New York, NY - A new analysis of the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) has shown that ibuprofen, relative to the COX-2 inhibitor lumiracoxib (Prexige, Novartis Pharmaceuticals), increases the risk of thrombotic and congestive heart failure events among high-cardiovascular-risk patients with osteoarthritis currently taking aspirin [1]. The results, say investigators, are consistent with the ability of ibuprofen to interfere with the effects of aspirin on platelet aggregation.

"In this group of high-risk patients, when we look specifically at those taking aspirin in the lumiracoxib-vs-ibuprofen study arm, patients treated with ibuprofen have a significantly higher risk for myocardial infarction, whereas in the lumiracoxib and naproxen comparison there are very similar outcomes with both treatments," lead investigator Dr Michael Farkouh (Mount Sinai School of Medicine, New York, NY) told heartwire. "Interestingly, in the group not taking aspirin, lumiracoxib and ibuprofen behaved almost identically. We believe that this is an example, the first time in a randomized trial, that demonstrates that there is a potential interaction between ibuprofen and aspirin and that it does have clinical ramifications."

The results of the TARGET analysis are published online April 5, 2007 in the Annals of the Rheumatic Diseases.

TARGET investigators randomized 18 325 patients who were 50 years or older with osteoarthritis to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (n=4754), or ibuprofen 800 mg three times daily (n=4415) in two substudies of identical design. Approximately one quarter of the patients in TARGET were taking low-dose aspirin for cardiovascular prophylaxis. The primary cardiovascular end point was nonfatal and silent MI, stroke, or cardiovascular death.

Study results, published in 2004 [2], and previously reported by heartwire, showed no difference in the incidence of MI between lumiracoxib and the two comparator nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen and ibuprofen, in patients with osteoarthritis. This most recent analysis sought to determine cardiovascular outcomes in high-risk patients—specifically those with previous MI, stroke, diabetes, or additional risk factors—with osteoarthritis treated with ibuprofen, naproxen, or lumiracoxib.

Overall, 3042 patients met the definition of high cardiovascular risk. Of these, 1699 patients were in the naproxen substudy and 1343 were in the ibuprofen substudy. Approximately 60% in both study arms were taking low-dose aspirin for cardiovascular protection.

In high-risk patients taking aspirin, patients in the ibuprofen study arm had more primary events than those taking lumiracoxib, whereas event rates were similar among patients taking naproxen and those taking lumiracoxib. High-risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib, but there was no difference between those taking ibuprofen and those taking the COX-2 inhibitor.

In addition to these outcomes, investigators found that congestive heart failure developed more often with ibuprofen than with lumiracoxib, but there was no difference in the naproxen and lumiracoxib users in the naproxen substudy.

"We think that ibuprofen should be avoided in high-risk cardiovascular patients," said Farkouh. "Second, to reiterate what the American Heart Association guidelines outline, we think all NSAIDs should be given at their lowest dose and at the least frequency."

Because of the nature of post hoc analyses, Farkouh cautioned that the results should be considered hypothesis generating. He said that given the continued debate about the cardiovascular safety of nonselective NSAIDs and COX-2 inhibitors, research focusing on patients at high cardiovascular risk and on interactions with aspirin is needed. One such trial currently underway is the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION), a 20 000-patient trial assessing the safety of pain relievers in osteoarthritis patients with coronary artery disease or multiple risk factors for heart disease.