Efficacy and Safety of Fully Covered Self- Expandable Metallic Stents in Biliary Complications After Liver Transplantation: A Preliminary Study

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1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Efficacy and Safety of Fully Covered Self- Expandable Metallic Stents in Biliary Complications After Liver Transplantation: A Preliminary Study Mario Traina, 1 Ilaria Tarantino, 1 Luca Barresi, 1 Riccardo Volpes, 1 Salvatore Gruttadauria, 1 Ioannis Petridis, 1 and Bruno Gridelli 1 1 Mediterranean Institute for Transplantation and Advanced Specialized Therapies/University of Pittsburgh Medical Center, Palermo, Italy After liver transplantation, the most common biliary complication is the anastomotic stricture, which is followed by biliary leakage. Studies have focused on the endoscopic treatment of biliary complications in transplanted patients with duct-to-duct reconstruction, showing a success rate of 70% to 80% after orthotopic liver transplantation and of 60% after living-related liver transplantation. Once the endoscopic approach fails, surgical treatment with a Roux-en-Y choledochojejunostomy is the sole alternative treatment. The aim of this prospective observational study was to analyze the efficacy and safety of fully covered self-expandable metallic stents for the treatment of posttransplant biliary stenosis and leaks in patients in whom conventional endoscopic retrograde cholangiopancreatography (ERCP) failed. From January 2008 to January 2009, 16 patients met the criteria of endoscopic treatment failure, and instead of surgery, a fully covered stent was placed. All patients had at least 6 months of follow-up (mean follow-up of 10 months). After removal, 14 patients showed immediate resolution of both the biliary stenosis and leak. After a mean of 10 months of follow-up, only 1 patient showed biliary stenosis recurrence. No major complications occurred in any of the patients, except for stent migration in 6 patients, although these presented with no clinical consequences. In conclusion, in patients not responding to standard endoscopic treatment, the placement of fully covered metal stents is a valid alternative to surgery. A cost analysis should be performed in order to evaluate whether to treat transplanted patients suffering from biliary complications with covered self-expandable metallic stent placement as first-line therapy. Liver Transpl 15: , AASLD. Received February 24, 2009; accepted July 14, Biliary complications are the most frequent complications after liver transplantation. Available data show a rate of biliary complications in transplant recipients ranging from 8% to 35%. This complication rate is higher for living-related liver transplantation (LRLTx) versus orthotopic liver transplantation (OLTx). 1,2 Biliary complications include strictures, biliary leaks, stones or debris, and Oddi dysfunction. The most common biliary complication is the anastomotic stricture, which is followed by biliary leakage, although patients often develop more than 1 complication. 3 Depending on the type of surgical biliary reconstruction (ie, choledochojejunostomy or duct-to-duct anastomosis), biliary complications can be treated by percutaneous transhepatic cholangiography or by endoscopic retrograde cholangiopancreatography (ERCP). ERCP is currently considered the diagnostic gold standard for patients with duct-to-duct anastomosis because it allows a direct approach for interventional procedures. 2 Several studies have evaluated the endoscopic treatment of biliary complications in patients with duct-to-duct reconstruction and have shown a success rate of approx- Abbreviations: ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LRLTx, living-related liver transplantation; OLTx, orthotopic liver transplantation; SEMS, selfexpandable metallic stent. Address reprint requests to Ilaria Tarantino, Mediterranean Institute for Transplantation and Advanced Specialized Therapies/University of Pittsburgh Medical Center, Via Tricomi 1, Palermo, Italy Telephone: ; FAX: ; itarantino@ismett.edu DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 1494 TRAINA ET AL. imately 70% to 80% in cases of OLTx and of about 60% in LRLTx cases. 4-8 Thuluvath 1 found that strictures appearing within 1 year after transplantation have a very good response after 1 or 2 balloon dilatation and stent placement sessions (repeated every 2-3 months). Late anastomotic strictures (appearing after 12 months) require longterm stenting, although with an acceptable success rate (close to 70%). Other reports have shown the same success rate for OLTx but lower rates for LRLTx. 4,6,8-10 If endoscopic therapy fails, surgical treatment with a Roux-en-Y choledochojejunostomy is the current alternative solution. In patients successfully responding to endoscopic therapy, there is still the risk of biliary stricture recurrence. In a study by Alazmi et al., 11 the rate of cholestasis recurrence with evidence of biliary strictures at ERCP, after transitory initial success with endoscopic therapy, was around 18%. Bile leakage is the second most frequent biliary complication after liver transplantation. If a T-tube is placed, the diagnosis is easily made with a trans-t-tube cholangiogram. The treatment consists of keeping the T-tube in place and placing an endoscopic stent. The T-tube can be removed soon after the stent placement, and the stent remains in place for 1 to 2 months. In patients without a T-tube but with suspicion of a biliary leak, ERCP is also recommended together with stent placement. The success rate of endoscopic treatment has been 90% in the different series. 