Meta-analysis: rectal indomethacin for the prevention of post-ERCP pancreatitis.

BACKGROUND: Despite initial evidence in the literature, nonsteroidal anti-inflammatory drugs (NSAIDs) have not been widely used to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). AIM: To complete a meta-analysis of high-quality RCTs that included the latest available literature published after past meta-analytical efforts METHODS: A comprehensive electronic literature search was carried out for RCTs comparing peri-procedural rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed by the Cochrane risk of bias tool. Fixed model Mantel-Haenszel meta-analysis, Q test and I(2) index were used. Several subgroup and sensitivity analyses were planned. RESULTS: A total of four of 61 retrieved trials between 2007 and 2012 (n = 1470) were included. No significant publication bias existed. All studies used similar criteria to detect pancreatitis. The pooled proportion estimate of the rate of pancreatitis was 5.1% with indomethacin and 10.3% with placebo. After excluding the high-risk patients, the rates were 3.9% and 7.9% respectively. Fixed model meta-analysis showed that the rate of pancreatitis was significantly lower using indomethacin as compared with placebo [OR = 0.49(0.34-0.71); P = 0.0002]. Number needed to treat was 20. There was no significant statistical or clinical heterogeneity. In subgroup analysis, the difference remained unchanged for average-risk population [OR = 0.49(0.28-0.85); P = 0.01] or in preventing severe PEP [OR = 0.41(0.21-0.78); P = 0.007]. The result of the main outcome remained robust in multiple sensitivity analyses. CONCLUSIONS: Rectal indomethacin used immediately before or after ERCP significantly reduces the risk of PEP to half in both low- and high-risk patients, and with both statistically and clinically significant conclusions. These results suggest that a possible change in routine practice for patients at both low and high risk of developing PEP should be advocated.

Randomised clinical trial: MRCP-first vs. ERCP-first approach in patients with suspected biliary obstruction due to bile duct stones.

BACKGROUND: The preferred initial investigation with either magnetic resonance (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) in patients with suspected biliary obstruction remains controversial in many clinical settings. AIM: To assess the effectiveness of an initial MRCP vs. ERCP in the work-up of patients at moderate likelihood of a suspected biliary obstruction. METHODS: Patients with an unconfirmed benign biliary obstruction, based on laboratory and ultrasound findings, were randomised to an ERCP-first or MRCP-first strategy, stratified by level of obstruction. The primary outcome was the occurrence of a disease or procedure-related bilio-pancreatic adverse events within the next 12 months. Secondary outcomes were the number of subsequent bilio-pancreatic procedures, duration of hospitalisation, days away from activities of daily living (ADL), quality of life (SF-36) and mortality. RESULTS: We randomised 126 patients to ERCP-first and 131 to MRCP-first (age 54 ± 18 years, 62% female, 39% post-cholecystectomy). In follow-up, 18/126 (14.3%) ERCP-first and 25/131 (19.1%) MRCP-first patients experienced a procedure- or disease-related complication (P = 0.30) (disease-related in 13 and 18 patients, and procedure-related in 5 and 7 patients respectively). A cause of biliary obstruction was found in 39.7% vs. 49.6% of patients (P = 0.11). Sixty-six (50%) patients in the MRCP-first group ended up avoiding an ERCP in follow-up. ERCP-first and MRCP-first patients were away from usual activities for 3.4 ± 7.7 days and 2.0 ± 4.8 days respectively (P < 0.001). CONCLUSION: A strategy of MRCP-first decreased the need for subsequent MRCPs, but not complications. Further study is required to define factors influencing the eventual use of MRCP vs. ERCP in appropriately selected patients (ClinicalTrial.gov: NCT01424657).

Red blood cell transfusion is associated with increased rebleeding in patients with nonvariceal upper gastrointestinal bleeding.

