Effect of a distal attachment cuff on adenoma detection rate in screening colonoscopy: Randomized controlled trial in the Spanish population

Abstract

Background and study aims

Endocuff Vision (EV) is a disposable device designed to improve polyp detection. The primary aim of this study was to evaluate the effect of EV on adenoma detection rate (ADR) and mean number of adenomas per patient (MAP).

Patients and methods

This multicenter randomized controlled trial compared EV-assisted colonoscopy (EAC) and standard colonoscopy (SC). Patients were referred due to a positive fecal immunochemical test (FIT) in a bowel cancer screening program (BCSP), direct screening colonoscopy without prior FIT, surveillance colonoscopy, or family history of colorectal cancer.

Results

In total, 1437 patients (55.9% male; median age, 59 years) were randomized at eight Spanish university hospitals. No significant differences were found in either the ADR (EAC vs. SC, 55.8% vs. 54.3%; P = 0.576) or the MAP (1.60 vs. 1.35; P = 0.03). Compared with SC, EAC was not associated with a significant improvement in detection rates for advanced adenomas, sessile serrated lesions, or advanced sessile serrated lesions. There was no difference in cecal intubation rate but the successful ileal intubation rate, among patients in whom it was attempted, was lower with EAC (64.3% vs. 86.5% with SC; P = 0.001).

Conclusions

EV did not improve either ADR or MAP. EV may increase difficulty of ileal intubation whenever it is attempted.

Keywords

Endoscopy Lower GI Tract - Polyps / adenomas / ... - Colorectal cancer - CRC screening

Introduction

Colonoscopy is the gold standard for polyp detection and removal and has significantly reduced the incidence of invasive colorectal cancer (CRC) [1]. However, the procedure misses 20% to 26% of adenomas [2] .

The adenoma detection rate (ADR) is considered the most crucial quality indicator in CRC prevention because it is inversely associated with CRC-related death [3]. ADR is also an independent predictor of the risk of interval CRC [3], defined as CRC diagnosed between a negative screening colonoscopy and a scheduled surveillance colonoscopy [3]. The expected ADR of CRC screening programs in Western populations ranges from 20% to 30% [4] when colonoscopy is the initial strategy and exceeds 40% when it is performed in selected populations with positive fecal immunochemical test (FIT) results [5]. However, the ADR is unable to measure the total number of adenomas per individual, leading to the “one and done” phenomenon [6].

To overcome this limitation and highlight the presence of adenomas, the mean number of adenomas detected per colonoscopy (MAP) has been defined as the total number of adenomas detected divided by the total number of colonoscopies performed [6]. The expected MAP in Western populations remains to be defined, but the MAP of colonoscopies performed for evaluating a positive FIT is significantly higher than the MAP of conventional screening colonoscopy [4]. Therefore, measurement of the MAP in addition to the ADR is suggested in the literature to provide additional information about colonoscopy performance [6].

To improve the ADR and MAP, several distal attachment devices for colonoscopy have been developed. One of these devices is the Endocuff Vision (EV) (Arc Medical Design Ltd., Leeds, UK), a 2-cm-long flexible polypropylene cap with a single circular row of eight soft projections (Supplementary Fig. 1). It was developed as a relatively simple technique in 2015 as a modification of the first-generation Endocuff (2012), which had eight flexible but shorter and firmer branches arranged in two rows [7].

Results from the literature are still controversial regarding the impact of EV on adenoma detection and, thus, prevention of CRC development. No studies have evaluated EV in a Spanish asymptomatic screening population with the most common indications for colonoscopy. Accordingly, we designed a multicenter randomized controlled trial (RCT) to compare the ADR and MAP between EV-assisted colonoscopy (EAC) and standard colonoscopy (SC).

Patients and methods

Study design

This multicenter, superiority RCT was conducted between June 2018 and April 2019. Patients were recruited from eight tertiary university hospitals in Madrid (Spain). Puerta de Hierro and La Paz University Hospitals were the two coordinating institutions, and the study was led by independent investigators and industry-funded. The funders had no role in study design, data collection, data analysis, data interpretation, or manuscript drafting. To ensure the quality and integrity of the data collected during the study, the Spanish Clinical Research Network (https://scren.eu/) provided external data monitoring services including oversight of the monitoring process, evaluation of its impact on data quality, and comprehensive documentation and reporting.

All 42 participating endoscopists were experienced physicians with between 1 and 20 years’ experience; due to the study design and the high turnover of residents in the participating departments, no residents were involved. The physicians had to have performed at least five procedures with EV prior to patient enrollment. Endoscopist baseline ADR was calculated from the 50 previous colonoscopies performed on a regular basis with indications to the inclusion criteria (Supplementary Table 1). We limited participants with an indication-positive FIT in a bowel cancer screening program (BCSP) to less than 50% of the total enrolled population to avoid a very high baseline ADR, based on prior studies [8]. Endoscopists were stratified into low (≤ 35%), intermediate (36%-49%), high (50%-69%), and very high (≥ 70%) detectors based on their baseline ADR.

