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791 Use of Selective Serotonin Receptor Inhibitors (SSRIs) Is Not Associated With Increased Risk of Endoscopy-Refractory Bleeding, Rebleeding or Mortality in Patients With Peptic Ulcer Bleeding
AGA Abstracts
gut epithelial homeostasis remains unknown. In this study, we generated conditional knockout mouse strain with intestinal epithelial tissue-specific deletion of a4 (IE-a4-/-) to test the hypothesis that a4 is essential for normal gut mucosal growth and maturation. Methods: IE-a4-/- mice were generated by crossing a4flox/flox mice with mice carrying Villin-Cre. Phenotype analysis of age-matched IE-a4-/- mice with their littermates were carried out to characterize morphological changes and to define the biological function of a4. The levels of a4 mRNA and protein in the intestinal mucosa and other tissues were measured by RTPCR and Western immunoblotting analyses; histological features were examined by H&E staining. Mucosal growth was measured by BrdU incorporation and immunohistochemistry staining. Results: Levels of a4 mRNA and protein in the small and large intestinal mucosa of IE-a4-/- mouse were undetectable, although a4 expression was normal in other tissues including liver, lung, heart, spleen, and kidney. IE- a4-/- mice exhibited a decrease in body weight and a reduction in gastrointestinal gross morphology compared with those observed in control littermates. Interestingly, IE-a4-/- mice displayed a significant disruption of intestinal mucosal regeneration and maturation as indicated by as shrinkage in the villus, hyperplasia in the crypt, and changes in villus/crypt ratio. The lengths of villus in the small intestinal mucosa decreased by ~60% after targeted a4 deletion, but the crypt areas increased by ~2folds in IE-a4-/- mice. Cell proliferation markers such as PCNA protein levels and rate of DNA synthesis in the crypt area as measured by BrdU labeling also increased in the intestinal mucosa of IE-a4-/- mouse compared with littermates. Moreover, the levels of PP2A, the immediately downstream target of a4, decreased dramatically in the IE-a4-deficient mucosa, suggesting the involvement of inactivation of PP2A/ b-Pix/Rac1 signals in the mechanism underlying this process. Conclusion: These results indicate that a4 plays a pivotal role in the regulation of intestinal mucosal regeneration and maturation through PP2A/ b-Pix/Rac1 signaling pathway.
discriminative ability of each score for predicting outcome is shown in table 1. The GBS had a high discriminative ability for predicting need for intervention or death and predicted this endpoint better than all other scores (P<0.0001). GBS £1 was optimal for predicting survival with no need for intervention. GBS was also the best pre-endoscopic score for predicting need for endoscopic therapy (P<0.0001), although the predictive ability was only fair (see table 1). GBS ‡2 was the best threshold for predicting endoscopic therapy. The PNED had the highest ability to predict rebleeding (P<0.0001) and was the only score with an acceptable AUROC for predicting this endpoint. All risk scores had poor abilities for predicting LOS >3 days. PNED and AIMS65 had similar discriminative abilities for predicting mortality, with PNED having better discriminative ability than ARS (P=0.03), FRS (P=0.03), and GBS (P<0.0001). AIMS65 had better discriminative ability for predicting mortality than GBS (P<0.0001), but was not better than ARS and FRS. Regarding thresholds, PNED ‡4, AIMS65 ‡2, ARS ‡4, and FRS ‡5 were best at predicting death (table 1). Conclusion: This study shows that GBS has the best accuracy for predicting need for hospital-based intervention or mortality. The optimum score threshold for directing low risk patients to out-patient management is GBS£1. Although GBS is best at predicting need for endoscopic therapy, and AIMS65 and PNED best at predicting 30-day mortality, the AUROC levels were relatively low which limit accuracy and clinical utility. Apart from PNED (which includes data on rebleeding) all scores were poor at predicting rebleeding and no score could accurately predict LOS. Table 1. Discriminative abilities of the five risk scores for predicting outcome
789 A Novel Dominant Negative Frame-Shift Mutation of NEUROGENIN-3 in a Child with Enteric Anendocrinosis Martin G. Martin, R. Sergio Solorzano-Vargas, Manuel Garcia-Careaga, Senta Georgia, Jiafang Wang, Matthew Bjerknes, Hazel Cheng Background & Aims: Neurogenin-3 (Neurog3) is a basic helix-loop-helix transcription factor that is required for the production of endocrine cells in the pancreas and intestine. Homozygous mutations of the NEUROG3 gene have been associated with a rare disorder named enteric anendocrinosis that results in severe neonatal intestinal failure and diabetes mellitus in late infancy. The aim of this study was to characterize a unique variant identified in the NEUROG3 gene in a specific proband, and we believed that this would provide important insight into how this gene induces endocrine cell fate. Methods: We studied the clinical features of a single unique index case with a severe NEUROG3 variant and assessed the residual function of the mutant protein. We used qPCR, Westerns, MTT, FACs, Ki67 and SA-b-Gal staining. We studied its function in a human BON cell line (herein called BON4), and human intestinal enteroids. Results: We identified a rare biallelic variant of the NEUROG3 gene that results in a protein product that does not contain an activation domain which we hypothesized would function as a dominant negative (NEUROG3DN). We determine whether the NEUROD1 promoter - a down-stream target of NEUROG3WT can be activated by NEUROG3DN. We found