Celecoxib: Good News but No Cause to CELEBrate

abstract & commentary

Source: Silverstein FE, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS Study: A randomized controlled trial. JAMA 2000;284:1247-1255.

Nonsteroidal anti-inflammatory drug (nsaid) therapy carries a risk of developing significant injury to the upper gastrointestinal (GI) tract. The annualized incidence rate of symptomatic GI ulcers and ulcer complications in NSAID users ranges from 2% to 4% (1%-2% for ulcer complications alone). These side effects generally are considered a consequence of cyclooxygenase (COX)-1 inhibition. This study attempts to determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.

The Celecoxib Long-term Arthritis Safety Study (CLASS) was a double-blind, randomized, controlled trial conducted from September 1998 to March 2000 at 386 clinical sites in the United States and Canada. A total of 8059 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled. A total of 4573 patients (57%) received treatment for six months. Patients were randomly assigned to receive 400 mg celecoxib bid (two and four times the maximum RA and OA dosages, respectively; n = 3987); 800 mg ibuprofen tid (n = 1985); or 75 mg diclofenac bid (n = 1996). Aspirin use for cardiovascular prophylaxis (£ 325 mg/d) was permitted. The incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (perforation, obstruction, and bleeding [POBs]) and other adverse effects was measured during the six-month treatment period. Patients were excluded if they took NSAIDs (except for stable aspirin use £ 325 mg/d); anti-ulcer drugs (except for occasional antacid use); antibiotics alone or in combination with omeprazole, lansoprazole, and ranitidine for treatment of Helicobacter pylori infection; or antineoplastics (except methotrexate or azathioprine for RA). Use of oral, intramuscular, and intra-articular glucocorticoids and disease-modifying antirheumatic drugs was permitted.

For all patients, the annualized incidence rates of upper GI ulcer complications (POBs) were 0.76% for celecoxib and 1.45% for NSAIDs (P = 0.09). The incidence of POBs and symptomatic ulcers for celecoxib vs. NSAIDs was 2.08% vs. 3.54%, respectively (P = 0.02). For patients not taking aspirin, the annualized incidence rates of POBs alone and POBs combined with symptomatic ulcers for celecoxib vs. NSAIDs were 0.44% vs. 1.27% (P = 0.04) and 1.40% vs. 2.91% (P = 0.02). For patients taking aspirin, the annualized incidence rates of POBs alone and POBs combined with symptomatic ulcers for celecoxib vs. NSAIDs were 2.01% vs. 2.12% (P = 0.92) and 4.70% vs. 6.00% (P = 0.49). Fewer celecoxib patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events, irrespective of aspirin use.

Celecoxib, at doses greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and POBs—as well as other clinically important toxic effects—compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest in patients not taking aspirin concomitantly.

Comment by Richard J. Hamilton, MD, FAAEM, ABMT

COX-1 is a ubiquitous constitutive isozyme producing prostaglandins responsible for homeostatic functions such as maintenance of GI mucosal integrity. COX-2 is largely a cytokine-induced isozyme producing prosta-glandins that mediate pain and inflammation. The search for a drug that would inhibit COX-2 without causing all the COX-1 inhibition side effects has been a pharmaceutical holy grail. Celecoxib is the first of this series of drugs with anti-inflammatory properties and reduced side effects.

Does it live up to the hype? The POB incidence in celecoxib users not taking aspirin is similar to the POB incidence in the general population. In addition, the authors would argue that the high therapeutic dosages used in this study were responsible for the higher than expected rate of POBs and symptomatic ulcers. Indeed, celecoxib appears to reduce the rate of symptomatic ulcers and complications over NSAIDs, but it does not eliminate them. Prudent use of the drug for patients with severe RA and OA is appropriate, especially if the patients are taking aspirin at cardioprotective doses. In my opinion, celecoxib’s use purely as an analgesic in routine settings is of limited value when compared to NSAIDs or the mild narcotic combination therapies currently available.