Fast track — ArticlesCardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in the world and are often taken long term by patients with osteoarthritis and rheumatoid arthritis. A major factor limiting use of NSAIDs is concern for the development of gastrointestinal complications such as bleeding. Cyclo-oxygenase-2 (COX-2) selective inhibitors were developed to decrease the risk of gastrointestinal tract injury and avoid the anti-platelet effect of traditional NSAIDs, and large outcome trials have shown a decrease in upper gastrointestinal complications with COX-2 selective inhibitors as compared with traditional NSAIDs.1, 2, 3 However, randomised trials have shown an increased risk of thrombotic cardiovascular events with COX-2 selective inhibitors compared with placebo.4, 5, 6, 7, 8 Comparable long-term, placebo-controlled trials in patients with arthritis assessing the risk of thrombotic cardiovascular events with traditional NSAIDs are not available, although results of observational studies suggest that some traditional NSAIDs (eg, diclofenac, ibuprofen) also increase cardiovascular risk compared with no NSAID therapy.9, 10, 11 These safety data for COX-2 selective inhibitors and traditional NSAIDs raise concerns for patients with arthritis taking NSAIDs long term, and add a new element to decisions about the choice of therapy in these patients. Large, long-term prospective trials specifically designed to assess the cardiovascular risk with different agents have been called for to help inform these choices.12, 13 We designed the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long Term) programme to assess the relative cardiovascular safety of two long-term anti-inflammatory treatments for patients with osteoarthritis and rheumatoid arthritis.14 The aim was to estimate precisely the relative risk of thrombotic cardiovascular events with etoricoxib compared with the widely used traditional NSAID diclofenac, using a non-inferiority trial design. We sought to study a broad range of patients to simulate the general population of individuals with arthritis, enrolling patients with a range of cardiovascular risk factors (including pre-existing cardiovascular disease) and gastrointestinal risk factors.
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Study design and patients
The design of the MEDAL programme has been presented in detail elsewhere.14 In brief, this study was done between June, 2002, and May, 2006, at 1 380 sites in 46 countries. The MEDAL programme was prospectively designed to pool data from three randomised, double-blind clinical trials: the MEDAL study, the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) study, and the EDGE II study. Similar entry criteria, including the same diseases and doses, across
Results
Figure 1 shows the overall trial profile for the 34 701 patients in the MEDAL programme. 23 504 patients were randomised in the MEDAL study, 7111 in EDGE, and 4086 in EDGE II, including 24 913 (72%) patients with osteoarthritis and 9 787 (28%) with rheumatoid arthritis. Baseline characteristics were similar in both treatment groups (table 1). 14 396 (41%) patients were aged 65 years or older; 3665 (11%) had diabetes; 10 131 (29%) had dyslipidaemia; 16 330 (47%) had hypertension; 4024 (12%) had
Discussion
Our results show that patients with arthritis treated with the COX-2 selective NSAID etoricoxib and those given the traditional NSAID diclofenac have nearly identical rates of thrombotic cardiovascular events. The robustness of this finding was supported by consistency of results across several prespecified analyses. Furthermore, the similarity in rates was consistent across all subgroups assessed. The results of subgroup analyses suggest that cardiovascular risk factors and low-dose aspirin
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