that NEUROG3DN, like NEUROG3R93L and NEUROG3R107S, fails to activate the NEUROG3-regulated cis-element of NEUROD1's promoter. NEUROG3DN's failure to activate the NEUROD1 promoter, despite having intact DNA-recognition and binding motifs, suggested that it might possess DN activity. These data support the notion that the NEUROG3DN protein functions as DN mutant by inhibiting NEUROG3-induced activity on the NEUROD1 promoter. We have recently demonstrated that NEUROG3 induces cell cycle arrest in BON4 cells. We found this novel variant is incapable of inducing cell cycle arrest included cellular quiescence and senescence, and therefore the mature endocrine phenotype. Furthermore, these findings demonstrate that NEUROG3DN both fails to induce cellular senescence on its own, and also represses the ability of NEUROG3WT to induce cellular arrest and senescence, further supporting the notion that NEUROG3DN acts as a DN. Moreover, we found that overexpression of the variant was capable of inhibiting the action of the wild type NEUROG 3protein, confirming that this nonsense mutation functions as an authentic dominant negative variant. Conclusions: In this study of a single child with residual pancreatic endocrine function, we identified a unique homozygous mutation of the NEUROG3 gene that had no residual activity and functions as a dominant negative protein. These findings indicate that unlike in mice, pancreatic endocrine cell fate in humans is not entirely dependent on NEUROG3 expression, and suggests unidentified redundant pathways are sufficient to produce at least a minimally sufficient beta-cell population.
ARS: Admission Rockall score; AUROC: Area under receiver operating characteristics curves; FRS: Full Rockall score; GBS: Glasgow Blatchford score. AUROC: Fair=0.700-0.799; Good= 0.800-0.899; Excellent=0.900-1.000. Optimal thresholds, sensitivity, and specificity determined only if AUROC >0.75 and if endpoint of interest was not directly included in evaluated score
791 Use of Selective Serotonin Receptor Inhibitors (SSRIs) Is Not Associated With Increased Risk of Endoscopy-Refractory Bleeding, Rebleeding or Mortality in Patients With Peptic Ulcer Bleeding Stig B. Laursen, Adrian Stanley, Grigorios Leontiadis, Jesper Hallas, Ove B. Schaffalitzky de Muckadell
790 International, Multicentre Prospective Study Comparing Risk Scoring Systems for Patients Presenting With Upper Gastrointestinal Bleeding Stig B. Laursen, Loren Laine, Harry Dalton, Rozeta Abazi, Jing Hieng Ngu, Michael Schultz, Liam Zakko, Susan Thornton, Kelly Wilkinson, Amelia Holloway, Christopher Jen Lock Khor, Tracey Steiner, Iain A. Murray, Adrian Stanley
Introduction: Observational studies have consistently shown an increased risk of peptic ulcer bleeding (PUB) in users of SSRIs, probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often paused in patients with PUB. However, abrupt discontinuation of SSRIs is associated with withdrawal symptoms in one-third of patients. Further data is needed in order to clarify if treatment with SSRIs is associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality supporting discontinuation of treatment. Aims & Methods: To identify if treatment with SSRIs is associated with increased risk of: 1. endoscopy-refractory bleeding, 2. rebleeding, and 3. in-hospital mortality in PUB. Analyses were performed on prospectively collected data on consecutive patients admitted with PUB in Denmark in the period 2006-2014. Logistic and cox regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for confounding factors including age, sex, comorbidity, anaemia, medication use, circulatory failure at hospital admission, location of ulcer, stigmata of bleeding, and weekend admission. Sensitivity and subgroup analyses were performed in order to evaluate the validity of the findings. Results: A total of 14343 patients were included.
Introduction: Several risk scoring systems have been developed for the assessment of patients with upper gastrointestinal bleeding (UGIB). We compared the ability of five risk scoring systems to predict: 1. Need for hospital-based intervention or mortality, 2. Endoscopic therapy, 3. Rebleeding within 7 days, 4. Length of hospital stay (LOS), 5. 30-day mortality. Methods: Consecutive patients presenting with UGIB at six centres in USA, UK, Denmark, Singapore, and New Zealand were prospectively included over a 12-month period. Using area under receiver operating characteristics curves (AUROC) we compared the pre-endoscopic scores (Glasgow Blatchford score (GBS), AIMS65, and admission Rockall score (ARS)), and the post-endoscopic scores (full Rockall (FRS) and PNED scores) in their ability to predict outcomes. We also examined optimum score thresholds to identify both low and high risk patients by need for intervention or death, endoscopic therapy and mortality. Results: 3012 patients were included. Median age was 65 years; 45% needed hospital-based intervention or died, 5% rebled, median LOS was 3 days, and mortality was 7%. The
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Table 1. Hospitalization rate (cases per 100,000 population) of UGIH by etiology, 2002-2012
AGA Abstracts
Following adjustment, treatment with SSRIs were neither associated with increased risk of endoscopy-refractory bleeding (Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.01 [0.781.30]), rebleeding (OR [95% CI]: 0.94 [0.81-1.10]), or in-hospital mortality (Hazard Ratio [95% CI]: 0.84 [0.68-1.05]). This finding was supported by sensitivity and subgroup analyses. Discussion: According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or in-hospital mortality in PUB. Continuation of SSRI treatment in patients with PUB seems safe.
