Several weeks after the US Food and Drug Administration (FDA) called for sweeping changes to the labels of prescription and over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs), a new study confirms that they indeed carry increased cardiovascular risk.
Despite its limitations, which include the use of discharge diagnoses, lack of data on OTC NSAIDs, channeling and protopathic bias, and confounding by diet and lifestyle, the study suggests that "continued attention to the cardiovascular safety of all nonaspirin NSAIDs appears warranted," Danish researchers report in the May 9 issue of Archives of Internal Medicine.1 "Because rofecoxib has already been withdrawn from the market, the focus should be shifted to the safety of other nonaspirin NSAIDs, in particular the other COX-2 selective NSAIDs."
Users of all classes of nonaspirin NSAIDs, including naproxen, were found to have higher risk for myocardial infarction (MI). Current users of rofecoxib had an 80% adjusted elevated risk for hospitalization for MI, compared with nonusers of any nonaspirin NSAID. Current users of celecoxib and other cyclooxygenase-2 (COX-2) selective inhibitors had increased risks of 25% and 45%, respectively. Among non-selective NSAIDs, naproxen users had an adjusted 50% greater risk and other conventional nonaspirin NSAIDs had an adjusted increased risk of 68%. Overall, the highest adjusted risk ratios were found among new users of all drugs studied.
Using data from Danish hospital discharge registries covering January 2000 to December 2003, before the FDA withdrawal of rofecoxib and valdecoxib, researchers performed a case-control analysis of 10,280 cases of first-time hospitalization for MI and 102,797 sex- and age-matched non-MI controls. They reviewed all prescriptions for nonaspirin NSAIDs filled before the date of hospital admission via population-based prescription databases, and calculated the risk for MI associated with each drug.
Their estimates were adjusted to account for a history of pre-existing diseases, including cardiovascular disease, hypertension, diabetes mellitus, chronic bronchitis or emphysema, alcoholism, liver cirrhosis, upper gastrointestinal bleeding, rheumatoid arthritis, and systemic lupus erythematosus. The use of other drugs before the date of admission for MI was also accounted for, including high-dose aspirin, platelet inhibitors, insulin or oral hypoglycemic drugs, antihypertensive drugs, lipid-lowering drugs, oral anticoagulants, nitrates, penicillamine, gold, oral glucocorticoids, and hormone therapy.
"The level of evidence for COX-2 inhibitors suggesting increased risk of adverse CV events has been documented for the three FDA-approved agents, but unfortunately we lack studies with the methodological rigor to implicate causality with regard to traditional NSAIDs both at prescription and OTC dosages," says Mark Fendrick, MD, professor of internal medicine and health management and policy at the University of Michigan Health System in Ann Arbor. "The fact that this and other numerous observational studies might suggest increased CV risk for traditional NSAIDs requires us to study these agents in a way that will answer the question definitively."
COX-2 inhibitors often used by those without GI risk
The Danish population study was accompanied by data from a poll that examined COX-2 inhibitor use among individuals at low or high risk of gastrointestinal (GI) complications.2 Researchers found that in the last half of 2003, most adults who were prescribed a COX-2 inhibitor did not, in fact, have a history of GI problems. Of 80 users, 71% were in the low-risk category, according to results from the Slone Survey conducted by telephone between June and November of 2003. Subjects were asked about medication use and their history of duodenal ulcer; gastritis, esophagitis, or duodenitis; upper GI bleeding; cirrhosis or other liver disease; cancer of the stomach, colon, or intestines; or other bleeding disorders.
"Our findings provide documentation of the fact that the majority of COX-2 inhibitor users in the US in 2003 were not at high risk of having the gastrointestinal complications that occur with standard NSAIDs; that is, the drugs were prescribed to many people who did not 'need' them in terms of their GI risk profile," notes lead author David W. Kaufman, ScD, associate director of the Slone Epidemiology Center in Boston, Massachusetts, and professor of epidemiology at Boston University School of Public Health. When asked if doctors are more cautious after the recent controversy over these agents and their risk/benefit profiles, Dr. Kaufman replies, "I cannot speculate about whether the lessons have been learned by prescribers, but it is clear from many sources that the use of these drugs has dropped substantially since Vioxx was removed from the market."
Dr. Fendrick adds that "this is one of many confirmatory stories suggesting that most of the prescribing of COX-2 inhibitors were not directed at those who were most likely to benefit from proposed GI safety advantage."
He remains concerned about the threat of GI complications posed by nonselective NSAIDs, however. "Given that GI safety was the driving force behind this class, I find it extremely interesting to see the number of COX-2 [prescriptions] plummet, yet there has been no real increase in the concomitant increase in gastroprotective agents with nonselective NSAIDs."
References:
- Johnsen SP, Larsson H, Tarone RE, et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med. 2005;165:978-984.
- Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Are cyclooxygenase-2 inhibitors being taken only by those who need them? Arch Intern Med. 2005;165:1066-1067.