Celecoxib (Celebrex®) Long-Term Arthritis Safety Study (CLASS)
The CLASS study (Silverstein, et al , JAMA 28451247-1255, 2000) is a 6-month, double-blind, randomized controlled trial to determine whether celecoxib, a COX-2 specific inhibitor, is associated with a lower incidence of serious upper gastrointestinal (UGI) ulcer complications compared with conventional nonsteroidal anti-inflammatory drug (NSAIDs). Serious UGI ulcer complications were defined as bleeding, perforation, or obstructions (POB).
Study Design: 7,968 patients with either rheumatoid arthritis (RA) or osteoarthritis (OA) were randomly assigned to treatment with 400 mg bid of celecoxib (n=3987), 800mg tid ibuprofen (n=1985), or 75mg bid diclofenac (n=1996). The celecoxib dose was 2 to 4 times the maximum FDA approved effective dosage. The celecoxib and NSAID groups had 1441 and 1384 total patients-years of exposure, respectively. All potential upper GI ulcer complications were evaluated based on a prespecified algorithm structured to reproduce clinical practice norms.
Results:
| For All Patients: |
Annualized Incidence | Relative Risk | P Value | |
| Celecoxib (n=1441) |
NSAIDs (n=1384) |
|||
| POB | 0.76% | 1.45% | 0.53 | 0.09 |
| POB + symptomatic ulcers |
2.08% | 3.54% | 0.59 | 0.02 |
| For Patients Not Taking Aspirin: |
Annualized Incidence | Relative Risk | P Value | |
| Celecoxib (n=1143) |
NSAIDs (n=1101) |
|||
| POB | 0.44% | 1.27% | 0.35 | 0.04 |
| POB + symptomatic ulcers |
1.40% | 2.91% | 0.48 | 0.02 |
| For Patients Taking Concurrent Low-Dose Aspirin: |
Annualized Incidence | Relative Risk | P Value | |
| Celecoxib (n=298) |
NSAIDs (n=283) |
|||
| POB | 2.01% | 2.12% | 0.95 | 0.82 |
| POB + symptomatic ulcers |
4.7% | 6.0% | 0.78 | 0.49 |
Although there was a lower incidence of POBs in the celecoxib treated group, compared to NSAID group, it was not statistically significant. When the incidence of symptomatic ulcers was combined with POBs, there was a statistical difference. Low dose aspirin users had similar rates of POBs and symptomatic ulcers regardless of whether they took celecoxib or NSAIDs. Corticosteroids did not enhance the risk for POBs. Adverse renal events and hypertension were significantly lower in patients treated with celecoxib than in patients treated with NSAIDs. The incidence of cardiovascular adverse events was similar in both treatment groups. The withdrawal rate for adverse events and lack of therapeutic efficacy was less in the celecoxib treatment group (18.4% and 12.6%, respectively), compared to the NSAID treatment group (20.6% and 14.8%, respectively).
Editorial Comment: Endoscopic ulcer rates have been shown in previous studies to occur at considerably lower rates in patients receiving COX-2 inhibitors compared to conventional NSAIDs. However, this is the first study to query and demonstrate lower rates of serious ulcer complications in COX-2 compared to NSAID patients. However, it is important to note that this difference was not statistically significant. Only when the incidence of symptomatic ulcers was added to POBs was the difference between the celecoxib and NSAID groups statistically different. It is likely, though, that if the number of patients studied had been larger or had been followed for a longer time, the difference would have become significant.
Another critically important point about this study is that the use of low dose aspirin concomitantly with celecoxib negated the protective effect of celecoxib. Thus, the rate of POBs in celecoxib/aspirin users was similar to that in the NSAID/aspirin users. This makes sense since aspirin is a selective COX-1 inhibitor and gastric protection is thought to be mediated by COX-1 generated prostaglandins. Elderly individuals have a much higher risk of serious ulcer complications from NSAIDs than younger individuals, and they are also the most likely to be using low dose aspirin. The use of selective COX-2 inhibitors in this group of patients may convey no benefit in terms of gastroprotection.