BACKGROUND: There exists considerable practice variation and little evidence to guide red blood cell (RBC) transfusion in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). Studies in other critically ill cohorts suggest associations between transfusions and adverse patient outcomes. AIM: To characterise any possible clinically-relevant association between RBC transfusion following NVUGIB with rebleeding and mortality. METHODS: Observational study utilising the Canadian Registry of patients with Upper Gastrointestinal Bleeding and Endoscopy (RUGBE). Multivariable logistic regression models were used to examine and quantify independent associations between RBC transfusion and clinical outcomes. RESULTS: Overall, 1677 patients were included (66.2 ± 16.8 years, 61.7% male, 2.5 ± 1.7 comorbid conditions, initial haemoglobin, 96.8 ± 27.2 g/L); 53.7% received RBC transfusions (2.9 ± 1.6 units of blood), 31.6% had haemodynamic instability, 5.1% fresh blood on rectal examination and 8.6% in the nasogastric tube aspirate. Endoscopic haemostasis was performed in 35.2%. Overall rebleeding (defined as continuous bleeding, rebleeding or surgery) and mortality rates were 17.9% and 5.4%, respectively. After adjusting for potential confounders, transfusion of RBC within 24 h of presentation was significantly and independently associated with an increased risk of rebleeding (OR: 1.0, 95% CI: 0.6-1.8), but not death (OR: 1.5, 95% CI: 0.94-2.23). CONCLUSIONS: This study suggests an association between RBC transfusion following NVUGIB and subsequent rebleeding, after appropriate and extensive adjustment for confounding. Prospective randomised trial evidence is needed to identify the most efficacious and cost-effective transfusional strategies in these patients.

Systematic review: the presenting international normalised ratio (INR) as a predictor of outcome in patients with upper nonvariceal gastrointestinal bleeding.

BACKGROUND: The prognostic value of an elevated international normalised ratio (INR) as part of initial risk stratification in nonvariceal upper gastrointestinal bleeding (NVUGIB) remains poorly characterised. AIM: To assess the usefulness of the initial INR in patients with NVUGIB. METHOD: After a systematic review, we included the presenting INR and other validated prognosticators in multivariable models predicting rebleeding and mortality. Data are reported as odd ratios and 95% confidence intervals. RESULTS: Only two of 769 candidate studies were useful, but reported disparate, highly selected NVUGIB patients with varying threshold initial INR values, yielding conflicting results on predictive ability. The RUGBE cohort included 1869 patients (mean age 66.3 ± 16.8, 38.1% female) with a mean presenting INR of 1.5 ± 1.7. 462 (24.7%) patients had an elevated INR (INR > 2.5 in 7.6%). INR did not add to the prediction of rebleeding. An INR >1.5, in contradistinction, significantly predicted mortality (OR: 1.96; 95% CI: 1.13-3.41). CONCLUSIONS: An elevated INR at initial presentation does not predict rebleeding in NVUGIB. A value 1.5 or greater, however, is associated with increased patient mortality after adjustment for validated prognosticators. The INR appears most useful as proxy of co-morbid burden at the time of initial assessment in NVUGIB.

Wait times for gastroenterology consultation in Canada: the patients' perspective.

Long wait times for health care have become a significant issue in Canada. As part of the Canadian Association of Gastroenterology's Human Resource initiative, a questionnaire was developed to survey patients regarding wait times for initial gastroenterology consultation and its impact. A total of 916 patients in six cities from across Canada completed the questionnaire at the time of initial consultation. Self-reported wait times varied widely, with 26.8% of respondents reporting waiting less than two weeks, 52.4% less than one month, 77.1% less than three months, 12.5% reported waiting longer than six months and 3.6% longer than one year. One-third of patients believed their wait time was too long, with 9% rating their wait time as 'far too long'; 96.4% believed that maximal wait time should be less than three months, 78.9% believed it should be less than one month and 40.3% believed it should be less than two weeks. Of those working or attending school, 22.6% reported missing at least one day of work or school because of their symptoms in the month before their appointment, and 9.0% reported missing five or more days in the preceding month. A total of 20.2% of respondents reported being very worried about having a serious disease (ie, scored 6 or higher on 7-point Likert scale), and 17.6% and 14.8%, respectively, reported that their symptoms caused major impairment of social functioning and with the activities of daily living. These data suggest that a significant proportion of Canadians with digestive problems are not satisfied with their wait time for gastroenterology consultation. Furthermore, while awaiting consultation, many patients experience an impaired quality of life because of their gastrointestinal symptoms.

