Keywords
Endoscopy Small Bowel - Endoscopy Lower GI Tract - Quality and logistical aspects
- Performance and complications - Endoscopic resection (polypectomy, ESD, EMRc, ...)
Introduction
Deep vein thrombosis (DVT) is one of the major complications in patients who have
undergone surgery and in immobile patients hospitalized for a medical illness [1]. Untreated DVT can cause pulmonary thromboembolism (PE), which has a potentially
fatal outcome [2]. Therefore, early diagnosis and prevention of DVT are important issues to reduce
risk of thrombosis-related complications.
Orthopedic surgery is associated with a high risk of DVT and PE [3]. Abdominopelvic surgery is also a potential risk for DVT and PE [4]. Therefore, perioperative patients must be treated with appropriate DVT prophylaxis,
such as using graduated compression stockings (GCS), intermittent pneumatic compression,
low-dose unfractionated heparin, and low-molecular-weight heparin, based on the results
of preoperative risk evaluation [4]
[5]. To stratify risk of DVT/PE, the Caprini and Padua risk assessment models have been
used in patients undergoing surgery and patients hospitalized in Internal Medicine
[4]
[6]
[7]
[8]. However, how to perform risk assessment of DVT before endoscopy and whether DVT
prophylaxis is required for patients undergoing endoscopic treatment remain unclear.
Advances in medical devices for endoscopy have made it possible to diagnose and treat
small intestinal diseases and to resect large colorectal tumors en bloc [9]
[10]
[11]
[12]. Double-balloon endoscopy (DBE) is a useful procedure that enables definitive diagnosis
and endoscopic treatment for small intestinal diseases [9]
[12]
[13]. However, DBE requires a high degree of skill technique and takes longer than esophagogastroduodenoscopy
and total colonoscopy. Previous studies have reported that the median insertion time
required for panenteroscopy was over 120 minutes [9]
[12], which may be a potential risk for DVT after DBE. In addition, DBE is frequently
employed for diagnosis of patients with inflammatory bowel disease (IBD), who have
a higher incidence of DVT/PE than those with other digestive diseases [14]
[15].
Compared with endoscopic mucosal resection, colorectal endoscopic submucosal dissection
(ESD) allows en bloc resection of large colorectal tumors, which leads to accurate
pathological diagnosis and lower rates of recurrence [16]
[17]. However, colorectal ESD also requires a more advanced technique than esophageal
and gastric ESD. Furthermore, colorectal ESD requires a long operative time similar
to DBE. In lesions measuring > 40 mm, median operative time for colorectal ESD was
> 2 hours [16]
[18].
DBE and colorectal ESD require that patients to remain in the same position for a
long time and that air insufflation to the small and large intestines is continuous,
resulting in increased abdominal pressure and venous insufficiency. Thus, DBE and
colorectal ESD are the most invasive endoscopic procedures, and they and other surgical
procedures may place patients at risk for DVT and PE. However, no prospective studies
have examined incidence of DVT after DBE and colorectal ESD. Incidence of DVT after
invasive endoscopy including DBE and colorectal ESD remains unknown. Thus, this multicenter,
prospective, cohort study (De-ViT study) aimed to clarify risk of DVT and PE after
highly invasive endoscopic procedures such as DBE and colorectal ESD.
Patients and methods
Patients and ethics
Patients who met all the inclusion criteria except for no DVT received screening whole-leg
ultrasonography (US) or contrast-enhanced computed tomography (CECT), and patients
who met all the inclusion criteria were prospectively enrolled from September 2020
to June 2022. Inclusion criteria were as follows: (1) patients who were scheduled
to undergo colorectal ESD for superficial colorectal neoplasms or DBE for suspected
small intestinal disease; (2) no DVT on whole-leg US or CECT before DBE or ESD; (3)
age ≥ 20 and ≤ 89 years; and (4) agreement with signed informed consent. Exclusion
criteria were as follows: (1) previous history of DVT/PE; (2) central venous access;
(3) history of cerebral stroke within 3 months; (4) history of bone fracture within
3 months; (5) history of major surgery under general anesthesia within 3 months; (6)
history of acute infection within 3 months; (7) history of an acute coronary syndrome
within 6 months; (8) hematologic diseases including congenital or acquired coagulation
abnormalities; (9) severe heart, lung, liver, and kidney dysfunction and severe diabetes;
(10) arteriosclerosis obliterans or varicose veins; (11) lower extremity dermatitis
or skin ulcers; (12) peripheral neuropathy; (13) poor status (Eastern Cooperative
Oncology Group performance status ≥ 3); (14) pregnancy; (15) mental disorders and
dementia such that there was inability to understand the study contents; and (16)
unfit by physician’s judgment.
