, bowel preparation, distal-attachment cap use, water-jet
scope use, SRH type (active bleeding vs. non-active bleeding), and location. The left-sided
colon was defined as the descending and sigmoid colon and the rectum, and right-sided
colon as all other locations. The clipping and EBL techniques used have been described
in detail elsewhere [4 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[12 ]
[13 ]
[14 ].
The outcome of most interest was the rate of early rebleeding. Early rebleeding was
defined as rebleeding within 30 days of endoscopic treatment for CDH. The other outcomes
evaluated were the rate of late rebleeding, the success rate of initial hemostasis,
mortality after endoscopic treatment (within 30 days and 1 year), thromboembolism
during hospitalization, need for interventional radiology (IVR) or surgery, red blood
cell transfusion, length of hospital stay (LOS) after endoscopic treatment, and endoscopically
relevant AEs.
Late rebleeding was defined as rebleeding within 1 year [1 ]
[4 ], which was determined from the clinical data collected during follow-up. Rebleeding
was defined as the presence of significant amounts of fresh, bloody, or wine-colored
stools after initial hemostasis. Rebleeding included events both during hospitalization
and after discharge. Thromboembolism included a cardiovascular event, cerebrovascular
event, pulmonary embolism, or deep vein thrombosis. Endoscopically relevant AEs included
perforation and diverticulitis. Perforation was diagnosed based on clinical signs
and symptoms (e. g. abdominal pain) and CT findings (e. g. free intraperitoneal air)
[18 ]. Diverticulitis was diagnosed based on symptoms such as abdominal pain and fever,
CT findings, and blood test results (e. g. elevated C-reactive protein) [19 ].
Statistical analysis
Categorical data were compared using the χ2 test or Fisher’s exact test as appropriate. Continuous data were compared using the
Mann–Whitney U test. The association between endoscopic treatment and clinical outcomes was analyzed
using univariate and multivariate logistic regression models.
The multivariate analysis was adjusted for age, sex, and the following 15 factors
that were potentially clinically important variables, most of which were found to
have at least borderline significance (P < 0.10) on univariate analysis: current drinker, systolic blood pressure ≤ 100 mmHg,
loss of consciousness, hemoglobin < 12 g/dL, white blood cell > 10 000 /µL, blood
urea nitrogen > 25 mg/dL, antiplatelet use, anticoagulant use, corticosteroid use,
extravasation on CT, location of the SRH, early colonoscopy, bowel preparation, use
of distal attachment, and use of water-jet scope. In the analysis of need for IVR,
multivariate analysis was adjusted for age, sex, and four factors that were found
to be significant (P < 0.01) on univariate analysis between the groups because at least 10 events per
confounder were needed [20 ]. Although this dataset has very few missing values despite its retrospective design
([Table 1 ]), we considered the effect of missing values on the outcomes. We used multiple imputation
to handle missing values, and compared the results with the complete case analysis
[21 ]
[22 ].
Table 1
Characteristics of patients who underwent endoscopic band ligation or clipping for
colonic diverticular hemorrhage.
Band ligation (n = 638)
Clipping (n = 1041)
P value
Age ≥ 70 years
397 (62.2)
662 (63.6)
0.57
Sex, male
444 (69.6)
735 (70.6)
0.66
Body mass index > 25 kg/m2
171 (28.0)
287 (29.6)
0.49
Current drinker
308 (56.1)
451 (50.1)
0.03
Current smoker
106 (18.6)
151 (16.5)
0.29
Performance status ≥ 2
63 (9.9)
92 (8.8)
0.47
Systolic blood pressure ≤ 100 mmHg
57 (9.0)
134 (13.2)
0.01
Pulse ≥ 100 beats per minute
120 (19.1)
220 (21.7)
0.20
Loss of consciousness
57 (8.9)
59 (5.7)
0.01
Laboratory data
330 (51.7)
604 (58.0)
0.01
68 (10.7)
143 (13.7)
0.07
85 (13.3)
152 (14.6)
0.47
39 (6.3)
79 (7.9)
0.22
110 (17.3)
