Elsevier

The Lancet

Volume 364, Issue 9435, 21–27 August 2004, Pages 665-674
The Lancet

Articles
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)16893-1Get rights and content

Summary

Background

Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce ulcer complications compared with non-selective non-steroidal anti-inflammatory drugs, but evidence is limited, and the possibility that these inhibitors increase cardiovascular events has been raised. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.

Methods

18 325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) for 52 weeks, in two substudies of identical design (lumiracoxib vs ibuprofen or naproxen). Randomisation was stratified for low-dose aspirin use and age. The primary endpoint was the difference in time-to-event distribution of upper gastrointestinal ulcer complications (bleeding, perforation, or obstruction); analysis was by modified intention to treat. The principle measure of adverse cardiovascular events was the Antiplatelet Trialists' Collaboration endpoint (myocardial infarction, stroke, or cardiovascular death); this analysis was intention to treat.

Findings

81 (0·44%) patients did not start treatment and 7120 (39%) did not complete the study. In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1·09% (95% CI 0·82–1·36) with non-steroidal anti-inflammatory drugs (64 events) versus 0·25% (95% CI 0·12–0·39) with lumiracoxib (14 events; hazard ratio 0·21 [95% CI 0·12–0·37], p<0·0001). Reductions in ulcer complications were also significant in the overall population (0·34 [0·22–0·52], p<0·0001) but not in those taking aspirin (0·79 [0·40–1·55], p=0·4876). In the overall population, 0·55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0·65% (59/9117) of those on lumiracoxib reached the cardiovascular endpoint (1·14 [0·78–1·66], p=0·5074).

Interpretation

Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with non-steroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis.

Introduction

Non-selective non-steroidal anti-inflammatory drugs are widely used by patients with acute or chronic pain due to osteoarthritis and rheumatoid arthritis.1, 2, 3 Unfortunately, people taking these drugs are at increased risk for incurring clinically important damage to the mucosa of the gastrointestinal tract.4 Estimates suggest that non-steroidal anti-inflammatory drugs lead to admission for ulcer complications (bleeding and perforation) in 0·25–1·58% of users per year5, 6 and result in at least 7000 deaths annually in the USA6 and 1000 deaths every year in the UK.7 Therefore, development of drugs that reduce or abolish these gastrointestinal side-effects is important. Selective inhibitors of the inducible cyclo-oxygenase 2 (COX2) enzyme might reduce this burden.8

To date, two groups of investigators have attempted to show a reduction in serious gastrointestinal outcomes with COX2-selective inhibitors compared with non-selective non-steroidal anti-inflammatory drugs.9, 10 Both studies were of similar size (about 8000 patients) but differed in several ways—eg, the endpoints.11 The Celecoxib Long-term Arthritis Safety Study (CLASS)9, 12 compared celecoxib with either ibuprofen or diclofenac in patients with osteoarthritis or rheumatoid arthritis and failed to show a significant benefit for celecoxib for the primary endpoint of upper gastrointestinal ulcer complications for the full duration of the study. The Vioxx GI Outcomes Research (VIGOR) study10 compared rofecoxib with naproxen in patients with rheumatoid arthritis and showed a significant benefit for rofecoxib for the broader primary endpoint of clinical upper gastrointestinal events (defined as symptomatic upper gastrointestinal ulcers and ulcer complications [perforations, ulcers, and bleeds]).

Patients receiving low-dose aspirin were excluded from VIGOR,10 so the effect of concomitant low-dose aspirin and rofecoxib on gastrointestinal outcomes could not be ascertained. Nevertheless, findings of a 12-week endoscopy study showed that the incidence of gastroduodenal ulcers in individuals taking low-dose aspirin and rofecoxib was similar to that in patients taking ibuprofen (800 mg three times daily) alone.13 The exclusion of low-dose aspirin use in the VIGOR study10 could have contributed to a much higher rate of cardiovascular thrombotic events, particularly myocardial infarctions, in patients taking rofecoxib compared with those taking naproxen. Unanswered is whether the increase in thrombotic events happened by chance; whether it represented a beneficial (antithrombotic) effect of naproxen, a harmful effect of rofecoxib, or a combination of all three; and whether the differences were specific to rofecoxib or related to comparisons between naproxen and COX2 inhibitors as a class of drugs.14 These issues remain unresolved.

Lumiracoxib is a novel COX2-selective inhibitor that differs structurally from other drugs in the class.15, 16 The other inhibitors contain a tricyclic ring and a sulfone or sulfonamide group,17 whereas lumiracoxib is a phenyl acetic acid derivative with a pKa of 4·7.16 It has the highest selectivity and a fairly short plasma half-life (3–6 h) compared with other COX2-selective inhibitors.18 The effectiveness of lumiracoxib is superior to placebo in patients with osteoarthritis at doses of 100 mg and 200 mg once daily.19, 20 In endoscopic studies, this drug has been associated with a rate of acute gastric injury and chronic ulcer formation that does not differ from placebo21 and is significantly lower than with the non-selective non-steroidal anti-inflammatory ibuprofen.22, 23

To establish the gastrointestinal safety of lumiracoxib, the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) was planned to test the hypothesis that patients with osteoarthritis, randomised to lumiracoxib at two or four times the recommended dose for osteoarthritis, had significantly fewer complicated ulcers than patients randomised to either ibuprofen or naproxen at the therapeutic dose. To address the issues raised as a result of previous studies, TARGET was, by design, much larger than the CLASS and VIGOR outcome trials.

Section snippets

Patients and methods

Details of the methodology and implementation of the TARGET study have been published elsewhere24 and are summarised briefly here.

Results

figure 1 and table 1 and table 2 show the disposition of patients included in the study. All demographic variables were comparable across the treatment groups and within the two substudies, with two notable differences. The substudy that compared naproxen with lumiracoxib included more patients with cardiovascular risk factors and evidence of Helicobacter pyloriinfection by positive serology than did the substudy that compared ibuprofen with lumiracoxib.

Compliance was similar between

Discussion

The results of the TARGET study show a 79% reduction in ulcer complications in patients taking lumiracoxib compared with two frequently used anti-inflammatory drugs in a non-aspirin population. Similar reductions were noted when lumiracoxib was compared individually with ibuprofen (83% reduction) or naproxen (76% reduction). These overall three to four-fold proportional differences are very similar to findings of endoscopic studies.22, 23 Results of epidemiological studies suggest non-steroidal

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