4,10,12 Surgical biliary reconstruction, consisting of a Roux-en-Y choledochojejunostomy, is required when conservative treatments fail or when the leak is too large. Recently, Kahaleh et al. 13 reported a large cohort of patients with benign strictures of the common bile duct, including strictures after liver transplantation, who underwent the placement of a partially covered metal stent for cholestasis treatment. This approach appears to be promising but has some limitations, including chiefly the risk of biliary wall damage by the uncovered tract (leading to a hyperplasic reaction), the risk that the stent could worsen the biliary wound because of its radial force in the case of a concomitant leak, and finally the risk of stent migration and perforation. Our aim was to analyze the efficacy and safety of fully covered self-expandable metallic stent (SEMS) placement to treat posttransplantation biliary stenosis and leakage for patients in whom ERCP had failed. PATIENTS AND METHODS The number of transplants per year in our center is about 90 to 100 (approximately 25% from living donors), and our data show that the rate of biliary complications is 30% and 60% for OLTx and LRLTx recipients, respectively. In patients with biliary complications, our rate of failure in solving the biliary problem with conventional ERCP is 19% in the OLTx group and 38.6% in the LRLTx group. Our conventional endoscopic therapy includes sphincterotomy plus stent placement for biliary leaks, progressive pneumatic dilatation (from 4 to 8-10 mm), and double stent placement for strictures (10F or 11.5F if possible) for biliary stenosis alone. For cases requiring more than 1 procedure, ERCP is repeated every 3 months. Failure of endoscopic therapy is defined as evidence of continuous bile leakage despite endoscopic stent placement or the persistence of stenosis after 1 year despite multiple dilatation and stent placement. Failure is also defined as the persistence of stenosis if both a persistent stricture on fluoroscopy and recurrence of cholestatic liver enzymes after stent removal are present. After ERCP failure, the sole alternative therapy is surgery with a Roux-en-Y choledochojejunostomy, but in the case of patients not suitable for surgery, we prefer to directly adopt a percutaneous approach with biliary catheter placement rather than continuing with endoscopic treatment. We do this to avoid frequent inpatient admission and sedation for the performance of ERCP. The following information was obtained from a prospective database: patient demographics (gender and age), indication for transplantation, type of transplantation, number of biliary anastomoses, time between transplant and detection of complications, number of intervention sessions for all procedures (ERCP, balloon dilatation and stent exchange, and all percutaneous transhepatic biliary dilation), and procedure-related complications (eg, cholangitis, pancreatitis, and bleeding). From January 2008 to January 2009, all adult patients who developed biliary strictures and/or leaks after OLTx and LRLTx with duct-to-duct anastomosis and showed the criteria of failure of endoscopic therapy were included in the study. In these patients, after an assessment of conventional endoscopic treatment failure, ERCP (in place of surgery) was performed with fully covered stent placement (Niti-S ComVi fully covered biliary stent, Taewoong Medical, Korea). The stent was placed soon after the failure assessment. If stents were not available at the time, biliary catheters were placed with the transhepatic percutaneous approach (as per the surgeon s preference in order to avoid repeated sedation and intubation, which are required for ERCP). The covered metal stent was kept in place for 2 months, after which ERCP was performed to remove the stent and assess the biliary anatomy. The stent retrieval was performed with a polypectomy snare. Even in patients who spontaneously lost the stent, ERCP was performed to obtain a cholangiogram. We decided to verify the results in patients who had almost 6 months of follow-up after metal stent retrieval. After metal stent removal, the patients were called by our clinical coordinators every 15 days to verify clinical conditions. Liver function tests were recorded immediately after stent removal, at 3 and 6 months, and every 3 months in patients with a longer follow-up time. Data Analysis The medical records of all 16 patients were reviewed for additional data after appropriate institutional review LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases

