Video Capsule Endoscopy to Prospectively Assess Small Bowel Injury With Celecoxib, Naproxen Plus Omeprazole, and Placebo

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Video Capsule Endoscopy to Prospectively Assess Small Bowel Injury With Celecoxib, Naproxen Plus Omeprazole, and Placebo JAY L. GOLDSTEIN,* GLENN M. EISEN, BLAIR LEWIS, IAN M. GRALNEK, STEVE ZLOTNICK, and JOHN G. FORT ON BEHALF OF THE INVESTIGATORS *University of Illinois at Chicago, Chicago, Illinois; Oregon Health and Sciences University, Portland, Oregon; The Mount Sinai Medical Center, New York, New York; VA Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA, Los Angeles, California; and Pfizer, Inc, Peapack, New Jersey Background & Aims: Data indicate that cyclooxygenase- 2 specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. Methods: We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n 118), or placebo (n 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. Results: Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were , 55% for naproxen/omeprazole compared to , 16% for celecoxib and , 7% for placebo (P <.001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P.04). Conclusions: Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE. Data from uncontrolled case series and epidemiologic studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause small bowel lesions, including ulcerations. 1 4 Clinically relevant complications of so-called small bowel NSAID-associated enteropathy may include the development of webs, strictures/ obstructions, acute bleeding, perforations, and occult gastrointestinal bleeding, which may lead to the development of iron-deficiency anemia. 1 7 Although small bowel enteroscopy has been used in clinical practice to examine suspected small bowel pathologies, its utility has been limited by technical difficulties, relative discomfort for the patient, and incomplete evaluation of the small bowel. A noninvasive video capsule endoscopy (VCE) system providing detailed digital imaging of the small bowel has been recently approved by the Food and Drug Administration and is recommended as a first-line diagnostic tool for detecting small bowel pathologies (Given Diagnostic System; Given Imaging Ltd, Yoqneam, Israel) The gastroduodenal ulcer complications associated with nonspecific NSAID use have been attributed to cyclooxygenase-1 (COX-1) inhibition. 11 In contrast, COX-2 specific inhibitors spare COX-1 at therapeutic doses, and their use has been associated with lower rates of endoscopic gastroduodenal ulcers and ulcer complications Because COX-1 is constitutively expressed in the human small bowel, 19 we hypothesized that COX-2 specific inhibitors would also be less injurious than nonspecific NSAIDs in the small bowel. Although there have been no prospectively designed enteroscopic studies directly comparing these 2 drug classes with regard to small bowel mucosal injury, this hypothesis is supported by the greater rate of fecal 51 Cr RBC loss reported in healthy subjects treated with the nonspecific NSAID ibuprofen compared to the COX-2 specific inhibitor rofecoxib. 20 Moreover, and of clinical relevance, in the Celecoxib Long-term Arthritis Safety Study, significantly more patients receiving therapeutic doses of ibuprofen or diclofenac had decreases in hematocrit 10% and/or decreases in hemoglobin 2 g/dl compared to those receiving a supratherapeutic dose of celecoxib (400 mg twice daily). 12 This difference per- Abbreviations used in this paper: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; VCE, video capsule endoscopy by the American Gastroenterological Association /05/$30.00 PII: /S (04)

2 134 GOLDSTEIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 2 Table 1. Small Bowel Lesion Assessment Table Category Description 1 Petechiae 2 Mucosal break without hemorrhage 3 Mucosal break with hemorrhage 4 Web/stricture without mucosal break and without hemorrhage 5 Web/stricture without mucosal break and with hemorrhage 6 Web/stricture with mucosal break and without hemorrhage 7 Web/stricture with mucosal break and hemorrhage 8 Presence of blood (hemorrhage) without visualized lesions 9 Other lesions NOTE. There were 9 categories of small bowel lesions. Each lesion was evaluated and assigned a category. Mucosal breaks included any lesion that appeared as an erosion or ulcer, regardless of perceived size. Hemorrhage was defined as visible blood. sisted even when potential upper gastroduodenal ulcer complications were removed from the analysis, suggesting that this anemia might have resulted from occult blood loss from beyond the upper gastrointestinal tract. To better understand and quantify the differential small bowel injury pattern of nonspecific NSAIDs and COX-2 specific inhibitors, we designed a prospective, double-blind, randomized study to evaluate the incidence of small bowel lesions in healthy subjects treated with celecoxib compared to naproxen plus omeprazole or placebo by using VCE. We purposely elected to study the NSAID in combination with a proton pump inhibitor in an attempt to achieve balance among the treatment groups with regard to the upper gastrointestinal