792 Do Concurrent Gastroprotective Agents Impact Gastrointestinal Bleeding Rates in Edoxaban Users? Results From the ENGAGE-AF TIMI 48 Trial James Aisenberg, Prapti Chatterjee, Kathryn B. Friedman, Jay Desai, Jeffrey Weitz, Robert Giugliano, Christian Ruff, Francesco Nordio, Michele Mercuri, Youngsook Choi, Elliott Antman, Eugene Braunwald Background: Major gastrointestinal bleeding (MGIB) is a feared complication of anticoagulation. In patients taking direct oral anticoagulants (DOACs), the impact of gastroprotective agents (GPAs) such as histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) on GIB risk is uncertain. Methods: The ENGAGE AF TIMI 48 trial (n=21,105) compared a higher-dose edoxaban regimen (HD-ER), a lower-dose edoxaban regimen (LDER) and warfarin for stroke prevention in atrial fibrillation. Here, we report a pre-specified analysis comparing major GIB (MGIB) events in users versus non-users of GPAs, as assessed at the time of randomization. Results: A total of 579 patients (2.75%) experienced >1 MGIB event (annual event rate: 1.22%/yr), of which 61% were upper GI tract bleeds. HD-ER was associated with a small increase in MGIB versus warfarin (1.51 %/yr vs.1.23%/yr, p=0.03), equivalent to approximately 3 additional MGIB per 1,000 patients per year. LD-ER was associated with a lower rate than warfarin and HD-ER (0.82%/yr, p=0.001). A total of 1,691 patients reported daily PPI use (8%). Of PPI users, 91 (5.4%) experienced >1 MGIB event, compared to 488 (2.5%) of non-PPI users (HR 2.23, p<0.001). Daily PPI use was associated with an increased rate of MGIB in all study arms (warfarin, HR 1.84 [1.20-2.81] p=0.005; LD-ER, HR 2.76 [1.78-4.26] p<0.001; HD-ER, HR 2.24 [1.59-3.18] p<0.001; p-interaction = 0.37). For LD-ER and HD-ER users but not warfarin users, daily PPI use was associated with an increased rate of upper GI tract MGIB (p=0.001, p=0.01 and p=0.08, respectively; p-interaction 0.55). For all three arms, PPI use was associated with increased risk of lower GI tract MGIB (LD-ER, p< 0.001; HD-ER, p<0.001; warfarin, p=0.04; p-interaction 0.33). A total of 349 study patients took daily H2RAs (2%). Of these, 20 (5.7 %) experienced >1 MGIB event, compared to 559 (2.6%) of non-H2RA users (HR 1.90, p=0.003). In HD-ER users, daily H2RA use was associated with an increased rate of MGIB (HR 2.76 [1.49-5.10] p=0.001), as well as major upper GI tract bleeding (HR 3.04 [1.40-6.63] p=0.005), but not an increased rate of lower GI tract bleeding. In LD-ER users and in warfarin users daily H2RA use was not associated with increased MGIB. Conclusions: In edoxaban-treated, as in warfarin-treated AF patients, the use of daily GPAs is associated with an increased MGIB risk. The explanation for this association is uncertain, but it may reflect underlying prior GI pathology in GPA users, or (in the case of PPIs) alterations in the luminal microbiome. Attention to GIB prevention in anticoagulated patients receiving concurrent GPAs is indicated. Note: At the time of abstract presentation, we will also present data demonstrating increased risk of total, upper, and lower MGIB related to use of aspirin and thienopyridines in edoxaban and warfarin users in this trial.
