Reappraisal of Endoscopic Papillary Balloon Dilation Versus Sphincterotomy for Choledocholithiasis—Time for a New Trial

Accepted Manuscript Reappraisal of Endoscopic Papillary Balloon Dilation vs Sphincterotomy for Choledocholithiasis —Time for a New Trial Andrew Y. Wang, MD, AGAF, FACG, FASGE

PII: DOI: Reference:

S1542-3565(17)30924-2 10.1016/j.cgh.2017.07.038 YJCGH 55375

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 23 July 2017 Please cite this article as: Wang AY, Reappraisal of Endoscopic Papillary Balloon Dilation vs Sphincterotomy for Choledocholithiasis —Time for a New Trial, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.07.038. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Reappraisal of Endoscopic Papillary Balloon Dilation vs Sphincterotomy for Choledocholithiasis —Time for a New Trial

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Author: Andrew Y. Wang, MD, AGAF, FACG, FASGE

Affiliation: Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA.

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Corresponding author: Andrew Y. Wang, MD, AGAF, FACG, FASGE

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Associate Professor of Medicine Chief, Section of Interventional Endoscopy

Division of Gastroenterology and Hepatology Box 800708 University of Virginia Health System

Tel: 434-924-1653 Fax: 434-244-7590

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Disclosures:

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E-mail: [email protected]

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Charlottesville, VA 22908

Dr. Andrew Wang receives research support from Cook Medical on the topic of metal biliary stents.

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Endoscopic sphincterotomy (EST) was first performed in 1973 and reported shortly after by Nakajima et al1 and by Classen and Demling.2 The earliest report of endoscopic papillary balloon dilation (EPBD) was by Staritz et al in 1982.3 In the intervening three to four decades there have

optimally remove stones from the bile duct by ERCP persists.

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been many advances in the field of pancreatico-biliary endoscopy, but the debate as how to most

There are many considerations for the endoscopist in approaching ERCP for biliary stone removal. The number and size of stones, the width of the duct above and below the level of the

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stone(s), ampullary features (such as papillary size, presence and location of a periampullary diverticulum), the anticipated stone composition (harder cholesterol stones vs. softer pigmented

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brown bilirubinate stones),4 the presence of surgically altered gastroduodenal anatomy, and other clinical issues such as bleeding diatheses as well as use of antiplatelet or anticoagulant medications must all be taken into consideration when planning endoscopic treatment of choledocholithiasis.

In this issue of the journal, Dr. Kuo and colleagues5 report the long-term results of a trial

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examining patients without prior biliary EST, who had choledocholithiasis, and were randomized to receive either short-duration EBPD over 1 min or long-duration EBPD over 5 min, using a 10-mm dilating balloon irrespective of bile duct size. The key finding of this well-conducted study was that

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at a median follow-up time of 7.4 years for the short-duration EBPD group and 6.9 years for the long-duration EBPD group, there were no significant differences in the rate of recurrent

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choledocholithiasis or cholangitis (primary outcome) or the rate of overall hepatobiliary complications (secondary outcome) between these two groups. Amazingly, no patients were lost to follow-up. In an exploratory secondary analysis, the investigators found the rate of recurrent choledocholithiasis or cholangitis to be higher in patients who required rescue EST vs. EPBD (of any dilation duration) alone (33.3% vs. 11.2%, P=0.02). While the hazard ratio for recurrent biliary stones following rescue EST was significant on univariate analysis, the association lost statistical

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significance on multivariate analysis after adjusting for confounders, possibly due to a lack of statistical power. At first glance, this appears to be a well-conceived and executed, long-term, follow-up study

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with negative results. Although it provides important long-term data on the safety of long-duration EPBD, it was not intended to and cannot directly address the issue of EST vs. EPBD for treatment of choledocholithiasis. A 2015 American Society for Gastrointestinal Endoscopy (ASGE) guideline stated that “Endoscopic sphincterotomy and stone extraction are successful in more than 90% of

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cases, with an overall rate of adverse events of approximately 5% and a mortality rate of less than 1% in expert hands.”6 Furthermore, as most biliary endoscopists in the United States or in the

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Western hemisphere typically perform a large or “complete” biliary sphincterotomy to facilitate removal of small- to medium-sized stones and would consider a “modest” EST followed by endoscopic papillary large balloon dilation (EPLBD, ≥12 mm) for large biliary stones7 prior to endoscopic lithotripsy, the temptation is to overlook the results of this study as not being relevant to clinical practice. In fact, current dogma is that EPBD of the native papilla is dangerous, as

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emphasized by the outcome of a multicenter randomized controlled trial (RCT) comparing EST to EPBD up to 8 mm (duration of dilation of 1 min), which was stopped early due to markedly increased rates of pancreatitis (15.4% vs. 0.8%) and death (1.7% vs. 0%) attributed to pancreatitis

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in the EPBD arm.8 A meta-analysis by Baron and Harewood9 in 2004 also found a higher initial success rate of stone clearance for EST compared to EPBD (79.8% vs. 70.0%, P=0.001).

