Primary Selection Criteria

The selection criteria for all topics in this report were:

1. Full-length report in peer-reviewed medical journals.
2. Published in English.
3. Reported outcomes relevant to this systematic review.
4. Where there were multiple reports of a single study, only the report judged to be most recent and complete, based on number of included patients and length of followup, was included. If additional relevant outcomes were included in the duplicate reports, these data were abstracted and added to the data from the primary report with citation to the supplementary articles.
5. Prospective in design, or if retrospective, enrolled consecutive patients or used appropriate sampling methods (e.g., case-control sampling method).

To keep readers informed of ongoing studies, studies published only in abstract form since 1999 and judged to be important are noted in this systematic review. Data were not abstracted into the evidence tables.

Studies of diagnostic performance met the following additional selection criteria:

1. Compared ERCP and at least one of the relevant diagnostic alternatives or compared two ERCP alternatives.
2. Subjected at least 90 percent of participants to both ERCP and the relevant diagnostic alternative.
3. Addressed a relevant patient population.
4. Included at least 25 subjects.
5. Reported sufficient information to be able to calculate 2x2 contingency tables of diagnostic performance.

Studies of therapeutic outcomes met the following additional selection criteria:

1. Compared ERCP strategies with at least one of the relevant therapeutic alternatives.
2. Addressed a relevant patient population.
3. Included at least 25 subjects in each treatment group being analyzed separately.
4. Reported on at least one relevant outcome measure.
5. Was a contemporaneous comparison study. If not contemporaneous, the populations and treatment setting were comparable.

Studies of predictors of ERCP complications met the following additional selection criteria:

• Included a multivariable analysis of the relationship between patient, procedure, or operator factors and ERCP complications.
• Enrolled at least 100 patients if a cohort study, or at least 25 cases if a case-control study.
• Addressed potential confounding variables in either the selection of subjects or analysis.

• Reported the association of either (a) specific risk factors of interest and the presence of a common bile duct stone (specific risk factors of interest were jaundice, liver function test results, and ultrasound finding of a dilated common bile duct), or (b) a prediction rule or model predicting likelihood of having a common bile duct stone and the presence of a common bile duct stone.
• Enrolled at least 100 patients.
• Reported sufficient information to be able to calculate 2x2 contingency tables of diagnostic performance in the prediction of presence or absence of a common bile duct stone.

Secondary Selection Criteria

There was a paucity of literature that met the primary selection criteria for questions on ERCP treatment of chronic pancreatitis (Topic 3b) and ERCP treatment of chronic abdominal pain of possible pancreaticobiliary origin (Topic 4b). To examine these questions, the original study selection criteria were relaxed for these topics to include:

1. Randomized controlled trials or otherwise concurrently controlled studies of an ERCP intervention compared to a relevant therapeutic alternative, regardless of sample size for pancreatitis.
2. Single arm pre-post-intervention studies which selected a well-defined population with a predictable natural history ascertained by baseline evaluation over 3 months. These studies must also have used an appropriate well-designed outcome measure over at least 6 months of followup.

Diagnostic Performance of ERCP Compared to Alternatives

• The search and selection process yielded 10 studies on MRCP (total n=834), 9 studies on EUS (total n=601), and 6 studies with 7 sets of findings on CTC (total n=266), but reference standards were not consistent among studies.

• Individual studies were relatively small and unlikely to have adequate power to detect a statistically significant difference; and no studies reported tests of statistical significance. Thus, it is not possible to determine with confidence whether the diagnostic performance is similar or poorer than ERCP or to accurately quantify any difference.

• The evidence comparing EUS to ERCP employs a reference standard that permits inferences regarding comparative performance. The evidence suggests that EUS is similar to ERCP in detecting common bile duct stones.

• MRCP has a degree of concordance with ERCP that results in sensitivities and specificities greater than 90 percent in most studies. Concordance of CTC with ERCP appears to be lower, with sensitivities as low as 80 percent in some studies.

• The role of alternative tests in the management of patients with suspected common bile duct stones cannot be determined strictly by diagnostic performance. The costs and risks of the tests, and the costs and risks of actions based on test results, along with the pretest probability of stones must all be considered to determine the optimal management strategy.

ERCP Treatment Strategies Compared to Surgical or Medical Management

• In order to evaluate ERCP treatment strategies, studies must account for patients through the diagnostic and treatment process, including additional procedures needed when initial treatment fails, and total morbidity of the alternative strategies. Overall, the literature is very thin and spread out over many different comparisons of interest, preventing strong conclusions about any specific comparison of treatment strategies.