Table 2. All-cause case fatality (deaths per 100 cases) of UGIH by etiology, 2002-2012
794 What is the Clinical Profile of "Life-Threatening" Gastrointestinal Bleeding in Anticoagulated Patients? A Sub-Analysis of the RE-LY Trial Prapti Chatterjee, Kathryn B. Friedman, Jennifer M. Kolb, Jay Desai, Lars Wallentin, Michael Ezekowitz, Salim Yusuf, Stuart Connolly, Paul Reilly, Martina Brueckmann, Janice Pogue, John Ilgenfritz, James Aisenberg Background: Severe gastrointestinal bleeding (GIB) is a feared complication of anticoagulation in atrial fibrillation (AF) patients. The characteristics and outcomes of such bleeding are not well understood. Methods: The RE-LY trial (n=18,113) compared dabigatran 110 mg (D110) and dabigatran 150 mg (D150) twice daily to adjusted-dose warfarin for stroke prevention in AF. Using primary source documents, 2 blinded gastroenterologists independently evaluated major GIB events (including repetitive events) in RE-LY and extracted lifethreatening (LT) GIB events, defined by International Society for Thrombosis and Hemostasis (ISTH) as major GIB (MGIB) events that are fatal, result in > 5g/dL hemoglobin drop, require >4 units of transfused red blood cells, require inotropic support, or necessitate surgery. Statistical analysis was conducted using c2 test. Results: Of 593 evaluated MGIBs, 260 (44%) met LT-GIB criteria. There were 67 LT-GIBs in warfarin users (0.57%/year), 112 in D150 users (0.94%/year), and 81 in D110 users (0.69%/year) (D150 vs. warfarin, p<0.0001; D110 vs. warfarin, p=0.17; D150 vs. D110, p=0.005). Among 235 patients with LT-GIB for whom chronicity data was available, 110 (47%) presented acutely, 49 (21%) sub-acutely (2-7 days), and 76 (32%) presented chronically (>7 days). The rate of acute LT-GIB was similar among the 3 treatment arms (p=0.35), as were rates of LT-GIB-related hospitalization, ICU admission, packed red blood cell transfusion, and surgery. There were 4 LT-GIB deaths among warfarin users (6.0%), 7 among D150 users (6.2%), and 5 among D110 users (4.5%) (p=n.s.). An upper GI tract LT-GIB source was identified in 37 warfarin users (55%), versus 46 D150 users (41%), and 25 D110 users (31%) (D150 vs. warfarin, p=0.07; D110 vs. warfarin, p=0.003). A lower GI tract source was identified in 11 warfarin users with LTGIB (16%), 33 D150 users (29%) and 25 D110 users (31%) (D150 vs. warfarin, p<0.05; D110 vs. warfarin, p=0.04). No definitive bleeding source could be identified in 98/260 (38%) of LT-GIBs (warfarin, 34%; D150, 37%; D110, 42%; p =0.60), despite endoscopic or radiologic investigation in 230/260 patients (88%). Commonly identified sources of LTGIB included: gastroduodenal ulcer/erosion, colonic diverticulosis, and luminal GI tract cancer (Figure 1). Conclusions: Although ISTH-defined "life-threatening" GIB in anticoagulated AF patients occurs in approximately 1/200 patients/year, over half of LT-GIBs present non-acutely. In approximately 1/3 of patients, no source of bleeding is identified with standard endoscopy. LT-GIB events in AF patients occur more frequently with D150 than warfarin or D110. In comparison with warfarin, dabigatran is associated with a higher risk of LT lower GI tract bleeding, but a lower risk of LT upper GIB. Outcomes among LT-GIB patients treated with D150, D110, and warfarin are similar.
793 Trends in Upper Gastrointestinal Hemorrhage in United States Hospitalized Patients Brandon Wuerth, Don C. Rockey Background: Upper gastrointestinal hemorrhage (UGIH) is common and carries substantial morbidity and mortality requiring frequent hospitalizations. Objective: To investigate trends in etiology and outcome of UGIH in hospitalized patients in the United States. Design: Retrospective, observational cohort study of the Nationwide Inpatient Sample (NIS) from 2002-2012. UGIH was identified in hospitalizations with a principle ICD-9-CM diagnosis of UGIH, or clinical symptoms and signs consistent with UGIH (hematemesis, blood in stool or gastrointestinal bleeding). Only patients with an upper endoscopy performed during the hospitalization were included. Results: The hospitalization rate of UGIH in the U.S. decreased by 18% from 2002 to 2012, from 80 to 65/100,000 population (p<0.01, Table 1). Men and patients ‡85 years old had the highest hospitalization rate of UGIH, 79 and 561/100,000 population respectively. The most common etiology of UGIH was peptic ulcer disease (PUD, 49%), followed by gastritis (17%), esophagitis (15%), angiodysplasia (6%), Mallory-Weiss tear 6%, neoplasm (3%), esophageal varices (2%), and Dieulafoy lesion (2%). The greatest change in etiology of bleeding occurred for PUD and gastritis, which declined by 27% and 46%, respectively (p<0.01). The greatest increases were in neoplasm, angiodysplasia, and esophagitis (by 38%, 33% and 13%, respectively (p<0.01)). The all-cause case fatality rate of UGIH decreased 27% from 2.1 per 100 cases in 2002 to 1.6 in 2012 (p<0.01, Table 2), with the highest mortality being in patients with esophageal variceal hemorrhage and neoplasm, which also had the greatest improvements in mortality. Conclusion: The epidemiology of UGIH hemorrhage appears to be shifting, with a decline in gastric disorders, an increase in the rate of hospitalization with UGIH for neoplasm, angiodysplasia, and esophagitis. Mortality also appears to be decreasing. The decreasing hospitalization rate and all-cause case fatality rate of UGIH suggests population trends in use of treatments for PUD, and improved overall medical care.