Seven Japanese institutions participated in the De-ViT study. The study protocol was
approved by each institution’s ethics committee. The trial was performed according
to the ethical guidelines of the 1975 Declaration of Helsinki (7th revision, 2013).
Written informed consent was obtained from all participants before study enrollment.
Before the trial commenced, it was registered with the University Hospital Medical
Information Network Clinical Trials Registry (UMIN-CTR, UMIN000041789). The De-ViT
study complied with the STROBE statement [19]. All authors had access to the study data and reviewed and approved the final manuscript.
Study design and procedures
The De-ViT study was a multicenter, prospective, cohort study that assessed incidence
of DVT/PE following colorectal ESD or DBE. Patients undergoing colorectal ESD for
superficial colorectal neoplasms or DBE for suspected intestinal diseases were prospectively
enrolled. All enrolled patients were confirmed to have no DVT on whole-leg US or CECT
within 21 days before ESD or DBE, and each investigator registered the patient in
the central data center.
Risk assessment for DVT was performed using the Caprini score [4] and the Padua score [6] before ESD/DBE. All patients routinely underwent whole-leg US and blood examination
including D-dimer between Days 1 and 7 after ESD or DBE. Before post-ESD/DBE whole-leg
US, all patients were assessed for the possibility of DVT using the Wells score. Whenever
patients were diagnosed with DVT by whole-leg US or suspected of having DVT/PE, they
had to undergo a chest CECT. In accordance with the preplanned protocol, patients
who underwent emergent surgery or interventional radiology between enrollment and
post-ESD/DBE whole-leg US were excluded from the analysis.
Colorectal ESD was performed using a single-channel endoscope (PCF-H290TI; Olympus
Co., Tokyo, Japan). DBE (EI-580BT, EN-580T; Fujifilm Co., Tokyo, Japan), which has
two inflatable balloons. The insertion route was selected depending on the target
lesion inferred from other examinations before DBE, such as peroral insertion and
transanal insertion for a suspected jejunal and ileal lesion, respectively. Carbon
dioxide insufflation was used during colorectal ESD and DBE. Use of GCS for periprocedural
DVT prophylaxis was determined beforehand, depending on the institution. No institutions
used GCS for DBE. Regarding colorectal ESD, three institutions used GCS for all participants,
but four institutions never used GCS.
Sample size and statistical analysis
The primary endpoint of this study was incidence of DVT within 30 days after colorectal
ESD and DBE. Secondary endpoints were incidence of PE after ESD/DBE, adverse events,
risk factors for DVT after ESD/DBE, conventional risk scores (Caprini, Padua, and
Wells scores), and establishment of a novel risk stratification of post-ESD/DBE DVT.
Incidence of DVT before ESD/DBE was also analyzed to predict risk of pre-ESD/DBE DVT.
This study was a novel prospective study, given the scarcity of available data on
DVT post-endoscopic procedure. Only one study investigated post-endoscopic DVT, in
which incidence of DVT after gastric ESD was 10% [20]. When incidence of DVT is 10%, the sample size estimated with ± 5% of 95% confidence
interval (CI) was 162 for colorectal ESD and the sample size estimated with ± 8% of
95% CI was 69 cases for DBE. The final preplanned sample size was 170 patients for
colorectal ESD and 75 for DBE, allowing for a dropout rate of approximately 10% because
of withdrawal of consent or other reasons.
