Post-marketing reports of pancreatitis in eluxadoline-treated patients pre and post US label change.

BACKGROUND: Eluxadoline, a United States Food and Drug Administration (FDA)-approved treatment for irritable bowel syndrome with diarrhea (IBS-D), underwent a change to its US prescribing information on 21 April 2017, contraindicating it in patients without a gallbladder due to increased risk of pancreatitis. This study aimed to elucidate the potential role of eluxadoline's label change on the number of reported spontaneous adverse events (AEs) of pancreatitis. METHODS: A pharmacovigilance database (Oracle Argus) was searched for eluxadoline use and spontaneously reported pancreatitis cases from 1 January 2016 to 30 June 2018. Pancreatitis cases were reported as a proportion of the total number of reported AE cases in the safety database. The FDA's adverse event reporting system (AERS) was also interrogated for cases of pancreatitis concomitantly reported with eluxadoline use. RESULTS: In patients who received eluxadoline, 273 reported cases of pancreatitis were recorded (total AEs n = 2191; 12.5%). When known, 28.2% of patients reporting pancreatitis had intact gallbladders (49/174). Eluxadoline was withdrawn in 97.5% of cases, with 87.1% of patients improving or recovered at time of reporting. Importantly, the reporting proportion of pancreatitis cases decreased from 14.4% to 8.9% post label change. Findings were supported by the AERS results, which demonstrated a decrease in reporting proportion from 21.2% to 12.8%. CONCLUSIONS: While cautious interpretation is warranted, post-marketing data indicate that the contraindication of eluxadoline in patients without a gallbladder led to reduced reported cases of pancreatitis, with no additional reports of moderately severe or severe cases. Eluxadoline is a safe and well-tolerated treatment option for IBS-D when used according to the label.

Who is Responsible for What Happens Before, During, and After Colonoscopy? Results of a National Survey of Primary Care Physicians.

BACKGROUND AND AIMS: Primary care providers (PCPs) play a critical role in colon cancer screening by initiating referrals to gastroenterologists for colonoscopy, but little is known about their role in pre-colonoscopy bowel preparation selection and pre-colonoscopy follow-up care. This study aimed to better understand coordination of care between PCPs and gastroenterologists as well as the current availability of "open-access" screening colonoscopy. METHODS: A multiple-choice survey was developed to assess PCPs' experiences with open-access colonoscopy, their involvement in the pre-colonoscopy process, and follow-up after colonoscopy. The survey was distributed electronically to a nationally representative sample of PCPs, via the American College of Physicians (ACP) Research Center's Internal Medicine Insider Research Panel. RESULTS: Of 442 PCPs invited to participate, 210 responded (response rate, 210/442, 48%), and 29 were ineligible (spent <25% of their time on clinical care or placed no referrals to colonoscopy), yielding 181 completed surveys. A total of 39% reported that open access was "rarely" or "never" available in their practice setting. The majority reported that pre-colonoscopy care was coordinated by gastroenterologists rather than PCPs. For example, 93% reported that gastroenterologists were responsible for bowel preparation selection in their practice setting. Post-colonoscopy, 54% of PCPs reported that they were responsible for ordering subsequent colonoscopies. CONCLUSIONS: PCPs frequently coordinate follow-up care postprocedure but play a relatively minor role in the pre-colonoscopy bowel preparation process. Open access availability for screening colonoscopy remains limited in this national sample of PCPs.

Factors Associated with Surveillance Adenoma and Sessile Serrated Polyp Detection Rates.