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gut epithelial homeostasis remains unknown. In this study, we generated conditional knockout mouse strain with intestinal epithelial tissue-specific deletion of a4 (IE-a4-/-) to test the hypothesis that a4 is essential for normal gut mucosal growth and maturation. Methods: IE-a4-/- mice were generated by crossing a4flox/flox mice with mice carrying Villin-Cre. Phenotype analysis of age-matched IE-a4-/- mice with their littermates were carried out to characterize morphological changes and to define the biological function of a4. The levels of a4 mRNA and protein in the intestinal mucosa and other tissues were measured by RTPCR and Western immunoblotting analyses; histological features were examined by H&E staining. Mucosal growth was measured by BrdU incorporation and immunohistochemistry staining. Results: Levels of a4 mRNA and protein in the small and large intestinal mucosa of IE-a4-/- mouse were undetectable, although a4 expression was normal in other tissues including liver, lung, heart, spleen, and kidney. IE- a4-/- mice exhibited a decrease in body weight and a reduction in gastrointestinal gross morphology compared with those observed in control littermates. Interestingly, IE-a4-/- mice displayed a significant disruption of intestinal mucosal regeneration and maturation as indicated by as shrinkage in the villus, hyperplasia in the crypt, and changes in villus/crypt ratio. The lengths of villus in the small intestinal mucosa decreased by ~60% after targeted a4 deletion, but the crypt areas increased by ~2folds in IE-a4-/- mice. Cell proliferation markers such as PCNA protein levels and rate of DNA synthesis in the crypt area as measured by BrdU labeling also increased in the intestinal mucosa of IE-a4-/- mouse compared with littermates. Moreover, the levels of PP2A, the immediately downstream target of a4, decreased dramatically in the IE-a4-deficient mucosa, suggesting the involvement of inactivation of PP2A/ b-Pix/Rac1 signals in the mechanism underlying this process. Conclusion: These results indicate that a4 plays a pivotal role in the regulation of intestinal mucosal regeneration and maturation through PP2A/ b-Pix/Rac1 signaling pathway.
discriminative ability of each score for predicting outcome is shown in table 1. The GBS had a high discriminative ability for predicting need for intervention or death and predicted this endpoint better than all other scores (P<0.0001). GBS £1 was optimal for predicting survival with no need for intervention. GBS was also the best pre-endoscopic score for predicting need for endoscopic therapy (P<0.0001), although the predictive ability was only fair (see table 1). GBS ‡2 was the best threshold for predicting endoscopic therapy. The PNED had the highest ability to predict rebleeding (P<0.0001) and was the only score with an acceptable AUROC for predicting this endpoint. All risk scores had poor abilities for predicting LOS >3 days. PNED and AIMS65 had similar discriminative abilities for predicting mortality, with PNED having better discriminative ability than ARS (P=0.03), FRS (P=0.03), and GBS (P<0.0001). AIMS65 had better discriminative ability for predicting mortality than GBS (P<0.0001), but was not better than ARS and FRS. Regarding thresholds, PNED ‡4, AIMS65 ‡2, ARS ‡4, and FRS ‡5 were best at predicting death (table 1). Conclusion: This study shows that GBS has the best accuracy for predicting need for hospital-based intervention or mortality. The optimum score threshold for directing low risk patients to out-patient management is GBS£1. Although GBS is best at predicting need for endoscopic therapy, and AIMS65 and PNED best at predicting 30-day mortality, the AUROC levels were relatively low which limit accuracy and clinical utility. Apart from PNED (which includes data on rebleeding) all scores were poor at predicting rebleeding and no score could accurately predict LOS. Table 1. Discriminative abilities of the five risk scores for predicting outcome
789 A Novel Dominant Negative Frame-Shift Mutation of NEUROGENIN-3 in a Child with Enteric Anendocrinosis Martin G. Martin, R. Sergio Solorzano-Vargas, Manuel Garcia-Careaga, Senta Georgia, Jiafang Wang, Matthew Bjerknes, Hazel Cheng Background & Aims: Neurogenin-3 (Neurog3) is a basic helix-loop-helix transcription factor that is required for the production of endocrine cells in the pancreas and intestine. Homozygous mutations of the NEUROG3 gene have been associated with a rare disorder named enteric anendocrinosis that results in severe neonatal intestinal failure and diabetes mellitus in late infancy. The aim of this study was to characterize a unique variant identified in the NEUROG3 gene in a specific proband, and we believed that this would provide important insight into how this gene induces endocrine cell fate. Methods: We studied the clinical features of a single unique index case with a severe NEUROG3 variant and assessed the residual function of the mutant protein. We used qPCR, Westerns, MTT, FACs, Ki67 and SA-b-Gal staining. We studied its function in a human BON cell line (herein called BON4), and human intestinal enteroids. Results: We identified a rare biallelic variant of the NEUROG3 gene that results in a protein product that does not contain an activation domain which we hypothesized would function as a dominant negative (NEUROG3DN). We determine whether the NEUROD1 promoter - a down-stream target of NEUROG3WT can be activated by NEUROG3DN. We found that NEUROG3DN, like NEUROG3R93L and NEUROG3R107S, fails to activate the NEUROG3-regulated cis-element