Results
Patient characteristics
Between September 2020 and June 2022, 271 patients who were scheduled to undergo colorectal
ESD or DBE fulfilled the inclusion criteria and underwent screening whole-leg US or
CT before study enrollment. Among the 271 patients who fulfilled the inclusion criteria,
25 with colorectal ESD and one with DBE were not enrolled, and a total of 245 patients
(colorectal ESD cohort, n = 170; DBE cohort, n = 75) were enrolled in this study ([Fig. 1]) [21]. After study enrollment, one patient was excluded because colorectal ESD was not
performed and three patients in the DBE cohort were excluded because of enrollment
error: one patient had DVT on screening US, one had a duplicated enrollment, and another
patient did not undergo screening whole-leg US or CT before enrollment. Two patients
with emergency surgery post-ESD/DBE were excluded, and finally, 238 patients (colorectal
ESD cohort, n = 167; DBE cohort, n = 71) were analyzed in this study.
Fig. 1 Consort diagram in the main analysis [21]. CECT, contrast-enhanced computed tomography; DBE, double-balloon endoscopy; DVT,
deep vein thrombosis; ESD, endoscopic submucosal dissection; US, ultrasound.
Baseline characteristics are shown in [Table 1]. None of the patients had DVT before enrollment. Median age was 67 years. Primary
diseases necessitating colorectal ESD and DBE are also shown in [Table 1]. Median endoscopic procedure times were 110 and 64 minutes in the colorectal ESD
and DBE cohorts, respectively. Median Caprini scores were both 3 points in the colorectal
ESD and DBE cohorts. Median Padua scores were 1 and 0 points in the colorectal ESD
and DBE cohorts, respectively. All median values before colorectal ESD and DBE were
within reference ranges (Supplementary Table S1).
Table 1 Background characteristics of patients.
|
Colorectal ESD
(n = 167)
|
DBE
(n = 71)
|
Total
(n = 238)
|
|
BMI, body mass index; CECT, contrast-enhanced computed tomography; DBE, double-balloon
endoscopy; DVT, deep vein thrombosis; ESD, endoscopic submucosal dissection; PE, pulmonary
embolism; PE, pulmonary embolism US, ultrasound.
*Not including asthma.
|
|
Median age (years) [range]
|
70 [34–89]
|
51 [20–88]
|
67 [20–89]
|
|
Sex (male/female)
|
101/66
|
52/19
|
153/85
|
|
Median BMI (kg/m2) [range]
|
22.8 [15.1–38.8]
|
22.2 [14.5–34]
|
22.6 [14.5–38.8]
|
|
The Methods of screening for DVT (US/CECT)
|
136/31
|
32/39
|
168/70
|
|
Comorbidity
|
|
|
58 (34.7%)
|
9 (12.6%)
|
67 (28.2%)
|
|
|
27 (16.2%)
|
6 (8.4%)
|
33 (13.9%)
|
|
|
28 (16.8%)
|
5 (7%)
|
33 (13.9%)
|
|
Medical history
|
|
|
8 (4.8%)
|
6 (8.4%)
|
14 (5.9%)
|
|
|
5 (3%)
|
1 (1.4%)
|
6 (2.5%)
|
|
|
3 (1.8%)
|
41(57.7%)
|
44 (18.5%)
|
|
|
3 (1.8%)
|
2 (2.8%)
|
5 (2.1%)
|
|
Family history of DVT or PE
|
1 (0.6%)
|
0
|
1 (0.4%)
|
|
Medication
|
|
|
|
|
|
10 (6%)
|
3 (4.2%)
|
13 (5.5%)
|
|
|
6 (3.6%)
|
1 (1.4%)
|
7 (2.9%)
|
|
|
3 (1.8%)
|
2 (2.8%)
|
5 (2.1%)
|
|
|
1 (0.6%)
|
1 (1.4%)
|
2 (0.8%)
|
|
Primary disease
|
|
|
104 (62.3%)
|
0
|
104 (43.7%)
|
|
|
56 (33.5%)
|
0
|
56 (23.6%)
|
|
|
42 (25.1%)
|
0
|
42 (17.6%)
|
|
|
4 (2.4%)
|
0
|
4 (1.7%)
|
|
|
2 (1.2%)
|
0
|
2 (0.8%)
|
|
|
53 (31.7%)
|
0
|
53 (22.3%)
|
|
|
2 (1.2%)
|
0
|
2 (0.8%)
|
|
|
6 (3.6%)
|
0
|
6 (2.5%)
|
|
|
0
|
41 (57.7%)
|
41 (17.2%)
|
|
|
0
|
4 (5.6%)
|
4 (1.7%)
|
|
|
0
|
12 (16.9%)
|
12 (5%)
|
|
|
2 (1.2%)
|
14 (19.7%)
|
16 (6.7%)
|
|
Endoscopy procedure time (min) [range]
|
110 [15–1020]
|
64 [6–130]
|
89 [6–1020]
|
|
Median Caprini score [range]
|
3 [0–6]
|
3 [0–6]
|
3 [0–6]
|
|
Median Padua score [range]
|
1 [0–3]
|
0 [0–4]
|
0 [0–4]
|
Clinical outcomes after ESD and DBE
Clinical outcomes following colorectal ESD and DBE are shown in [Table 2]. Of the 238 patients, DVT occurred in only one patient following colorectal ESD.
