Vioxx (rofecoxib) belongs to a class of cyclo-oxygenase 2 (COX-2) inhibitor selective non-steroidal anti-inflammatory drugs (NSAIDs), which are prescribed for the treatment of arthritis. Vioxx was withdrawn from the pharmaceutical market at the end of September 2004 after use of the drug was linked to heart problems.
David J Graham (Office of Drug Safety, US Food and Drug Administration) and colleagues assessed whether coronary heart disease risk was increased with either high or standard doses of Vioxx compared with other (NSAIDs) or the COX-2 inhibitor celecoxib (Celebrex), a drug commonly used as an alternative to Vioxx.
They analysed data from 1.4 million people in California who had used NSAIDs from the beginning of 1999 to September 2004. Patients had received various NSAIDs, including celecoxib (around 40,000 users), ibuprofen (just under a million users), naproxen (around 435,000 users), and rofecoxib (around 27,000 users). The investigators found that 8,143 individuals had serious coronary heart disease, 1508 of which had sudden cardiac death. Each case was matched by age and sex to four controls to enable a comparison of coronary heart disease risk among people taking Vioxx and users of other NSAIDs.
People taking Vioxx had a 34% higher chance of coronary heart disease when compared with people who used other NSAIDs. Coronary heart disease was 1.6 times more likely among people currently taking standard-dose Vioxx compared with those currently taking celecoxib and 3.6 times more likely among high-dose users. The study also found that people taking naproxen had a 14% increased risk of coronary heart disease compared with other NSAIDs. Previous studies have suggested that naproxen protects against coronary heart disease.
Dr Graham comments: "An estimated 88,000-140,000 excess cases of serious coronary heart disease probably occurred in the USA over the market life of rofecoxib. The US national estimate of the case-fatality rate (fatal acute myocardial infarction plus sudden cardiac death) was 44%, which suggests that many of the excess cases attributable to rofecoxib use were fatal.
"In the future, when trials show that a new treatment confers a greater risk of a serious adverse effect than a standard treatment, we must be much more careful about allowing its unrestrained use."
In an accompanying commentary Simon RJ Maxwell and David J Webb (University of Edinburgh, UK) write that after the withdrawal of Vioxx increased attention will now focus on the cardiovascular safety of other COX-2 inhibitors (coxibs).
Professor Webb concludes: "It now falls to the manufacturers, under the careful review of the regulatory authorities, to provide the evidence that this class of drugs is safe, if necessary including studies that directly address cardiovascular morbidity as a primary outcome. Indeed, the experience with coxibs underlines the need for full publication of all clinical trial data generated in support of newly licensed drugs."
Dr David J Graham, Office of Drug Safety, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA.T) 301 827 3238 firstname.lastname@example.org
(comment) Professor David J Webb, Clinical Pharmacology Unit & Research Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, EDINBURGH, EH4 2XU, UK. T) 0131 537 2006 email@example.com