of NEUROD1's promoter. NEUROG3DN's failure to activate the NEUROD1 promoter, despite having intact DNA-recognition and binding motifs, suggested that it might possess DN activity. These data support the notion that the NEUROG3DN protein functions as DN mutant by inhibiting NEUROG3-induced activity on the NEUROD1 promoter. We have recently demonstrated that NEUROG3 induces cell cycle arrest in BON4 cells. We found this novel variant is incapable of inducing cell cycle arrest included cellular quiescence and senescence, and therefore the mature endocrine phenotype. Furthermore, these findings demonstrate that NEUROG3DN both fails to induce cellular senescence on its own, and also represses the ability of NEUROG3WT to induce cellular arrest and senescence, further supporting the notion that NEUROG3DN acts as a DN. Moreover, we found that overexpression of the variant was capable of inhibiting the action of the wild type NEUROG 3protein, confirming that this nonsense mutation functions as an authentic dominant negative variant. Conclusions: In this study of a single child with residual pancreatic endocrine function, we identified a unique homozygous mutation of the NEUROG3 gene that had no residual activity and functions as a dominant negative protein. These findings indicate that unlike in mice, pancreatic endocrine cell fate in humans is not entirely dependent on NEUROG3 expression, and suggests unidentified redundant pathways are sufficient to produce at least a minimally sufficient beta-cell population.
ARS: Admission Rockall score; AUROC: Area under receiver operating characteristics curves; FRS: Full Rockall score; GBS: Glasgow Blatchford score. AUROC: Fair=0.700-0.799; Good= 0.800-0.899; Excellent=0.900-1.000. Optimal thresholds, sensitivity, and specificity determined only if AUROC >0.75 and if endpoint of interest was not directly included in evaluated score
791 Use of Selective Serotonin Receptor Inhibitors (SSRIs) Is Not Associated With Increased Risk of Endoscopy-Refractory Bleeding, Rebleeding or Mortality in Patients With Peptic Ulcer Bleeding Stig B. Laursen, Adrian Stanley, Grigorios Leontiadis, Jesper Hallas, Ove B. Schaffalitzky de Muckadell
790 International, Multicentre Prospective Study Comparing Risk Scoring Systems for Patients Presenting With Upper Gastrointestinal Bleeding Stig B. Laursen, Loren Laine, Harry Dalton, Rozeta Abazi, Jing Hieng Ngu, Michael Schultz, Liam Zakko, Susan Thornton, Kelly Wilkinson, Amelia Holloway, Christopher Jen Lock Khor, Tracey Steiner, Iain A. Murray, Adrian Stanley
Introduction: Observational studies have consistently shown an increased risk of peptic ulcer bleeding (PUB) in users of SSRIs, probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often paused in patients with PUB. However, abrupt discontinuation of SSRIs is associated with withdrawal symptoms in one-third of patients. Further data is needed in order to clarify if treatment with SSRIs is associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality supporting discontinuation of treatment. Aims & Methods: To identify if treatment with SSRIs is associated with increased risk of: 1. endoscopy-refractory bleeding, 2. rebleeding, and 3. in-hospital mortality in PUB. Analyses were performed on prospectively collected data on consecutive patients admitted with PUB in Denmark in the period 2006-2014. Logistic and cox regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for confounding factors including age, sex, comorbidity, anaemia, medication use, circulatory failure at hospital admission, location of ulcer, stigmata of bleeding, and weekend admission. Sensitivity and subgroup analyses were performed in order to evaluate the validity of the findings. Results: A total of 14343 patients were included.
Introduction: Several risk scoring systems have been developed for the assessment of patients with upper gastrointestinal bleeding (UGIB). We compared the ability of five risk scoring systems to predict: 1. Need for hospital-based intervention or mortality, 2. Endoscopic therapy, 3. Rebleeding within 7 days, 4. Length of hospital stay (LOS), 5. 30-day mortality. Methods: Consecutive patients presenting with UGIB at six centres in USA, UK, Denmark, Singapore, and New Zealand were prospectively included over a 12-month period. Using area under receiver operating characteristics curves (AUROC) we compared the pre-endoscopic scores (Glasgow Blatchford score (GBS), AIMS65, and admission Rockall score (ARS)), and the post-endoscopic scores (full Rockall (FRS) and PNED scores) in their ability to predict outcomes. We also examined optimum score thresholds to identify both low and high risk patients by need for intervention or death, endoscopic therapy and mortality. Results: 3012 patients were included. Median age was 65 years; 45% needed hospital-based intervention or died, 5% rebled, median LOS was 3 days, and mortality was 7%. The
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Table 1. Hospitalization rate (cases per 100,000 population) of UGIH by etiology, 2002-2012
AGA Abstracts
Following adjustment, treatment with SSRIs were neither associated with increased risk of endoscopy-refractory bleeding (Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.01 [0.781.30]), rebleeding (OR [95% CI]: 0.94 [0.81-1.10]), or in-hospital mortality (Hazard Ratio [95% CI]: 0.84 [0.68-1.05]). This finding was supported by sensitivity and subgroup analyses. Discussion: According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or in-hospital mortality in PUB. Continuation of SSRI treatment in patients with PUB seems safe.