242 (23.4)
0.003
History of colorectal surgery
38 (6.0)
57 (5.5)
0.68
History of colonic diverticular hemorrhage
260 (40.8)
385 (37.0)
0.12
Modified Charlson co-morbidity index ≥ 2
346 (54.2)
593 (57.0)
0.27
Medication use
63 (9.9)
107 (10.3)
0.79
16 (2.5)
22 (2.1)
0.60
188 (29.5)
362 (34.8)
0.03
72 (11.3)
152 (14.6)
0.05
14 (2.2)
24 (2.3)
0.88
19 (3.0)
66 (6.3)
0.002
Extravasation on contrast-enhanced CT[1 ]
189 (29.6)
253 (24.3)
0.02
Stigmata of recent hemorrhage
373 (58.5)
623 (60.0)
0.58
190 (29.8)
311 (29.9)
0.97
Endoscopic factors
500 (78.4)
825 (79.3)
0.67
589 (92.3)
879 (84.4)
< 0.001
605 (94.8)
923 (88.7)
< 0.001
589 (92.3)
926 (89.0)
0.02
NSAID, nonsteroidal anti-inflammatory drug; CT, computed tomography; PEG, polyethylene
glycol. Note: data are presented as n (%). Missing values were as follows in the band
ligation and clipping group: 27 cases (4.2 %) and 72 cases (6.9 %) for “body mass
index,” 89 (13.9 %) and 131 (13.5 %) for “current drinker,” 67 (10.5 %) and 123 (11.8 %)
for “current smoker,” 6 (0.9 %) and 23 (2.2 %) for “systolic blood pressure,” 10 (1.6 %)
and 29 (2.8 %) for “pulse,” 17 (2.7 %) and 42 (4.0 %) for “albumin,” 2 (0.3 %) and
7 (0.7 %) for “blood urea nitrogen,” and 1 (0.2 %) and 1 (0.1 %) for “history of colonic
diverticular hemorrhage,” respectively.
1 Abdominal CT during hospitalization was performed for 474 patients (74.3 %) in the
band ligation group and 698 patients (67.1 %) in the clipping group. Contrast-enhanced
CT was performed in 397 patients (62.2 %) in the band ligation group and 541 patients
(52.0 %) in the clipping group. Patients who did not undergo CT were included in the
analysis as having no extravasation on contrast-enhanced CT.
2 In patients with non-active bleeding, a visible vessel was found in 127 (19.9 %)
and 178 patients (17.1 %) in the band ligation and clipping groups, respectively,
and an adherent clot was found in 143 (22.4 %) and 249 patients (23.9 %) in the respective
groups. There was no significant difference in the number of visible vessels or adherent
clots between the two groups.
3 Early colonoscopy is defined as that performed within 24 hours of admission.
In subgroup analysis, the rebleeding risk was also compared between EBL and clipping,
using univariate and multivariate logistic regression models, according to SRH type
(active bleeding vs. non-active bleeding), timing of colonoscopy (early colonoscopy
[within 24 hours of admission] vs. non-early colonoscopy), and location of the SRH
(right vs. left). Multivariate analysis in the subgroup analysis was adjusted for
age, sex, and factors found to be significantly different between the two groups (P < 0.05).
A two-sided P value of < 0.05 was considered statistically significant. All statistical analysis
was performed using STATA v.16 (StataCorp., College Station, Texas, USA).
Results
Patient characteristics and clinical outcomes
Characteristics of the patients who underwent band ligation or clipping (n = 1679)
are shown in [Table 1 ]. Some variables were found to be significantly different between the groups, including
current drinker, systolic blood pressure ≤ 100 mmHg, loss of consciousness, hemoglobin
< 12 g/dL, blood urea nitrogen > 25 mg/dL, antiplatelet use, corticosteroid use, extravasation
on CT, and some endoscopic factors.
As shown in [Table 2 ], in multivariate analysis, no significant differences were found between the two
treatments for endoscopic hemostasis rate. Compared with clipping, EBL was independently
associated with reduced risk of early rebleeding (adjusted odds ratio [OR] 0.46; 95 %CI
0.34–0.62; P < 0.001), and late rebleeding (adjusted OR 0.62; 95 %CI 0.49–0.79; P < 0.001). Kaplan–Meier analysis revealed a significantly lower probability of rebleeding
with EBL than with clipping during the mean follow-up period of 13.3 months (log rank
test, P < 0.001) (Fig. 1 s ).
Table 2
Effects of band ligation versus clipping on clinical outcomes.
