Reports cite cardiovascular risks of COX 2 inhibitors and NSAIDs New York Janice Hopkins Tanne Cyclo-oxygenase-2 (COX 2) inhibitors and some other non-steroidal anti-inflammatory drugs (NSAIDs) may present cardiovascular and renal risks, say two papers published online ahead of print publication in JAMA. And an accompanying editorial by David Graham, a Food and Drug Administration employee and whistleblower, criticises studies of COX 2 inhibitors and expresses hope that “the FDA’s concerns will now be squarely focused on patient safety rather than corporate profitability.” A meta-analysis of 23 studies by researchers from the University of Newcastle, New South Wales, published online on 12 September (http://jama.ama-assn.org/, doi: 10.1001/jama.296.13.jrv60011), found that the risk of cardiovascular events was higher with rofecoxib than with celecoxib, the only COX 2 inhibitor still on the market in the United States. The studies involved 75 520 users of COX 2 inhibitors, 375 619 users of NSAIDS, and 594 720 non-users. The authors report that a higher risk was evident with rofecoxib, when compared directly with celecoxib (relative risk 1.34 (95% confidence interval 1.14 to 1.56)). When compared with other NSAIDS (including diclofenac, indometacin, or both), naproxen was shown to have a lower risk of cardiovascular complications (relative risk 0.75 (0.63 to 0.88)). The difference in risk appeared within the first 30 days of use, they say. Celecoxib at doses of about 200 mg a day was not associated with a higher risk of myocardial infarction, but doses above 400 mg a day seemed to be “unsafe.” The researchers found that naproxen did not lower the risk of myocardial infarction, as had been indicated by an earlier study (New England Journal of Medicine 2000;343:1520-8). Diclofenac, another NSAID, increased the risk to a similar degree as rofecoxib did and “appears to be harmful at commonly used doses.” Indometacin also increased the risk of cardiovascular events, the authors say. The second study, from authors at Harvard, and also published online on 12 September (http://jama.ama-assn.org/, doi: 10.1001/jama.296.13/jrv60015), analysed 114 randomised, double blind clinical trials involving 116 094 participants who were using either rofecoxib, celecoxib, valdecoxib with parecoxib, etoricoxib, or lumiracoxib. They found that rofecoxib “was associated with increased renal and arrhythmia risks” and that “a COX 2 inhibitor class effect was not evident.” These authors say that their study was the first to note a higher risk of arrhythmia with rofecoxib, which might be related to “disturbance of electrolyte balance, especially hyperkalemia.” They call for increased safety monitoring. In the accompanying editorial Dr Graham, who gave evidence to a Senate committee about the drug in 2004 (BMJ 2004;329:1253), writes, “The allure of COX-2 inhibitors was the prospect of treating pain without gastrointestinal toxicity” (doi: 10.1001/jama.296.13.jed60058). He says that lurking in the background was the worry that COX 2 inhibition would leave COX 1 activity unopposed, favouring vasoconstriction, platelet aggregation, and thrombosis. An FDA official noticed safety problems in early studies of COX 2 inhibitors, and the increased risk of cardiovascular events appeared within months of the FDA’s approval of rofecoxib—in the Vioxx gastrointestinal outcomes research trial (VIGOR)—but the drug’s labelling remained unchanged for nearly two years. Rofecoxib’s heavy marketing claimed that it did not increase the risk of myocardial infarction. Merck withdrew rofecoxib from the market in 2004. Dr Graham writes, “What does all this mean? First, rofecoxib increased the risk of acute MI at low and high doses. This risk begins early in therapy … There is no initial 18-month period of immunity from risk. Celecoxib also increases risk at doses higher than 200 mg/day.” He continued, “Several other NSAIDS increase risk, including the COX-2 selective NSAIDS diclofenac and meloxicam, and the non-selective NSAID indomethacin, and probably ibuprofen … naproxen is neutral for MI risk … For most patients with arthritis or other conditions who require chronic pain relief, naproxen appears to be the safest NSAID choice from a cardiovascular perspective.” Dr Graham says that until Congress enacts legislation to create a separate and independent centre at the FDA to monitor post-marketing safety, patients may continue to be harmed by drugs whose safety problems have been ignored. The FDA must focus on patients’ safety rather than corporate profitability, he wrote.