Esomeprazole in Patients with Upper GI Symptoms Taking NSAIDs, Including COX-2 Inhibitors
Abstract & Commentary
By Malcolm Robinson, MD, FACP, FACG, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City, OK. Dr. Robinson serves as a consultant for TAP, Pfizer, Janssen, Eisai, J&J-Merck, and Procter & Gamble, is on the speaker’s bureau of Janssen, Eli Lilly, Solvay, TAP, and Aventis, and does research for Forest Labs.
Synopsis: Esomeprazole 20 mg and 40 mg daily improve upper GI symptoms occurring during NSAID therapy, including selective COX-2 inhibitors.
Source: Hawkey C, et al. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs. Am J Gastroenterol. 2005;100:1028-1036.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and clinically effective for control of musculoskeletal pain. However, up to 40% of NSAID recipients have any of a variety of upper GI symptoms such as dyspepsia, abdominal pain, and heartburn. These symptoms occur frequently with both conventional NSAIDs and the newer, selective, COX-2 inhibitors.
There is clearly a need to prevent the noxious symptoms associated with NSAID therapy. Since gastric and duodenal mucosal lesions occurring during NSAID therapy are known to be acid-mediated, acid suppression with proton pump inhibitors (PPIs) has been used to avert such damage and improve symptoms thought also to be related to acid. Hawkey and colleagues comment that the "greater" acid inhibition afforded by esomeprazole vs omeprazole, lansoprazole, pantoprazole, and rabeprazole might lead to particular efficacy in prophylaxis and treatment of NSAID symptoms. These 2 studies respectively involved 94 centers in 6 countries and 116 centers in 11 countries. Patients had to have a chronic condition such as osteoarthritis or rheumatoid arthritis which would require stable continuous NSAID therapy for > 7 months.
Endoscopy was done at baseline to rule out ulcerations in the esophagus, stomach, and duodenum and to check H. pylori status by histology. PPIs, H2RAs, and prostaglandins during the 2 weeks prior to endoscopy were forbidden; and other standard exclusions were applied. GI symptoms were recorded and quantified on a 6-point scale daily for 7-11 days at baseline. Patients with moderately severe symptoms (score of > 3) on at least 3 of the last 7 days were enrolled. Daily diary cards (heartburn and regurgitation, upper abdominal bloating, and nausea—along with pain, discomfort or burning involving the upper abdomen) were continued during 4 weeks of therapy with esomeprazole 20 mg, 40 mg, or placebo. Quality of life was also assessed at baseline and at 4 weeks. Studies included 595 and 554 patients randomized in each of the 2 trials. Ten percent of patients were found to be H. pylori positive. COX-2 use was 30% in the first study and 38% in the second one. Completion rates were 94% and 90%. Both doses of esomeprazole were superior to placebo for upper gastrointestinal (UGI) symptom relief, but placebo recipients also had substantial improvement in their symptoms. Antacid use was lowered from 2.2 antacid tablets a day to 0.72 and 1.06 with esomeprazole compared to 1.22 tablets daily for placebo recipients. Symptoms responsive to esomeprazole included heartburn and acid regurgitation, but nausea and upper abdominal bloating were far less responsive. There was no obvious impact of H. pylori positivity on response to therapy. The minimum change in UGI symptom score thought to be clinically significant has been set at 0.4, and esomeprazole 20 mg attained a 0.60 change while esomeprazole 40 mg produced a 0.48 change in score.
Commentary
The use of PPI therapy for UGI symptoms occurring with NSAID therapy is well accepted, and this approach is widely used. Now that the safety of COX-2 selective NSAIDs has become highly questionable, it is likely that nonselective NSAIDs along with concomitant PPIs will be even more frequently prescribed. The results of these huge esomeprazole studies are far from compelling, both because of the unexpectedly high placebo response and the relatively modest amelioration of symptoms achieved. If the makers of esomeprazole wish to convince us that this PPI is superior to other available PPIs for this indication, comparative studies would have to be done. It seems likely to this writer that such studies will not be forthcoming since they would not be likely to demonstrate any measurable difference between the available PPIs. This study and many other PPI studies indicated an odd disconnect between dose and efficacy in that the 20 mg dose seemed to be superior to the 40 mg dose. Although not directly addressed in this paper, the explanation of this finding could lie in nonspecific GI symptoms that could occur with the higher esomeprazole dose (particularly likely in individuals who are slow metabolizers of omeprazole/esomeprazole).
Esomeprazole 20 mg and 40 mg daily improve upper GI symptoms occurring during NSAID therapy, including selective COX-2 inhibitors.
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