tract risk of gastroduodenal mucosal injury, and because the protective effects of proton pump inhibitors would not be expected to occur within the remainder of the small bowel beyond the duodenum. Patients and Methods Healthy adults (18 70 years of age) who had no evidence of either a mucosal break or blood in the small bowel at the baseline VCE and who had no clinically significant laboratory or physical examination abnormalities were eligible for randomization. Important criteria for exclusion were active gastrointestinal disease or history of gastrointestinal ulcers or bleeding; known or suspected complete or partial stenosis of the small intestine; prior gastric or intestinal surgery (resection); established delayed gastric emptying or diabetic gastroparesis; hemoglobin 10 g/dl (women) or 12 g/dl (men); positive fecal occult blood test results at screening; frequent (more than 3 times per week) use of aspirin or other NSAIDs within 2 weeks before screening; use of any known or suspected ulcerogenic medication (including aspirin or other NSAIDs) within 2 weeks before the baseline VCE (run-in period); and use of antiulcer medications (ie, sucralfate, antacids, histamine-2-receptor antagonists, proton pump inhibitors, and misoprostol) within 4 weeks before the baseline VCE, which corresponds to at least 2 weeks before the initial screening visit and entry into the run-in period. Study Design This was a prospective, randomized, double-blind, tripledummy, placebo-controlled, multicenter study. After the initial screening visit, subjects underwent a 2-week run-in period, during which time alcohol consumption and use of any known or suspected ulcerogenic medications or antiulcer agents were prohibited. At the baseline visit, eligible subjects underwent a baseline VCE. If any mucosal break or blood was observed in the small bowel, or if small bowel visualization time was less than 2 hours, the subject was not eligible for randomization. Eligible subjects were subsequently randomly assigned to receive celecoxib (Celebrex; Pfizer, Inc, New York, NY) 200 mg twice daily, naproxen (Naprosyn; Roche Laboratories, Inc, Nutley, NJ) 500 mg twice daily plus omeprazole (Prilosec; AstraZeneca, Wilmington, DE) 20 mg once daily, or placebo for 2 weeks. After this 2-week treatment period, each subject underwent VCE for determination of the primary and secondary end points of the study. A computer-generated randomization technique was used to assign subjects in a 1:1:1 ratio. During the study, NSAIDs (including topical agents and aspirin), known or suspected ulcerogenic agents, analgesics (including opioids), and antiulcer medications were prohibited. Acetaminophen up to 4 g daily up to twice per week was permitted for general pain relief. The Institutional Review Boards at each of the 9 centers approved the protocol, and all subjects provided written informed consent at screening. Video Capsule Endoscopy Methodology VCE was performed by using the Given M2A video capsule system (Given Imaging Ltd). 8 This system has been described in detail elsewhere. 24 Smoking was prohibited for 24 hours before the procedure was initiated, and only liquids were to be ingested beginning at lunchtime of the day before the procedure. No purges were given, and no prokinetic medications were administered. Subjects fasted 12 hours before swallowing the capsule. A light snack was permitted 4 hours after capsule ingestion. Data were collected for up to 8 hours after capsule ingestion. Repeat VCEs as a result of system failures (image loss or low signal) were permitted only if capsule excretion was confirmed. Methodology for Review of Video Capsule Endoscopies Each local investigator as well as each member of the Small Bowel Events Committee were required to attend a standardized training session on the use of the Given Diagnostic System and to pass a certification examination to ensure proficiency with the use of the Given Diagnostic System and the evaluation of the M2A video images.

3 February 2005 SMALL BOWEL LESIONS/CELECOXIB, NAPROXEN, PLACEBO 135 Figure 1. Trial profile. The investigator at each center reviewed and interpreted the baseline (pretreatment) video capsule images for determination of eligibility into the trial. If no mucosal break or blood was observed, the subject was randomized to the 2-week, blinded treatment phase and, after that, underwent the end-of-study VCE. The investigator at each center (who was blinded to patient treatment) then reviewed and evaluated the end-of-study VCEs and marked all suspected small bowel abnormalities. These investigators were instructed to mark any significant lesion, regardless of whether they believed the image met the criteria of a mucosal break. The members of the independent Small Bowel Events Committee (J.L.G., G.M.E., I.M.G., and B.L.), who were blinded to subject, site, and treatment, then reviewed and adjudicated to consensus these blinded, marked videos, according to the prespecified Small Bowel Lesion Assessment criteria (Table 1) for determination of the primary and secondary end points. Figure 1 describes the flow of the patients during the duration of the trial.