3 EFFICACY AND SAFETY OF SEMS 1495 TABLE 1. Patients Baseline Characteristics Number of patients 16 Demographics Median age Number of men 8 (50%) Transplant indication HCV 5 (31.3%) HCC on HCV 10 (62.5%) Polycystic disease 1 (6.3%) Anastomosis Single duct-to-duct 13 Multiple duct-to-duct 3 Time of onset (months) No ERCP No plastic stents Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. board approval was received. The outcomes of interest were the resolution of the biliary stricture or biliary stricture plus biliary leak according to radiological evidence after metal stent removal and the rate of recurrence during the follow-up according to clinical and laboratory tests. Because of the small sample size, a descriptive analysis of the data, rather than a statistical analysis, was performed. RESULTS Patients From January 2008 to January 2009, 16 patients with duct-to-duct anastomosis who suffered from posttransplant biliary stenosis and leakage met the criteria of failure of endoscopic treatment and were enrolled in the study (Table 1 ). The mean follow-up time was months (a minimum of 6 months and a maximum of 14 months). Eight were male, and 8 were female, with a mean age of years. Eleven transplants were performed from cadaveric donors, and 5 were performed from living donors. Three patients with transplants from living donors had double anastomoses. The mean time for the diagnosis of biliary complications was months. In none of the patients was a liver biopsy requested to make the diagnosis. The clinical suspicion was confirmed in 5 patients by ultrasonography; in 11 patients, ultrasonography showed no biliary dilatation, and the diagnosis was made by magnetic resonance cholangiography (10) or computed tomography scanning (1). Eleven patients (68.8%) had biliary stenosis, and 5 (31.3%) had biliary leakage plus stenosis (Table 2). All 16 patients were initially treated with standard ERCP and with the conventional procedure: sphincterotomy plus stent placement for a stricture plus biliary leakage, sphincterotomy plus progressive pneumatic dilatation (from 4 to 10 mm), and double stent placement (10F or TABLE 2. Results Number of patients 16 Technical success 16 Immediate resolution 14 Mean ALT before SEMS placement (U/L) Mean ALT after SEMS retrieval (U/ L) Mean ALT at the end of follow-up (U/L) Mean bilirubin before SEMS 1,9 1.1 placement (mg/dl) Mean bilirubin after SEMS retrieval 1, (mg/dl) Mean bilirubin at the end of followup (mg/dl) Relapses 1 Complications 6 SEMS migration 6 Other complications 0 Mean follow-up (months) Abbreviations: ALT, alanine aminotransferase; SEMS, self-expandable metallic stent. 11.5F if possible) for a stricture alone. ERCP was repeated every 3 months or before the first 3 months if patients showed clinical signs of stent obstruction (high liver function tests and/or fever). The mean number of ERCP procedures was (a minimum of 1 and a maximum of 14). In all 16 patients, ERCP failed. There was evidence of continuous bile leakage despite endoscopic stent placement and/or persistence of stenosis after 1 year despite multiple dilatation and stent placement procedures (the mean number of stents placed per patient was ). No severe complications were observed after the endoscopic treatments; only 1 patient developed mild pancreatitis during the first ERCP procedure (hyperamylasemia and mild abdominal pain requiring 3 days of hospitalization and medical therapy). After the failure of ERCP, 7 patients were temporarily treated with percutaneous transhepatic cholangiography as per the surgeon s preference, and biliary catheters were placed because the fully covered metal stents were not immediately available. No complications associated with percutaneous transhepatic biliary dilation were observed. In all 16 patients, the fully covered metal stent was successfully placed. The metal stent was 1 cm in diameter and 6 to 8 cm long. After 2 months, ERCP was scheduled to retrieve the stent with a polypectomy snare. Six patients spontaneously lost the stent, although with no clinical complications (eg, obstruction or perforation). All patients who spontaneously lost the metal stent showed total solution of the stenosis. After removal, 14 patients (87.5%) showed immediate resolution of the biliary stenosis and leakage. This success was confirmed by liver function test normalization: bilirubin and alanine aminotransferase levels after stent removal were significantly reduced (P 0.05). LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases

4 1496 TRAINA ET AL. Figure 1. Biliary stenosis. Figure 3. Resolution of the stenosis. of stenosis and required other treatment (Table 2). This patient also received a liver from a living donor with a double biliary anastomosis. At cholangiography, both biliary anastomoses showed strictures, and the patient, because of the complexity of the surgical intervention, is currently being treated with a percutaneous transhepatic approach and biliary catheter placement. Figure 2. SEMS placement. Figures 1, 2, and 3 show the successful resolution of a case of anastomotic stenosis treated with SEMS placement. Two patients showed persistence of severe stenosis, and both had double biliary anastomoses. The sole complication related to the metal stents was the stent migration described in 6 patients, although this finding was without any clinical consequences. After 6 months of follow-up, 13 patients were consistent with the initial results, and 1 patient showed a relapse DISCUSSION Plastic stents have limited patency rates and become occluded within 3 to 6 months; frequent replacement and an increasing number of stents are required. 11 The major factor limiting plastic stent patency is the formation of a bacterial biofilm that leads to deconjugation of bile acid salts with sludge and stone formation related to the stent Efforts to prolong plastic stent patency by changes in stent design 29,30 or by the administration of ursodeoxycholic acid, aspirin, or antibiotics, 27,29,31,32 have had little impact on patency rates in vivo. Uncovered SEMS placement for benign biliary strictures has been reported, 14,15 but acceptance of this approach among clinicians has been limited by the observation of benign hyperplasia that compromises patency. 16,17 Studies comparing surgery to the placement of uncovered metal stents have demonstrated that surgery is superior, principally because of questions of patency and poor removability with uncovered stents. 18 In an attempt to improve the durability of patency, coverings for metal stents have been proposed 19,20 with good results. The improved patency in comparison with that of uncovered stents, 21 in combination with the theoretical ability to remove the stents, has led to studies that have assessed their utility in the setting of