Band ligation (n = 638)
Clipping (n = 1041)
Crude OR (95 %CI)
P value
Adjusted OR (95 %CI)
P value
Achievement of initial hemostasis
608 (95.3)
994 (95.5)
0.96 (0.60–1.53)
0.86
0.91 (0.53–1.56)
0.76
Rebleeding
84 (13.2)
256 (24.6)
0.46 (0.36–0.61)
< 0.001
0.46 (0.34–0.62)
< 0.001
173 (27.1)
389 (37.4)
0.62 (0.50–0.77)
< 0.001
0.62 (0.49–0.79)
< 0.001
Mortality after endoscopic treatment
1 (0.2)
2 (0.2)
0.82 (0.07–9.01)
0.87
NA
NA
9 (1.4)
13 (1.3)
1.13 (0.48–2.66)
0.78
NA
NA
Thromboembolism
3 (0.5)
9 (0.9)
0.54 (0.15–2.01)
0.36
NA
NA
0 (0)
3 (0.3)
NA
NA
NA
NA
3 (0.5)
4 (0.4)
1.22 (0.27–5.49)
0.79
NA
NA
0 (0)
2 (0.2)
NA
NA
NA
NA
Need for IVR
14 (2.2)
50 (4.8)
0.44 (0.24–0.81)
0.008
0.37 (0.19–0.76)
0.006
Need for surgery
4 (0.6)
5 (0.5)
1.31 (0.35–4.89)
0.69
NA
NA
Red blood cell transfusion needed[3 ]
193 (30.3)
351 (33.7)
0.85 (0.69–1.05)
0.14
0.97 (0.74–1.26)
0.80
Length of hospital stay after endoscopic treatment > 7 days[4 ]
145 (22.7)
476 (45.7)
0.35 (0.28–0.44)
< 0.001
0.35 (0.27–0.45)
< 0.001
OR, odds ratio; DVT, deep vein thrombosis; IVR, interventional radiology; NA, not
applicable.
Note: data are presented as n (%) or median (interquartile range). The multivariate
analysis was adjusted for age, sex, and the following 15 factors that were potentially
clinical important variables, most of which were found to have at least borderline
significance (P < 0.10) on univariate analysis: current drinker, systolic blood pressure ≤ 100 mmHg,
loss of consciousness, hemoglobin < 12 g/dL, white blood cell > 10 000 /µL, blood
urea nitrogen > 25 mg/dL, antiplatelet use, anticoagulant use, corticosteroid use,
extravasation on computed tomography, location, early colonoscopy, bowel preparation,
use of distal attachment, and use of water-jet scope. In the analysis of IVR need,
multivariate analysis was adjusted for age, sex, and four factors found to have significance
(P < 0.01) on univariate analysis between the groups because at least 10 events per
confounder were needed. Outcomes with a smaller number of events were described as
NA in multivariate analysis. Outcomes that included a sample size of zero were excluded
from the analysis.
1 Early rebleeding is defined as rebleeding within 30 days of initial hemostasis.
2 Late rebleeding is defined as rebleeding within 1 year of initial hemostasis.
3 Units of red blood cell transfused were 4 (2–6) in the band ligation group and 4
(2–6) in the clipping group, among only the patients who required red blood cell transfusion
(P = 0.003). The mean number of units transfused was 5.1 in the band ligation group
and 5.7 in the clipping group.
4 Length of hospital stay after endoscopic treatment was 5 (4–7) days in the band ligation
group and 7 (5–10) days in the clipping group (P < 0.001).
No significant differences were noted in mortality within 30 days or 1 year of endoscopic
treatment, or in-hospital thromboembolism ([Table 2 ]). Compared with clipping, EBL independently reduced the risk of needing IVR (adjusted
OR 0.37; 95 %CI 0.19–0.76; P = 0.006) and prolonged LOS (adjusted OR 0.35; 95 %CI 0.27–0.45; P < 0.001), whereas the need for surgery and the need for transfusion were not significantly
different between the two treatments. There were no significant differences in the
results when the missing values were imputed using the multiple imputation method
(Table 2 s ).
Endoscopic treatment and rebleeding risk according to bleeding type, timing of colonoscopy,
and location
Uni- and multivariate logistic regression models revealed that, relative to clipping,
EBL had significantly lower ORs for early and late rebleeding in patients with active
bleeding (P < 0.05; [Table 3 ]). In patients with early colonoscopy, EBL had a significantly lower OR of early
and late rebleeding relative to clipping (P < 0.05). In patients with non-early colonoscopy, EBL also had a significantly lower
OR for early rebleeding, although not for late rebleeding, compared with clipping.