4 136 GOLDSTEIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 2 Study End Points The primary end point was the mean number of small bowel mucosal breaks (defined as any break in the mucosa, as depicted by categories 2, 3, 6, and 7 in Table 1) per subject. There was no attempt to differentiate between ulcers and erosions, because video capsule technology cannot accurately assess either lesion size or depth. 24 There were 3 secondary end points: the percentage of subjects with 1 or more small bowel mucosal breaks; the total number of small bowel lesions with or without hemorrhage (categories 2, 3, 4, 5, 6, 7, and 9; Table 1); and the percentage of subjects with visible blood in the small bowel but without visualized lesions in small bowel (category 8, Table 1). We also performed 2 post hoc analyses. One was an analysis of the mean number of mucosal breaks among those subjects with at least 1 mucosal break. The second was an analysis of the distribution of small bowel mucosal breaks across tertiles, which divided the area between the duodenum and cecum into 3 equal parts, on the basis of each subject s specific small bowel transit time. Any video in which the cecum could not be identified was excluded from this specific analysis. Overall safety was assessed by physical examination, laboratory tests, and observed or reported adverse events. Statistical Analysis Descriptive statistics were used for subject demographics and clinical characteristics and for the outcome variables. The primary end point (number of small bowel mucosal breaks) and the secondary end point (number of small bowel lesions with or without hemorrhage) were not normally distributed, and therefore their rank scores were analyzed with Cochran-Mantel-Haenszel test, stratified by site. The nonparametric test was a Kruskal-Wallis test for the overall comparison and a Wilcoxon rank sum test for the pairwise comparison. The remaining secondary end points (percentage of subjects with mucosal breaks and percentage of subjects with visible blood without visualized lesions) also used Cochran-Mantel-Haenszel test, stratified by site, for overall and pairwise comparisons. A post hoc analysis with a nonparametric test (Friedman chi-square) was performed to assess whether within each treatment group a difference existed in the distribution of small bowel mucosal breaks across tertiles, and pairwise comparisons across treatments were analyzed by a Wilcoxon rank sum test. All analyses were performed on the modified intention-to-treat cohort (defined as all randomized subjects who completed 2 weeks of double-blind therapy and who had valid end-ofstudy VCEs). Because of current interest in the gastrointestinal mucosal effects of COX-2 specific inhibitors compared to nonspecific NSAIDs, we also performed a post hoc analysis of the mean number of mucosal breaks among the subgroup of subjects who had at least 1 mucosal break. The nonparametric test was a Kruskal-Wallis test for the overall comparison and a Wilcoxon two-sample test for the pairwise comparisons. All hypothesis tests were conducted by using a Type I error rate of 5%, and all tests were 2-tailed, with two-sided 95% confidence intervals provided. SAS Version 8.2 (SAS Institute, Inc, Cary, NC) was used for all analyses. Results Patients Between September 2002 and March 2003, we screened 462 healthy adult subjects from 9 centers (8 centers in the United States and 1 center in Israel). A total of 40 subjects did not meet general inclusion and/or exclusion criteria, and in 9 other subjects the baseline videos were technical failures. Of the remaining 413 subjects, 57 (13.8%) were found to have lesions at the baseline VCE and were not eligible for randomization. The remaining 356 subjects underwent randomization: 120 to celecoxib, 118 to naproxen plus omeprazole, and 118 to placebo (Figure 1). Adverse events resulted in the withdrawal of 4 celecoxib subjects and 1 naproxen/omeprazole subject. A total of 351 subjects completed the study and underwent a final video capsule examination. Technical failures of the video occurred in 12 subjects. The remaining 339 subjects constituted the modified intention-to-treat cohort. These subjects (as well as all randomized subjects) had similar baseline characteristics (Table 2). Primary End Point As shown in Table 3, the mean number of small bowel mucosal breaks per subject was significantly higher in the naproxen/omeprazole group (2.99) compared to the celecoxib (0.32) and placebo groups (0.11) (P.001 for both comparisons). The difference between celecoxib and placebo was also significant (P.04). A representative lesion meeting the criteria for category 2 (mucosal break without hemorrhage) is shown in Figure 2. Secondary and Other End Points A significantly higher percentage of subjects in the naproxen/omeprazole group (55%) had mucosal breaks compared to those in the celecoxib (16%) and placebo (7%) groups (P.001 for both comparisons); the difference between celecoxib and placebo was also significant (P.04). The number of small bowel lesions with or without hemorrhage was significantly higher in the naproxen/omeprazole group (4.18) than in the celecoxib (0.50) and placebo groups (0.14) (P.001 for both comparisons); there was no difference between celecoxib and placebo (P.09) (Table 3).