Incidence of DVT was 0.4% (95% CI 0–1.2) in total, including 0.6% (95% CI 0–1.8) after
colorectal ESD and 0% after DBE. Baseline characteristics and preprocedure values
of the patient with DVT following ESD are shown in Supplementary Table S2. The patient was an 81-year-old woman with hypertension as a comorbidity. No specific
abnormalities were found, and the Caprini and Padua scores before colorectal ESD were
4 and 1, respectively. She completed colorectal ESD without any complications in 148
minutes; however, an asymptomatic DVT was found on whole-leg US on post-ESD Day 4.
Follow-up without specific medication was selected, and the DVT naturally disappeared
on whole-leg US 1 month after colorectal ESD. In contrast, no PE was observed in the
entire cohort. One patient died within 30 days following DBE because of hypoxic encephalopathy,
and the mortality rate within 30 days after ESD/DBE was 0.4% (95% CI 0–1.2).
Table 2 Adverse events After ESD and DBE.
|
Colorectal ESD (n = 167)
|
DBE (n = 71)
|
Total (n = 238)
|
|
Rates of DVT, PE, mortality, and adverse event represent are 30 days after ESD or
DBE. CI, confidence interval; DBE, double-balloon endoscopy; DVT, deep vein thrombosis;
ESD, endoscopic submucosal dissection; PE, pulmonary embolism; PECS, post endoscopic
submucosal dissection electrocoagulation syndrome.
|
|
DVT (n) (% [95%CI])
|
1 (0.6 [0–1.8])
|
0 (0% [0–0])
|
1 (0.4% [0–1.2])
|
|
PE (n) (% [95%CI])
|
0 (0% [0–0])
|
0 (0% [0–0])
|
0 (0% [0–0])
|
|
Mortality (% [95%CI])
|
0 (0% [0–0])
|
1 (1.4% [0–4.2])
|
1 (0.4% [0–1.2])
|
|
Other adverse events (% [95%CI])
|
14 (8.4% [4.2–12.6])
|
2 (2.8% [0–6.7])
|
16 (6.7% [3.5–9.9])
|
|
Delayed bleeding
|
3 (1.8% [0–3.8])
|
0 (0% [0–0])
|
3 (1.2% [0–2.7])
|
|
PECS
|
9 (5.4% [2.0–8.8])
|
0 (0% [0–0])
|
9 (3.8% [1.4–6.2])
|
|
Delayed perforation
|
2 (1.2% [0–2.8])
|
0 (0% [0–0])
|
2 (0.8% [0–2.0])
|
|
Pneumonia
|
0 (0% [0–0])
|
1 (1.4% [0–4.2])
|
1 (0.4% [0–1.2])
|
|
Others
|
0 (0% [0–0])
|
1 (1.4% [0–4.2])
|
1 (0.4% [0–1.2])
|
|
D-dimer (μg/mL) [range]
|
0.6 [0.03–5.76]
|
0.5 [0.1–8.2]
|
0.6 [0.03–8.2]
|
|
Wells score [range]
|
0 [–2–1]
|
0 [0–1]
|
0 [–2–1]
|
Incidence of DVT with or without GCS after colorectal ESD and DBE is shown in Supplementary Table S3. A patient with DVT following colorectal ESD used prophylactic GCS. No significant
differences were found in incidence of DVT between patients using or not using GCS.