The OR of early and late rebleeding after EBL compared with clipping was significantly
lower in the right-sided colon (P < 0.05), but not in the left-sided colon.
Table 3
Comparison of rebleeding risks between endoscopic band ligation and clipping for colonic
diverticular hemorrhage according to type of bleeding (active bleeding vs. non-active
bleeding) on colonoscopy, the timing of colonoscopy, and bleed location (right vs.
left) in logistic regression models.
Active bleeding(n = 996)
Band ligation(n = 373)
Clipping(n = 623)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
53 (14.2)
181 (29.1)
0.40 (0.29–0.57)
< 0.001
0.41 (0.29–0.57)
< 0.001
Late rebleeding[2 ]
114 (30.6)
265 (42.5)
0.59 (0.45–0.78)
< 0.001
0.59 (0.45–0.78)
< 0.001
Non-active bleeding (n = 683)
Band ligation (n = 265)
Clipping (n = 418)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
31 (11.7)
75 (17.9)
0.61 (0.39–0.95)
0.03
0.69 (0.43–1.11)
0.13
Late rebleeding[2 ]
59 (22.3)
124 (29.7)
0.68 (0.47–0.97)
0.03
0.69 (0.47–1.00)
0.05
Early colonoscopy
[3 ]
(n = 1325)
Band ligation
(n = 500)
Clipping (n = 825)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
73 (14.6)
211 (25.6)
0.50 (0.37–0.67)
< 0.001
0.47 (0.34–0.66)
< 0.001
Late rebleeding[2 ]
138 (27.6)
319 (38.7)
0.60 (0.48–0.77)
< 0.001
0.60 (0.46–0.79)
< 0.001
Non-early colonoscopy (n = 354)
Band ligation
(n = 138)
Clipping (n = 216)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
11 (8.0)
45 (20.8)
0.33 (0.16–0.66)
0.002
0.35 (0.17–0.72)
0.004
Late rebleeding[2 ]
35 (25.4)
70 (32.4)
0.71 (0.44–1.14)
0.16
0.79 (0.48–1.29)
0.34
Right-sided colon (n = 1178)
Band ligation (n = 448)
Clipping (n = 730)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
48 (10.7)
180 (24.7)
0.37 (0.26–0.52)
< 0.001
0.37 (0.26–0.53)
< 0.001
Late rebleeding[2 ]
108 (24.1)
265 (36.3)
0.56 (0.43–0.73)
< 0.001
0.56 (0.42–0.73)
< 0.001
Left-sided colon (n = 501)
Band ligation (n = 190)
Clipping (n = 311)
Crude OR (95 %CI)
P
value
Adjusted OR (95 %CI)
P
value
Early rebleeding[1 ]
36 (18.9)
76 (24.4)
0.72 (0.46–1.13)
0.15
0.86 (0.52–1.41)
0.55
Late rebleeding[2 ]
65 (34.2)
124 (39.9)
0.78 (0.54–1.14)
0.21
0.89 (0.59–1.35)
0.59
CT, computed tomography.
Note: data are presented as n (%). Multivariate analysis was adjusted for age, sex,
and the factors found to have at least significance (P < 0.05) on univariate analysis between the two groups as follows: in a subgroup analysis
of active bleeding, blood urea nitrogen > 25 mg/dL, anticoagulant use, bowel preparation,
and use of distal attachment; in a subgroup analysis of non-active bleeding, hemoglobin
< 12 g/dL, albumin < 3.0 g/dL, blood urea nitrogen > 25 mg/dL, corticosteroid use,
extravasation on CT, bowel preparation, use of distal attachment, and use of water-jet
scope; in a subgroup analysis of early colonoscopy, current drinker, systolic blood
pressure ≤ 100 mmHg, loss of consciousness, hemoglobin < 12 g/dL, white blood cell
> 10 000 /µL, blood urea nitrogen > 25 mg/dL, antiplatelet use, anticoagulant use,
corticosteroid use, extravasation on CT, bowel preparation, and use of distal attachment;
in a subgroup analysis of early colonoscopy, current drinker, systolic blood pressure
≤ 100 mmHg, loss of consciousness, hemoglobin < 12 g/dL, white blood cell > 10 000 /µl,
blood urea nitrogen > 25 mg/dL, antiplatelet use, anticoagulant use, corticosteroid
use, extravasation on CT, bowel preparation, and use of distal attachment; in a subgroup
analysis of non-early colonoscopy, active bleeding, use of distal attachment, and
use of water-jet scope; in a subgroup analysis of right-sided colon, systolic blood
pressure ≤ 100 mmHg, loss of consciousness, blood urea nitrogen > 25 mg/dL, modified
Charlson co-morbidity index ≥ 2, extravasation on CT, bowel preparation, use of distal
attachment, and use of water-jet scope; in a subgroup analysis of left-sided colon,
current smoker, antiplatelet use, corticosteroid use, and bowel preparation.