5 February 2005 SMALL BOWEL LESIONS/CELECOXIB, NAPROXEN, PLACEBO 137 Table 2. Baseline Demographic Characteristics of the Subjects All randomized subjects Modified intention-to-treat cohort Characteristic Celecoxib (n 120) Naproxen/omeprazole (n 118) Placebo (n 118) Celecoxib (n 115) Naproxen/omeprazole (n 111) Placebo (n 113) Age (y) Gender, no. of subjects (%) Male 51 (42) 47 (40) 42 (36) 50 (43) 46 (41) 39 (35) Female 69 (58) 71 (60) 76 (64) 65 (57) 65 (59) 74 (65) Race, no. of subjects (%) White 93 (78) 92 (78) 85 (72) 88 (77) 87 (78) 84 (74) Black 9 (8) 12 (10) 12 (10) 9 (8) 12 (11) 11 (10) Asian 10 (8) 8 (7) 16 (14) 10 (9) 7 (6) 15 (13) Other a 8 (7) 6 (5) 5 (4) 8 (7) 5 (5) 3 (3) NOTE. Plus-minus values are means standard deviations. a Other includes other racial groups and where the race was not allowed to be asked. The percentage of subjects with blood (without visualized lesions) in the small bowel (category 8, Table 1) was similar for celecoxib (7%) and naproxen/ omeprazole (8%), and each of these treatments was significantly different from placebo (1%) (P.01 for both comparisons) (Table 3). When including all subjects with hemorrhage (categories 3,5,7, and 8; Table 1), the percentages remained the same for celecoxib and placebo and increased to 14% for naproxen/omeprazole. Only the difference between the active treatment groups and placebo, however, was significant (P.01 for both comparisons). Post Hoc Analyses In a post hoc analysis, we calculated the mean number of mucosal breaks among those subjects who developed at least 1 mucosal break; there was a significant difference between celecoxib and naproxen/ omeprazole. The mean number ( standard error) of mucosal breaks for the celecoxib group was , which was significantly lower (P.004) than the mean observed in the naproxen/omeprazole group ( ), but not significantly different from that observed in the placebo group ( ) (P.58 for celecoxib vs placebo). The difference between naproxen/omeprazole and placebo was also significant (P.01). The distribution of subjects with 1 or more mucosal breaks is shown in Figure 3. An additional post hoc analysis found that there was no statistically significant difference in the distribution of mucosal breaks throughout tertiles of the small bowel within each treatment group (Table 4). Furthermore, the pattern of the treatment difference for the comparison of naproxen/omeprazole to celecoxib and placebo was consistent within each tertile and similar Table 3. Small Bowel Lesions After Two Weeks of Treatment End point Celecoxib (n 115) Naproxen/omeprazole (n 111) Placebo (n 113) P value a Primary end point Number of small bowel mucosal breaks per subject Secondary end points Subjects with small bowel mucosal breaks, no. of subjects (%) Number of small bowel lesions with or without hemorrhage per subject Subjects with blood in the small bowel, without visualized lesions, no. of subjects (%) (16) 61 (55) 8 (7) (7) 9 (8) 1 (1).04 d.04 d.09 d.75 b.007 c.01 d NOTE. Modified intention-to-treat cohort. Plus-minus values are unadjusted means standard errors. a P value based on Wilcoxon rank sum method for the end points relating to number of lesions and on Cochran-Mantel-Haenszel for end points relating to percentage of subjects with small bowel lesions or blood. b Celecoxib vs naproxen/omeprazole. c Naproxen/omeprazole vs placebo. d Celecoxib vs placebo.