The ENDOCOLES study was approved by the Research Ethics Committee of Puerta de Hierro University Hospital and was registered on ClinicalTrials.gov as NCT03436004. Study procedures were performed in accordance with the principles of the Declaration of Helsinki. The study has been reported according to CONSORT guidelines for RCTs [9]. A completed CONSORT Statement checklist is available as supporting information. All patients signed a written informed consent form before study inclusion.

Patients

Inclusion criteria included patients aged ≥ 18 years referred from a BCSP with a positive FIT, direct screening colonoscopy without prior FIT, surveillance colonoscopy, and family history of CRC (Supplementary Table 1). Clinical and demographic data were collected from all patients. After signing the informed consent form, all participating patients were randomized into two groups: an EAC group and a SC group ([Fig. 1]).

Fig. 1 CONsolidated Standards of Reporting Trials (CONSORT) study flow chart [9] for the ENDOCOLES trial. ¹Previously unidentified exclusion criteria: inadequate BBPS (a segment score = 0), IBD personal history, prior complete colonoscopy with good visualization of all colonic anatomy (total BBPS ≥6, with all segments score ≥ 2) or previous colectomy. ²Included by mistake: failure in the computer system. ³Obstruction: new cancer diagnosis or colonic stricture. ⁴Poor BBPS (total BBPS < 6, with a segment score ≤ 1). ⁵Technical aspects: angulation/fixed sigmoid colon. BBPS, Boston Bowel Preparation Scale; EAC, Endocuff-assisted colonoscopy; IBD, inflammatory bowel disease; IC, informed consent; SC, standard colonoscopy.

Procedure

All colonoscopies were performed with the high-definition (HD) or standard-definition equipment available at the study centers. Patients underwent the procedure under deep sedation by anesthesiologists or non-anesthesiologists according to the standard hospital protocol. Intraprocedural use of carbon dioxide insufflation or conventional air insufflation was also documented. Routine cecal intubation was performed, whereas ileal intubation was attempted only according to the medical criteria of the endoscopist. Time spent on insertion and withdrawal was also recorded. A meticulous mucosal inspection technique during withdrawal was recommended to all participating endoscopists.

Patients received bowel preparation instructions according to the standard hospital protocol. Bowel cleanliness was determined by the endoscopist using the Boston Bowel Preparation Scale. The number, morphology using Paris classification, size, anatomic location, optical diagnosis, and histology of each polyp were documented. NICE classification (used only for Olympus devices with a narrow-band imaging system) was applied for optical diagnosis. All retrieved polyps were sent for histopathologic examination in separate specimen containers.

Adverse events (AEs) during or immediately after the procedure and within a 30-day follow-up period were recorded, including bleeding, perforation, mortality, and other device- or colonoscopy-related complications, such as abdominal pain. Patients were contacted by telephone at between 30 and 45 postprocedure days, and a clinician reviewed the medical history in detail to identify potential complications. A serious AE was defined as one requiring hospitalization; prolongation of a previous hospitalization; new endoscopic, radiological, or surgical treatment; blood transfusion; and/or resulting in death.

Randomization

Patients were randomized to EAC or SC in a 1:1 ratio using a confidential computer-generated randomization list. This computer system was developed specifically for this trial by an independent biostatistician and then set offline upon study completion. Randomization was stratified by center. The patient was blinded to the allocation, but the endoscopist was not. After entering each patient's allocation data into the computer, the endoscopist could see the randomization arm assigned to each patient.

Outcomes

The primary outcome was to determine if there was a difference in the ADR and MAP between the EAC and SC groups. Secondary outcomes included determining if there were differences in the remaining variables listed in Supplementary Table 2 between the two groups. The ADR and MAP were also analyzed by colonoscopy indication, endoscopist baseline ADR, use of HD colonoscopy, and maximum polyp size by patient. The safety profile was also documented.

Sample size and statistical analysis

Sample size calculation was based on the preliminary endoscopist ADR (46% and 35%) and MAP (0.9 and 0.8) data from the two coordinating centers and initial Endocuff studies [7] [10]. For a hypothesized 10% increase in the ADR and 30% increase in the MAP (0.3 points between the two groups assuming a standard deviation of 1.9 in a statistically significant manner (P < 0.05) with a power of 80%, it was considered necessary to recruit 631 patients per group, that is, to randomize at least 1262 patients. With an estimated loss rate of 15% (190 patients), at least 1452 patients needed to be recruited.

Descriptive analysis of the sample was performed using absolute and relative frequencies for categorical variables and median and 25th and 75th percentiles or mean and standard deviation for numerical variables, as appropriate, assuming normality. An intention-to-treat (ITT) analysis was performed, including all randomized patients and comparing each group (EAC vs. SC), and was considered the primary analysis of the trial. A per-protocol (PPT) analysis was also conducted. Patients were excluded from the per-protocol analysis in the case of incomplete colonoscopy (technical aspects, bowel obstruction/stenosis, poor bowel preparation, or intolerance to sedation), EV removal, or de novo diagnosis of polyposis, colitis, or inflammatory bowel disease (exclusion criteria).