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However, biliary sphincterotomy is not without risks. Aside from the immediate to short-term risks of bleeding (2%, range: 1-4%), perforation (<1%), and pancreatitis (3.5%, range: 2-16%),10-12 EST has been associated with long-term adverse events including papillary stenosis and stricturing (2-8%), stone recurrence and/or cholangitis due to duodenal-biliary reflux (3-18%), and cholecystitis (4-7%).13-16 In contrast, studies regarding EBPD have universally demonstrated the risk of bleeding approaches 0%, with rates of perforation also quite low (<1%).9, 17 Theoretically, EBPD may be advantageous as it might preserve some sphincter function, which ultimately might

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decrease the risk of choledocholithiasis and biliary complications that are associated with longterm duodenal-biliary reflux. So what are we to make of these contrasting perspectives when approaching a problem

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(choledocholithiasis) that biliary endoscopists encounter so commonly? My views on this topic have shifted over time, altered by emerging data on the nuances of EPBD. Having been trained in gastroenterology and interventional endoscopy in the United States around the time the trial by DiSario et al8 and meta-analysis by Baron and Harewood were published,9 I believed that EPBD of

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an intact papilla was dangerous. However, in the intervening decade, investigators mainly in Asian countries, including Dr. Liao in Taiwan, have theorized that EBPD of the native papilla was found to

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have reduced rates of stone clearance and increased frequency of pancreatitis in prior studies because of inadequate sphincter dilation. In the case of EPBD, but possibly not EPLBD, the main reason may be insufficient duration of balloon dilation. Because EPBD only loosens the ampullary and biliary sphincters without completely disrupting them, it has been posited that inadequate dilation duration leads to 1) a reduced opening of the biliary orifice that may impede stone

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extraction and 2) an increased likelihood of compartment syndrome of the ampulla due to intramucosal hemorrhage, inflammation, and edema that can occur within 2 hours of EPBD, which when combined with an inadequately loosened sphincter ampullae might compromise pancreatic

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duct (PD) outflow and increase the risk of post-ERCP pancreatitis (PEP). If a change as simple as extending the duration of EPBD (to >1 min) could improve the

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efficacy of biliary stone extraction and reduce the risk of PEP, then this would positively impact clinical practice. Therefore, I commend these authors for continuing to rigorously pursue and advance their theory in a field where the accepted clinical practice has been entrenched for some time.

The results of this paper take on added significance when considered together with the initial study on this same group of patients that randomized patients to 1-min vs. 5-min EPBD for the removal of common bile duct (CBD) stones.17 This trial demonstrated that failed stone

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extraction with EPBD alone was less frequent with 5-min EPBD (7.1%) than with 1-min EPBD (19.8%), with a relative risk (RR) of 0.36 (P=0.024). The frequency of pancreatitis was also lower with 5-min EPBD (4.8%) than with 1-min EPBD (15.1%), with an RR of 0.32 (P=0.038). Multivariate

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logistic regression analyses supported that 5-min EPBD reduced the risk of failure with EPBD alone (odds ratio [OR] 0.19, P=0.010) and pancreatitis (OR 0.28, P=0.035). While PD stenting was allowed in this study, no patients received a PD stent. To further study the impact of longer-

duration EPBD, Liao et al18 also conducted a meta-analysis that was published in CGH in 2012 that

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compared EST vs. short-duration EPBD vs. long-duration EPBD. This study reported that shortduration EPBD had a higher risk for pancreatitis (OR 3.9; 95% CI: 1.1-13.8) but long-duration

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EPBD did not pose a higher risk of pancreatitis (OR 1.1, 95% CI: 0.6-2.4) when compared to EST. In network meta-analysis, long-duration EPBD was associated the highest probability of avoiding overall complications (90.3%). Long-duration EPBD had a 43.9% probability of being the safest strategy vs. 55.9% for EST vs. 0.2% for short-duration EPBD, in terms of avoiding PEP. Partly because of these data, a 2016 European Society of Gastrointestinal Endoscopy

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(ESGE) Clinical Guideline11 went so far as to advise “EPBD as an alternative to EST for extracting CBD stones <8 mm in patients without anatomical or clinical contraindications, especially in the presence of coagulopathy or altered anatomy…For performance of EPBD, a 8-mm diameter

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balloon is recommended irrespective of the CBD diameter, and papillary dilation following waist disappearance should last for a minimum of 2 minutes. Data on the duration of dilation are

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conflicting, but 1 minute of dilation may have a higher rate of complications than 5 minutes.” One interesting point brought out by these studies5, 17 and also emphasized by the ESGE guideline is that “balloon size should not be selected on the basis of the diameter of the CBD or stone.”11 In the predicate study,17 there were no perforations caused by using a 10-mm dilating balloon in patients whose bile ducts ranged from 5 to 22 mm (median diameter: 10 mm) in size. The speculative ideas here are that most bile ducts can accommodate a 10-mm balloon and that there might be a minimum adequate balloon size required to sufficiently dilate the sphincters

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choledochus and ampullae. It should be noted that this idea of dilation irrespective of duct size should not be applied to EPLBD, as when dilating to a diameter ≥12 mm the width of the more proximal bile duct should not be exceeded for fear of perforation.7