5 EFFICACY AND SAFETY OF SEMS 1497 benign distal biliary strictures. 22,23 A case report 24 described the placement of a partially covered metal stent and its removal 6 months later in a patient with an anastomotic stricture after OLTx. A recent series 25 has described the percutaneous placement of a partially covered metal stent in 3 patients with strictures after OLTx and 1 stricture of an unknown etiology. One patient developed a biliary-hepatic arterial fistula in the side contralateral to stent placement, which was successfully treated with coil embolization. One patient developed an infection that was treated conservatively. All stents were removed percutaneously, except one that was removed by a combined anterograde and retrograde approach. Interestingly, the study reported no episodes of stent migration, and all stents remained patent for the duration of placement. More recently, Kahaleh et al. 13 reported the results of partially covered metal stent placement in a series of 65 patients, posting a success rate of 59 of 65 patients (90%). In this series, 15 of 16 patients with post-oltx strictures responded well to this treatment. Early complications occurred in 6 patients (8%), half of which were related to the stent. Late complications occurred in 11 patients (14%), 8 of which (73%) were related to the stent. Eleven patients had distal stent migration. The preliminary results of our study show the usefulness and safety of fully covered metal stent placement in patients who have developed biliary strictures or biliary strictures plus leaks after liver transplantation and who do not respond to conventional endoscopic therapy. Our results are limited in generalizability by a short follow-up time (a mean of 10 months). During the study period, we observed 2 failures and 1 recurrence after a temporary response, all in patients who received their livers from living donors and who also had double biliary anastomoses. Stent migration occurred in 6 patients, although with no clinical consequences. Because of the high success rate of endoscopic treatment in patients with posttransplant biliary complications (about 70%-80%), at present this therapy should be restricted to patients with previous failure of endoscopic treatments. No cost analysis was performed because of the small cohort of patients, but this would become imperative if the cohort were large. In conclusion, our preliminary data show that in patients who do not respond to standard endoscopic treatment, the placement of a fully covered metal stent can be a valid alternative to surgery. If these results were to be confirmed in larger cohorts with longer follow-up periods, endoscopic fully covered metal stent placement could replace surgical reconstruction and thus change the clinical history of these patients. REFERENCES 1. Thuluvath PJ. Biliary complication after liver transplantation: the role of endoscopy. Endoscopy 2005;37: Bentabak K. Adult-to-adult living related liver transplantation: preliminary results of the Hepatic Transplantation Group in Algiers. Transplant Proc 2005;37: Thulavath PJ, Atassi T, Lee J. An endoscopic approach to biliary complications following orthotopic liver transplantation. Liver Int 2003;23: Tarantino I, Barresi L, Petridis I, Volpes R, Traina M, Gridelli B. Endoscopic treatment of biliary complications after liver transplantation. World J Gastroenterol 2008;14: Boraschi P, Braccini G, Gigoni R, Sartoni G, Neri E, Filipponi F, et al. Detection of biliary complications after orthotopic liver transplantation with MR cholangiography. 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6 1498 TRAINA ET AL. 20. Thurnher SA, Lammer J, Thurnher MM, Winkelbauer F, Graf O, Wildling R. Covered self-expanding transhepatic biliary stents: clinical pilot study. Cardiovasc Intervent Radiol 1996;19: Isayama H, Komatsu Y, Tsujino T, Sasahira N, Hirano K, Toda N, et al. A prospective randomised study of covered versus uncovered diamond stents for the management of distal malignant biliary obstruction. Gut 2004;53: Kahaleh M, Tokar J, Le T, Yeaton P. Removal of selfexpandable metallic Wallstents. Gastrointest Endosc 2004;60: Familiari P, Bulajic M, Mutignani M, Lee LS, Spera G, Spada C, et al. Endoscopic removal of malfunctioning biliary self-expandable metallic stents. Gastrointest Endosc 2005;62: Trentino P, Falasco G, d Orta C, Coda S. Endoscopic removal of a metallic biliary stent: case report. Gastrointest Endosc 2004;59: Kuo MD, Lopresti DC, Gover DD, Hall LD, Ferrara SL. Intentional retrieval of Viabil stent-grafts from the biliary system. J Vasc Interv Radiol 2006;17: LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases