Most discussions of data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of lumiracoxib overlooked a major finding, Michael E. Farkouh, MD, cardiologist and lead author of TARGET, told CIAOMed. Specifically, the cardiovascular (CV) signal of lumiracoxib appeared only in subjects not taking aspirin (35 events vs 27 events; P = .43). Aspirin users experienced nearly the same number of events whether they took lumiracoxib or a traditional NSAID (24 events vs 23 events; P = .89).¹ "It looks very good when patients are on aspirin," said Dr. Farkouh, associate professor of medicine at New York University School of Medicine, New York. "People on aspirin have fewer events."

Dr. Farkouh postulated that "aspirin protects from the [CV] toxicity" of lumiracoxib. "I'm concerned about the low-[CV] risk people" taking lumiracoxib, he said. "The high-risk people are taking aspirin."

For those not on aspirin, "the risk of having an MI is slightly increased but not so high that the drug (lumiracoxib) is not safe," Dr. Farkouh noted, adding that the nonsignificant increased risk in those not using aspirin "may not be clinically important."

He pointed out that this finding "ie, that patients presumably at higher baseline CV risk due to aspirin use experienced lower CV risk with lumiracoxib" overturns conventional notions. "There are very few examples in medicine where something gets safer as you go to higher-risk groups," Dr. Farkouh said.

Evidence of lumiracoxib?s CV risk emerges only in the comparison to naproxen, he said. CV events were more common among lumiracoxib than naproxen patients, though not to a significant degree (40 events [1.1 per 100 person-years] versus 27 events [.76 per 100 person-years]; P = .13). This contrasts with the ibuprofen substudy, in which CV events were more common among those taking the traditional NSAID (ibuprofen 23 events [.74 per 100 person-years] versus lumiracoxib 19 events [.59 per 100 person-years], P = .38).

Told of Dr. Farkouh's conclusion that the CV risk with lumiracoxib applies to those not taking aspirin, Claire Bombardier, MD, professor of medicine at the University of Toronto, responded, "You can't extrapolate that" because there were too few events. "I wouldn't base my practice on that."

She also stated that the study was underpowered to detect significant differences in MI, a point supported by Leslie Crofford, MD, professor of internal medicine and chief of rheumatology at the University of Kentucky College of Medicine, Lexington. "That's what happened with all prior studies with Vioxx: too short, and not powered for CV endpoints," Dr. Crofford commented.

Lee S. Simon, MD, rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts, noted that lumiracoxib in TARGET "has a numerically associated CV signal, a low event rate, and a lot of dropouts." The safety population included all those who took at least 1 dose of study medication, but 38% to 44% of each treatment group (lumiracoxib, naproxen, ibuprofen) withdrew from therapy. "The inconsistency of this dropout rate across groups leads to an imbalance and flaws the trial," Dr. Simon said.

TARGET "did not show a CV signal in the overall population" and is therefore "reassuring at one level," said Steven B. Abramson, MD, rheumatologist and professor in the department of rheumatology/medicine at New York University School of Medicine, New York. However, in the substudy with naproxen, "naproxen did better," he indicated. Dr. Abramson also found it intriguing that ibuprofen was associated with a higher risk of CV events than was lumiracoxib in patients with CV risk factors.

Dr. Farkouh echoed the rheumatologists' hope for long-term data. "The longer [patients] are studied, the more events occur." He suggested that lumiracoxib could be approved with a 'black box' warning before long-term data are available. "I don't know if I'd hold up approval of the drug" pending longer-term studies, Dr. Farkouh said.

Reference

1. Farkouh ME, Kirshner H, Harrington RA, et al, for the TARGET study group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004;364:675-684.