The effect of duration time on the efficacy and safety during endoscopic papillary balloon dilation for choledocholithiasis treatment CURRENT STATUS: REVIEW

Background Endoscopic papillary balloon dilation (EPBD) has been widely accepted as an alternative to endoscopic sphincterotomy (EST) during therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis treatment. No consensus has been established to define the precise duration of EPBD. Methods The PubMed, EMBASE, Cochrane Library database were systematically searched up to 31 May 2019 for research comparing short duration (≤ 30 seconds) and long duration (≥ 1 minute) of EPBD. Results Seven studies demonstrated that EPBD with long duration was superior than short duration in the stone clearance rate during the first ERCP (OR 0.61, 95%CI [0.48, 0.77], P < 0.001). Long duration exhibited a trend of higher efficacy in total stone removal across all ERCP sessions (OR 0.98, 95%CI [0.73, 1.31], P = 0.89), less frequency of mechanical lithotripsy use (OR 1.22, 95%CI [0.79, 1.89], P = 0.37). Compared with long duration, short balloon time had lower rate of overall complications (OR 0.85, 95%CI [0.70, 1.04], P = 0.11) and post-ERCP pancreatitis (OR 0.81, 95%CI [0.63, 1.03], P = 0.09). No significance was identified in hemorrhage (OR 0.86, 95%CI [0.30, 2.44], P = 0.77), perforation (OR 0.54, 95%CI [0.14, 2.14], P = 0.38) and cholangitis (OR 1.15, 95%CI [0.80, 1.66], P = 0.44). heterogeneity random-effect retrograde cholangiopancreatography; CBDS, common bile duct stones; SO, sphincter of Oddi; PEP, post-ERCP pancreatitis; ESGE, European Society of Gastrointestinal Endoscopy; EPLBD, endoscopic papillary large balloon dilation; RCT, randomized controlled trial; RCS, retrospective cohort trial; ESBD, endoscopic sphincterotomy with balloon dilation; ESLBD, endoscopic sphincterotomy with large balloon dilation;


Conclusion
Long duration (≥ 1 minute) could significantly increase the efficacy of EPBD in stone removal rate during first ERCP session, manifesting higher rate of total CBD stone clearance and less mechanical lithotripsy. Short EPBD contributed to less overall complications than long EPBD but not significantly.

Background
Approximately 10% of the global adult are diagnosed with symptomatic gallstones and common bile duct stones (CBDS) accounted for 10%-15% symptomatic cholelithiasis [1]. For patients with choledocholithiasis, the therapeutic effect and prophylaxis has been obviously improved with the rapid progress of endoscopic techniques. Endoscopic sphincterotomy (EST) was firstly implemented in 1975 and gradually accepted as a common technique to enlarge the sphincter of Oddi (SO) during endoscopic retrograde cholangiopancreatography (ERCP) [2]. But EST also demonstrated failure of stone removal and post-procedure complications including post-ERCP pancreatitis (PEP), hemorrhage, perforation, cholangitis. As a potential method for preserving the function of SO, endoscopic papillary balloon dilation (EPBD) was invented and suggested as an alternative intervention to sphincterotomy for efficient and safe removal of CBDs with less hemorrhage events [3][4][5][6][7]. But higher incidence of PEP was reported in patients suffering EPBD. Recently, EPBD appears to be combined with preceding EST to treat large or difficult CBD stones, which could improve efficacy of stone removal and reduce the risk of related complications [8][9][10][11].
Although EPBD has been widely adopted for removal and extraction of CBD stones, no consensus of accurate duration time has been established. ERCP guideline of European Society of Gastrointestinal Endoscopy (ESGE) weakly recommends ≥ 2-minute papillary dilation should be maintained after waist disappearance [4]. Endoscopic guideline for common bile duct stones of ESGE illustrated that EPBD duration should be maintained between 30 and 60 seconds from waist disappearance [12]. Conflicting conclusions were drawn from present published data. A network meta-analysis illustrated that EPBD with long dilation duration is safer than EPBD with short dilation duration and EST because ≤ 1-minute dilation could increase the risk of PEP and long EPBD had a lower rate of overall complications [13].
Another meta-analysis indicated no significant difference in CBD stone clearance between endoscopic papillary large balloon dilation (EPLBD) and EST, despite EPLBD being taken with either short dilation time (≤ 30 seconds) or long dilation time (≥ 1 minute) [14]. Besides, it was reported that 30-second ballooning duration showed a lower tendency in the incidence of post-procedural pancreatitis than 2minute ballooning duration [15].
Our meta-analysis and systematic review will aim to evaluate the efficacy and safety between short dilation duration (≤ 30 seconds) or long dilation duration (≥ 1 minute) during removal of CBD stones by EPBD.

