# Presentation: 696437

## Small Bowel Toxicity of Nonselective NSAIDs Revealed by Capsule Endoscopy: Results From a Pivotal  Clinical Trial

**Glenn M. Eisen, M.D., M.P.H.**
**Associate Professor of Medicine**
**Oregon Health and Science University,**
** ****Portland, Oregon**

## NSAIDs and Small Intestinal Damage

*****
**8.4%**

**0.6%**

**0**

**2**

**4**

**6**

**8**

**Nonspecific ulcers**

**NSAID group (n = 249)**
**Control group (n = 464)**

**10**

********P***** < 0.001**
**Allison, et al. *****N Engl J Med*****. 1992;327:749–754.**

**% of Subjects With Small Intestinal Ulcers**

## NSAID Use Is Associated With Both Upper and Lower GI Bleeding

- Case-controlled study of upper GI bleeding (UGIB) and lower GI bleeding (LGIB)
- Use of NSAIDs within 1 week of admission was documented

*** P < 0.05**
**OR = odds ratio; AOR = OR adjusted for age, race, and gender.**
**Wilcox CM, et al. *****Dig Dis Sci.***** 1997;42:990–997.**

## Rates of Serious Lower GI Events per 100 Patients-Years in Patients Receiving Rofecoxib vs Naproxen

**0.41**

**0.89**

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**% of Patients with Serious Lower GI Events per 100 Patient-Years**

**Rofecoxib**

**(n = 4,047)**

**Naproxen**

**(n = 4,029)**

**Relative Risk (95% CI)**
**     ****0.46(0.22-0.93)**
***            ******P *****= 0.03**

**Laine, et al. *****Gastroenterology*****. 2003;124:288-292.**

## CLASS: Decreases in Hct ≥ 10% and/or

**Celecoxib**
**Diclofenac**
**Ibuprofen**

**10**

**% of Patients**

**0**

**2**

**4**

**6**

**8**

**All Patients**

**Patients Without Complications**

********P *****< 0.05 vs celecoxib**
**FDA Arthritis Advisory Committee Meeting. February 7, 2001. Gaithersburg, Maryland, USA.**

**2.4**

*****
**5.7**

*****
**4.5**

*****
**3.7**

**2.0**

*****
**4.4**

**CLASS: Decreases in Hct ≥ 10% and/or**
**Hgb > 2 g/dL**
** **

## Hypothesis  

**The combination of a non-specific NSAID + PPI will be associated with a rate of small bowel mucosal breaks that is significantly higher than the rate for placebo or for a COX-2 specific inhibitor**

## Inside the M2A Capsule

## NSAID-Induced Lesions

## Study Design

**Celecoxib 200 mg BID**

**Placebo ****	**

**	**

**Start study drug**** **

**Study Design**

**Naproxen 500 mg BID *****plus***
**omeprazole 20 mg QD**

**2-week run-in period**

**Screening**

**Randomization**

**Final**

**M2A video capsule**
**(baseline)**

**M2A video capsule**
**(final)**

**2-week Tx period**

**Healthy Subjects**

## Primary End Point (mITT) 

**0**

**1**

**2**

**3**

**Celecoxib**
**(n = 115)**

**Naproxen + PPI**
**(n = 111)**

**Placebo**
**(n = 113)**

**Mean # of SB  Mucosal Breaks (Grades 2, 3, 6, and 7)**

** *****P***** < 0.001**

** *****P *****< 0.001**

**Goldstein J, Eisen G, Gralnek I, Clin Gastroenterol and Hepatol Feb 2005**

**   ****0.32**

**0.11**

-   **2.99**

**Mean Number of Small-Bowel Mucosal Breaks (Grades 2, 3, 6, and 7)**

** *****P***** = 0.042**

## Capsule Endoscopy StudySecondary End Point (mITT)

|  | Celecoxib

(n = 115) | Naproxen + omeprazole
(n = 111) | Placebo

(n = 113) | P value* |
| --- | --- | --- | --- | --- |
| Incidence of mucosal breaks, N (%) | 
18 (16%) | 
61 (55%) | 
8 (7%) | 
< 0.001 |

**Incidence of Small Bowel Mucosal Breaks**

***Across three treatments corresponding to general association of the Cochran-Mantel-Haenszel test having stratified by site**

## Conclusions

**These findings extend the original COX-1 sparing hypothesis beyond the upper GI tract and into the small bowel**

**Conclusions**

## Conclusions (2)

- Use of NS-NSAIDs can potentially lead to mucosal lesions, gastrointestinal bleeding beyond the ligament of Treitz
- PPI use does not protect against NSAID induced damage to the small/large intestine
- Capsule endoscopy provides a noninvasive assessment of the small bowel, which may be clinically useful in patients at risk for small bowel injury