Risk factors for DVT before colorectal ESD or DBE
Risk factors of DVT before colorectal ESD or DBE were analyzed ([Table 3]). Of the 271 patients who had undergone screening, 269 who received screening with
whole-leg US or CECT were analyzed in this subset analysis. Among them, DVT was found
in eight patients (3.0%) (pre-ESD, n = 6; pre-DBE, n = 2) (Supplementary Fig. S1). The proportion of female patients was significantly higher in the DVT group than
in the non-DVT group (P < 0.001). Frequency of mental disorder was also significantly
higher in the DVT group than in the non-DVT group (P < 0.001). No significant difference
was found in Caprini score between the two groups, whereas the Padua score before
ESD/DBE were significantly higher in the DVT group than in the non-DVT group (P =
0.004). All patients with DVT were observed without any specific medication therapy.
Table 3 Characteristics of patients with DVT before colorectal ESD or DBE.
|
Non-DVT (n = 261)
|
DVT (n = 8)
|
P value
|
|
CECT, contrast-enhanced computed tomography; DBE, double-balloon endoscopy; DVT, deep
vein thrombosis; ESD, endoscopic submucosal dissection; PE, pulmonary embolism; US,
ultrasound. *Mann-Whitney U test.
†Fisher’s exact probability test.
|
|
Median age (years) [range]
|
67 [20–89]
|
73.5 [48–84]
|
0.069*
|
|
Sex (male/female)
|
169/92
|
0/8
|
< 0.001†
|
|
Methods of screening for DVT (US/CECT)
|
190/71
|
5/3
|
0.520†
|
|
ESD/DBE
|
189/72
|
6/2
|
> 0.999†
|
|
Primary disease
|
|
Colorectal neoplasms
|
187 (71.6%)
|
6 (75%)
|
0.835†
|
|
Inflammatory bowel disease
|
42 (16.1%)
|
0
|
0.216†
|
|
|
4 (1.5%)
|
1 (12.5%)
|
0.141†
|
|
|
12 (4.6%)
|
1 (12.5%)
|
0.330†
|
|
|
16 (6.2%)
|
0
|
> 0.999†
|
|
Family history of DVT or PE
|
1 (0.4%)
|
0
|
> 0.999†
|
|
Mental disorder
|
0
|
2 (25%)
|
< 0.001†
|
|
Oral contraceptives or hormone therapy
|
5 (1.9%)
|
1 (12.5%)
|
0.167†
|
|
Chemotherapy within 1 month
|
1 (0.4%)
|
1(12.5%)
|
0.058†
|
|
Median Caprini score [range]
|
3 [0–6]
|
3 [2–4]
|
0.838*
|
|
Median Padua score [range]
|
0 [0–4]
|
1 [1–1]
|
0.004*
|
Discussion
To the best of our knowledge, this is the first multicenter, prospective study to
determine incidence of DVT and PE following invasive endoscopic procedures including
colorectal ESD and DBE. Our findings demonstrated the low risk of DVT and PE even
after highly invasive endoscopic procedures. Furthermore, screening with whole-leg
US or CECT before colorectal ESD and DBE may be useful for detecting asymptomatic
DVT. In addition, being female and presence of a mental disorder were significant
risk factors for detection of DVT before colorectal ESD and DBE.
Several studies have reported a high incidence of DVT (10%-40%) after abdominal surgery
[22]
[23]. However, a few studies have focused on incidence of and risk factors for gastrointestinal
endoscopy-related DVT or PE. Regarding ESD, only one study reported incidence of DVT,
i.e., 10.0% after gastric ESD [20]. Although this was a prospective study, it analyzed a small number of cases (n =
60) at a single center, and background characteristics of the enrolled patients were
unclear. A previous retrospective case-control study showed that patients with DVT
or PE were more frequently subjected to gastrointestinal endoscopy within 3 months
before disease onset than patients without DVT or PE (10.3% vs. 3.2%), suggesting
that gastrointestinal endoscopy may enhance risk of DVT [24]. However, whether gastrointestinal endoscopy is a risk factor for DVT is still inconclusive
because this study did not describe in detail baseline characteristics or presence
or absence of other procedures.
