Vienna, Austria - The largest NSAID study to date—one that is reportedly bigger than all other studies combined—has put coxibs back in the limelight, this time suggesting a class effect of all nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. Presenting here at the European League Against Rheumatism (EULAR) 2005 meeting, the researchers have mapped out for clinicians the odds ratios for myocardial infarction (MI) of various products, and some of what they found is quite surprising. Lead author Dr Gurkirpal Singh (Stanford University, CA) sat down with heartwire to discuss his group's findings.

Dr Gurkirpal Singh

"What we wanted to do is put this issue into perspective and look at all of the drugs," Singh said. "And what we found is that drug selectivity doesn't really matter—some were selective and some were not, but many of the drugs increased the risk of MI." Among the top MI offenders, Singh and his team identified indomethacin with a 71% increased risk, sulindac 41%, and meloxicam 37%. Among the COX-2 inhibitors, rofecoxib showed the highest risk at 32%, followed by celecoxib at 9%. The researchers point out that high-dose valdecoxib could not be studied since most use in the current analysis was at the dosing level of 20 mg or less.

Commenting about the study, session cochair and incoming EULAR president Dr Tore Kvien (Diakkonhjemmet Hospital, Oslo, Norway) said, "This is an important high-quality database study. It provides information on all NSAIDs associated with an increased risk of MI and also provides us with information about the magnitude of this risk."

Dr Tore Kvien

During an interview Singh said, "The hysteria in the media about COX-2 inhibitors has been a bit of an overreach. All of the news about how these drugs cause heart attacks and kill has been excessive, because we simply did not have data for the other drugs." He added, "Absence of evidence is not evidence of absence."

Using data from the California-based Medicaid program, his group conducted a nested case control study of all patients over 18 with physician-diagnosed arthritis treated with an NSAID between January 1999 and June 2004. Cases of acute MI were risk-set matched with four controls on age, gender, and date of acute MI. The researchers compared current exposure to COX-2 selective and nonselective NSAIDs with remote exposure to any drug. The group reports that all analyses were adjusted for 38 confounding risk factors as well as concomitant aspirin treatment.

"This does appear to be a class effect of the NSAIDs with some variation," Singh said during the presentation of his findings. Summarizing the results, he told the audience, "MI risk appears to be common in a large number of NSAIDs, and decisions regarding their use need to be made in consultation with a physician who knows the patient well and can take into account their individual risk factors."

During a press conference following the session, Singh told reporters that naproxen, ibuprofen, and diclofenac would be good choices for comparators in future clinical trials. When asked whether he thought rofecoxib should be returned to the market, Singh answered, "It is my personal opinion that it is unlikely that it will come back."

Putting his work into perspective for the press, Singh explained that while daily smoking at least doubles the risk of MI, the risk from NSAIDs is only about 12%, "which is not really very high," he said.

"It's important to keep this in perspective," Kvien told heartwire. "Smoking increases the risk of MI by about 200% or 300%, and people are still allowed to buy cigarettes, but some patients are not allowed to use these drugs, which can relieve pain."