OXFORD, UK – A major meta-analysis of cardiovascular risk associated with cyclooxygenase-2 (COX-2) inhibitors shows significantly higher vascular risk for selective COX-2 inhibitors (coxibs) and for most traditional nonsteroidal anti-inflammatory drugs (NSAIDs), but also supports the contention that naproxen has some protective effects.

Lead author Patricia M. Kearney, MD, of the Clinical Trial Service Unit at the University of Oxford, UK, writes, "Overall, we found no significant difference in the incidence of a serious vascular event between selective COX-2 inhibitors and traditional NSAIDs."

"Rather than lamenting the loss of COX-2 inhibitors—an intervention that was more popular than proved—we will best serve our patients by thinking creatively about other approaches to their pain," Drs. Allen F. Shaughnessy and Andrea E. Gordon of Tufts University in Malden, Massachusetts, comment in an accompanying editorial.² "Have we lost a truly superior option? Probably not."

Dr. Kearney's meta-analysis includes published and unpublished tabular data from 138 randomized trials (145,373 patients). The studies selected for the meta-analysis compared a selective COX-2 inhibitor either to placebo or to a traditional NSAID, lasted at least 4 weeks, and included information on myocardial infarction (MI), stroke, and vascular death rates in treated patients.

The analysis was conducted to answer lingering questions about the magnitude of any treatment-associated excess risk of MI, stroke, or vascular mortality; whether the excess risk is dose related; and whether traditional NSAIDs, which also inhibit COX-2, increase vascular risk. Due to questions about naproxen raised during discussions of the VIGOR study, the investigators also prospectively specified that analyses of a selective COX-2 inhibitor versus NSAID were to be subdivided by whether they involved naproxen or a non-naproxen NSAID.

Placebo-controlled selective COX-2 inhibitor trials

Vascular events occurred at the rate of 1.2% per year in patients treated with selective COX-2 inhibitors, versus 0.9% per year in the placebo group, a 42% proportional increase in the incidence of a first serious vascular event associated with COX-2 inhibitors.

"We found no evidence that the proportional excess incidence of vascular events varied among the different selective COX-2 inhibitors," the investigators write. This corresponds to an excess of three people with a vascular event per 1000 allocated to a selective COX-2 inhibitor.

The MI rate almost doubled in patients taking COX-2 inhibitors compared to placebo, with a hazard ratio of 1.86 (P = .0003). This corresponds to an excess of three people with MI per 1000 taking a selective COX-2 inhibitor per year.

The difference in stroke rates was not statistically significant but corresponded to an excess of one patient with stroke per 1000 allocated to selective COX-2 inhibitors per year.

Nine of the 121 placebo-controlled trials included treatment lasting 1 year or longer, and about two-thirds of the vascular events occurred in those trials. There was also a significant trend toward increased incidence of serious vascular events with higher daily doses of celecoxib (P = .05). Data were not sufficient to permit a dose-response analysis for other selective COX-2 inhibitors.

Selective COX-2 inhibitors vs traditional NSAIDs

The risk of a vascular event was significantly higher in patients allocated to a selective COX-2 inhibitor versus naproxen, and those patients had a twofold increased risk of an MI(rate ratio 2.04, P = .0002). There were no significant differences in the incidence of vascular events, MI, or vascular death with selective COX-2 inhibitors compared with traditional non-naproxen NSAIDs, but COX-2 inhibitors were associated with a significantly lower incidence of stroke (rate ratio 0.62, P = .03).

The meta-analysis showed that high-dose ibuprofen (800 mg tid) and high-dose diclofenac (75 mg bid) were both associated with an increased risk of vascular events, while the risk associated with high-dose naproxen (500 mg bid) were "substantially smaller."

Experts recommend sustained-dose acetaminophen as first option

Drs. Shaughnessy and Gordon note that COX-2 inhibitors "rose to market prominence on the basis of premarketing and postmarketing studies showing less ulceration, on endoscopy, of the gastrointestinal tract. However, ulceration is neither intrinsically harmful nor a surrogate marker for harm associated with use of NSAIDs." They point out that the kind of damage found on endoscopy in these studies does not generally lead to serious problems such as gastric perforation, outlet obstruction, and bleeding, and that there is little difference in the incidence of adverse effects or dyspepsia with COX-2 inhibitors versus older NSAIDs. "The common assumption that COX-2 inhibitors are safer than other NSAIDs has not been borne out," they write.

For older patients, Drs. Shaughnessy and Gordon recommend trying acetaminophen at sustained doses before resorting to other analgesics, combining misoprostol with NSAIDs if they are used, and considering opioids for severe pain with the caveat that low-potency opioids such as dextropropoxyphene and tramadol are little better than acetaminophen.

References

1. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Brit Med J. 2006;332:1302-1305.
2. Shaughnessy AF, Gordon AE. Life without COX-2 inhibitors (editorial). Brit Med J. 2006;332:1287-1288.