BACKGROUND: Adenoma detection rate (ADR) and sessile serrated polyp detection rate (SSPDR) data in surveillance colonoscopy are limited. AIMS: Our aim was to determine surveillance ADR and SSPDR and identify associated predictors. METHODS: A retrospective review of subjects who underwent surveillance colonoscopy for adenoma and/or SSP at an academic center was performed. The following exclusion criteria were applied: prior colonoscopy ≤ 3 years, incomplete examination, or another indication for colonoscopy. Patient, endoscopist, and procedure characteristics were collected. Predictors were identified using multivariable logistic regression. RESULTS: Of 3807 colonoscopies, 2416 met inclusion criteria. Surveillance ADR was 49% and, SSPDR was 8%. Higher ADR was associated with: age per year (OR 1.03; 95% CI 1.02-1.04), male gender (OR 1.55; 95% CI 1.29-1.88), BMI per kg/m2 (OR 1.02; 95% CI 1.01-1.04), withdrawal time per minute (OR 1.09; 95% CI 1.07-1.10), and endoscopists' screening ADR (OR 1.01; 95% CI 1.00-1.03). Years since training (OR 0.99; 95% CI 0.98-0.99) was associated with lower ADR. Family history of CRC (OR 1.58; 95% CI 1.02-2.27) and endoscopists' screening ADR (OR 1.40; 95% CI 1.15-1.74) were associated with higher SSPDR. African-American race (OR 0.36; 95% CI 0.10-0.75) and diabetes (OR 0.41; 95% CI 0.21-0.76) were associated with lower SSPDR. CONCLUSIONS: For surveillance colonoscopy, nearly half of patients had an adenoma and one in twelve had an SSP. In addition to established factors, BMI, endoscopists' screening ADR, and years since training were associated with ADR, whereas African-American race and diabetes were inversely associated with SSPDR. Further studies are needed prior to integrating surveillance ADR and SSPDR into quality metrics.

Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea.

OBJECTIVES: Eluxadoline is a mixed µ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were five events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.

How Efficacious Are Patient Education Interventions to Improve Bowel Preparation for Colonoscopy? A Systematic Review.

BACKGROUND: Bowel preparation is inadequate in a large proportion of colonoscopies, leading to multiple clinical and economic harms. While most patients receive some form of education before colonoscopy, there is no consensus on the best approach. AIMS: This systematic review aimed to evaluate the efficacy of patient education interventions to improve bowel preparation. METHODS: We searched the Cochrane Database, CINAHL, EMBASE, Ovid, and Web of Science. Inclusion criteria were: (1) a patient education intervention; (2) a primary aim of improving bowel preparation; (3) a validated bowel preparation scale; (4) a prospective design; (5) a concurrent control group; and, (6) adult participants. Study validity was assessed using a modified Downs and Black scale. RESULTS: 1,080 abstracts were screened. Seven full text studies met inclusion criteria, including 2,660 patients. These studies evaluated multiple delivery platforms, including paper-based interventions (three studies), videos (two studies), re-education telephone calls the day before colonoscopy (one study), and in-person education by physicians (one study). Bowel preparation significantly improved with the intervention in all but one study. All but one study were done in a single center. Validity scores ranged from 13 to 24 (maximum 27). Four of five abstracts and research letters that met inclusion criteria also showed improvements in bowel preparation. Statistical and clinical heterogeneity precluded meta-analysis. CONCLUSION: Compared to usual care, patient education interventions appear efficacious in improving the quality of bowel preparation. However, because of the small scale of the studies and individualized nature of the interventions, results of these studies may not be generalizable to other settings. Healthcare practices should consider systematically evaluating their current bowel preparation education methods before undertaking new interventions.

Predictors of suboptimal bowel preparation in asymptomatic patients undergoing average-risk screening colonoscopy.