6 138 GOLDSTEIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 2 Figure 2. Mucosal break without hemorrhage (category 2 lesion), as defined in Table 1. Note the loss of mucosal integrity with surrounding erythema. to the overall results (which did not control for tertile location). However, in each tertile, the difference between celecoxib and placebo was no longer statistically significant, possibly because of fewer small bowel mucosal breaks in each tertile. General Safety All treatments were well tolerated, and there were no significant differences among the groups in the incidence of adverse events. Adverse events caused study withdrawal in 4 celecoxib-treated subjects (gastrointestinal symptoms, renal calculi, cholelithiasis, pneumonia) and 1 naproxen/omeprazole-treated subject (allergic reaction). Discussion We found a 9-fold lower mean number of small bowel mucosal breaks per subject in healthy individuals who received 2 weeks of treatment with celecoxib 200 mg twice daily compared to the combination of naproxen 500 mg twice daily plus omeprazole 20 mg once daily (0.32 vs 2.99; P.001). The celecoxib group also had a significantly smaller percentage of subjects with mucosal breaks (16% vs 55%, P.001). In addition, in our post hoc analysis among subjects who developed at least 1 mucosal break, the mean number of breaks was significantly greater in the naproxen/omeprazole group than in the celecoxib group (5.44 vs 2.06, respectively; P.004). These findings are consistent with published reports of the beneficial gastroduodenal effects of COX-2 specific inhibitors compared to nonspecific NSAIDs alone We also performed a post hoc analysis of mucosal break distribution within the small bowel to investigate whether any treatment had a local irritant/ topical effect on the proximal small bowel versus a more systemic effect throughout the small bowel. There was no statistically significant difference in the distribution of mucosal breaks throughout tertiles of the small bowel within each treatment group. In addition, across treatments, the pattern in the individual tertiles was similar to that observed for the primary end point. Small bowel injury and clinically relevant complications associated with the use of nonspecific NSAIDs are well recognized. 1 5 In the landmark study assessing small bowel injury at the time of autopsy, the prevalence of nonspecific small bowel ulcerations was 8.4% in patients taking nonspecific NSAIDs within 6 months before death (n 249) as compared to 0.6% in control subjects (no reported NSAID exposure) (n 464) (P.001). 2 Because the nonspecific NSAID group constituted a broad range of documented NSAID use (intermittent or daily use within 6 months before death), the results likely do not represent a true incidence. The findings of our study (55% of healthy subjects in the nonspecific NSAID group developed mucosal breaks) are in better agreement with those of a recently reported small bowel VCE study in arthritis patients (n 40). 25 In that study, Graham et al 25 found that 58% of nonspecific NSAID users (duration, 3 months) had small bowel lesions compared to 17% of nonusers (taking acetaminophen alone or nothing). This preliminary study, however, did not compare COX-2 specific inhibitors with nonspecific NSAIDs. No. of Subjects celecoxib naproxen+omeprazole placebo >15 No. of Mucosal Breaks Figure 3. Distribution of mucosal breaks among subjects with at least 1 mucosal break. The mean number of mucosal breaks was greater in subjects treated with naproxen omeprazole than in subjects treated with either celecoxib or placebo.

7 February 2005 SMALL BOWEL LESIONS/CELECOXIB, NAPROXEN, PLACEBO 139 Table 4. Number of Small Bowel Mucosal Breaks per Tertile of the Small Bowel Length Tertile Celecoxib (n 115) Naproxen/omeprazole (n 111) Placebo (n 113) P value a First Second Third P e d.14 d 0.17 d NOTE. Modified intention-to-treat cohort. Plus-minus values are unadjusted means standard errors. a P value based on Wilcoxon rank sum test. b Celecoxib vs naproxen/omeprazole. c Naproxen/omeprazole vs placebo. d Celecoxib vs placebo. e P value based on Friedman 2 test. A surprising and unexpected finding in our study was that 13.8% (57/413) of healthy subjects were not eligible for randomization because of the detection of small bowel lesions at the baseline VCE. The primary lesion in most of these subjects (44/57) was a mucosal break. Thus, 10.65% (44/413) of healthy subjects had mucosal breaks during the run-in period of the study when no medication was given, which is not dissimilar from the 7% of placebo subjects who developed mucosal breaks during the 2-week study period. Although the clinical consequences and applicability of mucosal breaks in healthy subjects and in subjects taking anti-inflammatory agents are unknown, our findings support our methodology of assessing small bowel lesions and, furthermore, emphasize the need for a control group in future prospective studies examining potential drug-induced effects on the small bowel. The use of a blinded events committee also strengthens the reliability of our methodology. In several of the end points measured in our study, celecoxib was found to be statistically significantly different from placebo. Although the cause is unknown, it might possibly be explained by the upregulation or importance of COX-2 in healing injured mucosa. 