Methods
Interventions and presented according to Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines [16].

Literature search
We searched and identified research from PubMed, EMBASE, and Cochrane Library (including CENTRAL) database from the January 1st, 1990 to May 31st, 2019. Besides, we broaden the search for available or similar studies from review articles and academic conferences. No language restriction was achieved during our searching. The following keywords involved in our searching were "endoscopic retrograde cholangiopancreatography", "ERCP", "endoscopic papillary balloon dilation", According to Cochrane guideline and consensus, we collected baseline clinical data from included research and converted them to a common data extraction form [16,18]. Baseline information includes first author, publication year, trial design, country, male proportion, patients age, past indicator determination (0-3). A RCS with ≥ 7 points NOS score was defined as a highly qualified study and included in final analysis [19].

Statistical analysis
A pooled odds ratio (OR) and 95% confidence interval (CI) was adopted in our statistical analysis. The pooled continuous data are presented as a form of means ± standard error. Two-tailed with P < 0.05 was considered statistically significant. Subgroup analysis was performed to assess the effect of prior EST, large balloon and 5-minute strategy on the efficacy and safety of EPBD. We also assessed publication bias via funnel plot asymmetry and Egger test [20]. P ≥ 0.1 was considered to indicate no significant publication bias. The statistical heterogeneity was evaluated by Higgins I 2 statistic and the chi square-based Q statistic [21]. Heterogeneity was defined to be not significant when P > 0.1 and I 2 < 50%. Fixed-effect model was selected without significant heterogeneity and random-effect model was used if heterogeneity is significant. Sensitivity analysis was also performed to confirm the stability of our results. All the analyses described above were performed with STATA 15.0 statistical software (Stata Corp., College Station, TX, USA).

Results
Literature search and basic characteristics of included trials database. After screening titles, abstracts and full text, seven full-length published trials were ultimately selected (Fig. 1 [15,27]. A summary of detailed baseline characteristics from all included trials are reviewed and presented in Table 1.  Figure S1) and Egger's test (P = 0.45, Figure S2).

Efficacy comparison
All included trials reported total CBD stone clearance rate across all ERCP sessions, which was compared between short duration group and long duration group. As shown in Fig. 2

Subgroup analysis
As shown in Table 2

Discussion
EPBD has been widely accepted as a potential method for preserving the function of SO during ERCP but no consensus is established to define explicit duration of EPBD. Our review and meta-analysis were the first systematic investigation to figure out the effect of EPBD duration on the efficacy and safety of therapeutic ERCP for choledocholithiasis by comparing short duration dilation (≤ 30 seconds) and long duration (≥ 1 minute) dilation. There were also some potentially confounding factors including preceding EST, the use of large balloon dilation and 5-minute long duration. Subgroup analyses were taken to identify their effect on the efficacy and safety of ERCP for CBD stones. Both RCTs and RCSs were included in our analysis due to limited number of trials showing the comparison between short and long dilation time.
During the first ERCP session, a significantly higher efficiency in complete removal of CBD stones was shown in the EPBD group with long dilation duration. Intriguingly, subgroup analysis indicated that the efficacy of stone removal during the first ERCP session was improved by preceding EST especially for ≤ 30-second dilation because there was no significance in the rate of stone removal between shortand long-time dilation with preceding EST. Recently, a network meta-analysis has identified ESBD has a significant higher rate of stone removal during the first endoscopic session compared with EST and EPBD[28]. Besides, ≥ 1-minute dilation duration of EPBD demonstrated a trend of higher rate of total stone clearance and less frequency of mechanical lithotripsy use although no significance was verified.
After comparing the efficiency between two groups, we compared a total rate of overall early complications. The result revealed that short duration of EPBD could have a trend to reduce the risk of overall complications and pancreatitis compared with long duration of EPBD. Our result was opposed to an earlier meta-analysis demonstrating duration of EPBD is inversely associated with pancreatitis risk [13]. Their results were mainly based on indirect comparison with EST and only one trial was included in the comparison between short and long EPBD despite Bayesian statistical approach was Declarations Ethics approval and consent to participate Not applicable.

Consent for publication
All authors read and approved the final manuscript.
Availability of data and material Not applicable.

Competing Interests
The authors declare no conflict of interest.

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