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QUESTION: In patients with rheumatoid arthritis (RA), is celecoxib as efficacious (in anti-inflammatory and analgesic effects) and safe (in avoiding endoscopic upper gastrointestinal [GI] ulcers) as naproxen?
Randomised (allocation concealed*), blinded (patients, clinicians, and outcome assessors),* placebo controlled, 12 week trial.
79 US and Canadian clinical sites.
1149 patients (mean age 54 y, 73% women) who had RA (American College of Rheumatology criteria) for >3 months. Inclusion criteria were age ≥18 years and receipt of stable medications; oral steroids and disease modifying antirheumatic drugs were allowed. Exclusion criteria were active GI tract, renal, hepatic, or coagulation disorders; history of cancer or gastric or duodenal surgery; or recent or current oesophageal or gastroduodenal ulcers or ≥10 erosions. 60% of patients completed the study; follow up was >99%.
Symptomatic RA was confirmed after non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics were stopped for 2 to 7 days. Patients were then allocated to celecoxib, 100 mg twice/d (n=240), 200 mg twice/day (n=235), or 400 mg twice/day (n=218); naproxen, 500 mg twice/day (n=225); or placebo (n=231). NSAIDs, injectable corticosteroids, anticoagulants, and antiulcer drugs were prohibited.
Main outcome measures
Improvement in signs and symptoms of RA (8 measures), proportion of patients with endoscopic GI ulcers at 12 weeks, and adverse effects.
Patients in the celecoxib and naproxen groups had similar outcomes, with more improvements at 12 weeks in signs and symptoms of RA than with placebo (5 of 8 measures for the celecoxib, 100 mg group; 7 of 8 measures for the celecoxib, 200 mg and 400 mg groups; and 4 of 8 measures for the naproxen group). Similar patterns were shown at 2 and 6 weeks. Patients in the placebo group withdrew from the study more often because of treatment failure than did patients in the celecoxib or naproxen groups (p<0.001 for all comparisons). The placebo and celecoxib groups did not differ for endoscopic GI ulcers; more patients in the naproxen group had ulcers than did those in the other 4 groups (p<0.001), although endoscopy was done in only 57% of patients. The rate of total adverse effects was 19% for placebo; 28%, 25%, and 26% for the 100 mg, 200 mg, and 400 mg celecoxib groups, respectively; and 31% for naproxen.
Celecoxib was as effective as naproxen for improving signs and symptoms of rheumatoid arthritis with similar rates of adverse effects and withdrawals. Celecoxib was associated with fewer endoscopic gastrointestinal ulcers.
Most clinicians are aware of the discovery of 2 forms of cyclooxygenase (COX): COX-1, the constitutional form, produces prostaglandins involved in physiological functions; COX-2, an inducible form, produces inflammatory prostaglandins. The distinction between the 2 forms led to a search for drugs that inhibit COX-2, sparing COX-1, in the expectation that such agents would be free of the serious GI toxicity caused by conventional (non-selective) NSAIDs. The first 2 COX inhibitors, celecoxib and rofecoxib, enjoyed successful launches in North America before any publications were available to assess their effectiveness and toxicity. In late 1999, 4 full reports, including these studies by Laine and Simon and their colleagues and 2 others by Langman and Emery,1, 2 were published; accompanying editorials raised doubts about the true value of these agents.3, 4 Overall, the 4 reports describe the experience of >7000 patients with RA or OA treated for 6 to 52 weeks (table 2).
Accepting that the COX-2 inhibitors are of similar efficacy to non-selective NSAIDs, the main clinical interest is in avoiding clinically important GI damage. During endoscopy, small and superficial ulcers that do not usually cause symptoms are frequently seen in the stomach and duodenum of patients taking conventional NSAIDs. The rates of these mainly non-clinical events with COX-2 inhibitors are approximately 25% of that with conventional NSAIDs. Physicians and patients are, however, more concerned with GI symptoms. Dyspepsia was reduced by only 2% to 3% with a COX-2 inhibitor. Although many patients have been studied in trials of COX-2 inhibitors, few instances of serious GI complications, such as bleeding or perforation, have occurred. The frequency of these potentially serious outcomes is approximately 1% with conventional NSAIDs; COX-2 inhibitors appear to provide a reduction of 0.5% to 1%. This means that 100 to 200 “typical” patients will have to be treated (NNT) with a COX-2 NSAID instead of a conventional NSAID to avoid 1 additional serious complication. In low risk groups, the NNT for serious complications may be around 500.4
Many patients who are unable to tolerate several conventional NSAIDs will probably be switched to the newer agents, and some will benefit. Although not yet the topic of a published study, patients who are at high risk for serious GI complications (eg, a history of ulcers or GI bleeding) and who need to take an NSAID will probably be the group for whom COX-2 inhibitors will be the most cost effective. Considering the high cost of these new drugs and the widespread use of NSAIDs in most communities, the routine prescription of COX-2 inhibitors cannot be supported.
Related BMJ news item
Merck withdraws arthritis drug worldwide
BMJ 2004;329:816, doi:10.1136/bmj.329.7470.816-a
Source of funding: GD Searle & Co.
For correspondence: Dr LS Simon, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 5C, Boston, MA 02215, USA. Fax +1 617 632 7795.