1 Early rebleeding is defined as rebleeding within 30 days of initial hemostasis.
2 Late rebleeding is defined as rebleeding within 1 year of initial hemostasis.
3 Early colonoscopy is defined as that performed within 24 hours of admission.
Endoscopically relevant adverse events
Colonic diverticulitis was identified in one patient (0.16 %) following EBL and two
patients (0.19 %) following clipping ([Table 4 ]). Colonic perforation developed in two patients (0.31 %) following EBL, but in none
following clipping. No significant differences in AEs were found between the two treatments.
Table 4
Characteristics and clinical outcomes of patients with endoscopically relevant adverse
events for colonic diverticular hemorrhage.
Case number
1
2
3
4
5
Age, years
79
80
83
60
83
Sex
Female
Female
Male
Male
Male
BMI, kg/m2
20
17
23
23
15
Current drinker/smoker
No/No
No/No
Unknown/No
Yes/Yes
Yes/No
Laboratory data on admission
Hemoglobin, g/dL
7.6
11.2
12.2
9.6
8.3
Albumin, g/dL
2.6
4.2
3.9
3.7
2
Co-morbidities
Hypertension, chronic renal failure on hemodialysis
None
Hypertension, diabetes mellitus, ischemic heart disease, chronic renal failure
Hypertension, diabetes mellitus, chronic hepatitis
Hypertension, diabetes mellitus, hyperlipidemia, cerebrovascular disease
Medication
Antithrombotic agent
No
No
Low-dose aspirin, warfarin
Warfarin
Low-dose aspirin
NSAIDs
No
No
No
No
No
Corticosteroid
No
No
No
No
No
Stigmata of recent hemorrhage
Active bleeding
Active bleeding
Active bleeding
Adherent clot
Adherent clot
Location
Descending colon
Sigmoid colon
Sigmoid colon
Ascending colon
Ascending colon
Endoscopic treatment
Band ligation
Band ligation
Clipping
Clipping
Band ligation
Endoscopically relevant adverse event
Perforation
Perforation
Diverticulitis
Diverticulitis
Diverticulitis
Time until adverse event after endoscopic treatment, days
5
4
1
3
4
Treatment for adverse event
Surgery
Surgery
Conservative therapy
Conservative therapy
Conservative therapy
BMI, body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs.
Discussion
Analysis of our large nationwide dataset for acute hematochezia has revealed detailed
baseline characteristics and clinical outcomes relevant to endoscopic therapy for
CDH. Notably, we found that EBL significantly lowered both the early and late rebleeding
rates after endoscopic treatment for CDH compared with clipping, regardless of active
bleeding or early colonoscopy. Moreover, EBL was associated with less need for IVR
and shorter LOS. Both endoscopic treatments achieved high success rates of initial
hemostasis, with low rates of death and thromboembolism. Finally, analysis of our
large dataset (n = 1679) revealed very few AEs related to EBL or clipping, with diverticulitis
developing in 0.16 % (1/638) and 0.19 % (2/1041) of patients, respectively, and colonic
perforation in 0.31 % (2/638) and 0 % (0/1041) of patients.
This study revealed that EBL was better able to prevent early rebleeding compared
with clipping. EBL allows for occlusion of the underlying artery, thereby contributing
to the prevention of early rebleeding, whereas the risk of early rebleeding following
clipping depends on whether or not the endoclips are placed directly on the visible
vessel [4 ]
[9 ]. In our experience, even though we usually place multiple endoclips for CDH with
SRH, hemostasis may be difficult to achieve, especially in patients with active bleeding,
a small diverticular orifice, or where the site of hemorrhage is at the base of the
diverticulum, and early rebleeding may still occur. This led us to hypothesize that
EBL would have the advantage of achieving hemostasis and reducing rebleeding compared
with clipping in patients with active bleeding. As we hypothesized, EBL did significantly
decrease the rate of early and late rebleeding relative to clipping, regardless of
active bleeding.
