Effect of cap-assisted esophagogastroduodenoscopy on examination of the major duodenal papilla: a noninferior, randomized controlled trial

• Abstract
• Introduction
• Methods
• Patients
• Randomization and masking
• Endoscopic procedure
• Data collection and outcome measurements
• Statistical analysis
• Results
• Study population and baseline characteristics
• Efficacy of the MDP examination
• Parameters related to endoscopic examination
• Exploration of incomplete examination
• Discussion
• References

Abstract

Background Cap-assisted esophagogastroduodenoscopy (CA-EGD) using a transparent cap fitted to the tip of the scope has emerged as an alternative method for examination of the major duodenal papilla (MDP). However, it remains unclear whether CA-EGD is noninferior to standard duodenoscopy for MDP examination. The aim of this study was to compare the efficacies of the two methods for complete examination of the MDP.

Methods This prospective, noninferior, randomized controlled study was conducted at two endoscopy centers. Consecutive patients who underwent endoscopic retrograde cholangiopancreatography were randomized (1:1) to undergo CA-EGD or standard duodenoscopy for MDP examination. The primary outcome was complete examination of the MDP, defined as visualization of the upper end, opening, and lower end of the papilla. Secondary outcomes included endoscopic findings and the time taken for the MDP examination.

Results The study was terminated for futility after the interim analysis. A total of 171 patients were randomly allocated to CA-EGD (n = 85) or standard duodenoscopy (n = 86). The baseline characteristics were comparable between the two groups. Complete examination of the MDP was achieved in 58/85 patients (68.2 %) in the CA-EGD group and in 74/86 (86.0 %) in standard duodenoscopy group. The difference in proportions was – 17.81 percentage points (95 % confidence interval [CI] –28.14 to –7.48) by intention-to-treat analysis and – 18.22 percentage points (95 %CI –28.34 to –8.10) by per-protocol analysis, both of which were significantly lower than the noninferiority margin of –5 %, and therefore the noninferiority of CA-EGD could not be confirmed. Examination time was significantly longer with CA-EGD (69.5 [SD 46.4] vs. 33.0 [SD 28.9] seconds; P < 0.001).

Conclusions Although complete examination of the MDP can be achieved by CA-EGD in most patients, it could not replace duodenoscopy as the standard method for examination of the MDP.

Introduction

Examination of the major duodenal papilla (MDP) is important for patients with suspected ampullary or periampullary lesions [1] [2] [3]. However, the MDP is often difficult to evaluate using standard esophagogastroduodenoscopy (EGD) because of the tangential angle, the presence of periampullary diverticulum (PAD) or loop formation of the scope [4] [5] [6]. A side-viewing duodenoscope is recommended for optimal visualization of the MDP [7]. However, duodenoscopes are not available in many endoscopy centers. Furthermore, duodenoscopy can only be performed by endoscopists who have received some training in the use of a side-viewing scope [4]. Therefore, the detection of MDP-related lesions may be hampered by either the limited availability of the equipment or a lack of training in duodenoscopy.

Cap-assisted esophagogastroduodenoscopy (CA-EGD) is a simple technique that uses a transparent plastic cap attached to the tip of the gastroscope. It has been reported that CA-EGD could increase the complete examination rate of MDP by straightening the mucosal folds and by pressing down on the areas surrounding a lesion [4] [8] [9] [10]. Recently, a randomized controlled study showed that 97 % of MDPs could be examined completely by CA-EGD [11]. These promising results motivated us to perform a prospective, randomized controlled trial to compare the efficacy of CA-EGD vs. standard duodenoscopy for complete examination of the MDP. The study aimed to investigate whether CA-EGD is noninferior to standard duodenoscopy for examination of the MDP.

Methods

Patients

The study was conducted at two endoscopy centers in China (Xijing Hospital of Digestive Diseases and the Second Affiliated Hospital of Chongqing Medical University). Consecutive patients aged 18 – 70 years with a native papilla who were scheduled to undergo endoscopic retrograde cholangiopancreatography (ERCP) were eligible. Exclusion criteria included: 1) prior surgery of the upper gastrointestinal (GI) tract; 2) prior history of endoscopic sphincterotomy; 3) prior history of MDP treatment; 4) known or suspected stricture of the upper GI tract; 5) patients in poor condition who were considered unsuitable for CA-EGD or standard duodenoscopy; 6) women who were pregnant or breastfeeding; 7) patients who were unwilling or unable to give informed consent.

The study protocol and informed consent forms were approved by the Ethics Committee of the two participating institutions. Written informed consent was obtained from all patients. This study was registered at ClinicalTrials.gov (NCT03219619).