In the present study, of the 238 patients who underwent colorectal ESD or DBE, only
one had DVT after colorectal ESD. Thus, incidence of DVT was 0.4% in total, including
0.6% after colorectal ESD and 0% after DBE. These results suggest the extremely low
risk of DVT after colorectal ESD and DBE when appropriate risk assessment is conducted
before procedures. Furthermore, no significant difference was found in incidence of
DVT between use and non-use of GCS to prevent DVT. This suggests that DVT prophylaxis
such as GCS during invasive endoscopy might not be necessary for patients who are
determined to be at low risk for DVT based on risk assessment before colorectal ESD
or DBE.
Given that DVT/PE development following surgery can lead to fatal outcomes, preoperative
assessment stratifying risk of DVT/PE is important. However, the significance of preoperative
DVT screening using whole-leg US or CECT remains unclear for asymptomatic patients
who undergo surgery. In addition, no study has reported risk factors for asymptomatic
DVT before invasive endoscopy. In patients with gastric cancer, preoperative incidence
of DVT with screening whole-leg US was 4.4% (7/160) [25]. Moreover, Tanizawa et al. showed that of 1140 patients with gastric cancer, 86
(7.5%) had DVT preoperatively [26]. In the present study, among 269 patients who underwent screening with whole-leg
US or CECT before colorectal ESD and DBE, DVT was found in eight patients (3.0%) (pre-ESD,
n = 6; pre-DBE, n = 2). Our findings revealed that DVT can be identified in not only
patients with gastrointestinal cancer or IBD, who have been reported as at risk for
DVT, but also patients categorized as having a low risk for DVT through preprocedure
screening. Notably, being female and having a mental disorder were significant risk
factors for DVT detection before colorectal ESD or DBE. Antipsychotic agent use was
reported as a risk factor for DVT/PE [27], which is consistent with our results. Based on these findings, to prevent postoperative
DVT, preoperative whole-leg US or CECT screening may be useful for identifying asymptomatic
DVT, particularly in patients with these risk factors.
The Caprini and Padua scores have been used as models for DVT/PE risk assessment in
patients undergoing surgery and patients hospitalized in Internal Medicine, respectively
[4]
[6]
[7]
[8]. However, no study has reported on how to assess risk for DVT before an invasive
endoscopy. In the present study, the Padua score before ESD/DBE was significantly
higher in the DVT group than in the non-DVT group (P = 0.004). In contrast, previous
studies have reported that the Caprini score was more effective than the Padua score
in identifying inpatients at risk for DVT/PE [28]
[29]. Results of the present study and previous studies are different because of the
differences in backgrounds of patients recruited in each study. Despite the significant
difference in the Padua score between the non-DVT and DVT groups, the median score
was 0 in the non-DVT group and 1 in the DVT group, and a tiny difference might be
clinically meaningless. Moreover, the reported cutoff value of the Padua score was
4 for risk of venous thromboembolism in patients hospitalized in the Internal Medicine
department [6]. Further research is needed to determine whether the Padua score is useful for screening
pre-endoscopic DVT.
This study has some limitations. First, because incidence of DVT/ PE in the current
study was much lower than expected, the sample size may be low for finding the true
incidence of DVT/PE after colorectal ESD and DBE. However, the most important and
novel finding of this study is that incidence of DVT/PE after colorectal ESD and DBE
is very low. Second, patients at high risk of DVT were excluded from this study because
not employing prophylactic procedures for high-risk patients could present an ethical
concern. Therefore, incidence of DVT and PE after invasive endoscopy in high-risk
patients could not be evaluated. Because patients at high risk for DVT might have
a higher risk for DVT and PE after invasive endoscopy than regular patients, screening
with whole-leg US or CECT before endoscopy might be useful for early detection of
DVT in the high-risk population.
Conclusions
In conclusion, risk of DVT and PE following highly invasive endoscopic procedures
including colorectal ESD and DBE is extremely low, and patients without high-risk
factors would not require DVT prophylaxis such as GCS. In contrast, screening with
whole-leg US or CECT before colorectal ESD and DBE may be useful to identify DVT even
in patients who are at low risk for DVT.