792 Do Concurrent Gastroprotective Agents Impact Gastrointestinal Bleeding Rates in Edoxaban Users? Results From the ENGAGE-AF TIMI 48 Trial James Aisenberg, Prapti Chatterjee, Kathryn B. Friedman, Jay Desai, Jeffrey Weitz, Robert Giugliano, Christian Ruff, Francesco Nordio, Michele Mercuri, Youngsook Choi, Elliott Antman, Eugene Braunwald Background: Major gastrointestinal bleeding (MGIB) is a feared complication of anticoagulation. In patients taking direct oral anticoagulants (DOACs), the impact of gastroprotective agents (GPAs) such as histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) on GIB risk is uncertain. Methods: The ENGAGE AF TIMI 48 trial (n=21,105) compared a higher-dose edoxaban regimen (HD-ER), a lower-dose edoxaban regimen (LDER) and warfarin for stroke prevention in atrial fibrillation. Here, we report a pre-specified analysis comparing major GIB (MGIB) events in users versus non-users of GPAs, as assessed at the time of randomization. Results: A total of 579 patients (2.75%) experienced >1 MGIB event (annual event rate: 1.22%/yr), of which 61% were upper GI tract bleeds. HD-ER was associated with a small increase in MGIB versus warfarin (1.51 %/yr vs.1.23%/yr, p=0.03), equivalent to approximately 3 additional MGIB per 1,000 patients per year. LD-ER was associated with a lower rate than warfarin and HD-ER (0.82%/yr, p=0.001). A total of 1,691 patients reported daily PPI use (8%). Of PPI users, 91 (5.4%) experienced >1 MGIB event, compared to 488 (2.5%) of non-PPI users (HR 2.23, p<0.001). Daily PPI use was associated with an increased rate of MGIB in all study arms (warfarin, HR 1.84 [1.20-2.81] p=0.005; LD-ER, HR 2.76 [1.78-4.26] p<0.001; HD-ER, HR 2.24 [1.59-3.18] p<0.001; p-interaction = 0.37). For LD-ER and HD-ER users but not warfarin users, daily PPI use was associated with an increased rate of upper GI tract MGIB (p=0.001, p=0.01 and p=0.08, respectively; p-interaction 0.55). For all three arms, PPI use was associated with increased risk of lower GI tract MGIB (LD-ER, p< 0.001; HD-ER, p<0.001; warfarin, p=0.04; p-interaction 0.33). A total of 349 study patients took daily H2RAs (2%). Of these, 20 (5.7 %) experienced >1 MGIB event, compared to 559 (2.6%) of non-H2RA users (HR 1.90, p=0.003). In HD-ER users, daily H2RA use was associated with an increased rate of MGIB (HR 2.76 [1.49-5.10] p=0.001), as well as major upper GI tract bleeding (HR 3.04 [1.40-6.63] p=0.005), but not an increased rate of lower GI tract bleeding. In LD-ER users and in warfarin users daily H2RA use was not associated with increased MGIB. Conclusions: In edoxaban-treated, as in warfarin-treated AF patients, the use of daily GPAs is associated with an increased MGIB risk. The explanation for this association is uncertain, but it may reflect underlying prior GI pathology in GPA users, or (in the case of PPIs) alterations in the luminal microbiome. Attention to GIB prevention in anticoagulated patients receiving concurrent GPAs is indicated. Note: At the time of abstract presentation, we will also present data demonstrating increased risk of total, upper, and lower MGIB related to use of aspirin and thienopyridines in edoxaban and warfarin users in this trial.