Clinical trial: intravenous pantoprazole vs. ranitidine for the prevention of peptic ulcer rebleeding: a multicentre, multinational, randomized trial.

BACKGROUND: Controlled pantoprazole data in peptic ulcer bleeding are few. AIM: To compare intravenous (IV) pantoprazole with IV ranitidine for bleeding ulcers. METHODS: After endoscopic haemostasis, 1256 patients were randomized to pantoprazole 80 mg+8 mg/h or ranitidine 50 mg+13 mg/h, both for 72 h. Patients underwent second-look endoscopy on day 3 or earlier, if clinically indicated. The primary endpoint was an overall outcome ordinal score: no rebleeding, rebleeding without/with subsequent haemostasis, surgery and mortality. The latter three events were also assessed separately and together. RESULTS: There were no between-group differences in overall outcome scores (pantoprazole vs. ranitidine: S0: 91.2 vs. 89.3%, S1: 1.5 vs. 2.5%, S2: 5.4 vs. 5.7%, S3: 1.7 vs. 2.1%, S4: 0.19 vs. 0.38%, P = 0.083), 72-h clinically detected rebleeding (2.9% [95% CI 1.7, 4.6] vs. 3.2% [95% CI 2.0, 4.9]), surgery (1.9% [95% CI 1.0, 3.4] vs. 2.1% [95% CI 1.1, 3.5]) or day-3 mortality (0.2% [95% CI 0, 0.09] vs. 0.3% [95% CI 0, 1.1]). Pantoprazole significantly decreased cumulative frequencies of events comprising the ordinal score in spurting lesions (13.9% [95% CI 6.6, 24.7] vs. 33.9% [95% CI 22.1, 47.4]; P = 0.01) and gastric ulcers (6.7% [95% CI 4, 10.4] vs. 14.3% [95% CI 10.3, 19.2], P = 0.006). CONCLUSIONS: Outcomes amongst pantoprazole and ranitidine-treated patients were similar; pantoprazole provided benefits in patients with arterial spurting and gastric ulcers.

The safety of endoscopic sphincterotomy in patients receiving antiplatelet agents: a case-control study.

OBJECTIVE: To determine whether antiplatelet agents are associated with endoscopic sphincterotomy-related haemorrhage as few well-controlled data exist on this controversial issue. METHODS: A case-control study in a tertiary care setting included cases with bleeding following endoscopic sphincterotomy, matched with 2-3 controls selected according to age +/- 15 years, sex, and procedural date+/- 2 years. Cases and controls were compared for possible risk factors of postendoscopic sphincterotomy bleeding (presence of a coagulopathy and cholangitis). The main outcome measurement was the association between the use of antiplatelet medications and postendoscopic sphincterotomy bleeding after adjustment for possible confounding. RESULTS: The 40 cases [mean age 68 +/- 17 (s.d.) years, 50% female] and 86 controls [68 +/- 16 years, 50% female] were comparable except for differences noted in International Normalized Ratio (INR) (>2 in four cases vs. two controls), and pre-endoscopic sphincterotomy cholangitis (45% vs. 20%). Amongst cases, 13% were on aspirin and 3% on clopidogrel; 17% of controls took aspirin, and 4% a non-steroidal anti-inflammatory drug. 53% of cases bled immediately; the remainder haemorrhaged at 2 +/- 3 days. After adjustment for an elevated INR and cholangitis, exposure to antiplatelet agents was not significantly associated with procedure-related bleeding (odds ratio = 0.41, 95% CI [ 0.13; 1.31]). CONCLUSION: This case-control study provides controlled data suggesting that antiplatelet agents do not significantly increase the risk of clinically-important bleeding related to endoscopic sphincterotomy. The low prevalences of non-steroidal anti-inflammatory drugs and clopidogrel use limit any definite conclusion on their elective use before endoscopic sphincterotomy.

Predictors of inappropriate utilization of intravenous proton pump inhibitors.

