Lumiracoxib May Be Useful for Osteoarthritis Without Worsening Cardiac Risk

Laurie Barclay, MD

August 20, 2004

Aug. 20, 2004 — Lumiracoxib may be useful for osteoarthritis without worsening cardiac risk, according to two reports of the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) published in the Aug. 21 issue of The Lancet. However, the editorialists advocate a cautious consideration of risks and benefits.

Although cyclooxygenase 2 (COX-2)-selective inhibitors should theoretically reduce ulcer complications compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), evidence is limited and raises the possibility that COX-2 inhibitors could increase the risk of cardiovascular events.

After stratification for low-dose aspirin use and age, 18,325 patients with osteoarthritis, aged 50 years or older, were randomized to lumiracoxib 400 mg once daily (n = 9,156), naproxen 500 mg twice daily (n = 4,754), or ibuprofen 800 mg three times daily (n = 4,415) in two substudies of identical design (lumiracoxib vs. ibuprofen or naproxen). Of the randomized patients, 81 (0.44%) did not begin treatment, and 7,120 (39%) did not complete the 52-week study.

The primary end point was the difference in time to upper gastrointestinal ulcer complications, including bleeding, perforation, or obstruction; and the Antiplatelet Trialists' Collaboration end point of myocardial infarction, stroke, or cardiovascular death was the main measure of adverse cardiovascular events.

In patients not taking aspirin, the cumulative one-year incidence of ulcer complications was 1.09% (95% confidence interval [CI], 0.82 - 1.36) with NSAIDs (64 events), and 0.25% (95% CI, 0.12 - 0.39) with lumiracoxib (14 events; hazard ratio [HR], 0.21 [95% CI, 0.12 - 0.37]; P < .0001). Reductions in ulcer complications with lumiracoxib were also significant in the overall population (HR, 0.34 [95% CI, 0.22 - 0.52]; P < .0001), but not in those taking aspirin (HR, 0.79 [95% CI, 0.40 - 1.55]; P = .4876).

In the overall population, there was no significant difference in cardiovascular events between those receiving NSAIDs (0.55% [50 of 9,127] and in those receiving lumiracoxib (0.65% [59 of 9,117]; HR, 1.14 [95% CI, 0.78 - 1.66]; P = .5074).

"Lumiracoxib showed a three- to fourfold reduction in ulcer complications compared with NSAIDs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis," coauthor Michael Doherty, from the University of Nottingham in the U.K., says in a news release.

Novartis Pharma AG, manufacturer of lumiracoxib, supported this study and employs several of its authors. Some of the authors also report financial arrangements with AstraZeneca, Berlex, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Nitromed, Novartis, Pfizer, Sanofi-Synthelabo, Takeda, and/or Wyeth.

The second report of cardiovascular outcomes in TARGET also showed that the incidence of nonfatal and silent myocardial infarction, stroke, or cardiovascular death was low in the patient population and was not statistically significantly different between treatment groups or when analyzed by aspirin use, age, sex, high cardiovascular risk, or cerebrovascular history.

"The fact that we enrolled osteoarthritis patients in the study who already had high blood pressure or other risk factors for coronary heart disease was important," says lead author Michael E. Farkouh, from New York University School of Medicine in New York City.

At one-year follow-up, incidence of the primary end point of nonfatal and silent myocardial infarction, stroke, or cardiovascular death was 0.65% for lumiracoxib (59 events) and 0.55% for NSAIDs (50 events; HR, 1.14; 95% CI, 0.78 - 1.66; P = .5074).

In the naproxen substudy, the incidence of clinical and silent myocardial infarction in the overall population was 0.38% with lumiracoxib (18 events) and 0.21% with naproxen (10 events). Rates of clinical and silent myocardial infarction did not differ significantly between groups in the subgroup not taking low-dose aspirin (HR, 2.37; 95% CI, 0.74 - 7.55; P = .1454), overall (HR, 1.77; 95% CI, 0.82 - 3.84; P = .1471), and in the subgroup taking aspirin (HR, 1.36; 95% CI, 0.47 - 3.93; P = .5658).

In the ibuprofen substudy, the incidence of clinical and silent myocardial infarction in the overall population was 0.11% with lumiracoxib (five events) and 0.16% with ibuprofen (seven events). Rates were not significantly different between lumiracoxib and ibuprofen in the subgroup not taking low-dose aspirin (HR, 0.75; 95% CI, 0.20 - 2.79; P = .6669), overall (HR, 0.66; 95% CI, 0.21 - 2.09; P = .4833), and in the subgroup taking aspirin (HR, 0.47; 95% CI, 0.04 - 5.14; P = .5328).

"The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use," the authors write. "This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low dose aspirin."

In the second report, some of the authors report financial arrangements with Arginox, Berlex, Novartis, Wyeth, Sanofi-Synthelabo, Bristol-Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, ONO, Fujisawa, Janssen, Forest, Solvay, ESP Pharma, Bayer AG, Roche, Eli Lilly, Pharmacia Upjohn, Merck, AAI Pharma, GlaxoSmithKline, McNeil Consumer Healthcare, Winston, Ortho-McNeil, Amgen, Arakis, Aventis Pharmaceutical, Genzyme, Laboratories NEGMA, Procter and Gamble Pharmaceutical, Purdue Pharma, Scios, Takeda Pharmaceuticals North America, and/or Johnson & Johnson.

In an accompanying commentary, Eric J. Topol and Gary W. Falk, from the Cleveland Clinic Foundation in Ohio, put in context the overall low frequency of myocardial events in TARGET. Nearly all patients with myocardial infarction, stroke, coronary artery bypass surgery, or congestive heart failure were excluded, and less than 2% had a previous myocardial infarction or a revascularization procedure.

"Unfortunately, this trial, like all others in the clinical development of coxibs, purposefully excluded patients with known and significant pre-existing coronary artery disease," Dr. Topol and Falk write.

They also point out that compared with naproxen alone, lumiracoxib is associated with increased risk of liver toxicity and myocardial infarction. For patients not taking aspirin, there is an absolute reduction with lumiracoxib of 0.72% in ulcer complications, but there is also an excess of 2.0% in liver function test abnormalities. If naproxen is the comparative NSAID, lumiracoxib is also associated with a 0.17% excess of myocardial infarction.

"TARGET quantifies lumiracoxib's narrow benefit over two NSAIDs with a trade-off," Drs. Topol and Falk write. "For patients taking low-dose aspirin, it is hard to justify the coxib: there is no benefit in ulcer complication reduction, but the risks of myocardial infarction and hepatotoxicity persist."

Dr. Falk is a consultant to AstraZeneca; Dr. Topol reports no financial conflict of interest.

Lancet. 2004;364:639-640, 665-674, 675-684

Reviewed by Gary D. Vogin, MD

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