ADRs were compared between groups using the chi-square test. Binary logistic regression models were used to adjust by center and stratifying by other known factors associated with the ADR, including endoscopist baseline ADR, HD equipment, colonoscopy indication, maximum polyp size by patient, age, and sex. Adjusted odds ratios (aORs) are shown with the corresponding 95% confidence interval (95% CI). Advanced ADR (AADR), serrated lesion detection rate (SDR), and adenoma serrated lesion detection rate (ASDR) were analyzed similarly.

The MAP was compared between groups and adjusted for the center using a Poisson regression model. The adjusted incidence-rate ratio (aIRR) is shown with the corresponding 95% CI. Similar analyses were also conducted stratifying on known factors associated with MAP, including endoscopist baseline ADR, HD equipment, colonoscopy indication, maximum polyp size by patient, age, and sex. Mean advanced adenomas per patient (MAAP), mean serrated lesions per patient (MSP), and mean advanced serrated lesions per patient (MASP) were analyzed similarly.

Other secondary variables (successful cecal intubation rate, EV removal rate, cecal intubation time, withdrawal time, successful ileal intubation rate, and successful rectal and ascending colon retroflexion rate) were analyzed using the Mann-Whitney U test due to a non-normal distribution of the data. Time required for biopsies or polypectomies and bowel cleansing was not included in calculation of withdrawal time. Two-sided P < 0.05 was considered to indicate statistically significant differences, except for the primary outcomes, to which the Bonferroni multiple comparison correction was applied. Because there were two primary outcomes, the significance level was corrected to 0.025 for these comparisons.

Additional subanalyses were performed to examine differences in polyp morphology, location, and size between groups using a chi-square, Fisher, or Mann-Whitney U test, depending on type of variable. The 95% CIs and P values of secondary analyses were not adjusted for multiplicity and should be considered exploratory. No missing values were detected in the main variables so a complete case analysis was performed.

All analyses were performed using Stata version 16 software for Windows by a biostatistician.

Results

Between June 2018 and April 2019, 1453 patients were invited to participate in the study; 16 were excluded. Of the 1437 enrolled patients, 695 were assigned to EAC and 742 to SC. All patients were included in the ITT analysis, which was the primary analysis of the trial. After excluding 46 patients post-randomization, the PPT analysis was completed in 1391 patients. The CONSORT trial flow chart [9] is illustrated in [Fig. 1].

Groups were comparable in terms of demographic characteristics, center distribution, and other endoscopic aspects independent of EV ([Table 1]). Anatomic location, size, morphology, optical diagnosis, and histology of the resected polyps are shown in [Table 2].

Table 1 Baseline demographic characteristics, number of colonoscopies per center, and colonoscopy characteristics.

	EAC (n = 695), %	SC (n = 742), %
ASA classification, American Society of Anesthesiologists Physical Status classification; BBPS, Boston Bowel Preparation Scale; EAC, Endocuff Vision-assisted colonoscopy; EV, Endocuff Vision; FIT, fecal immunochemical test; PEG, polyethylene glycol; PEG-ELS, polyethylene glycol-electrolyte solution; SC, standard colonoscopy; SD, standard deviation. *High risk: a first-degree relative with colorectal cancer < 60 years old or ≥ 2 first-degree relative with colorectal cancer. Percentage based on the total number of patients in each group.
Male sex, n (%)	400 (57.5%)	404 (54.4%)
Median age, years (SD)	59.6 (9.3)	59.1 (9.2)
ASA classification
ASA I	287 (41.3%)	306 (41.3%)
ASA II	339 (48.8%)	383 (51.7%)
ASA III	67 (9.5%)	52 (7%)
ASA IV	2 (0.3%)	0
Antiplatelet therapy	48 (6.9%)	60 (8.1%)
Anticoagulant therapy	27 (3.9%)	17 (2.3%)
Prior abdominal surgery	209 (30%)	234 (31.5%)
Prior colonoscopy	249 (35.8%)	265 (35.7%)
Bowel preparation
PEG-ELS	224 (32.2%)	257 (34.7%)
PEG 3350 (low volume)	248 (35.6%)	230 (31%)
Magnesium citrate	222 (31.9%)	254 (34.3%)
Other preparation	2 (0.3%)	0
Morning procedures	384 (55.2%)	407 (54.9%)
Split-dosing (morning procedures)	257 (66.9%)	269 (66.1%)
No. of colonoscopies per center (%)
Center 1	157 (22.6%)	158 (21.3%)
Center 2	144 (20.7%)	166 (22.3%)
Center 3	117 (16.8%)	148 (19.9%)
Center 4	76 (10.9%)	60 (8.1%)
Center 5	59 (8.5%)	71 (9.6%)
Center 6	66 (9.5%)	60 (8.1%)
Center 7	51 (7.3%)	51 (6.9%)
Center 8	25 (3.6%)	28 (3.8%)
Colonoscopy indication
BCSP (FIT test+)	395 (56.8%)	427 (57.5%)
Surveillance colonoscopy (adenomas)	128 (18.4%)	124 (16.7%)
Family history of colorectal cancer (low risk)	77 (11.1%)	97 (13.1%)
Family history of colorectal cancer (high risk*)	65 (9.3%)	70 (9.4%)
Screening colonoscopy (no prior FIT test)	30 (4.3%)	24 (3.2%)
Anesthesiologist	403 (58%)	447 (60.2%)
Use of carbon dioxide	572 (82.3%)	605 (81.5%)
High-definition colonoscope	610 (87.8%)	644 (86.8%)
BBPS, mean	8 (7–9)	9 (7–9)

Table 2 Polyp characteristics: location, size, morphology, optical diagnosis, and histology.

