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Cardiac Risk With COX-2 and NSAID Drugs

Not all of these drugs impart the same level of risk


Updated November 13, 2011

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

As anyone who has been reading the papers for the last few years knows, COX-2 drugs - a group of non-steroidal anti-inflammatory drugs (NSAIDs) commonly used to treat inflammation and pain - have been associated with an increased incidence of heart attack and other cardiovascular events. Most notably, the drug company Merck has been in the papers frequently since 2004 for one lawsuit or another associated with its COX-2 drug Vioxx (rofecoxib). Furthermore, studies have have suggested that it's not only the COX-2 drugs that are a problem, and that even the older NSAIDs may pose increased cardiac risk. (Technically, COX-2 drugs are a sub-category of NSAIDs.)

An analysis of available data from several studies now strongly suggests that most NSAIDs, whether a COX-2 drug or not, worsen cardiac outcomes in people who have heart disease or have increased risk for heart disease. But these drugs are not all equally dangerous. In fact, one drug -- naproxen (Aleve, Naprosyn) -- may not increase cardiac risk at all.

An observational study published in 2009 retrospectively analyzed the use of NSAIDs in more than 48,000 patients with coronary artery disease, and another published in 2010 examined the use of NSAIDs in 2.5 million apparently healthy people in Denmark. While neither of these large studies was a randomized trial (a randomized trial looking at cardiovascular risk with NSAIDs is expected to be reported some time in 2011), both showed nearly the same thing. Based on these trials, the following generalizations can be made:

Drugs that seem very likely to increase risk: Vioxx, ibuprofen (Advil, Motrin), Voltaren (diclofenac), Indocin (indomethacin), and Mobic (meloxicam). Of these drugs, it appears at this point that Voltaren (interestingly, not a COX-2 drug) may increase cardiac risk more than the others.

Drugs that may increase risk: Celebrex (celecoxib). (Some data suggests that, while Celebrex probably increases cardiac risk at high doses, at more routine doses -- up to 200 mg/day -- there is relatively little evidence for increased risk.)

Drugs that may not increase risk: Naproxen.

Given all the publicity that COX-2 drugs have received, and especially because Vioxx was taken off the market because of presumed cardiac risk, it is at least a little bit interesting that some of the older, more commonly-used NSAIDs now appear to increase risk nearly as much, if not more.

The bottom line is that, until randomized trials are completed -- which should offer more definitive evidence as to the magnitude of cardiac risk with NSAIDs -- naproxen is probably the best choice if a NSAID is needed when cardiovascular risk is a concern.


Fosbøl EL, Folke F, Jacobsen S, et al. Cause-specific CV risk associated with NSAIDs among healthy individuals. Circ Cardiovasc Qual Outcomes 2010; DOI:10.1161/CIRCOUTCOMES.109.861104.

Graham DJ. COX-2 Inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense. JAMA2006; DOI:10.1001/JAMA.296.13.jed60058. See: http://www.jama.com.

Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes 2009; 2:155-163.

McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase-2. JAMA2006; DOI: 10.1001/JAMA.296.13.jrv60011. See: http://www.jama.com.

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