January 21, 2011 — New data showing nonsteroidal anti-inflammatory drugs (NSAIDs) have cardiovascular risks are putting the well-known pain relievers back in the headlines. Investigators evaluating available evidence report they have found little to suggest that any of the investigated options are safe.

Regulatory agencies have already pointed to cardiovascular signals with NSAIDs, but these concerns are based mainly on observational evidence. This new study provides a comprehensive analysis of all randomized controlled trials of the drugs.

During an interview with Medscape Medical News, senior investigator Peter Jüni, MD, from the University of Bern in Switzerland, said his team expected to see an increased risk but was surprised by the magnitude of the signal. "We never thought we'd see 2- and 4-fold increased risks," he said. "The doses were admittedly high," he pointed out, "however, this is clearly clinically relevant."

Several earlier meta-analyses were unable to resolve the debate over risk because they failed to include all randomized evidence in 1 study. This new network meta-analysis, published online January 11 in BMJ, includes all available evidence.

Investigators saw an increase in myocardial infarctions, stroke, and cardiovascular death in patients taking all of these NSAIDs. Not surprisingly, rofecoxib was associated with the highest risk for myocardial infarction, with a rate ratio of 2.12. The drug's manufacturer, Merck, voluntarily withdrew the product marketed as Vioxx in 2004 because of concerns over cardiotoxicity.

Lumiracoxib had the next highest rate of myocardial infarction in the current study. Ibuprofen was associated with the highest risk for stroke with a rate ratio of 3.36 followed by diclofenac at 2.86. Etoricoxib was linked to the highest rate of cardiovascular death at 4.07 followed by diclofenac at 3.98.

Dr. Jüni recommends that physicians take special care in evaluating patients prone to cardiovascular events. Those who require treatment should take the lowest possible dose for the shortest period.

Dr. Jüni says he would like to see black box warnings added to drug packaging for the products still available on the market.

Of all the NSAIDs, naproxen seemed least harmful in this study. The finding is in agreement with recommendations made by regulatory agencies when rofecoxib was first removed from the market and physicians were evaluating alternatives.

"I think we should reserve our final judgment on naproxen until after we've completed the overall safety study," Dr. Jüni said. His team is currently studying the gastrointestinal safety of the drug and weighing the benefits and risks from that perspective.

"With naproxen, we tend to need a proton pump inhibitor to protect the stomach," Dr. Jüni added. "This is far from ideal."

No Clear Link Between Specificity and Risk

In an interesting twist, investigators found no clear relation between specificity of cyclooxygenase-2 inhibitors and risk for cardiovascular events. This finding contrasts with previous claims that increased selectivity for cyclooxygenase-2 inhibitors is associated with cardiovascular risk.

Several mechanisms have been proposed, but the hypothesis of an imbalance between prostacyclin and thromboxane A2 leading to an increased risk for thrombotic events is the most well known.

The researchers suggest the lack of a clear association between specificity of cyclooxygenase-2 inhibitors and cardiovascular risk implies that other mechanisms should be considered. "Multiple effects most probably contribute to the increased risk of cardiovascular events, including differential effects on prostacyclin and thromboxane A2 synthesis, endothelial function, nitric oxide production, blood pressure, volume retention, and other renal effects," they note.

Millions of Patients Taking NSAIDs

"Given that both mechanistic and clinical data suggest that individual NSAIDs may have different cardiovascular risk profiles," Dr. Ray noted, "a natural question is, 'Which NSAID is safest for patients with high cardiovascular risk?'"

He points out the ongoing PRECISION trial, otherwise known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen, will eventually provide more information on the relative cardiovascular safety of these options. "Until these results become available, naproxen seems to be the best choice with regard to cardiovascular safety."

Dr. Ray says the controversy and confusion about the cardiovascular safety of these products provides an important lesson. "Drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects. NSAIDs are not an ideal treatment with respect to efficacy or safety. Perhaps it is time for a larger more systematic evaluation of a broader range of alternatives."

Clinical Implications

A previous meta-analysis found that acetaminophen was more effective compared with placebo in the treatment of OA, but it was not as effective as NSAIDs. However, NSAIDs were more likely to promote gastrointestinal discomfort vs acetaminophen.
In the current study, naproxen was associated with the best cardiovascular safety among the NSAIDs.