Additionally, EBL also reduced the rate of late rebleeding in this study, consistent
with the finding of previous small cohort studies [4 ]
[23 ]. Because scar formation at the previous treatment site is observed in most patients
and the diverticulum itself disappears after ligation [4 ]
[23 ], rebleeding from the same diverticulum treated with EBL theoretically cannot occur,
so EBL may prevent late rebleeding as well as early rebleeding. However, we often
have CDH patients who experience repeated bleeding in the long term, with rebleeding
often occurring at a site different from the previously treated one [4 ]. Regrettably, in this study, we could not confirm whether rebleeding was from the
original site. Most patients have multiple diverticula, and increasing numbers of
patients have various risk factors for CDH (e. g. advanced age, obesity, arteriosclerotic
disease, and medication use) [24 ]. Taken together, it appears that endoscopic hemostasis alone is not enough to prevent
rebleeding in the long term. Therefore, in addition to effective endoscopic treatment,
the rebleeding risk should be reduced by, for example, avoiding the administration
of antithrombotic agents or NSAIDs.
Consistent with previous studies, the need for IVR was lower with EBL than with clipping
[10 ]. We believe that this reduction in rebleeding during hospitalization following EBL
led to the reduced need for IVR, which in turn probably led to the shorter LOS seen
with EBL. Indeed, the association between rebleeding and need for IVR was found to
be significant in the entire CODE BLUE-J study population [15 ]
[16 ]. In contrast, the number of patients needing surgery, developing thromboembolism,
or dying was too small to reach statistical significance between the two treatments.
Most reports on endoscopic treatment for CDH have focused on effectiveness, and limited
data exist regarding procedure-related AEs because of their rarity. However, clarifying
the rates of AEs is important in determining treatment strategy and providing appropriate
information for informed consent. In this study, the endoscopically relevant AEs were
diverticulitis (0.18 %) with each treatment and perforation (0.12 %) with EBL. To
date, diverticulitis after clipping has not been reported, while two cases have been
reported after EBL [4 ]
[25 ]. Mechanical tissue damage following an endoscopic procedure causes an ulcer to form
on the intestinal mucosa, which assists in the invasion of gut commensal bacteria
and may lead to local colonic inflammation. In relation to endoscopy treatment-related
perforation, we should consider the potential risk of delayed perforation following
hemostasis with the ligation method because of the absence of the muscular layer in
the colonic diverticulum [26 ]
[27 ]
[28 ]. The incidence of colonic perforation is generally estimated to be 0 %–0.33 % for
whole therapeutic colonoscopies (n = 74 630) [29 ], suggesting that our result of 0.12 % in CDH treatment is not so high compared with
other endoscopic treatments.
We acknowledge that this study has some limitations. First, this was not a randomized
controlled trial. Such trials are challenging to conduct in the emergency setting
of acute lower gastrointestinal bleeding because of the lengthy time they would take
to complete [30 ]. Second, endoscopic clipping was not classified as direct or indirect placement
in this study, and we plan to compare the effectiveness of these two methods in a
separate study. Third, we could not consider the time period of endoscopic devices
such as new clips or EBL in the analysis because we could not obtain detailed information
on the prevalence of each treatment method at each institution.
The strengths of our study include the very large number of cases analyzed (n = 1679)
and few missing data values [15 ]
[16 ]. This large long-term dataset enabled us to make a detailed analysis of baseline
characteristics, endoscopic information, and SRH type and location, which are all
factors that may affect clinical outcome, but which have not been examined fully in
previous studies. Moreover, we could evaluate the long-term rebleeding and mortality
rates after endoscopic therapy for CDH.
In conclusion, this nationwide multicenter cohort study revealed the effectiveness
and AEs related to endoscopic therapy for CDH. EBL had the advantages of both lower
early and late rebleeding rates, reduced need for IVR, and shortened LOS. Our findings
can offer patients and physicians useful information on the safety and effectiveness
of endoscopic therapy and help in the selection of endoscopic treatment technique
for diverticular hemorrhage.
