Drug Insight: Cyclo-Oxygenase-2 Inhibitors--A Critical Appraisal

Burkhard Hinz; Bertold Renner; Kay Brune


Nat Clin Pract Rheumatol. 2007;3(10):552-560. 

In This Article

Gastrointestinal Safety Profile of COX2 Inhibitors

The hypothesis that COX2 inhibitors provide an improved risk profile in terms of gastrointestinal safety as compared with NSAIDs was tested in three large phase III clinical trials that included a total of approximately 35,000 patients. In the Vioxx® Gastrointestinal Outcomes Research (VIGOR) study[19] and in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET),[20] the risk of confirmed gastrointestinal events (including ulcerations, bleedings and perforations) was reduced by more than 50% in patients receiving rofecoxib (Vioxx®; Merck & Co., Whitehouse Station, NJ) and lumiracoxib in comparison with patients receiving NSAIDs. Notably, the TARGET trial revealed aminotransferase increases of more than three times the upper limit of normal in 2.6% of patients receiving 400 mg lumiracoxib, which was more than those produced by NSAIDs (0.6%), but these increases were reversible on drug discontinuation.[21]

In the Celecoxib Long-term Arthritis Safety Study (CLASS), however, a significant beneficial effect of celecoxib was only evident when the definition of upper gastrointestinal endpoints was expanded to include symptomatic ulcers.[21] Moreover, outcomes of the first 6 months were published instead of the complete 1-year data of this study, the latter revealing no significant difference in gastrointestinal end points between patients receiving celecoxib, diclofenac or ibuprofen.[22] In addition, both the CLASS and TARGET studies have clearly shown that patients receiving low-dose aspirin for cardiovascular protection do not benefit from the gastrointestinal safety of these drugs.

In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program, significantly fewer upper gastrointestinal clinical events were observed with etoricoxib than with diclofenac because of a decrease in uncomplicated events, but there was no decrease in the more serious complicated events. The reduction in uncomplicated events with etoricoxib was maintained in patients treated with proton-pump inhibitors or regular low-dose aspirin use.[23] Additionally, significantly fewer patients discontinued etoricoxib because of dyspepsia than discontinued diclofenac. When interpreting these results, however, it should be considered that the primary endpoint of the MEDAL program was thrombotic cardiovascular events rather than the question of whether etoricoxib limits gastrointestinal toxicity.

An alternative therapeutic approach to COX2 inhibitors is co-therapy with proton-pump inhibitors, which can prevent peptic ulcers in high-risk patients using NSAIDs.[24,25] This combination, however, does not provide protection against damage caused by NSAIDs in the lower gastrointestinal tract. NSAIDs frequently cause small bowel inflammation: a study using wireless capsule enteroscopy[26] showed that NSAIDs taken even on a short-term basis (i.e. 2 weeks' administration of slow-release diclofenac) can cause macroscopic injury to the small intestine in 68–75% of volunteers. In a double-blind, placebo-controlled trial using capsule endoscopy,[27] celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole.


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