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Established clinical practice patterns are hard to change. It seems clear that short-duration (≤1 min) EPBD without EST should not be performed. However, the short- and now long-term data supporting the efficacy and safety of long-duration EBPD are intriguing and provocative, and suggest that long-duration EPBD could be an alternative to EST in patients with small- to medium-

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sized (≤8-10 mm) biliary stones. As was similarly suggested in an ASGE Technical Review7

concerning EPLBD vs. EST, a multicenter RCT comparing EST to EPBD (using a longer duration

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of dilation) in patients with a native major papilla and extrahepatic bile duct stones would be essential to further confirm this theory. For a future study, and in current clinical practice in situations where EPBD without EST might be preferable or where EST is not possible, dilatingballoon size should be standardized at 8 mm or 10 mm, stone size should be limited to 8-10 mm depending on the balloon size, and dilation duration should probably be between 3-5 min following

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full expansion of the dilating balloon.

In 2017, the way in which ERCP is performed has also evolved. Wire-guided access, use of per rectal indomethacin, and recognition of the role of prophylactic PD stenting have all impacted

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and improved procedural outcomes, in particular that of post-ERCP pancreatitis.12 Coupled with emerging high-quality safety and efficacy data on short- and long-term outcomes following long-

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duration EPBD, such as those presented by this paper,5 there is now sufficient equipoise to justify a large multinational trial randomizing patients to extended-duration EPBD vs. EST for treatment of choledocholithiasis. Such a trial would address issues of generalizability (by having a more diverse patient population) and could result a paradigm shift in how we perform ERCP.

References 1. Nakajima M, Kimoto K, Fukumoto K, et al. Endoscopic sphincterotomy of the ampulla of Vater and removal of common duct stones. Am J Gastroenterol. 1975;64(1):34-43. 6

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2. Classen M, Demling L. [Endoscopic sphincterotomy of the papilla of vater and extraction of stones from the choledochal duct (author's transl)]. Dtsch Med Wochenschr. 1974;99(11):496-7. 3. Staritz M, Ewe K, Meyer zum Buschenfelde KH. Endoscopic papillary dilatation, a possible alternative to endoscopic papillotomy. Lancet. 1982;1(8284):1306-7. 4. Tsai WL, Lai KH, Lin CK, et al. Composition of common bile duct stones in Chinese patients during and after endoscopic sphincterotomy. World J Gastroenterol. 2005;11(27):4246-9.

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5. Kuo YT, Wang HP, Chang CY, et al. Comparable Long-term Outcomes of 1-minute vs 5minute Endoscopic Papillary Balloon Dilation for Bile Duct Stones. Clin Gastroenterol Hepatol. 2017. 6. Committee ASoP, Chathadi KV, Chandrasekhara V, et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015;81(4):795-803.

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7. Kim TH, Kim JH, Seo DW, et al. International consensus guidelines for endoscopic papillary large-balloon dilation. Gastrointest Endosc. 2016;83(1):37-47. 8. Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology. 2004;127(5):1291-9.

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9. Baron TH, Harewood GC. Endoscopic balloon dilation of the biliary sphincter compared to endoscopic biliary sphincterotomy for removal of common bile duct stones during ERCP: a metaanalysis of randomized, controlled trials. Am J Gastroenterol. 2004;99(8):1455-60. 10. Committee ASoP, Anderson MA, Fisher L, et al. Complications of ERCP. Gastrointest Endosc. 2012;75(3):467-73. 11. Testoni PA, Mariani A, Aabakken L, et al. Papillary cannulation and sphincterotomy techniques at ERCP: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. 2016;48(7):657-83.

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12. Wang AY, Strand DS, Shami VM. Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: Medications and Techniques. Clin Gastroenterol Hepatol. 2016;14(11):1521-32 e3. 13. Prat F, Malak NA, Pelletier G, et al. Biliary symptoms and complications more than 8 years after endoscopic sphincterotomy for choledocholithiasis. Gastroenterology. 1996;110(3):894-9.

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14. Pozsar J, Sahin P, Laszlo F, et al. Endoscopic treatment of sphincterotomy-associated distal common bile duct strictures by using sequential insertion of multiple plastic stents. Gastrointest Endosc. 2005;62(1):85-91.

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15. Szary NM, Al-Kawas FH. Complications of endoscopic retrograde cholangiopancreatography: how to avoid and manage them. Gastroenterol Hepatol (N Y). 2013;9(8):496-504. 16. Yasuda I, Fujita N, Maguchi H, et al. Long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation for bile duct stones. Gastrointest Endosc. 2010;72(6):1185-91. 17. Liao WC, Lee CT, Chang CY, et al. Randomized trial of 1-minute versus 5-minute endoscopic balloon dilation for extraction of bile duct stones. Gastrointest Endosc. 2010;72(6):1154-62. 18. Liao WC, Tu YK, Wu MS, et al. Balloon dilation with adequate duration is safer than sphincterotomy for extracting bile duct stones: a systematic review and meta-analyses. Clin Gastroenterol Hepatol. 2012;10(10):1101-9.

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