A study published in the Journal of the American Medical Association has raised the question of whether the use of selective cyclooxygenase-2 (Cox-2) inhibitors might be associated with an increased incidence of cardiovascular events.
Cox-2 selective inhibitors were developed in an attempt to reduce the adverse gastrointestinal events associated with the use of traditional, non-specific non-steroidal anti-inflammatories (NSAIDs). This was based on the premise that Cox-1 predominates in the gastric mucosa and yields protective prostaglandins, whereas Cox-2 is induced in inflammation and leads to pain, swelling and discomfort. However, selective Cox-2 inhibitors are known to decrease vascular prostacyclin (PGI2) production and may affect the balance between prothrombotic and antithrombotic eicosanoids, perhaps leading to increased cardiovascular thrombotic events. Cox-1 inhibitors afford a measure of platelet inhibition that reduces this effect.
A recent meta-analysis suggests that there may be an increase in cardiovascular events in patients taking Cox-2 inhibitors relative to those taking traditional, non-specific NSAIDs. The researchers analyzed the rates of cardiovacular events occurring in participants in 4 trials: the VIGOR trial, the CLASS study, and Study 085 and Study 090, submitted to the US Food and Drug administration.
The study suggested that patients taking rofecoxib had a relative risk of 2.38 (p<0.001) for developing a cardiovascular event when compared to those taking the traditional NSAID, naproxen. In contrast, the analysis of patients taking celecoxib as compared to ibuprofen or diclofenac did not show the same results--there was no significant increase in cardiovascular events in this group.
There are many caveats to the study and critics have pointed out major flaws in the analysis. The differences in the rates of cardiovascular events between patients taking rofecoxib and those taking naproxen may result from a number of factors. Most of the patients involved in the VIGOR study suffered from rheumatoid arthritis, a condition known to predispose patients to a higher risk for MI. Further analysis is required in a more representative sampling of patients. In addition, the trials analyzed in this study focused solely on continuous use of Cox-2 inhibitors and did not examine the more common method of using the drugs sporadically for musculoskeletal pain.
Finally, it remains to be determined whether the higher rate of cardiovascular events associated with rofecoxib relative to naproxen results from a negative impact of rofecoxib or from a positive impact of naproxen on platelet inhibition. This result would more readily explain the lack of difference in cardiovascular events seen with the CLASS study comparing celecoxib to ibuprofen and diclofenac, two NSAIDs that do not have the same antiplatelet effects as naproxen.
Source
- Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective Cox-2 inhibitors. JAMA. 2001:286:954-9.
