Ibuprofen Cancels Heart Benefit of Aspirin

NEW YORK, April 5 -- When low-dose aspirin is taken for cardiovascular risk reduction and ibuprofen for the pain of osteoarthritis, the heart is the loser, found investigators here.

Among osteoarthritis patients with a high risk for cardiovascular events, ibuprofen (Advil, Motrin) taken on top of daily aspirin was associated with an increased relative risk of thrombotic events and congestive heart failure, said Michael E. Farkouh, M.D., MSc., of the Mount Sinai Cardiovascular Institute.

In the high-risk patients the aspirin-ibuprofen regimen was associated with 2.14% primary cardiovascular event rate versus a 0.25% rate among patients taking lumiracoxib, an investigational selective Cox-2 inhibitor, and aspirin (P=0.038).

That finding, published online ahead of print in the Annals of Rheumatic Diseases, emerged from a post-hoc analysis of data from the 18,325-patient TARGET (Therapeutic Arthritis Research and Gastrointestinal Event Trial).

The ibuprofen finding, the authors wrote, supports earlier studies that suggested ibuprofen blocks aspirin-mediated inhibition of platelet aggregation, negating aspirin's ability to reduce the risk of thrombotic events.

Moreover, high-risk patients taking ibuprofen were also more likely to develop congestive heart failure compared with patients taking lumiracoxib (1.28% versus 0.34%, P=0.031).

Among high-risk patients who didn't use aspirin, there was no significant difference in the composite endpoint of thrombotic and congestive heart failure events between ibuprofen and lumiracoxib, he said.

By contrast, in a parallel trial that compared naproxen to lumiracoxib, high risk patients using naproxen but no low-dose aspirin had no events versus an event rate of 1.57% among patients using the Cox-2 inhibitor and without aspirin prophylaxis (P=0.027).

Among high-risk patients taking aspirin and naproxen, the event rate was 1.58% versus 1.48% for those taking lumiracoxib plus aspirin (P=0.899).

"These findings, although limited by the post hoc design of the study, and the small number of events in the subgroups of interest, suggest that caution is warranted in prescribing ibuprofen to high risk patients," the authors wrote.

TARGET was comprised of parallel substudies that compared lumiracoxib to either naproxen or ibuprofen. The post hoc analysis was performed by baseline cardiovascular risk, study treatment, and low-dose aspirin use.

The post hoc analysis identified 3,042 TARGET patients who were also at high risk for cardiovascular events and 15,283 who were low-risk. Fifty-six percent of the high-risk patients were in the study that compared naproxen and lumiracoxib and 44% were in the ibuprofen versus lumiracoxib study.

The ibuprofen substudy, however, included "a significantly higher number of patients with diabetes and dyslipidemia but a lower number of patients with a history of cerebrovascular or cardiovascular disease than the naproxen substudy (P<0.0001 for all comparisons)," the authors wrote.

In addition to the finding that ibuprofen use was associated with increased cardiovascular events, the study also found that naproxen at a daily dose of 500 mg demonstrated "relative cardiovascular safety" compared with 400 mg of lumiracoxib.

The authors noted that it is still not clear whether naproxen has cardioprotective effects, but among high-risk patients in this analysis, naproxen had the lowest cardiovascular risk of three drugs studied.

Because the study was a post hoc subgroup analysis, it "should be interpreted as a hypothesis-generative study," the authors wrote. They pointed out the possibility of type 1 errors due to the multiple comparisons made in the study and also pointed out that the incidence of cardiovascular events was low in both the low and high risk subgroups, thereby affecting the power of the analyses.

Additionally, because TARGET was a 12-month trial, the findings may not reflect long-term cardiovascular risks that have been reported for both non-selective NSAIDs such as naproxen and Cox-2 inhibitors such as lumiracoxib.