26,27 Celecoxib might have inhibited this effect, whereas placebo did not. Higher plasma concentrations of celecoxib as a result of a genetic polymorphism of CYP2C9 might possibly increase the incidence and/or severity of adverse events. 28 However, genotype screening was not performed, and the possible influence of this polymorphism in our population is unknown. A third possible explanation might be related to COX-1 inhibition, which is constitutively expressed in the small bowel. 19 Celecoxib might have caused some degree of COX-1 inhibition. However, platelet studies do not support significant inhibition of COX-1 by celecoxib at therapeutic doses 29 (as used in this study) or by COX-2 specific inhibitors in general, when taken in therapeutic or supratherapeutic doses Importantly, although there was a statistically significant difference between celecoxib and placebo with respect to the mean number of mucosal breaks per subject and the percentage of subjects with mucosal break, the magnitude of the difference is small compared to the differences observed when celecoxib and placebo are compared to naproxen/omeprazole (Table 3). Our study had several limitations. First, it was a short-term study and was conducted in a relatively young and healthy population. As such, the generalizablity of our results to a disease-relevant population using these drugs long-term is not clear. However, on the basis of similar findings in the gastroduodenal mucosa, it is likely that our results might be extrapolated to an older, higher risk population who take NSAIDs on a chronic basis. 12,34,35 Second, although we used state-of-art VCE to assess small bowel abnormalities, this technique lacks the capability to measure lesion size and depth. Nevertheless, VCE is superior to other small bowel examinations in detecting mucosal disease and is the only currently available technique to reasonably address the issue of NSAIDassociated enteropathy in a systematic way Moreover, it is important to recognize that the clinical relevance of the reported mucosal breaks in this trial has not been established. Further studies will be required to correlate the presence of mucosal breaks with the development of outcomes such as the development of anemia, overt bleeding, and other small bowel events such as perforations. Finally, although our primary and 2 of our secondary end points demonstrate a difference between the celecoxib and

8 140 GOLDSTEIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 2 naproxen/omeprazole arms, the third secondary end point (the percent of subjects with blood in the small bowel without visualized lesions) showed no difference between these 2 arms. We believe that this latter finding might be due to the low number of events. Moreover, we believe that this end point is the least specific because of the lack of visualized mucosal breaks. In conclusion, our study extends the understanding of the effects of nonspecific NSAIDs in the small bowel and provides insight into the small bowel mucosal effects of COX-2 specific inhibitors. We found that subjects treated with celecoxib had significantly fewer small bowel mucosal breaks than those treated with the combination of naproxen and a proton pump inhibitor. Further studies are needed to determine the clinical implications of small bowel mucosal breaks in the healthy untreated population as well as in the population of chronic users of NSAIDs and COX-2 specific inhibitors. Appendix Study Design Committee: J. Goldstein, B. Lewis, G. Eisen, I. Gralnek, J. Fort, S. Zlotnick. Small Bowel Events Committee: J. Goldstein, B. Lewis, G. Eisen, I. Gralnek. Data analysis and interpretation: J. Goldstein, J. Fort, S. Zlotnick, L. Simms, C. Chang. Data collection: J. Fort, S. Zlotnick, L. Simms, C. Chang. Writing Committee: J. Goldstein, J. Fort, L. Baer. The following investigators participated as site-specific Principal Investigators in the study and the authors would like to recognize their extremely collegial and collaborative work: Israel: Nadir Arber, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; United States: James Aisenberg, Research Associates of New York, New York, NY; Russell Brown, University of Illinois Chicago, Chicago, IL; Wilmot C. Burch, Vanderbilt University Medical Center, Nashville, TN; David Cave, St Elizabeth s Medical Center of Boston, Brighton, MA; Gareth Dulai, VA of Greater Los Angeles Healthcare System, Los Angeles, CA; Douglas Faigel, Oregon Health & Sciences University, Portland, OR; John Johanson, Rockford Gastroenterology Associates, Rockford, IL; Jonathan Leighton, Mayo Clinic Arizona, Scottsdale, AZ. References 1. Lengeling RW, Mitros FA, Brennan JA, et al. Ulcerative ileitis encountered at ileo-colonoscopy: likely role of nonsteroidal agents. 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Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 2002;325: Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95: Sikes DH, Agrawal NM, Zhao WW, et al. Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol 2002;14: Goldstein JL, Stenson W, Agrawal N, et al. Valdecoxib is associated with a significantly lower incidence of ulcer complications and symptomatic ulcers in arthritis patients compared to NSAID (abstr #T1403). Gastroenterology 2002;122(suppl 1):A Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. 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