	EAC (n = 1750), %	SC (n = 1638), %	P value
EAC, Endocuff Vision-assisted colonoscopy; G, granular-type; LST, laterally spreading tumor; n, number of lesions; NG, non-granular-type; SC, standard colonoscopy. *Paris classification. †NICE classification, Narrow-Band Imaging International Colorectal Endoscopic Classification (Olympus Medical). ‡Advanced adenomas: ≥ 10 mm or high-grade dysplasia. §Serrated polyps: hyperplastic polyps, sessile serrated lesions, and traditional serrated lesions. ¶Advanced serrated polyps: ≥ 10 mm or dysplasia.
Location			0.21
Right colon	1002 (57.3%)	901 (55%)
Ileum	0	1 (0.1%)
Cecum	136 (7.8%)	132 (8.1%)
Ascending colon	361 (20.6%)	325 (19.8%)
Hepatic flexure	108 (6.2%)	90 (5.5%)
Transverse colon	397 (22.7%)	353 (21.5%)
Left colon	748 (42.7%)	737 (45%)
Splenic flexure	18 (1%)	22 (1.3%)
Descending colon	197 (11.3%)	234 (14.3%)
Sigmoid colon	351 (20.1%)	301 (18.4%)
Rectum	182 (10.4%)	180 (11%)
Size			0.82
Diminutive (≤ 5 mm)	1136 (64.9%)	1048 (64%)
Small (6–9 mm)	308 (17.6%)	290 (17,7%)
Large (≥ 10 mm)	306 (17.5%)	300 (18.3%)
Morphology*			0.71
Polypoid	1110 (63.4%)	1010 (61.7%)
Paris 0-Is	905 (51.7%)	811 (49.5%)
Paris 0-Ip	173 (9.9%)	167 (10.2%)
Paris 0-Isp	32 (1.8%)	32 (1.9%)
Non-polypoid	623 (35.6%)	611 (37.3%)
Paris 0-IIa	532 (30.4%)	509 (31.1%)
Paris 0-IIb	56 (3.2%)	61 (3.7%)
Paris 0-IIc	1 (0.06%)	2 (0.1%)
Homogeneous-type LST-G	12 (0.7%)	18 (1.1%)
Nodular mixed-type LST-G	5 (0.3%)	4 (0.2%)
Flat-type LST-NG	12 (0.7%)	16 (1%)
Pseudodepressed-type LST-NG	12 (0.7%)	16 (1%)
Suspicious for invasive carcinoma	8 (0.5%)	15 (0.9%)
Others	9 (0.5%)	2 (0.1%)
Subepithelial appearance	2 (0.1%)	1 (0.1%)
Inflammatory appearance	7 (0.4%)	1 (0.1%)
Optical diagnosis (NICE† classification)	EAC (n = 1255), %	SC (n = 1162), %	-
Type 1	245 (19.5%)	246 (21.2%)	-
Type 2	995 (79.3%)	896 (77.1%)	-
Type 3	15 (1.2%)	20 (1.7%)	-
Histology	EAC (n = 1658), %	SC (n = 1534), %	P value
Adenomas	1158 (69.8%)	1049 (68.4%)	0.18
Advanced adenomas‡	238 (14.3%)	226 (14.7%)	0.87
Serrated polyps§	233 (14%)	224 (14.6%)	0.76
Advanced serrated polyps¶	31 (1.9%)	27 (1.8%)	0.78
Advanced colorectal neoplasms	19 (1.2%)	31 (2%)	0.15
Non-assessable, negative, or indefinite for neoplasia/dysplasia lesions	237 (14.3%)	222 (14.5%)	0.15
Others	11 (0.7%)	8 (0.5%)	0.15

Endoscopists were stratified into low (≤ 35%), intermediate (36%-49%), high (50%-69%), and very high (≥ 70%) detectors according to their previously calculated baseline ADR. Percentages of endoscopists in each group were 9.7%, 30.6%, 38.9%, and 20.7%, respectively. Our global ADR was 54% and more than 90% of the endoscopists had a baseline ADR exceeding 35%.

Adenoma detection rate

ADR was similar in both groups in both ITT analysis (EAC vs. SC, 55.8% vs. 54.3% [aOR 0.94, 95% CI 0.76–1.16, P = 0.576]) and PPT analysis (EAC vs. SC, 57% vs. 55.5% [aOR 0.93, 95% CI 0.75–1.16, P = 0.542]) ([Table 3]). No differences were found when the ADR analysis was also adjusted for hospital, colonoscopy indication, endoscopist baseline ADR, use of HD equipment, and maximum lesion size by patient (Supplementary Table 3).

Table 3 Primary outcome: ADR and MAP.