BACKGROUND: Inappropriate use of intravenous proton pump inhibitors is prevalent. AIM: To assess appropriateness of intravenous proton pump inhibitor prescribing. METHODS: Retrospective review of in-patient prescribing of intravenous pantoprazole over a 2-month period in 2004, in an academic centre. Prescribing was deemed appropriate before and after endoscopic haemostasis, and in fasting individuals requiring a proton pump inhibitor. RESULTS: Amongst 107 patients, 49 (46%) had upper gastrointestinal bleeding. Overall, 33 (31%, 95% CI: 22-41%) received appropriate therapy (indication, dose and duration), 61 (57%, 95% CI: 47-67%) had an inappropriate indication, and 13 (12%, 95% CI: 7-20%) had an incorrect treatment dose or duration. Therapy was appropriate in 20 (41%, 95% CI: 27-55%) with upper gastrointestinal bleeding, and 13 (22%, 95% CI: 12-33%) in the non-upper gastrointestinal bleeding group. Appropriate prescribing rates decreased (from 41% to 16%, 95% on difference CI: 14-38%) when considering intravenous proton pump inhibitor use while awaiting endoscopy as inappropriate. Significant predictors of inappropriate use were increasing age and decreasing mean daily dose, with a trend for prescriptions written during evening shifts. CONCLUSION: Inappropriate intravenous proton pump inhibitor utilization was most frequent in the non-upper gastrointestinal bleeding group, mostly for unrecognized indications. Educational interventions to optimize utilization should target prescribing in older patients, those receiving lower mean daily doses, and, perhaps, prescribing outside regular hours.

Hospitalization for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs among elderly patients using low-dose aspirin: a retrospective cohort study.

OBJECTIVES: Many elderly patients are prescribed both low-dose aspirin (ASA), for cardiovascular protection and non-steroidal anti-inflammatory drugs (NSAIDs) for pain control. Compared with non-selective NSAIDs (NS-NSAIDs), celecoxib has a superior gastrointestinal (GI) safety profile in general. It is unclear, however, whether this fact holds good among patients taking ASA. We compared GI hospitalization rates among elderly patients taking celecoxib, NS-NSAIDs, celecoxib and ASA or NS-NSAIDs and ASA. METHODS: This was a retrospective cohort study using Quebec government databases. All patients 65 yrs of age or older who filled a prescription for celecoxib or an NS-NSAID between April 1999 and December 2002 were included. Cox regression models were used to compare the GI hospitalization rates between the four exposure categories adjusting for potential confounders. RESULTS: A total of 332 491 patients were included. Among 1 522 307 celecoxib prescriptions, 430 214 were filled by patients concurrently receiving ASA (celecoxib and ASA); 195 369 of 863 646 NS-NSAID prescriptions were filled by patients receiving ASA (NS-NSAID and ASA). Celecoxib without ASA was less likely than NS-NSAID without ASA to be associated with GI hospitalization [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.33-0.50]; celecoxib and ASA was also less likely to be associated with GI hospitalization than NS-NSAID and ASA (HR 0.62, 95% CI 0.48-0.80); GI hospitalization rates were similar for celecoxib and ASA and NS-NSAID without ASA (HR 1.01, 95% CI 0.81-1.25). CONCLUSION: Among elderly patients receiving cardiovascular protection with ASA and pain control with anti-inflammatory drugs, celecoxib may be safer with regards to GI toxicity than NS-NSAIDs.

Review article: acid-related disease--what are the unmet clinical needs?

Proton pump inhibitors have dramatically improved the management options available for patients with acid-related disorders. In patients with gastro-oesophageal reflux disease, currently available proton pump inhibitors provide an excellent outcome for the majority; however, they do not provide optimal pH control in many. Proton pump inhibitors co-therapy reduces, but does not eliminate, the risk of gastrointestinal ulcers and complications in patients taking non-steroidal anti-inflammatory drugs, while in patients with upper gastrointestinal bleeding, it may be difficult to reach and maintain the current therapeutic target of intragastric pH of 6-7. This article reviews the effectiveness of current antisecretory therapy in these three acid-related diseases and areas of unmet clinical need. The potential role of a proton pump inhibitor with an extended duration of action and enhanced acid control from a single daily dose, particularly improved control at night, is discussed. Finally, therapy that could be administered without regard to time of day and/or food intake would offer dosing flexibility and thus have a positive effect on patients' compliance.