The cyclo-oxygenase 2 (COX-2) inhibitor rofecoxib (Vioxx) was withdrawn by Merck on September 30 2004 because of adverse cardiovascular effects identified by the unpublished Adenomatous Polyp Prevention on Vioxx (APPROVe) study. An increased risk of heart attack had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to a protective effect of another non-steroidal anti-inflammatory drug, naproxen, rather than an adverse effect of Vioxx.

Peter Jni (University of Berne, Switzerland) and colleagues pooled the results of all randomised trials and observational studies involving Vioxx to establish whether the drug's poor safety profile was evident earlier than September 2004. This was done by searching bibliographic databases and relevant files of the US Food and Drug Administration. The investigators identified 18 randomised controlled trials and 11 observational studies. By the end of year 2000, 52 out of around 20,000 patients had a heart attack; this equated to more than a doubling of the risk in patients given Vioxx, compared to patients on placebo or other non-steroidal anti-inflammatory drugs.

Co-author Matthias Egger comments: "If Merck's statement in their recent press release that "given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take" was appropriate in September, 2004, then the same statement could and should have been made several years earlier, when the data summarised here had become available. Instead, Merck continued to market the safety of rofecoxib."

The Lancet is critical of both Merck and the FDA for their role in the Vioxx affair. Editor Richard Horton states in an accompanying commentary: "The
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Contact: Joe Santangelo
j.santangelo@elsevier.com
1-212-633-3810
Lancet
4-Nov-2004