AIM: To identify risk factors for a suboptimal preparation among a population undergoing screening or surveillance colonoscopy. METHODS: Retrospective review of the University of Michigan and Veteran's Administration (VA) Hospital records from 2009 to identify patients age 50 and older who underwent screening or surveillance procedure and had resection of polyps less than 1 cm in size and no more than 2 polyps. Patients with inflammatory bowel disease or a family history of colorectal cancer were excluded. Suboptimal procedures were defined as procedure preparations categorized as fair, poor or inadequate by the endoscopist. Multivariable logistic regression was used to identify predictors of suboptimal preparation. RESULTS: Of 4427 colonoscopies reviewed, 2401 met our inclusion criteria and were analyzed. Of our population, 16% had a suboptimal preparation. African Americans were 70% more likely to have a suboptimal preparation (95%CI: 1.2-2.4). Univariable analysis revealed that narcotic and tricyclic antidepressants (TCA) use, diabetes, prep type, site (VA vs non-VA), and presence of a gastroenterology (GI) fellow were associated with suboptimal prep quality. In a multivariable model controlling for gender, age, ethnicity, procedure site and presence of a GI fellow, diabetes [odds ratio (OR) = 2.3; 95%CI: 1.6-3.2], TCA use (OR = 2.5; 95%CI: 1.3-4.9), narcotic use (OR = 1.7; 95%CI: 1.2-2.5) and Miralax-Gatorade prep vs 4L polyethylene glycol 3350 (OR = 0.6; 95%CI: 0.4-0.9) were associated with a suboptimal prep quality. CONCLUSION: Diabetes, narcotics use and TCA use were identified as predictors of poor preparation in screening colonoscopies while Miralax-Gatorade preps were associated with better bowel preparation.

Advances in IBS 2016: A Review of Current and Emerging Data.

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide.

Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.

BACKGROUND: Comparative effectiveness data pertaining to competing colorectal cancer (CRC) screening tests do not exist but are necessary to guide clinical decision making and policy. OBJECTIVE: To perform a comparative synthesis of clinical outcomes studies evaluating the effects of competing tests on CRC-related mortality. DESIGN: Traditional and network meta-analyses. Two reviewers identified studies evaluating the effect of guaiac-based fecal occult blood testing (gFOBT), flexible sigmoidoscopy (FS), or colonoscopy on CRC-related mortality. INTERVENTIONS: gFOBT, FS, colonoscopy. MAIN OUTCOME MEASUREMENTS: Traditional meta-analysis was performed to produce pooled estimates of the effect of each modality on CRC mortality. Bayesian network meta-analysis (NMA) was performed to indirectly compare the effectiveness of screening modalities. Multiple sensitivity analyses were performed. RESULTS: Traditional meta-analysis revealed that, compared with no intervention, colonoscopy reduced CRC-related mortality by 57% (relative risk [RR] 0.43; 95% confidence interval [CI], 0.33-0.58), whereas FS reduced CRC-related mortality by 40% (RR 0.60; 95% CI, 0.45-0.78), and gFOBT reduced CRC-related mortality by 18% (RR 0.82; 95% CI, 0.76-0.88). NMA demonstrated nonsignificant trends favoring colonoscopy over FS (RR 0.71; 95% CI, 0.45-1.11) and FS over gFOBT (RR 0.74; 95% CI, 0.51-1.09) for reducing CRC-related deaths. NMA-based simulations, however, revealed that colonoscopy has a 94% probability of being the most effective test for reducing CRC mortality and a 99% probability of being most effective when the analysis is restricted to screening studies. LIMITATIONS: Randomized trials and observational studies were combined within the same analysis. CONCLUSION: Clinical outcomes studies demonstrate that gFOBT, FS, and colonoscopy are all effective in reducing CRC-related mortality. Network meta-analysis suggests that colonoscopy is the most effective test.

Quality indicators for colorectal cancer screening for colonoscopy.

The growing importance of colonoscopy in the prevention of colorectal cancer has stimulated an effort to identify and track quality indicators for this procedure. Several factors have been identified so far which are readily measurable and in many cases have been associated with improved patient outcomes. There is also ample evidence of variations in performance of this procedure. As a result, gathering data about quality indicators may play a vital role in the process of continuous quality improvement. Quality indicators for colonoscopy in colorectal cancer prevention are described along with the evidence that supports their use in benchmarking, quality reporting, and continuous quality improvement.

Intraprocedural quality in endoscopic retrograde cholangiopancreatography: a meta-analysis.

