Common OTC Drug Could Pose Serious Risk For Some

Sep 16 2008 - 9:48am
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In 2004, rofecoxib, better known by its brand name, Vioxx, was withdrawn from the market due to concerns about possible increased risk of heart attack and stroke. Not long after, valdecoxib, marketed as Bextra, was removed for the same reason. Since then, anxieties surrounding the cardiovascular safety of nonselective NSAIDs (nonsteroidal antiinflammatory drugs), as well as other selective coxibs (Cox 2 inhibitors), have escalated among arthritis patients and the doctors who treat them. Now, researchers from Brigham and Women's Hospital (BWH) have performed one of a few randomized controlled trials to measure the cardiovascular risks for the millions of daily users of all Cox 2s and NASIDs, including over-the-counter pain relievers.

How dangerous are Cox 2s and NSAIDs? Do all users face a dramatically increased risk of suffering a crippling or fatal cardiovascular event? For answers, Daniel H. Solomon, MD, a researcher in the Rheumatology, Immunology & Allergy Department at BWH and lead author of the study and his colleagues examined cardiovascular events in specific subgroups of patients prescribed Cox 2s or NSAIDs. Featured in the August issue of Arthritis Care & Research, their findings support the cardiovascular safety of taking most NSAIDs and Cox 2s for most arthritis patients. Certain patients, however, may be at an increased risk when using some medications. This study also raises a red flag for all patients who routinely take ibuprofen. Ibuprofen, the analgesic agent in Advil and Motrin, and the now-banned rofecoxib were the only drugs consistently associated with an increased risk for cardiovascular events across patient subgroups.

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The patient subgroups were drawn from two databases of Medicare recipients enrolled in drug benefit programs. Patients covered by Pennsylvania’s Pharmaceutical Assistance Contract for the Elderly (PACE) were the primary subjects, with participants in New Jersey’s Pharmaceutical Assistance for the Aged and Disabled (PAAD) designated as a secondary cohort. Researchers chose 1999 to 2004, prior to the restrictions on coxib use, for their study period.

In the primary group, researchers identified 76,082 new users of Cox 2s, either rofecoxib, valdecoxib, or celecoxib, also known as Celebrex, and 53, 014 new users of nonselective NSAIDs, including prescription diclofenac, naproxen, ibuprofen, and a composite of all other available oral NSAIDs, excluding aspirin. For comparison, 46, 558 patients receiving medication for thyroid problems or glaucoma were identified as nonusers. The only major difference between Cox 2s and NSAID users and nonusers was that nonusers were less likely to have been diagnosed with arthritis. The mean age of the study population was 80 and nearly 85 percent were white women. Defined by patient characteristics, subgroups included age and sex; prior myocardial infarction (MI), congestive heart failure (CHF), stroke, or any cardiovascular (CVD) event; hypertension, diabetes, or any CVD risk factor; chronic renal disease; rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD); and use of a statin or angiotensin.

For each subgroup, researchers assessed the increased cardiovascular risk associated with using specific Cox 2s and/or nonselective NSAIDs. They calculated not only the relative risk (RR) for MI, CHF, stroke, or cardiovascular death, but also the attributable proportion (AP) of risk due to the biological interaction between the specific patient characteristic and the individual drug. As a whole, the group experienced 7,262 CVD events during the 64,136 person-years of followup. The incidence rates varied substantially across the exposure groups, with rofecoxib users experiencing the highest rates, naproxen users experiencing the lowest rates, and nonusers midway between the two. When calculating the AP, researchers found 7 characteristics linked to an increased risk of CVD events among Cox 2s and NSAID users: age 80 years and older, hypertension, prior MI, prior CVD, RA, chronic renal disease, and COPD. When comparing the incidence rates by agent, rofecoxib and ibuprofen users experienced more CVD events in every subgroup. For example, among patients with a prior MI, rofecoxib users suffered 9.4 more CVD events and ibuprofen users 11.4 more events per 100 person-years compared with nonusers.

Solomon acknowledges the study's limitations. For one, the subjects were overwhelmingly frail, elderly patients. For another, researchers had no information on aspirin use, smoking history, body mass index, or other potential confounders. For still another, possible effects of drug dosage differences were not considered. Despite these limitations, the results have potential clinical relevance. “Our findings suggest that rofecoxib and ibuprofen are the only agents consistently associated with an increased risk for CVD events among specific patient subgroups,” Dr. Solomon notes. “The fact that we did not observe a similar concentration in risk among subgroups of patients using many of the other agents may be of even greater relevance. These results should bolster physicians’ and patients’ confidence that most Cox 2s and nonselective NSAIDs are not associated with an elevated risk of CVD events in many patient subgroups using typical doses.”

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