Increased Cardiovascular Risk Associated With NSAID Use

Charles H. Brown, MSPharm, RPH, CACP
Published Online: Tuesday, July 10, 2012

Post-marketing data for rivaroxaban and new understandings about NSAIDs and cardiovascular disease are presented.

The reasons behind the apparent increased risk of cardiovascular events from taking the COX inhibitor class of nonsteroidal antiinflammatory drugs (NSAIDs) may finally be understood after approximately 13 years of debate. Over the past 8 years, a number of NSAIDs that inhibit COX-1 and/or COX-2 enzymes have either been removed from the US market or had boxed warnings included on their labels because of these risks.

Two recent papers from the Perelman School of Medicine at the University of Pennsylvania report how anti-inflammatory drug use is thought to lead to increased cardiovascular risk. The researchers observed that NSAIDs suppress prostacyclin synthesis in humans, as reflected by its major metabolite in urine, PGI-M. Prostacyclin’s cardioprotective properties were due to its ability to relax blood vessels and unglue platelets in animal experiments. The team hypothesized that shutting down this protection with inhibitors would increase the risk of heart attacks and strokes.

Eight placebo-controlled, randomized trials showed that NSAIDs present a cardiovascular hazard on the magnitude of that resulting from being a chronic smoker or diabetic. The team found that the loss of nitrous oxide in the body, which magnifies the effects of losing prostacyclin, is also involved. Although there are perhaps other relevant mechanisms that are yet to be determined, these 2 papers support the assertion that otherwise healthy patients taking NSAIDs for prolonged periods may gradually increase their risk of heart attacks and strokes.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.


1. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2011.

2. Turpie AG, Jamal W, Schmidt A, et al.Xamos: A non-interventional study comparing oral rivaroxaban with conventional regimens for thromboprophylaxis after major surgery of the hip and knee. British Society of Hematology 2012 Scientific Meeting; April 16-18, 2012; Glasgow, Scotland.

3. Perrone M. FDA says Xarelto reduced deadly heart attacks. Associated Press, Accessed May 30, 2012.

4. FDA panel votes against new use for J&J’s Xarelto. Business Week Accessed May 30, 2012.

5. NSAIDs and Cardiovascular Risk Explained. ScienceDaily website. Accessed May 8, 2012.

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