	Analysis	EAC (n = 695), %	SC (n = 742), %	aOR	95% CI	P value
ADR, adenoma detection rate; aIRR, adjusted incidence-rate ratio by the stratification variable “Hospital”; aOR, adjusted odds ratio by the stratification variable “Hospital”; EAC, Endocuff Vision-assisted colonoscopy; ITT, intention-to-treat analysis; MAP, mean number of adenomas per patient; PPT, per-protocol analysis; SC, standard colonoscopy.
ADR	ITT	388 (55.8%)	403 (54.3%)	0.94	0.76–1.16	0.576
	PPT	381 (57%)	401 (55.5%)	0.93	0.75–1.16	0.542
	Analysis	EAC (n = 695)	SC (n = 742)	aIRR	95% CI	P value
MAP	ITT	1.66	1.41	0.85	(0.73–0.98)	0.029
	PPT	1.70	1.44	0.84	(0.73–0.98)	0.030

Mean number of adenomas per patient

Compared with SC, EV was not associated with a significantly higher MAP in both ITT analysis (EAC vs. SC, 1.60 vs. 1.35 [aIRR 0.85, 95% CI 0.73–0.98, P = 0.029]) and PPT analysis (EAC vs. SC, 1.63 vs. 1.38 [aIRR 0.85, 95% CI 0.73–0.98, P = 0.030]).

Additional factors influencing differences in the MAP between the two groups were also examined. The MAP was slightly higher in BCSP patients with a positive FIT in both ITT analysis (EAC vs. SC, 2.15 vs. 1.80 [IRR in the SC group 0.83, 95% CI 0.69–0.99, P = 0.04]) and PPT analysis (EAC vs. SC, 2.20 vs. 1.83 [IRR in the SC group 0.83, 95% CI 0.69–0.99, P = 0.04]) ([Table 3]). The MAP was also significantly higher in certain subgroups in both ITT and PPT analyses: high-detector endoscopists (baseline ADR 50%-69%) and use of HD equipment (Supplementary Table 4).

Advanced adenomas and serrated lesions

When evaluating advanced adenomas, AADR was also similar in both groups in ITT analysis (EAC vs. SC, 22.4% vs. 21.6% [95% CI 0.74–1.22, P = 0.56]) and PPT analysis (EAC vs. SC, 22.7% vs. 21.8% [95% CI 0.74–1.22, P = 0.69]). For serrated lesions, no differences in SDR and ASDR were found, even after additional adjustment for hospital, colonoscopy indication, endoscopist baseline ADR, use of HD equipment, and polyp size (Supplementary Table 5).

No differences were observed between groups in MAAP and MSP (Supplementary Table 6).

Colonoscopy outcomes directly related to EV

No significant differences were found between groups in successful cecal intubation rate (> 97% in both groups), cecal intubation time (mean of 4 minutes in both groups), withdrawal time (9–10 minutes in both groups), and effect of EV on rectal and ascending colon retroflexion (similar in both groups).

Thirty patients, without differences between groups, had an incomplete colonoscopy for the reasons listed in [Table 4]. The elective EV removal rate was 1.4% (10 patients). The cecal pole was eventually reached in nine of these 10 patients. In only one case, the examination could not be completed due to patient anthropometric characteristics. No cases of involuntary EV loss were documented. However, the successful ileal intubation rate was significantly different between the EAC (64.3%) and SC (86.5%) groups (P < 0.001), with a similar intubation attempt rate in both groups (EAC vs. SC, 42.3% vs. 45.0%, P = 0.3). The odds ratio (EAC vs. SC) was 0.28 (95% CI 0.19–0.41, P = 0.001).

Table 4 Colonoscopy technical outcomes stratified by group.

	EAC (n = 695), %	SC (n = 742), %	P value
EAC, Endocuff Vision-assisted colonoscopy; EV, Endocuff Vision; SC, standard colonoscopy. *Poor BBPS (Boston Bowel Preparation Scale): total BBPS < 6, with a segment score ≤ 1. †Attempted intubation of the ileum: Total number of attempted intubations of the terminal ileum in all patients. ‡Successful ileal intubation rate: Total number of successful ileal intubations divided by the total number of colonoscopies in which ileal intubation had been attempted in each group. §¶Total number of patients in whom ascending colon and rectum retroflexion was performed: retroflexion was possible in all of these patients.
Successful cecal intubation rate	683 (98.3%)	724 (97.6%)	0.58
Cecal intubation failure (causes):			0.30
Technical aspects (angulation/fixed sigmoid colon)	0	3 (0.4%)
Obstruction (neoplasia, colonic stricture, inguinal hernia)	4 (0.6%)	4 (0.5%)
Poor BBPS*	8 (1.1%)	6 (0.8%)
Intolerance of sedation	0	5 (0.7%)
Median cecal intubation time, minutes (SD)	4 (3–6)	4 (3–6)	0.49
Attempted intubation of the ileum†	294 (42.3%)	334 (45%)	0.30
Successful ileal intubation rate‡	189 (64.3%)	289 (86.5%)	0.001
Median withdrawal time, minutes (SD)	10 (7–12)	9 (7–11)	0.32
Attempted ascending colon retroflexion§	81 (11.6%)	83 (11.2%)	0.78
Successful ascending colon retroflexion rate	81 (100%)	83 (100%)	0.78
Attempted rectal retroflexion¶	465 (66.9%)	516 (69.5%)	0.28
Rectal retroflexion rate	465 (100%)	516 (100%)	0.28
EV voluntary removal rate	11 (1.4%)	--	--
EV involuntary loss rate	0	--	--

Adverse events

AEs were documented in 39 patients (2.7%), with no differences between the EAC and SC groups regarding type of complication, severity, time of onset, need for hospitalization, or duration of the event ([Table 5]).

