The British Journal of Rheumatology, Vol 37, 937-945, Copyright © 1998 by British Society for Rheumatology
C Hawkey, A Kahan, K Steinbruck, C Alegre, E Baumelou, B Begaud, J Dequeker, H Isomaki, G Littlejohn, J Mau and S Papazoglou
Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are
associated with a high incidence of gastrointestinal (GI) side- effects.
Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the
efficacy and toxicity of NSAIDs. The discovery of two COX isoforms,
constitutive COX-1 and inducible COX-2, has led to the hypothesis that
selective inhibition of COX-2 will minimize the potential for GI toxicity
without compromising efficacy. The Meloxicam Large-scale International
Study Safety Assessment (MELISSA) trial reported here was therefore set up
to investigate the tolerability of meloxicam, a preferential inhibitor of
COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind,
randomized, international, prospective trial, conducted over 28 days in
patients with symptomatic osteoarthritis. Patients received either
meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses
for the treatment of osteoarthritis. Evaluation of the profile of adverse
events was the main aim of the trial, together with assessment of efficacy.
A total of 9323 patients received treatment (4635 and 4688 in the meloxicam
and diclofenac groups, respectively). Significantly fewer adverse events
were reported by patients receiving meloxicam. This was attributable to
fewer GI adverse events (13%) compared to diclofenac (19%; P < 0.001).
Of the most common GI adverse events, there was significantly less
dyspepsia (P < 0.001), nausea and vomiting (P < 0.05), abdominal pain
(P < 0.001) and diarrhoea (P < 0.001) with meloxicam compared to
diclofenac. Five patients on meloxicam experienced a perforation, ulcer or
bleed vs seven on diclofenac (not significant). No endoscopically verified
ulcer complication was detected in the meloxicam group compared to four
with diclofenac. There were five patient days of hospitalization in
patients on meloxicam compared to 121 with diclofenac. Adverse events
caused withdrawal from the study in 254 patients receiving meloxicam
(5.48%) compared to 373 (7.96%) on diclofenac (P < 0.001). These
differences were attributable to differences in reported GI adverse events
(3.02% on meloxicam vs 6.14% on diclofenac; P < 0.001). Differences in
efficacy, as assessed by visual analogue scales, consistently favoured
diclofenac. In all instances, 95% confidence intervals did not cross zero,
suggesting a statistically significant effect. However, differences were
small (4.5- 9.01% difference) and did not reach pre-determined levels of
clinical significance. Nevertheless, significantly more patients
discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49
out of 4688; P < 0.01). The MELISSA trial confirms earlier studies
suggesting that meloxicam has a significantly improved GI tolerability
profile in comparison with other NSAIDs, including diclofenac. These
results may in part reflect the preferential COX-2 selectivity of
meloxicam, although the dose and other aspects of tolerability may be
important. These results may provide support for the hypothesis that
selective inhibition of COX-2 relative to COX-1 might be an effective
approach towards improved NSAID therapy.
ORIGINAL PAPERS
Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment [published erratum appears in Br J Rheumatol 1998 Oct;37(10):1142]
University Hospital, Queen's Medical Centre, Nottingham.
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