Vioxx became the center of a COX-2 controversy that erupted following its withdrawal from the pharmaceutical market at the end of September 2004 because research linked it to heart problems.

Coronary Heart Disease Risk Assessment

In the study published in The Lancet, Dr. 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 Celebrex (celecoxib), a drug commonly used as an alternative to Vioxx.

They analyzed data from 1 million to 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, 1,508 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.

Vioxx May Have Caused 'Many Fatalities'

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 to 6 times more likely among people currently taking standard-dose Vioxx compared with those currently taking celecoxib, and 3 to 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.

"An estimated 88,000-140,000 excess cases of serious coronary heart disease probably occurred in the USA over the market life of rofecoxib," Dr. Graham comments. 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," he notes.

"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," says Dr. Graham.

Need for Full Publication of All Clinical Trial Data

In an accompanying commentary, Simon R.J. Maxwell and David J. Webb of the University of Edinburgh, UK, write that after the withdrawal of Vioxx, increased attention now will focus on the cardiovascular safety of other COX-2 inhibitors (coxibs).

"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," says Professor Webb.

"Indeed, the experience with coxibs underlines the need for full publication of all clinical trial data generated in support of newly licensed drugs," Professor Webb concludes.