Randomization and masking

Block randomization (four in each block) was used. The randomization list was computer generated, and stratified according to participating center. Before ERCP, patients were assigned randomly in a 1:1 ratio to either CA-EGD or standard duodenoscopy. Investigators who collected demographic data or participated in assessing outcomes and post-procedure complications were not blinded to group allocation. Patients and endoscopists were unable to be masked.

Endoscopic procedure

Before endoscopy, all patients received conscious sedation with midazolam and pethidine. Patients lay in a lateral position. Endoscopic examination was performed by one of four endoscopists who were familiar with both CA-EGD (> 10 cases) and duodenoscopy (> 1000 cases).

In the CA-EGD group, patients underwent CA-EGD first, followed by standard duodenoscopy for ERCP. A transparent soft cap (D-201 – 10704, outer diameter 11.4 mm, length from distal end of endoscope 4 mm; Olympus Medical Systems, Tokyo, Japan) was fitted to the tip of the forward-viewing gastroscope (GIF-H180J; Olympus Optical Co., Ltd., Tokyo, Japan). During MDP examination, the cap was used to depress and flatten mucosal folds to expose the MDP (see [Fig. e1] and [Video 1], available online). The lesions detected in the esophagus, stomach, and duodenum were recorded in detail. Immediately after CA-EGD, the same patient underwent standard duodenoscopy in order to perform ERCP. If the MDP examination was incomplete with CA-EGD, the reasons were determined during the subsequent duodenoscopy.

Video 1 Examination of the major duodenal papilla using cap-assisted esophagogastroduodenoscopy.

In the standard duodenoscopy group, the MDP was examined by a side-viewing duodenoscope (TJF-240 or TJF-260V; Olympus Optical Co., Ltd.) (see [Fig. e1] and [Video 2], available online). As duodenoscopy is currently considered the gold standard for examining the MDP, CA-EGD was not performed following duodenoscopy in the standard duodenoscopy group. No additional instruments (e. g. forceps or sphincterotome) were used during the direct examination of the MDP in either group.

Video 2 Examination of the major duodenal papilla using standard duodenoscopy.

Endoscopists were asked to first examine the MDP thoroughly. After this examination, ERCP was permitted to continue. Biopsy was performed for suspected MDP lesions or when a diagnosis was needed.

Data collection and outcome measurements

Demographic data and clinical characteristics of patients were prospectively collected at enrollment, including age, sex, body mass index, comorbidity, prior abdominal or pelvic surgery, indication for ERCP, and results of laboratory tests.

The primary outcome was the rate of complete examination of the MDP, defined as an examination score of 3, as described previously [11]. Briefly, the examination of the MDP was scored as follows: score 3, visualization of the upper end, lower end, and papillary orifice; score 2, visualization of the orifice but not the upper end, lower end or both; score 1, visualization of the upper or lower end, or both, but not the papillary orifice; score 0, MDP not visualized. Details and examples of the 0 – 3 score system are presented in [Fig. 2], [Video 1], and [Video 2] (see also [Table e1], available online). The score assessment was based on the endoscopic videos of the MDP examination by two independent investigators who were not blinded. Before the start of patient enrollment, these two investigators had been trained in the use of the scores during a face-to-face training session. They also had access to videos and images with standard examples of scoring for reference. If examination of the MDP was considered incomplete, the reason was further evaluated during subsequent standard duodenoscopy in the same patient, with or without the assistance of a sphincterotome (Olympus Medical Systems Co., Ltd.).

Secondary outcomes included endoscopic findings in the descending duodenum, overall endoscopic findings, duration of the MDP examination, and total MDP examination score. PAD was defined as duodenal diverticulum located within 2 cm of the ampulla of Vater. The relative position of the papilla was defined as type A when the papilla was situated out of the diverticulum and type B when the papilla was intradiverticular [12]. MDP examination time was recorded using a stopwatch and defined as the time from reaching the descending duodenum to the end of the MDP examination. Any complications related to endoscopic examination or ERCP were recorded. The former mainly included perforation and late bleeding related to endoscopic examination and biopsy. ERCP-related complications were mainly caused by cannulation, sphincterotomy, or incomplete drainage. Complications were defined by the criteria of Cotton et al. [13].

