Trial data for the coxibs, rofecoxib and celecoxib, were presented to the conference on June 22. Professor CLAIR BOMBARDIER (trial investigator) discussed the VIGOR (rofecoxib) study (see PJ, June 3, p835). Dr L. SIMON (trial investigator), presenting data on the CLASS study, said that it demonstrated gastrointestinal safety for celecoxib.
CLASS compared 4,000 patients taking 400mg celecoxib twice a day with 2,000 patients on diclofenac (75mg twice a day) and 2,000 patents on ibuprofen (800mg three times a day). The mean exposure was seven months (range six to nine months). Two-thirds of patients had osteoarthritis (OA) and one third rheumatoid arthritis (RA). Withdrawal due to lack of efficacy was highest in the ibuprofen group and withdrawal due to toxicity was highest for diclofenac. The incidence of ulcer complications in the celecoxib group was three-fold less than in the other groups. The risk of symptomatic ulcers and ulcer complication was reduced by 52 per cent.
The VIGOR study found a higher incidence of myocardial infarction in the rofecoxib group (see also PJ, June 3, p835). Searle and Pfizer, who jointly market celecoxib, say that the CLASS data show no statistically significant increase in cardiovascular events compared with non-steroidal anti-inflammatory drugs (NSAIDs).
Professor Bombardier said that it was difficult to compare the results of the two trials because the designs were so different. It was also difficult to compare coxibs with the combination of NSAID and proton pump inhibitor; a prospective study was required.
However, in a Merck-sponsored symposium, the company claimed that rofecoxib had advantages over celecoxib. Professor TORE KVIEN (Oslo City department of rheumatology, Diakonnjemmet hospital, Norway) said that daily doses of rofecoxib 25mg had been shown to be superior to celecoxib 200mg and paracetamol 4,000mg for relieving pain at rest and at night. The data had come from a six-week pilot study involving 382 patients with OA of the knee who were randomised to receive rofecoxib 12.5mg once daily, rofecoxib 25mg once daily, celecoxib 200mg once daily or paracetamol 1,000mg four times a day. [The licensed doses are: rofecoxib starting dose 12.5mg increasing to 25mg daily, celecoxib usual dose 200mg inceasing to 400mg if needed.] There were no differences between the groups in terms of adverse events, said Professor Kvien.
Dr Gregory Gebe (director of clinical development, Merck) said: "For most endpoints studied, there was a numerical ordering of effect, with paracetamol having the least effect, followed by celecoxib, then rofecoxib 12.5mg, with rofecoxib 25mg showing the greatest effect. In no case was celecoxib better than rofecoxib 25mg." He added that there was no statistical difference between celecoxib 200mg and rofecoxib 12.5mg on any endpoint.
The discovery of COX-1 and 2 some 10 years ago had resulted in the development of coxibs, said Dr K. BRUNE (department of experimental and clinical pharmacology, University of Erlangen, Germany).
Comparison with COX-2 selective NSAIDs had shown that coxibs were much more specifically selective for COX-2. For instance, typical NSAIDs had a COX-1:COX-2 selectivity ratio of 0.5. A COX-2 selective drug, meloxicam, had a ratio of 11.16. But celecoxib's ratio was greater than 100 and rofecoxib's greater than 200, he said.
Both rofecoxib and celecoxib were non-acidic drugs. Traditional NSAIDs were acidic, he said. Acidic drugs accumulated in the stomach and could cause gastrointestinal side effects. Non-acidic drugs such as paracetamol were distributed throughout the body and, while they did not cause GI side effects, they were much less effective. The non-acidic nature of celecoxib and rofecoxib, combined with their selectivity, resulted in reduced GI toxicity.
There had been some suggestions that coxibs had cardiovascular side effects. In trials, rofecoxib had had a higher infarct rate than naproxen and, while non-significant for celecoxib, its infarct rate was higher than that of ibuprofen and diclofenac, he said.
Dr Brune suggested that the reason for this was a change in the balance of vasodilation and vasoconstriction which was controlled by COX. While NSAIDs blocked both systems, coxibs only blocked one pathway, upsetting the balance. This also disturbed the balance of platelet aggregation. Therefore, he concluded that patients who needed aspirin should receive it while on coxib treatment.
COX-2 was also needed in other organs, including the kidney and eye. The enzyme had also been shown to have a major regulatory role in organ development pre-birth in mice. Avoiding coxibs in pregnancy or in women who may become pregnant was advisable for the time being, Dr Brune said. Therefore, he concluded: "We have to find the optimal conditions for use for these new specific drugs."
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