• The limited evidence available suggests that: laparoscopic common bile duct exploration may be better than ERCP strategies to manage cholecystectomy patients with the least resource use; definitive surgery with cholecystectomy prevents long term complications at acceptable short-term morbidity when compared to sphincterotomy alone in high-risk surgical patients with suspected common bile duct stones; and endoscopic treatment of acute cholangitis reduces short-term mortality when compared to emergency surgery.

• Limited evidence suggests that the following techniques have similar stone removal rates and short-term complications: intracorporeal and extracorporeal lithotripsy methods for removing large common bile duct stones; balloon dilation and sphincterotomy; and needle-knife fistulotomy and needle-knife precut papillotomy.

Diagnostic Value of Specific Risk Factors or Predictive Models for Assessing the Likelihood of Having A Common Bile Duct Stone

• The probability of a common duct stone is one important factor in determining diagnostic and treatment strategies. When preoperative probability is high, ERCP may be preferred. When probability is low, expectant management is preferred. Additional diagnostic tests may be used to discriminate among patients in the middle range of probability. The exact probability cutoffs depend on the risks and benefits of the diagnostic and treatment alternatives. The risk factor or prediction model with the best receiver-operating characteristics (ROC) would make the best decision rule if the cutoff threshold were set correctly.

• Thirteen studies (total n=7,409) reported multiple findings of sensitivities and specificities of a single or combination of risk factors to predict the presence of common bile duct stones. The single risk factors most commonly assessed were: clinical jaundice or elevated bilirubin, liver function tests, and ultrasound findings of a dilated common bile duct. All have significant associations with the presence of common duct stones, but none have both high sensitivity and specificity. Of the four studies testing prediction rules based on combinations of risk factors, only one study was a validation of an independently developed prediction rule. Multivariable prediction rules appear to have superior ROCs compared to individual risk factors.

• The absence of any risk factors for stones (or a discriminant function indicating absence of stones) is a very strong predictor of the absence of stones. Absence of any risk factor produces probabilities of stones that are in the same range as a negative ERCP exam in a patient with risk factors for stones (0 percent to 17 percent).

Diagnostic performance of ERCP Tissue Sampling Techniques In Establishing A Tissue Biopsy Diagnosis of Pancreaticobiliary Malignancy Compared To Each Other and To Alternative Nonsurgical Tissue Sampling Techniques

• Twelve studies comparing at least two tissue sampling techniques were identified in this systematic review. The available studies are limited by small size and do not consistently compare techniques in the same group of patients. Most studies do not report statistical tests, so it is not possible to determine with confidence whether reported differences in sensitivity are significantly different. While available evidence is suggestive, larger studies are needed to draw conclusions on relative performance of tissue sampling techniques.

• The available evidence suggests that sensitivity for detecting malignancy is similar or higher for brush cytology vs. bile aspiration cytology, similar for fine-needle aspiration (FNA) cytology vs. brush cytology, and similar or higher for forceps biopsy vs. brush cytology. Using combinations of two or more sampling techniques may increase overall sensitivity. No comparative studies evaluated whether incremental improvement could also be achieved by repeated sampling using the same technique.

• In the absence of comparative studies of endoscopic ultrasound (EUS)-FNA and ERCP-FNA, indirect comparison of single-arm studies was attempted. Results from 10 studies including at least 400 subjects with pancreatic mass suggest a range of sensitivity in detecting pancreatic malignancy of 60-94 percent with a specificity of 100 percent. Two studies of ERCP-FNA including 164 subjects with various pancreatobiliary tumors reported sensitivities ranging from 25 percent to 62 percent. While sensitivity reported in these studies appears to be lower than that for EUS-FNA, such a comparison is not valid due to differences in study populations, cytology techniques, and study settings.

Diagnostic Performance of ERCP Compared to Alternatives in Detecting Malignant Pancreaticobiliary Obstruction

• The available evidence directly comparing ERCP with either MRCP or EUS is modest in size and of varying methodologic quality. The evidence comparing ERCP with MRCP is some-what stronger than that comparing ERCP with EUS. Individual studies do not demonstrate statistically significant differences in diagnostic performance for ERCP vs. MRCP or for ERCP vs. EUS for characterizing malignant strictures. In sum, the available studies suggest that either MRCP or EUS provides similar diagnostic performance as ERCP in detecting pancreaticobiliary malignant obstruction.