Statistical analysis

The sample size was calculated for a noninferiority comparison of CA-EGD vs. standard duodenoscopy for the primary end point of complete MDP examination by using the z test. Group sequential noninferiority tests for the difference of two proportions were applied. The noninferiority margin of 5 % was determined by both the principal investigator and the statistician according to a previous report [14]. Based on previous studies [10] [11], the rate of complete MDP examination was assumed to be 97 % for both CA-EGD and standard duodenoscopy. Interim analyses were planned to be performed by the data and safety monitoring board after data collection had been completed for half of the enrolled patients. We assumed a type I error of 5 %, a power of 80 %, and a dropout rate of 5 %. The initial sample size estimation was 150. After performing an interim analysis, we discovered a mistake in the calculation. We recalculated the sample size and estimated that a total of 342 participants were needed. With the permission of the Ethics Committee, we were allowed to change the statistical plan and enroll more patients to meet the requirement of the modified interim analysis.

All randomized patients were included in an intention-to-treat (ITT) analysis. Per-protocol analysis was performed in patients who completed the endoscopy. The results of interim analyses were tested for futility using the O’Brien-Fleming spending function to determine the significance boundaries (an alpha level of 0.0017 and 0.042, respectively) and the futility boundaries (an alpha level of 0.35 and 0.042). For comparison of the examination efficacy of CA-EGD vs. standard duodenoscopy, noninferiority could be concluded if the lower limit of the 95 % confidence interval (CI) of the difference exceeded the noninferiority margin (–5 %) with a one-sided P value of < 0.0017, or noninferiority could be denied if the upper limit of the 95 %CI of the difference was lower than the margin of –5 % with a one-sided P value of > 0.35.

Results for continuous variables were expressed as mean and SD or median and range, and analyzed using the Student’s t test or the Mann-Whitney U test. Categorical variables were expressed as frequencies and percentages, and analyzed by chi-squared test or Fisher’s exact test when appropriate. P values were one or two sided and were considered statistically significant if the P value was < 0.05.

All analyses were performed using SPSS version 22.0 for Windows (IBM Corp., Armonk, New York, USA).

Results

Study population and baseline characteristics

Between July 2017 and November 2017, 336 consecutive patients undergoing ERCP were eligible for the study. The data and safety monitoring committee evaluated the data of half of the planned number of patients (n = 75) and asked for the enrollment of 11 additional patients. After finishing the enrollment in November 2017, the data of 86 patients were analyzed (see [Table e2] and [Table e3], available online). Unfortunately, the sample-size calculation was subsequently found to be incorrect. From May 2018 to July 2018, we continued to evaluate another 111 consecutive patients, 85 of whom were enrolled. Finally, a total of 171 patients were randomly allocated to the CA-EGD group (n = 85) or the standard duodenoscopy group (n = 86) ([Fig. 3]). Two patients in each group withdrew because of upper GI tract stricture. Finally, 83 patients in the CA-EGD group and 84 in the standard duodenoscopy group underwent endoscopy and were included in the per-protocol analysis. Baseline characteristics were comparable between the two groups ([Table 4]).

Efficacy of the MDP examination

As shown in [Table 5], by ITT analysis, the rates of complete examination of the MDP were 68.2 % (58/85) in the CA-EGD group and 86.0 % (74/86) in standard duodenoscopy group (odds ratio [OR] 2.87, 95 %CI 1.34 to 6.15; P = 0.01). Per-protocol analysis showed that the complete examination rates were 69.9 % (58/83) and 88.1 % (74/84), respectively (OR 3.19, 95 %CI 1.42 to 7.17; P = 0.004). The one-sided P value for noninferiority test was > 0.5 by ITT and > 0.5 by per-protocol analysis, both of which were higher than the 0.35 of the prespecified boundary. The difference in proportions was –17.81 percentage points (95 %CI –28.14 to –7.48) by ITT analysis and –18.22 percentage points (95 %CI –28.34 to –8.10) by per-protocol analysis, both of which were lower than the noninferiority margin of –5 % (see [Table e3], available online). Taken together, these results denied the noninferiority of CA-EGD.

The MDP could not be visualized (score 0) in 10/85 patients (11.8 %) in the CA-EGD group and in 1/86 patients (1.2 %) in the standard duodenoscopy group (P = 0.005).

Parameters related to endoscopic examination

[Table e6] (available online) shows that the mean time taken for the examination of the MDP was significantly longer in the CA-EGD group than in the standard duodenoscopy group (69.5 [SD 46.4] vs. 33.0 [SD 28.9] seconds; P < 0.001). CA-EGD detected more lesions in the upper GI tract overall (62.7 % vs. 45.2 %; P = 0.02), esophagus (12.0 % vs. 1.2 %; P = 0.005), and stomach (20.5 % vs. 2.4 %; P < 0.001). CA-EGD tended to detect more lesions in the duodenal bulb (9.6 % vs. 2.4 %; P = 0.23); however, the difference was not significant. Compared with CA-EGD, more lesions were detected in the descending duodenum by standard duodenoscopy (39.3 % vs. 20.5 %; P = 0.01). No complications occurred during endoscopic examination of the MDP or during subsequent ERCP in either group.

