Celecoxib, a COX-2 inhibitor, is safer than the non-steroidal anti-inflammatory
drugs ibuprofen and diclofenac in terms of gastrointestinal toxicity, according
to final results from the CLASS trial.
The CLASS (celecoxib long-term arthritis safety study) trial, which was funded
by Pharmacia, involved nearly 8,000 patients with osteoarthritis (OA) or rheumatoid
arthritis (RA) and was led by Dr Fred Silverstein (department of medicine, University
of Washington, US). It compared 3,987 patients taking celecoxib 400mg twice
a day with 3,981 taking a traditional NSAID. Of the NSAID group, half were on
ibuprofen 800mg three times a day and half on diclofenac 75mg twice a day. The
dose of celecoxib used in the trial was higher than the maximum daily dose licensed
in the UK (400mg a day for either RA or OA).
The study found an annualised incidence of upper GI ulcer complications plus
symptomatic ulcers of 2.08 per cent for celecoxib and 3.54 for NSAIDs. This
gave a relative risk for celecoxib of 0.59 compared with NSAIDs. The authors
comment that while this rate was significantly different, the rate for ulcer
complications alone was not. They suggest that the increase in ulcer complications
was attributable to higher than anticipated concurrent low–dose aspirin
use (which has been previously associated with ulcer complications). Low dose
aspirin was found to have a significant effect on the incidence of upper GI
complications in celecoxib-treated patients but not in NSAID-treated patients.
An analysis of non-aspirin users showed that celecoxib was associated with a
significantly lower incidence of upper GI ulcer complications than the NSAIDs.
The overall incidence of GI adverse symptoms, including dyspepsia and nausea,
was significantly lower in the celecoxib group compared with the NSAID group.
The incidence of bleeding-related adverse events and hepatic and renal adverse
effects was lower in the celecoxib group but skin reactions (rash and pruritus)
were higher in the celecoxib group.
The incidence of cardiovascular events were similar in both groups. The researchers
comment that it has been hypothesised that COX-2 inhibitors might increase the
risk of cardiovascular thromboembolic events via inhibition of vascular prostacyclin
synthesis without a corresponding inhibition of platelet thromboxane. This follows
observations of an increased rate of myocardial infarction in the VIGOR study
(a similar trial examining the safety of rofecoxib, see PJ, June 3, p835). However,
no difference in incidence of cardiovascular events, including myocardial infarction
and angina, was seen in the CLASS study (Journal of the American Medical Association
2000;284:1247).
The use of low-dose aspirin was not permitted in the VIGOR trial and its authors
have suggested that when a subset of trial participants who should have been
taking aspirin were excluded from the analysis, no difference in myocardial
infarction rates was seen.
Issues arising from the CLASS and VIGOR trials were discussed earlier this year
at the European League Against Rheumatism congress (PJ, July 15, p101)
and at the British Society of Rheumatology meeting (PJ, May 13, p717).
The National Institute for Clinical Excellence (NICE) is expected to publish
a review on celecoxib in January, next year, say Searle (part of Pharmacia)
and Pfizer, co-promoters of celecoxib (Celebrex). Last week, the Committee on
Safety of
Medicines and Medicines Control Agency reported in Current Problems in Pharmacovigilance
that the majority of adverse effects for rofecoxib reported on “yellow
cards” were for gastrointestinal and cardiovascular effects. A forthcoming
bulletin would review celecoxib, they said (PJ, September 16, p387).