Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial.
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
18325 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.


RESULTS
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).


CONCLUSIONS
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.
Schnitzer
Thomas J
TJ
Office of Clinical Research and Training, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Burmester
Gerd R
GR
Mysler
Eduardo
E
Hochberg
Marc C
MC
Doherty
Michael
M
Ehrsam
Elena
E
Gitton
Xavier
X
Krammer
Gerhard
G
Mellein
Bernhard
B
Matchaba
Patrice
P
Gimona
Alberto
A
Hawkey
Christopher J
CJ
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D004008:Diclofenac / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects* / Q000627:therapeutic use; D009930:Organic Chemicals / Q000009:adverse effects* / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy*; D010438:Peptic Ulcer Hemorrhage / Q000139:chemically induced*; D010439:Peptic Ulcer Perforation / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009930:Organic Chemicals; D004008:Diclofenac; D009288:Naproxen; D001241:Aspirin; C473384:lumiracoxib; D007052:Ibuprofen