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Cardiovascular Effects of COX-2 Inhibitors: The Jury's Still Out

TARGET results echo those of VIGOR -- fewer adverse gastrointestinal events, but slightly more myocardial infarctions, among arthritis patients assigned to COX-2 inhibitors than among those assigned to NSAIDs.

Controversy persists about the risks and benefits of cyclooxygenase (COX)-2-inhibitor therapy. In the Vioxx GI Outcomes Research (VIGOR) study (Journal Watch Dec 8 2000), patients with rheumatoid arthritis who received rofecoxib had significantly fewer upper gastrointestinal events -- but more myocardial infarctions -- than did comparable patients who received naproxen. Whether the difference in MI incidence was attributable to harmful effects of rofecoxib, cardioprotective effects of naproxen, or other factors was unclear.

In the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), researchers addressed this uncertainty by using lumiracoxib, a highly selective COX-2 inhibitor that has been approved in the U.K. but not yet in the U.S. TARGET was financed and partially conducted by the manufacturer of lumiracoxib. Investigators randomized 18,325 patients (age, >50) with osteoarthritis to lumiracoxib (400 mg daily), naproxen (500 mg twice daily), or ibuprofen (800 mg thrice daily) for 52 weeks. Randomization was stratified by age and current aspirin use.

Among patients who didn't take low-dose aspirin, the lumiracoxib group experienced significantly fewer ulcer complications than did the naproxen or ibuprofen groups; however, among patients who did take low-dose aspirin, no significant differences were found in ulcer complications among the groups. The ibuprofen group and the lumiracoxib group had similar incidences of the combined cardiovascular endpoint (MI, stroke, and cardiovascular death). Compared with naproxen patients, lumiracoxib patients exhibited a trend toward more MIs, which was particularly noticeable in the no-aspirin subgroup, but these differences were not statistically significant. A significant increase from baseline in liver enzyme abnormalities was seen in the lumiracoxib group, but very few cases of drug-induced clinical hepatitis were diagnosed in any group.

Comment: TARGET results confirm earlier evidence that ulcer complications occur less often with COX-2 inhibitors than with other nonsteroidal anti-inflammatory drugs (NSAIDs), but that advantage is not significant in patients who also take low-dose aspirin. The trend toward more MIs with lumiracoxib than with naproxen echoes the findings of the VIGOR trial, but the meaning of this finding remains elusive. Otherwise, lumiracoxib did not seem to be prothrombotic (no increase in deep-vein thromboses was noted, for example), nor has evidence shown that naproxen is antithrombotic. An editorialist points out that patients at highest risk for cardiovascular events were excluded from the study and that the trial was not powered to detect clinically significant differences in rates of MI. For the many patients with arthritis and cardiovascular risk factors, the questions surrounding the safety of COX-2 inhibitors remain unresolved. For patients who take low-dose aspirin, we have little reason to prescribe COX-2 inhibitors over less expensive NSAIDs.

— Bruce Soloway, MD

Published in Journal Watch General Medicine September 17, 2004

Citation(s):

Schnitzer TJ et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: Randomised controlled trial. Lancet 2004 Aug 21; 364:665-74.

• Medline abstract (Free)

Farkouh ME et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: Randomised controlled trial. Lancet 2004 Aug 21; 364:675-84.

• Medline abstract (Free)

Topol EJ and Falk GW. A coxib a day won't keep the doctor away. Lancet 2004 Aug 21; 364:639-40.

• Medline abstract (Free)