Table 5 Adverse events.

	EAC (n = 695), %	SC (n = 742), %	P value
EAC, Endocuff Vision-assisted colonoscopy; SC, standard colonoscopy. *A severe adverse event was considered to have occurred if the patient required hospitalization; prolongation of a previous hospitalization; new endoscopic, radiological, or surgical treatment; blood transfusion; and/or death occurred.
Total number of adverse events	22 (3.2%)	17 (2.3%)	0.40
Lower gastrointestinal bleeding	6 (0.9%)	4 (0.5%)	0.46
Severe lower gastrointestinal bleeding*	4 (0.6%)	1 (0.1%)	0.16
Endoscopic treatment	4 (0.6%)	0	0.14
Admission	2	1	0.61
Gastrointestinal perforation	0	2 (0.3%)	0.17
Severe gastrointestinal perforation*	0	2 (0.3%)	0.17
Surgical treatment	0	1 (0.1%)	0.33
Admission	0	2 (0.3%)	0.50
Death	0	0	0
Other adverse events	3 (0.4%)	2 (0.3%)	0.29
Abdominal pain	2 (0.3%)	1 (0.1%)	0.61
Hemorrhoid pain	0	1 (0.1%)	1.00
Fever	1 (0.1%)	0	0.48

Discussion

Summary of main results

In this multicenter RCT, we evaluated the EV device in an asymptomatic Spanish population with the most representative indications for colonoscopy. A total of 1437 patients were enrolled, making this one of the largest studies comparing the device with SC. Our results indicated no differences in either the ADR or the MAP between EAC and SC. An overview of previous studies of Endocuff or EV is shown in Supplementary Table 7.

Interpretation of results

Several studies of EV have shown conflicting results regarding the ADR. First-generation [10] [11] [12] [13] and second-generation [14] [15] [16] [17] Endocuff studies showed ADR improvements ranging from 4.7% to 17%. In contrast, studies by Van Doorn et al. [18], Bhattacharyya et al. [19], Jaensch et al. [20], Von Figura et al. [21], and Rex et al. [22] found no significant increase in the ADR. A systematic review by Aziz et al. [23] also found no significant improvement in ADR compared with HD colonoscopy.

A possible explanation for these findings is that studies reporting ADR improvements with Endocuff [10] [11] [12] [13] [14] [15] [16] [17] often had a low control-arm ADR (< 41%). Our high control-arm ADR (54%) was similar to that in studies where no benefit was observed, suggesting that reported improvements in some studies might reflect initially poor polyp detection rates. This could be due to endoscopist quality or experience or the type of population included [12]. For example, certain geographic areas, such as Latin America, may have a lower prevalence of adenomas [12].

In addition, several meta-analyses [24] [25] [26] [27] [28] suggested that Endocuff may benefit operators with a low ADR (< 30%-35%) more than those with a high ADR (>35%), but our study did not support that finding.

Consistent with most studies [17] [18] [22] [24] [29] [30], no significant difference was found between EAC and SC in AADR, SDR, and ASDR. The ItaVision Study [15] showed a 21% increase in AADR only in BCSP patients with a positive FIT. The ADENOMA study [16] found a small increase in SDR, but its clinical significance was questionable. Another RCT of serrated polyposis [31] also showed no significant differences.

In our study, EV did not improve MAP compared with SC. Several RCTs showed a MAP improvement with EV [15] [16] [17] [18], particularly in BCSP patients with a positive FIT [15] [16]. We also identified a slight increase in this last group of patients, but the difference between EAC and SC was modest (0.25, P < 0.003). Furthermore, this finding was exploratory because it was obtained from subanalyses, which could make the clinical relevance of this result debatable. Future studies could be useful to further evaluate the impact of EV on MAP and its correlation with CRC incidence, particularly in BCSP patients with a positive FIT.

No significant differences were found between EAC and SC in MAAP, MSP, and MSAP. Even though Endocuff was reported to assist in detection of smaller lesions in previous studies [10] [11] [13] [14] [18] [29] [32], we did not find differences in MAP according to maximum lesion size by patient, anatomical location [15] [30] [32] [33] [34], or morphology [15] [19] [32].

Use of EV improved MAP in operators with a high ADR (50%-69%) and HD devices, but the clinical significance of these findings should, again, be interpreted cautiously because this was a secondary subgroup analysis. HD device results in the literature are heterogeneous, because some studies did not collect endoscope model information [16] [22].