Exploration of incomplete examination

As shown in [Table 7], incomplete examination of the MDP occurred in 25 patients in the CA-EGD group: the papilla was not found in 10 patients (scored 0), the orifice was not seen in 2 patients (scored 1), and the lower or upper end of the papilla was not visualized in 13 patients (scored 2). Among the 25 patients with incomplete examination by CA-EGD, further complete examination of the MDP was achieved by standard duodenoscopy alone in 21 patients and by duodenoscopy with the assistance of a sphincterotome in 4 patients. The subsequent duodenoscopy in the same patients also revealed the reasons for incomplete examination in the CA-EGD group, including PAD (40 %), papilla hidden under folds (36 %), abnormal position of the papilla (16 %), and swollen papilla (8 %).

In the standard duodenoscopy group, incomplete examination of the MDP occurred in 10 patients: the papilla was not found in 1 patient, the orifice was not seen in 2 patients, and the lower or upper end of the papilla was not visualized in 7 patients. The reasons for incomplete examination included the presence of PAD (80 %) and the papilla hidden under folds (20 %).

Discussion

CA-EGD has emerged as a promising method for examination of the MDP. However, its efficacy needs to be further investigated in different clinical settings. Here, we showed that CA-EGD was inferior to standard duodenoscopy for examination of the MDP. Although complete MDP examination was achieved in 69.9 % (58/83) of patients, CA-EGD still could not replace duodenoscopy as the standard method for examination of the MDP. The duration of MDP examination was significantly longer with the CA-EGD method. To the best of our knowledge, this is the first randomized controlled trial comparing these two endoscopic methods in terms of the examination of MDP.

It has been suggested that CA-EGD could be used as a salvage method for complete visualization of the papilla when a standard EGD examination fails [4]. Four studies have reported the effects of examining the MDP by CA-EGD ([Table 8]) [4] [10] [11] [15]. The current study used a strict criterion for complete examination of the MDP, in which the opening, and upper and lower ends of the MDP needed to be well visualized ([Table e1], [Video 1], [Video 2]). These criteria were the same as those used for definition in the study by Abdelhafez et al [11]. Although these criteria seem more appropriate compared with previous definitions [4] [10] [15], which had visualization of the MDP as the only criterion, observation bias might exist due to relatively subjective judgment, especially for the upper end of the MDP. The interobserver and intraobserver consistency of this score system still needs to be further evaluated.

Although the MDP could be visualized in 88.0 % of patients (73/83), the complete examination rate was only 69.9 % in this study, which is significantly lower than the 97 % reported by Abdelhafez et al. [11]. There are several possible reasons for the difference between these two studies. First, the Abdelhafez study enrolled patients scheduled for EGD, whereas our study only included patients undergoing ERCP. The clinical characteristics of MDP in patients undergoing ERCP may be different from those scheduled for EGD. As shown in [Table 7], deeper location, the presence of PAD, abnormal appearance, or transverse folds could interfere with examination of the MDP or the opening, and could also partly explain the reasons for the biliary disease in these ERCP patients [16] [17] [18] [19] [20]. These characteristics of the MDP may be less common in patients scheduled for EGD.

Second, PAD may hamper the observation of MDP, especially the upper end. The rate of PAD was not reported in the Abdelhafez study. Compared with the CA-EGD group, more cases of PAD were found in the standard duodenoscopy group (23.8 % [20/84] vs. 14.5 % [12/83]) with borderline significance in our study, indicating that PAD might be missed by CA-EGD. The upper end of the papilla could be wrongly recognized if it was hidden deep within a PAD. As the upper end of the MDP in the CA-EGD group was further evaluated by the subsequent duodenoscopy in the same patients, we believe our study might be more accurate in evaluating the upper end in patients with PAD.

Third, a potential factor that could influence the examination of CA-EGD is the experience of the endoscopist [10]. Although endoscopists participating in this study had only performed > 10 CA-EGDs for the examination of MDP before enrollment, the relevant experience was similar to that in the Abdelhafez study.

