A review of widely used nonsteroidal anti-inflammatory drugs (NSAIDs) suggests naproxen and low-dose ibuprofen are least likely to raise cardiovascular risk, whereas diclofenac in doses available without a prescription heightens risk.

Researchers reviewed 30 case-control studies involving 184,946 cardiovascular events and 21 cohort studies that described outcomes in more than 2.7 million exposed individuals. Of the extensively studied drugs, the highest overall risks were seen with rofecoxib, with a relative risk (RR) of 1.45, and diclofenac, with an RR of 1.40. 

Ibuprofen (1.18) and naproxen (1.09) had the lowest risks, with both appearing to be free of risk at lower doses. Ibuprofen risk was seen only with higher doses, and naproxen was risk-neutral at all doses. (The majority of ibuprofen studies defined high doses as >1,200 mg/day; above that point, the drug doubled the risk of cardiovascular events.) 

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“The data here suggest that naproxen is superior to ibuprofen in terms of cardiovascular safety,” the researchers wrote. “This is the first evidence to show a significant difference between these two drugs.”

Diclofenac was associated with a statistically significant 22% increase in risk at low doses. In pair-wise analyses, celecoxib was indistinguishable from naproxen, but overall, celecoxib was associated with statistically significant risk increases. 

While calling naproxen the safest NSAID choice for patients at high risk of cardiovascular events, the authors acknowledged that its advantage over ibuprofen and celecoxib is small and must be balanced with GI risks. 

McGettigan P, Henry D. PLoS Med. 2011;8: e1001098.