Successful cecal intubation rate, cecal intubation time, withdrawal time, and successful rectal retroflexion were not affected by EV. EV removal rate was low at 1.4%; most colonoscopies were completed even when EV was removed. No involuntary loss of the EV was reported. However, differences in ileal intubation rates between groups were observed. Ileal intubation was only attempted according to the medical criteria of the endoscopist. Among patients in whom ileal intubation was attempted (42.3% EAC vs. 45% SC; P = 0.30), there was some degree of difficulty in ileal intubation with the EV device (64.3% EAC vs. 86.5% SC; P < 0.001). In addition, several endoscopists subjectively reported that the EV might hinder easy access to the ileum when bending the colonoscope due to the protruding rubber arms. This finding is consistent with those of other studies [7] [12] [14] [21], although many did not collect such information [15] [16] [17] [18] [19] [22] [32] and the conclusions remain unclear.

Studies with the first-generation Endocuff reported minor mucosal tears [7] [11] [25]. The second-generation EV appears to have addressed these issues [16] [19], and we found no AEs attributable to EV, such as perforation or bleeding.

Strengths and limitations

A significant strength of this study is the multicenter, randomized design involving eight university hospitals, which has obtained a large and representative sample of the Spanish population. This is the first study conducted in our geographical area with such broad colonoscopy indications, including CRC screening within a BCSP. Endoscopists with varying baseline ADRs performed the procedures after completing a training period with the EV, which enhances the generalizability of our findings.

Limitations include lack of blinding of the endoscopists, because the rubber arms of the EV are visible to the physician during colonoscopy. Another limitation was inability to calculate adenoma or serrated polyp loss rates, because this was not a tandem study. Although tandem studies are useful, they increase procedure risk, reduce patient enrollment, and could create a nonrealistic condition [13]. Although our global ADR was 54%, the sample size calculation was based on lower baseline ADRs, indicating that a potentially larger sample size might have been needed. Finally, all 42 participating endoscopists were experienced physicians, with between 1 and 20 years of practice. Although baseline ADRs varied among them, the proportion of low detectors (ADR ≤ 35%) was relatively low. This is likely attributable to the fact that the participating centers were actively involved in CRC screening programs and had a strong focus on endoscopic diagnosis training. Due to the study design, trainee residents were not included and that could be noted as a limitation.

Clinical implications

Our findings suggest that EV does not improve either the ADR, which aligns with the results of several large RCTs with high control-arm ADRs [18] [19] [21], or the MAP. The MAP was slightly higher in BCSP patients with a positive FIT, but the clinical relevance of this finding might be questioned, as it was secondary subgroup analysis. Based on our findings, we cannot recommend the systematic addition of EV to diagnostic colonoscopy but it should be tailored to the specific conditions of each center and endoscopist.

Conclusions

In conclusion, our results showed no significant difference in either the ADR or the MAP. Although EV is safe and feasible and does not increase procedure time, it may hamper ileal intubation in some cases. Future studies are necessary to further evaluate the impact of EV on the MAP and its correlation with CRC incidence.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

The authors would like to thank members of the SCReN (Spanish Clinical Research Network; https://scren.eu/), Data Monitoring Committee, research nurses, members of the research team and patients at all participating sites who took part in the study. We would like to acknowledge and thank NORGINE for their financial support in conducting this study.

