COX-2 inhibition and thrombotic tendency

In reply: The response from the Medical Director of Pharmacia to our article highlights some problems for all clinicians and independent scientists seeking to evaluate the balance of risks and benefits of pharmaceuticals and to validate the marketing messages of pharmaceutical companies. On the one hand, we lack the time and statistical resources to trawl through all data related to all trials with a test drug. On the other, our efforts to evaluate data are confounded by the publication and reporting biases associated with company-sponsored studies. In this regard, it is notable that the definitive results of CLASS1 have not been published, although the Food and Drug Administration (FDA) review of the data is available through an FDA website,2 as indicated by Fenn. While this document places data in the public domain, its location is neither within the pathway of MEDLINE search engines, nor is it known to the general body of clinicians.

As reported in the FDA presentation, CLASS was a very large, double-blind safety study of at least six months' treatment that failed to achieve its primary endpoint of reduced complicated upper gastrointestinal events with celecoxib relative to the comparator, non-steroidal anti-inflammatory drugs (NSAIDs). While an interim analysis at six months was published, with extrapolation of event rates to 12 months,3 failure to publish the final results has withheld important results from wider scrutiny. In essence, the FDA document shows no overall long-term safety advantage of celecoxib over standard NSAIDs.2

The FDA analysis4 of the VIGOR study5 also shows no overall safety advantage for rofecoxib compared with NSAID, with fewer complicated upper gastrointestinal events being offset by a highly statistically significant (P = 0.0016) increase in serious thrombotic cardiovascular events.

Collectively, these FDA analyses invalidate the promotion of selective cyclooxygenase-2 (COX-2) inhibitors as a safe alternative to NSAIDs, notwithstanding encouraging results from short-term trials. Further, although an increase in serious cardiovascular events was not seen in the CLASS study, its design was not optimal for detecting increased cardiovascular risk, and it is unlikely that CLASS was sufficiently powered to detect the degree of increased risk seen with rofecoxib in VIGOR. As explained in our article,6 unbalanced prothrombotic eicosanoid production associated with selective COX-2 inhibition (ie, a class effect) appears the most likely explanation for the increased cardiovascular events seen in VIGOR.

Finally, we wish to reassert that, for effective postmarketing surveillance, it is essential that prescribers be adequately informed about safety concerns associated with new drugs, particularly when they involve events that are common and not usually seen as unwanted drug effects.