New evidence of the cardiovascular and kidney risks posed by both

COX-2 inhibitors and NSAID painkillers has emerged from two major studies. The meta-analyses by experts in the US and Australia has confirmed the ability of Merck’s Vioxx (rofecoxib) to increase risk of heart and kidney damage. Merck is currently facing over 14,000 liability lawsuits from patients who took the drug.

And the Australian study found evidence that standard doses of the non-steroidal anti-inflammatory diclofenac, increased users’ risk of heart attack by 40%. The researchers, led by Dr Patricia McGettigan of the University of Newcastle in New South Wales, say in the Journal of the American Medical Association that diclofenac’s licence should be reviewed: “It appears to be harmful at commonly used doses. We believe there are grounds for reviewing its regulatory status."

In an accompanying editorial, Dr David Graham says the results also call into question the safety of another COX-2 inhibitor, Arcoxia (etoricoxib), for which Merck is currently seeking a US licence. Dr Graham notes that it has been assumed that Arcoxia poses no cardiovascular risk on the basis that it causes around the same number of cardiovascular events as diclofenac. But given this latest worrying evidence of a link between diclofenac and heart attacks, he says that Arcoxia’s safety must now be in doubt.

JAMA said it had posted the findings online ahead of schedule because of their “public health implications.” The articles are due to appear in the October 4 print issue of the journal. Dr Graham added: "If the lessons of recent history have been learned, the FDA's concerns will now be squarely focused on patient safety rather than corporate profitability, and, ultimately, common sense will prevail." Two COX-2 inhibitors, Vioxx and valdecoxib (Bextra), have already been withdrawn from the market.

In the other meta-analysis of 114 randomized trials of COX-2 inhibitors with 116,094 participants, which also appears in JAMA Online, Dr Jingjing Zhang of Harvard Medical School confirmed that Vioxx increased users’ risk of heart and kidney problems and high blood pressure.

Some good news for Celebrex

However, he said there was no link between other COX-2 inhibitors and renal events and arrhythmia, “indicating no overall evidence for a COX-2 inhibitor class effect.” In particular, he noted that while high-dose Vioxx increased the risk of heart attack more than two-fold, another COX-2 inhibitor Celebrex (celecoxib) was not associated with an elevated risk of vascular occlusion.

This will provide some cheer for the drug’s manufacturer Pfizer following safety concerns reported recently. Among the older painkillers, diclofenac had the highest increased heart attack risk of 40%. Naproxen, along with piroxicam and ibuprofen, appeared neutral in its heart effects, which "contradicts claims of a 'protective' effect of naproxen,” according to Dr Zhang.

He said that the controversy over the side-effect profile of painkillers illustrated the need for better ongoing safety studies. “The knowledge of all potential adverse effects is important and indeed time-sensitive, for physicians and patients both need complete information about risks and benefits to properly use COX-2 inhibitors and other clinical treatments. Future drug safety monitoring of emerging clinical treatments may benefit from continuous cumulative meta-analytic aggregation of safety data for all drug approval applications and experimental agents." Michael Day