Elsevier

The Lancet

Volume 369, Issue 9560, 10–16 February 2007, Pages 465-473
The Lancet

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Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

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Summary

Background

Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy.

Methods

A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with ClinicalTrials.gov, with the numbers NCT00092703, NCT00092742, and NCT00250445.

Findings

Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio [HR] 0·69, 95% CI 0·57–0·83; p=0·0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0·57, 0·45–0·74; p<0·0001); there was no difference in complicated events (0·91, 0·67–1·24; p=0·561). PPIs were used concomitantly for at least 75% of the study period by 13 862 (40%) and low-dose aspirin by 11 418 (33%) patients; treatment effects did not differ significantly in these individuals.

Interpretation

There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.

Introduction

Traditional non-steroidal anti-inflammatory drugs (NSAIDs) significantly increase the risk of upper gastrointestinal clinical events such as bleeding ulcers by about two to five times compared with no NSAID therapy.1 Strategies used to decrease the risk of NSAID-associated upper gastrointestinal clinical events include medical co-therapy with misoprostol or proton pump inhibitors (PPIs), or the use of cyclo-oxygenase (COX)-2 selective inhibitors.

PPIs are most frequently used as co-therapy with traditional NSAIDs,2 although no large clinical outcome studies have assessed this strategy. However, randomised trials in patients with complicated ulcers indicate that PPIs significantly decrease recurrent ulcer complications compared with Helicobacter pylori therapy in H pylori-positive patients taking naproxen3 and compared with placebo in patients taking low-dose aspirin.4

The incidences of upper gastrointestinal clinical events have been shown to be significantly less with COX-2 selective inhibitors than traditional NSAIDs in randomised gastrointestinal outcomes trials of 12 weeks to 12 months duration.5, 6, 7, 8 However, none of these trials simulated real-world practice because gastrointestinal protective therapies—eg, PPIs—were not allowed. Thus, the effect of COX-2 selective inhibitors versus traditional NSAIDs in patients taking PPIs is unknown.

Another area of controversy relates to the use of COX-2 selective inhibitors plus low-dose aspirin. Endoscopic trials indicate that the combination of a COX-2 selective NSAID and low-dose aspirin has an ulcer incidence comparable with a traditional NSAID,9 but still lower than the rate with a traditional NSAID plus low-dose aspirin.10, 11 An observational cohort study reported a significantly lower rate of upper gastrointestinal complications with COX-2 selective inhibitors than with traditional NSAIDs in low-dose aspirin users.12 However, subgroup analyses from randomised outcomes trials of COX-2 selective inhibitors versus traditional NSAIDs have not identified significant reductions in upper gastrointestinal clinical events with low-dose aspirin use.5, 7, 8

Although upper gastrointestinal clinical events raise greater concern among physicians, upper gastrointestinal symptoms such as dyspepsia are the most common side-effects that occur with NSAID use. Dyspepsia is reported weekly in up to about 30% of patients taking NSAIDs regularly, and in up to 15% daily.13 Furthermore, dyspepsia is the most common reason for discontinuation of NSAID therapy.14 Among patients without ulcers, PPIs have shown significant benefit in relief or prevention of NSAID-associated upper gastrointestinal symptoms.15, 16, 17 COX-2 selective inhibitors have also been reported to induce less dyspepsia than traditional NSAIDs.18, 19, 20, 21, 22 However, the relative benefit of traditional NSAIDs versus COX-2 selective inhibitors on upper gastrointestinal symptoms in PPI users has not been studied in a clinical trial.

The MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) programme provides a randomised comparison of the COX-2 selective inhibitor etoricoxib and the traditional NSAID diclofenac in 34 701 osteoarthritis and rheumatoid arthritis patients followed for a mean duration of 18 months.23, 24 The primary endpoint was thrombotic cardiovascular events, but upper gastrointestinal clinical events were also a predefined endpoint. Our aim was to assess upper gastrointestinal outcomes in a setting that simulated real-world practice, in which patients with gastrointestinal risk factors were encouraged to use protective PPI therapy and those with cardiovascular risk were encouraged to use low-dose aspirin.

Section snippets

Study design and patients

The design of the MEDAL programme and the results for cardiovascular outcomes have been presented in detail elsewhere.23, 24 In brief, this study was done between June, 2002, and May, 2006, at 1380 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 vs Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) study, and the EDGE II study. Similar entry criteria and

Results

34 701 patients were enrolled in the MEDAL programme (23 504 in the MEDAL study, 7111 in EDGE, and 4086 in EDGE II), including 24 913 (72%) with osteoarthritis and 9787 (28%) with rheumatoid arthritis. Baseline characteristics were much the same in the two study groups (table 2). Etoricoxib and diclofenac had similar efficacy for treatment of arthritis as measured by global assessment of disease status and discontinuations for lack of efficacy.

The figure shows the Kaplan-Meier estimates for

Discussion

Our results indicate that the rate of clinically important upper gastrointestinal events was lower with the COX-2 selective inhibitor etoricoxib than it was with the traditional NSAID diclofenac in a broad population including patients taking PPIs for gastrointestinal protection and low-dose aspirin for cardiovascular protection. This result was driven by the lower rate of uncomplicated ulcers in those treated with etoricoxib than in those treated with diclofenac; no significant difference was

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