• References

• 1 Sung H, Ferlay J, Siegel RL. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-249
• 2 Van Rijn JC, Reitsma JB, Stoker J. et al. Polyp miss rate determined by tandem colonoscopy: A systematic review. Am J Gastroenterol 2006; 101: 343-350
• 3 Kaminski MF, Regula J, Kraszewska E. et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med 2010; 362: 1795-1803
• 4 Rex DK, Schoenfeld PS, Cohen J. et al. Quality indicators for colonoscopy. Gastrointest Endosc 2015; 81: 31-53
• 5 Kligman E, Li W, Eckert GJ. et al. Adenoma detection rate in asymptomatic patients with positive fecal immunochemical tests. Dig Dis Sci 2018; 63: 1167-1172
• 6 Lee TJW, Rutter MD, Blanks RG. et al. Colonoscopy quality measures: Experience from the NHS Bowel Cancer Screening Programme. Gut 2012; 61: 1050-1057
• 7 Lenze F, Beyna T, Lenz P. et al. Endocuff-assisted colonoscopy: A new accessory to improve adenoma detection rate? Technical aspects and first clinical experiences. Endoscopy 2014; 46: 610-613
• 8 Cubiella J, Castells A, Andreu M. et al. Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs. United Eur Gastroenterol J 2017; 5: 255-260
• 9 Moher D, Hopewell S, Schulz KF. et al. CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. Int J Surg 2012; 10: 28-55
• 10 Biecker E, Floer M, Heinecke A. et al. Novel endocuff-assisted colonoscopy significantly increases the polyp detection rate. J Clin Gastroenterol 2015; 49: 413-418
• 11 Floer M, Meister T. Endoscopic improvement of the adenoma detection rate during colonoscopy - Where do we stand in 2015?. Digestion 2016; 93: 202-213
• 12 González-Fernández C, García-Rangel D, Aguilar-Olivos NE. et al. Higher adenoma detection rate with the endocuff: A randomized trial. Endoscopy 2017; 49: 1061-1068
• 13 De Palma GD, Giglio MC, Bruzzese D. et al. Cap cuff-assisted colonoscopy versus standard colonoscopy for adenoma detection: a randomized back-to-back study. Gastrointest Endosc 2018; 87: 232-240
• 14 Karsenti D, Tharsis G, Perrot B. et al. Adenoma detection by Endocuff-assisted versus standard colonoscopy in routine practice: A cluster-randomised crossover trial. Gut 2020; 69: 2159-2164
• 15 Zorzi M, Hassan C, Battagello J. et al. Adenoma detection by Endocuff-assisted versus standard colonoscopy in an organized screening program: the “ItaVision” Randomized Controlled Trial. Endoscopy 2021; 54: 138-147
• 16 Ngu WS, Bevan R, Tsiamoulos ZP. et al. Improved adenoma detection with Endocuff Vision: The ADENOMA randomised controlled trial. Gut 2019; 68: 280-288
• 17 Zimmermann-Fraedrich K, Sehner S, Rösch T. et al. Second-generation distal attachment cuff for adenoma detection in screening colonoscopy: a randomized multicenter study. Gastrointest Endosc 2022; 97: 1-9
• 18 Van Doorn SC, Van Der Vlugt M, Depla ACTM. et al. Adenoma detection with Endocuff colonoscopy versus conventional colonoscopy: A multicentre randomised controlled trial. Gut 2017; 66: 438-445
• 19 Bhattacharyya R, Chedgy F, Kandiah K. et al. Endocuff-assisted vsstandard colonoscopy in the fecal occult blood test-based UK Bowel Cancer Screening Programme (E-cap study): A randomized trial. Endoscopy 2017; 49: 1043-1050
• 20 Jaensch C, Jepsen MH, Christiansen DH. et al. Adenoma and serrated lesion detection with distal attachment in screening colonoscopy: a randomized controlled trial. Surg Endosc 2022; 36: 1-9
• 21 Von Figura G, Hasenöhrl M, Haller B. et al. Endocuff Vision-assisted vs standard polyp resection in the colorectum (the EVASTA study): A prospective randomized study. Endoscopy 2020; 52: 45-51
• 22 Rex DK, Slaven JE, Garcia J. et al. Endocuff Vision reduces inspection time without decreasing lesion detection: A clinical randomized trial. Clin Gastroenterol Hepatol 2020; 18: 158-162.e1
• 23 Aziz M, Haghbin H, Gangwani MK. et al. Efficacy of Endocuff Vision compared to first-generation Endocuff in adenoma detection rate and polyp detection rate in high-definition colonoscopy: a systematic review and network meta-analysis. Endosc Int Open 2021; 09: E41-E50
• 24 Jian HX, Feng BC, Zhang Y. et al. EndoCuff-assisted colonoscopy could improve adenoma detection rate: A meta-analysis of randomized controlled trials. J Dig Dis 2019; 20: 578-588
• 25 Williet N, Tournier Q, Vernet C. et al. Effect of Endocuff-assisted colonoscopy on adenoma detection rate: Meta-analysis of randomized controlled trials. Endoscopy 2018; 50: 846-860
• 26 Facciorusso A, Triantafyllou K, Murad MH. et al. Compared abilities of endoscopic techniques to increase colon adenoma detection rates: A network meta-analysis. Clin Gastroenterol Hepatol 2019; 17: 2439-2454.e25
• 27 Triantafyllou K, Gkolfakis P, Tziatzios G. et al. Effect of Endocuff use on colonoscopy outcomes: A systematic review and meta-analysis. World J Gastroenterol 2019; 25: 1158-1170
• 28 Patel HK, Chandrasekar VT, Srinivasan S. et al. Second-generation distal attachment cuff improves adenoma detection rate: meta-analysis of randomized controlled trials. Gastrointest Endosc 2021; 93: 544-553.e7
• 29 Cavallaro L, Hassan C, Lecis P. et al. The impact of Endocuff-assisted colonoscopy on adenoma detection in an organized screening program. Endosc Int Open 2018; 06: E437-E442
• 30 Jacob A, Schafer A, Yong J. et al. Endocuff Vision-assisted colonoscopy: a randomized controlled trial. ANZ J Surg 2019; 89: E174-E178
• 31 Rivero-Sánchez L, Arnau-Collell C, Herrero J. et al. White-light endoscopy is adequate for Lynch syndrome surveillance in a randomized and noninferiority study. Gastroenterology 2020; 158: 895-904.e1
• 32 Wada Y, Fukuda M, Ohtsuka K. et al. Efficacy of Endocuff-assisted colonoscopy in the detection of colorectal polyps. Endosc Int Open 2018; 06: E425-E431
• 33 Marsano J, Johnson S, Yan S. et al. Comparison of colon adenoma detection rates using cap-assisted and Endocuff-assisted colonoscopy: a randomized controlled trial. Endosc Int Open 2019; 07: E1585-E1591
• 34 Sola-Vera J, Catalá L, Uceda F. et al. Cuff-Assisted versus cap-assisted colonoscopy for adenoma detection: Results of a randomized study. Endoscopy 2019; 51: 742-749

Publication History

Received: 17 October 2024

Accepted after revision: 28 May 2025

Accepted Manuscript online:
02 June 2025

Article published online:
03 November 2025