OBJECTIVES: In 2006, the American College of Gastroenterology (ACG)/the American Society for Gastrointestinal Endoscopy (ASGE) Taskforce on Quality in Endoscopy published quality indicators for the major gastrointestinal procedures. Our primary aim was to use the published literature to assess current endoscopic retrograde cholangiopancreatography (ERCP) intraprocedural performance and compare it to the targets set by the ACG/ASGE taskforce. Our secondary aim was to determine whether performance varies across different health-care settings (academic and community), study designs (prospective and retrospective), and trainee participation. METHODS: A PubMed and EMBASE literature search from 1/1/2006 to 2/1/2013 was conducted. Articles were selected based on title, abstract, full text, and reporting of success rates for the intraprocedural quality indicators. Success rates, represented as numerical proportions, were collected from each study. For each success rate, a standard error and a 95% confidence interval (CI) was calculated. A random-effects meta-analysis model was used to weight each study, and a cumulative, weighted success rate (or effect size) for each indicator was determined. Random-effects meta-regression was then used to examine the impact of study setting, design, and trainee involvement on each quality indicator. RESULTS: A total of 8,005 articles were initially retrieved. Following the application of predefined criteria, 52 articles remained. The cumulative, weighted bile duct cannulation success rate was 89.3% (95% CI 0.866-0.919); pancreatic duct cannulation was 85.0% (95% CI 0.813-0.886); precut utilization rate was 10.5% (95% CI 0.087-0.123); common bile duct stone extraction rate was 88.3% (95% CI 0.825-0.941); and the rate of successful biliary stenting below the common bile duct bifurcation was 97.5% (95% CI 0.967-0.984). Subgroup analysis with meta-regression showed no statistically significant differences between academic and community settings, prospective and retrospective study designs, and trainee participation on success across bile duct cannulation, precut utilization, and common bile duct stone extraction (insufficient observations/variance for pancreatic duct cannulation and biliary stent placement). CONCLUSIONS: ERCP intraprocedural quality is in good standing. On the basis of this analysis, the two targets that could be potentially revised are precut utilization and biliary stenting. This analysis was confined to the published literature and therefore, in general, reflects the ERCP performance of institutions, primarily academic, that are conducting clinical research. Thus, it is difficult to generalize this performance assessment to the broader ERCP community as a whole.

Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis.

OBJECTIVES: There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of µ-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs). RESULTS: Fourteen eligible randomized controlled trials (RCTs) of µ-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54-0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis. CONCLUSIONS: µ-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear.

The impact of fair colonoscopy preparation on colonoscopy use and adenoma miss rates in patients undergoing outpatient colonoscopy.

BACKGROUND: The impact of fair bowel preparation on endoscopists' recommendations and adenoma miss rates in average-risk patients undergoing colonoscopy is unknown. OBJECTIVE: To assess the impact of fair bowel preparation on endoscopists' interval colonoscopy recommendations and miss rates in colonoscopies performed within 3 years of the index colonoscopy in average-risk patients undergoing colorectal cancer screening. DESIGN: Retrospective chart review. SETTING: Tertiary-care center. PATIENTS: Average-risk patients undergoing index colonoscopy for colorectal cancer screening between 2004 and 2006. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Endoscopists' interval recommendations, adenoma miss rates. RESULTS: A total of 16,251 colonoscopy records were reviewed over a 2-year period. Of these cases, 1943 colonoscopies were performed for the sole indication of average risk or screening. Of these, fair bowel preparation was reported in 619 patients (31.9%). A repeat colonoscopy within 5 years was recommended in 70.4% of patients. The follow-up colonoscopy compliance rate within 3 years was 55.9%. Adenoma detection rates at index and follow-up colonoscopy were 20.5% and 28.2%, respectively. Of the 39 patients with follow-up colonoscopy within 3 years, the overall adenoma miss rate was 28%. Of the patients with an adenoma identified on follow-up colonoscopy, 13.6% had normal colonoscopy results on index examination. LIMITATIONS: Retrospective design. CONCLUSION: Fair bowel preparation led to a deviation from national guidelines with early repeat colonoscopy follow-up recommendations in nearly 60% of average-risk patients with normal colonoscopy results. In patients who returned for repeat colonoscopy within 3 years, the overall adenoma miss rate was 28%. Further guidelines on timing for repeat colonoscopy for fair bowel preparation are needed.