Table 2. All-cause case fatality (deaths per 100 cases) of UGIH by etiology, 2002-2012
794 What is the Clinical Profile of "Life-Threatening" Gastrointestinal Bleeding in Anticoagulated Patients? A Sub-Analysis of the RE-LY Trial Prapti Chatterjee, Kathryn B. Friedman, Jennifer M. Kolb, Jay Desai, Lars Wallentin, Michael Ezekowitz, Salim Yusuf, Stuart Connolly, Paul Reilly, Martina Brueckmann, Janice Pogue, John Ilgenfritz, James Aisenberg Background: Severe gastrointestinal bleeding (GIB) is a feared complication of anticoagulation in atrial fibrillation (AF) patients. The characteristics and outcomes of such bleeding are not well understood. Methods: The RE-LY trial (n=18,113) compared dabigatran 110 mg (D110) and dabigatran 150 mg (D150) twice daily to adjusted-dose warfarin for stroke prevention in AF. Using primary source documents, 2 blinded gastroenterologists independently evaluated major GIB events (including repetitive events) in RE-LY and extracted lifethreatening (LT) GIB events, defined by International Society for Thrombosis and Hemostasis (ISTH) as major GIB (MGIB) events that are fatal, result in > 5g/dL hemoglobin drop, require >4 units of transfused red blood cells, require inotropic support, or necessitate surgery. Statistical analysis was conducted using c2 test. Results: Of 593 evaluated MGIBs, 260 (44%) met LT-GIB criteria. There were 67 LT-GIBs in warfarin users (0.57%/year), 112 in D150 users (0.94%/year), and 81 in D110 users (0.69%/year) (D150 vs. warfarin, p<0.0001; D110 vs. warfarin, p=0.17; D150 vs. D110, p=0.005). Among 235 patients with LT-GIB for whom chronicity data was available, 110 (47%) presented acutely, 49 (21%) sub-acutely (2-7 days), and 76 (32%) presented chronically (>7 days). The rate of acute LT-GIB was similar among the 3 treatment arms (p=0.35), as were rates of LT-GIB-related hospitalization, ICU admission, packed red blood cell transfusion, and surgery. There were 4 LT-GIB deaths among warfarin users (6.0%), 7 among D150 users (6.2%), and 5 among D110 users (4.5%) (p=n.s.). An upper GI tract LT-GIB source was identified in 37 warfarin users (55%), versus 46 D150 users (41%), and 25 D110 users (31%) (D150 vs. warfarin, p=0.07; D110 vs. warfarin, p=0.003). A lower GI tract source was identified in 11 warfarin users with LTGIB (16%), 33 D150 users (29%) and 25 D110 users (31%) (D150 vs. warfarin, p<0.05; D110 vs. warfarin, p=0.04). No definitive bleeding source could be identified in 98/260 (38%) of LT-GIBs (warfarin, 34%; D150, 37%; D110, 42%; p =0.60), despite endoscopic or radiologic investigation in 230/260 patients (88%). Commonly identified sources of LTGIB included: gastroduodenal ulcer/erosion, colonic diverticulosis, and luminal GI tract cancer (Figure 1). Conclusions: Although ISTH-defined "life-threatening" GIB in anticoagulated AF patients occurs in approximately 1/200 patients/year, over half of LT-GIBs present non-acutely. In approximately 1/3 of patients, no source of bleeding is identified with standard endoscopy. LT-GIB events in AF patients occur more frequently with D150 than warfarin or D110. In comparison with warfarin, dabigatran is associated with a higher risk of LT lower GI tract bleeding, but a lower risk of LT upper GIB. Outcomes among LT-GIB patients treated with D150, D110, and warfarin are similar.
793 Trends in Upper Gastrointestinal Hemorrhage in United States Hospitalized Patients Brandon Wuerth, Don C. Rockey Background: Upper gastrointestinal hemorrhage (UGIH) is common and carries substantial morbidity and mortality requiring frequent hospitalizations. Objective: To investigate trends in etiology and outcome of UGIH in hospitalized patients in the United States. Design: Retrospective, observational cohort study of the Nationwide Inpatient Sample (NIS) from 2002-2012. UGIH was identified in hospitalizations with a principle ICD-9-CM diagnosis of UGIH, or clinical symptoms and signs consistent with UGIH (hematemesis, blood in stool or gastrointestinal bleeding). Only patients with an upper endoscopy performed during the hospitalization were included. Results: The hospitalization rate of UGIH in the U.S. decreased by 18% from 2002 to 2012, from 80 to 65/100,000 population (p<0.01, Table 1). Men and patients ‡85 years old had the highest hospitalization rate of UGIH, 79 and 561/100,000 population respectively. The most common etiology of UGIH was peptic ulcer disease (PUD, 49%), followed by gastritis (17%), esophagitis (15%), angiodysplasia (6%), Mallory-Weiss tear 6%, neoplasm (3%), esophageal varices (2%), and Dieulafoy lesion (2%). The greatest change in etiology of bleeding occurred for PUD and gastritis, which declined by 27% and 46%, respectively (p<0.01). The greatest increases were in neoplasm, angiodysplasia, and esophagitis (by 38%, 33% and 13%, respectively (p<0.01)). The all-cause case fatality rate of UGIH decreased 27% from 2.1 per 100 cases in 2002 to 1.6 in 2012 (p<0.01, Table 2), with the highest mortality being in patients with esophageal variceal hemorrhage and neoplasm, which also had the greatest improvements in mortality. Conclusion: The epidemiology of UGIH hemorrhage appears to be shifting, with a decline in gastric disorders, an increase in the rate of hospitalization with UGIH for neoplasm, angiodysplasia, and esophagitis. Mortality also appears to be decreasing. The decreasing hospitalization rate and all-cause case fatality rate of UGIH suggests population trends in use of treatments for PUD, and improved overall medical care.
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AGA Abstracts