Aarhus, Denmark - While the spotlight has been on the cardiovascular risk associated with cyclooxygenase-2 (COX-2) inhibitors, some have overlooked the risk of more traditional nonsteroidal anti-inflammatory drugs (NSAIDs). In the May 9, 2005 issue of the Archives of Internal Medicine, researchers look at the risk of myocardial infarction (MI) associated with various nonaspirin NSAIDs, and they study whether the risk reported in clinical trials of drugs such as rofecoxib (Vioxx®, Merck) and celecoxib (Celebrex®, Pfizer) are present in routine practice.[1]

We found this was the case with naproxen as well, which was a bit surprising.

"We identified increased risk estimates with all kinds of NSAIDs, including what we might call conventional NSAIDs that are generally considered safe and even cardioprotective. We found this was the case with naproxen as well, which was a bit surprising," lead author Dr Soren Johnsen (Aarhus University Hospital, Denmark) told heartwire. "Similar observations have been made in accordance with our finding, so this may not be the result of chance." Recent recommendations have heralded the benefits of using naproxen with a proton pump inhibitor (PPI) as an alternative to COX-2 inhibitors to negate cardiovascular risk. Does this finding call the new recommendation into question? Johnsen says it is too early to tell. "We cannot say whether naproxen is safer or worse than other conventional NSAIDs. But we need to be aware of the potential risk of all NSAIDs." He adds that his group did not look at combination approaches such as adding a PPI to naproxen.

Johnsen notes that NSAIDs are the most commonly used drugs worldwide, and even a small increase in risk could have grave implications for millions. "It makes this issue very interesting from a clinical point of view." Johnsen says that it remains to be seen whether these findings represent a class effect of NSAIDs or whether the increased risk may actually be attributed to underlying disease.

In this population-based case-control study funded by the Western Danish Research Forum for Health Sciences and the International Epidemiology Institute in Rockville, MD, the researchers examined the risk of MI among users of various categories of nonaspirin NSAIDs.

Using data from hospital-discharge registries in the counties of North Jutland, Viborg, and Aarhus in Denmark and the Danish Civil Registration System, Johnsen and his team looked at more than 10 000 cases of first-time hospitalization for MI and more than 100 000 sex- and age-matched non-MI population controls. They identified all prescriptions for NSAIDs filled before the date of admission for MI using population-based prescription databases. Relative-risk estimates for MI were adjusted for a wide range of conditions and therapies, including a history of cardiovascular disease, hypertension, diabetes mellitus, rheumatoid arthritis, chronic bronchitis or emphysema, alcoholism, and the use of high-dose aspirin, platelet inhibitors, antihypertensive drugs, lipid-lowering drugs, oral anticoagulants, and nitrates, for example.

The investigators found that not only did rofecoxib confer the greatest risk, but this risk was present throughout treatment. The Adenomatous Polyp Prevention on Vioxx (APPROVE) trial, which led to the market withdrawal of rofecoxib, demonstrated no excess risk within the first 18 months of use. "We could not confirm the previous finding of APPROVE and found the risk was present with both short- and long-term use," Johnsen told heartwire.

The group found that current and new users of all classes of nonaspirin NSAIDs had elevated relative-risk estimates for MI. They write that although the increased risk estimates may partly reflect unmeasured bias, they indicate the need for further examination of the cardiovascular safety of all NSAIDs.

The researchers write, "Although our risk estimates for naproxen were not significantly elevated, our estimates were higher than previously reported and thus provide some support for the concerns regarding naproxen."

Among the strengths of the study, the investigators cite its size, population-based design, and the ability to examine specific types of NSAIDs. They say the data on exposures and possible confounding factors were prospectively recorded and extensive efforts were made to adjust the risk estimates for influence from possible confounding factors such as underlying inflammatory conditions. Among the limitations were the use of discharge diagnoses—well known for potential inaccuracies—and the observational nature of the work, which may have resulted in protopathic bias. Other limitations include a lack of data on dosing, over-the-counter sale of NSAIDs, compliance, and duration of therapy.

Johnsen points out that NSAIDs are considered relatively safe and are frequently used without many restrictions—often off label. "We could have a situation where it is important that we become active in changing our pattern of use."