Fourth, the diameter of the gastroscope might also contribute to the different results of MDP examination. Some of the procedures in the Abdelhafez study were conducted with a thinner scope (8.8 mm); however, the detailed information was not reported ([Table 8]). The cap diameter was also different between the two studies. Finally, similarly to two previous studies [4] [10], conscious sedation was used in our patients, whereas deep sedation was used in the Abdelhafez study. However, different sedation methods may not have a significant impact on the examination of the MDP.

The experience of endoscopists performing CA-EGD (> 10) and standard duodenoscopy (> 1000) in this study was strikingly different and all of them were quite familiar with ERCP. The endoscopists might subconsciously have preferred the view during duodenoscopy and this imbalance may introduce some bias in the results. Currently, CA-EGD is not a standard procedure for examination of the MDP, and therefore, the endoscopists participating in this study had limited experience of CA-EGD for the examination of the MDP, similarly to most endoscopists around the world. Limited experience was also reported in previous CA-EGD studies [10] [11]. It is likely that the ability to examine the MDP would be improved with increased experience with CA-EGD. However, the complete MDP examination rate was found to be similar between the first and second half of enrolled patients in the CA-EGD group (78.6 % [33/42] vs. 69.9 % [58/83]; P = 0.30), indicating that the improved experience during the current study period might not significantly influence the examination of MDP.

It has been reported that complete examination of the MDP could not be achieved even by standard duodenoscopy, especially in patients with intra-diverticulum papilla [21] [22] [23] [24] or duodenal stricture [25] [26] [27]. In the CA-EGD group, 25 patients had an incomplete examination. Even with the subsequent duodenoscopy, complete examination could not be achieved in 4 patients without the assistance of sphincterotomy, due to the presence of PAD or the interference of transverse folds. In the standard duodenoscopy group, the MDPs of 10 patients could not be fully examined for the same reasons. However, with the assistance of a sphincterotome, complete examination could be achieved in all of these patients during standard duodenoscopy. Further studies are needed to investigate whether the use of additional instrumentation during CA-EGD (e. g. sphincterotome, cannula or forceps) improves the rate of complete MDP examination. Choi et al. [4] showed that a long cap was useful in two patients in whom visualization of the MDP failed when using a short cap. The comparison of long cap vs. short cap needs to be further evaluated in studies with a larger sample size.

The transparent cap may facilitate the exposure of the MDP by providing an appropriate distance to maintain the focus and prevent loss of visualization, allowing efficient manipulation of a tangentially placed papilla, making it easier to access hidden areas, and by reducing loop formation of the gastroscope [4] [10] [11]. However, manipulation of the CA-EGD scope for examination of the MDP may be time-consuming. As shown in the current study, the duration of complete examination of the MDP was longer in the CA-EGD group compared with the standard duodenoscopy group. More nonpapillary lesions were detected in the CA-EGD group, which might be related to the limited field of view with the side-viewing duodenoscope [7].

There was a major flaw in the initial design of this study. The original sample size calculation (n = 150) was found to be incorrect. After correction of the sample size, we enrolled additional patients to meet the requirement of the modified interim analysis. Although the baseline characteristics and main outcomes of the two analyses seem to be consistent ([Table e2], [Table e3]), the initial planned interim analysis was changed twice (see Results), which predisposes the final results to some uncertainties.

There were some limitations to the current study. First, the study could not be blinded because the endoscopic views of CA-EGD and standard duodenoscopy are quite different (as shown in [Fig. e1], [Video 1], and [Video 2]). The lack of concealment of the endoscopic examination methods might introduce bias to the outcomes. Second, this study only included patients with indications for ERCP. Although CA-EGD was found to be inferior to standard duodenoscopy for the complete examination of the MDP in ERCP patients, further work is required to determine whether CA-EGD is noninferior to duodenoscopy for MDP examination in unselected patients. Third, the endoscopic examination was performed only by experienced endoscopists in two tertiary hospitals. The findings need to be confirmed in more common clinical settings.

In summary, complete examination of the MDP was achieved by CA-EGD in most of the patients undergoing ERCP. It may be appropriate to use CA-EGD as an initial method for patients with suspected MDP lesions in endoscopy centers where standard duodenoscopy is not available. However, CA-EGD could not replace duodenoscopy as a standard method for examination of the MDP.

Competing interests

None

Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81370585) and National Key Technology R&D Program (2015BAI13B07).

^* These authors contributed equally to the study.

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Corresponding author

• References

• 1 Ende A, Zopf Y, Konturek P. et al. Strategies for training in diagnostic upper endoscopy: a prospective, randomized trial. Gastrointest Endosc 2012; 75: 254-260
  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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