Treatment Outcomes Using ERCP Strategies To Treat Malignant Pancreaticobiliary Obstruction Compared To Using Surgical or Interventional Radiology Treatment

• Five studies compared endoscopic stent drainage with surgical bypass for palliation of malignant obstructive jaundice, and a randomized controlled trial of 204 patients provided the most robust evidence. There were no significant differences in overall survival, relief of jaundice, technical success, total hospitalization days, or perioperative mortality. Major complications were more frequent in the surgery group (11 percent vs. 29 percent, p=0.02); and stent replacement was required in 37 percent of patients treated with ERCP stents.

• Two randomized controlled trials (total n=206) and one nonrandomized trial (n=165) compared metal to plastic stents placed by ERCP for palliation of biliary obstruction due to malignancy. Both types of stents offer initial relief of jaundice and the available evidence does not conclusively show any difference in perioperative adverse events. Overall patient survival is not significantly different when stent occlusions are treated with stent exchange as needed. Total resource utilization including need for repeat ERCP, total hospital days, and costs was reported to be lower with metal stents compared with plastic stents.

• Six studies (total n=782), addressed preoperative stenting compared to no stenting prior to surgery for malignant pancreaticobiliary obstruction. The available evidence is of poor methodologic quality and fails to demonstrate that preoperative stenting improves health outcomes. Few studies report overall complications including both those related to the preoperative stent and the surgery, and these suggest that when complications of preoperative endoscopic stenting are considered along with the perioperative complications of surgery, preoperative stenting is associated with more complications. Preoperative stenting does appear to significantly improve elevated bilirubin and liver function tests, but the available evidence does not suggest that surgical outcomes are improved as a result.

Diagnostic Performance of ERCP Compared To Alternatives To Detect Underlying Causes or Complications of Pancreatitis That Are Amenable To Treatment

• Three studies (total n=190) were found which met selection criteria. Each study addresses a different potential cause or complication of pancreatitis amenable to treatment. The available evidence is insufficient to compare ERCP and other diagnostic modalities for the identification of treatable causes or complications of pancreatitis.

Treatment Outcomes of ERCP Strategies Compared To Surgical or Medical Therapy

• For treatment of acute pancreatitis, three randomized controlled trials (total n=554) compared early ERCP to delayed or selective ERCP. The available evidence suggests that early ERCP reduces complications in patient populations with acute pancreatitis and signs and symptoms suggesting biliary obstruction. In patients with low likelihood of biliary obstruction, delayed or selective ERCP permits many patients to avoid the procedure, and may result in lower complication rates. In addition, one retrospective associational study of a Veterans Administration database of patients with acute pancreatitis (n=2,075) suggests that outcomes of ERCP treatment are similar to those of surgery.

• For ERCP treatment in patients with acute recurrent or chronic pancreatitis, study selection criteria were relaxed as described above. Although the available evidence is sparse and largely uncontrolled, it suggests that ERCP treatment reduces emergency room visits and hospitalization in patients with pancreas divisum and acute recurrent pancreatitis. Evidence on ERCP drainage of pseudocysts is also sparse and poorly controlled, but suggests that pain relief with ERCP is similar to results of surgery.

Diagnostic Performance of ERCP with Sphincter of Oddi Manometry Compared with Alternatives To Identify A Pancreaticobiliary Origin of Pain

• The available evidence is not sufficient to permit conclusions on the diagnostic performance of biliary scintigraphy for sphincter of Oddi dysfunction. The body of evidence consists of three studies that included only 54 patients with sphincter of Oddi dysfunction; results of these studies cannot be synthesized due to differences in populations and methodology. There was substantial variability in the reported performance characteristics of biliary scintigraphy.

Treatment Outcomes of ERCP Strategies Compared To Surgical or Medical Therapy

• Two randomized controlled trials (total n=128) show that endoscopic sphincterotomy relieves pain in patients with pancreaticobiliary pain, sphincter of Oddi dysfunction, and elevated basal sphincter of Oddi pressure on manometry (greater than 40mm Hg). The results of five single arm studies (total n=183) corroborate these data and suggest that patients with a dilated common bile duct and/or delayed contrast emptying may also benefit from endoscopic sphincterotomy.

• There is insufficient evidence to determine whether endoscopic sphincterotomy improves outcomes in patients with normal manometry findings. For this group, the small studies included in this review do not report significant improvements in pain with endoscopic sphincterotomy.