Celecoxib (Celebrex™)
Rofecoxib (Vioxx™)

The Celecoxib Long-Term Arthritis Safety Study (CLASS). L Simon, USA.

The CLASS trial is a long-term safety study comparing a supratherapeutic dose of celecoxib (400 mg bid, n=4000) to therapeutic doses of diclofenac (75 mg bid, n=2000), and ibuprophen (800 tid, n=2000) for incidence of symptomatic ulcers and ulcer complications. Symptomatic ulcers were classified as ulcers documented as "for cause workup" and ulcer complications included bleed, perforation, and obstruction. It was a prospective, double-blind study based on clinical practice norms and targeted osteoarthritis (OA) and rheumatoid arthritis (RA) patients with a minimum of 6 months exposure to treatment. Patients in each treatment arm had similar demographics and were included regardless of history of gastrointestinal (GI) bleed, ulcer, and aspirin usage.

Results demonstrated that patients (not using aspirin) treated with celecoxib experienced a 3-fold reduction in ulcer complications (p=0.037) with a relative risk reduction of 65%, and a 2-fold reduction in symptomatic ulcers (p=0.02) with a relative risk reduction of 52%. Decreases in hematocrit (>10%) and/or hemoglobin (>2g/dL) in patients receiving celecoxib were comparable to those receiving placebo, but significantly different (p<0.05) from those patients receiving ibuprophen and diclofenac who experienced a 2-fold increase in the rate of hematocrit reduction when compared to the placebo group. LFT abnormalities were observed only in patients on diclofenac. When renal adverse events were evaluated, the incidence of any renal event in patients taking celecoxib (6.5%) and diclofenac (6.5%) was significantly lower when compared to patients taking ibuprophen (9.5%). No difference in results were seen in OA and RA patients.

Editorial Comments: These data demonstrate that patients treated with a supratherapeutic dose of celecoxib experienced a lower incidence of serious ulcer complications, including bleeding, as well as a reduced incidence of renal and hepatic events. This study, and a similar one with rofecoxib presented at these same meetings has been eagerly anticipated. Up to now, the apparent enhanced safety profile of celecoxib has been based on the demonstration of a reduced frequency of endoscopic ulcers compared to nonselective NSAIDs. The current study addresses the more clinically relevant issue of frequency of serious complications of ulcers in patients treated with COX-2 inhibitors vs nonselective NSAIDs, and the results are encouraging and exciting. An unanswered question is whether pharmacoeconomics, based on current costs, justify the use of COX-2 specific agents in any patient who requires NSAID treatment

There have been concerns based on animal studies, that COX-2 specific inhibitors may impair the healing of gastrointestinal lesions. The objective of this study was to monitor and compare the progression of gastric lesions in patients treated with celecoxib (n=2064), traditional NSAIDs (n=1458), or placebo (n=478). This analysis from 4 clinical trials reviewed endoscopic results from patients with > 1 gastric or duodenal mucosal erosion (but not an ulcer) and were not taking aspirin at any point during the study.

Results: Patients were categorized based on endoscopy results comparing baseline and up to 12 weeks following initiation of therapy.

Based on these data, celecoxib does not impair healing of gastrointestinal mucosal lesions.

Editorial Comments: Although COX-2 inhibitors are associated with a lower incidence of GI ulcers than traditional NSAIDs, there has been lingering concern that, for existing ulcers, COX-2 inhibitors may slow healing. This study suggests this is not the case. However, only erosions -and not ulcers- were analyzed here.

GI Outcome Trial (VIGOR). C Bombardier, Canada.

Dr. Bombardier presented the results from the Vioxx (rofecoxib) Gastrointestinal Outcomes Research Trial (VIGOR). Patients treated with rofecoxib (50 mg daily, n=4047) were compared to patients treated with naproxen (500 mg bid, n=4029) for incidence of complicated upper gastrointestinal (UGI) events including bleed, perforation, obstruction, and symptoms. Patient demographics were similar in both groups and aspirin users were excluded. Withdrawal rate in both groups was 29%.

There was a total of 177 confirmed UGI events, with 53 of those considered complicated. The breakdown of these results is reported in the table below.

The chance of bleed was constant over the study period with the rate of incidence in patients treated with rofecoxib remaining constantly lower through 13 months (p=<0.001) than in patients treated with comparator NSAIDs. There were no statistical differences in the incidence of cerebralvascular accidents (0.2% vs 0.2%), deaths due to cardiovascular events (0.2% vs 0.2%), and all deaths (0.5% vs 0.4%) when comparing patients treated with rofecoxib with patients treated with naproxen, respectively. A statistically significant difference was found in the incidence of myocardial inarction (MI) when patients treated with rofecoxib (.4%) were compared with patients treated with naproxen (0.1%). When patients with baseline risk factors for cardiovascular disease were removed from the analysis, the incidence of MI was 0.2% for patients receiving rofecoxib and 0.1% for patients receiving naproxen. The difference was not statistically significant. The rate of discontinuation due to lack of efficacy was 6.3% for rofecoxib and 6.5% for naproxen.

These data demonstrate that Rofecoxib reduced the annualized risk of clinical UGI events 54-62%. This benefit was maintained throughout the study period. Cardiovascular deaths in patients receiving rofecoxib were comparable to patients receiving naprosyn. 41 patients would need to be treated with Rofecoxib instead of naprosyn to avoid 1 UGI event in one year.

Editorial Comments: This study, and a similar one with celecoxib presented at these same meetings has been eagerly anticipated. Up to now, the apparent enhanced safety profile of rofecoxib has been based on the demonstration of a reduced frequency of endoscopic ulcers compared to nonselective NSAIDs. The current study addresses the more clinically relevant issue of frequency of serious complications of ulcers in patients treated with COX-2 inhibitors vs nonselective NSAIDs, and the results are encouraging and exciting. The pharmacoeconomic analysis does not favor the use of COX-2 drugs above nonselective NSAIDs for all patients, however. Clinicans will have to continue to weight cost vs risk of serious GI event for each individual patient.

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