Scientific evidence of increased heart attack risk associated with popular arthritis drug Vioxx was available as early as 2000, say Swiss scientists, although the drug was only withdrawn in September 2004.
Merck & Co, Inc, pulled its product from the market on 30 September after participants in a clinical trial of Vioxx鈥檚 effects on colon cancer started to show increased risk of heart attack.
But after analysing the results from 18 randomised clinical trials and 11 observational studies 鈥� many completed before 2001 鈥� Peter Juni at the University of Berne, Switzerland, and his colleagues believe that the decision could have been made much earlier.
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鈥淚f we can do this kind of analysis, it鈥檚 difficult to see why it wasn鈥檛 done by the drug company or the licensing authorities years ago,鈥� says co-author Matthias Egger.
By the time it was withdrawn, an estimated 80 million people worldwide had taken Vioxx (rofecoxib). A memo posted by the US Food and Drug Administration (FDA) on its website on 2 November 2004 suggests that Vioxx may have contributed to almost 28,000 heart attacks in the US between 1999 and 2003.
But Merck dismissed the validity of the new study, published on Friday, saying Merck had been 鈥渧igilant in monitoring and disclosing the cardiovascular safety of Vioxx and that the company absolutely disagrees with any implication to the contrary鈥�. A scientific critique, published by Merck in response, questions the methodology of the new study.
Questions of interpretation
Indications of Vioxx鈥檚 potential risks surfaced in 2000 from Merck鈥檚 study of the drug鈥檚 gastrointestinal side effects, dubbed VIGOR, say the Swiss team. The study compared Vioxx with naproxen, another type of non-steroidal anti-inflammatory drug (NSAID) used to treat arthritis.
VIGOR found that participants on Vioxx were five times more likely to have a heart attack than those on naproxen. However, the result was interpreted as a reflection of naproxen鈥檚 protective effect on heart health because, like aspirin, it reduces blood clotting.
鈥淣aproxen would have had to reduce the risk of myocardial infarction by 80% to have explained their results. If that were true, I think we would know about that by now,鈥� says Egger.
Juni and his colleagues pulled studies from published and unpublished trials from the FDA鈥檚 database. All together they represented more than 20,000 patients. They found a two-fold increase in heart attack risk. And this was not dependent on dose.
They also found no evidence to suggest that short exposures to Vioxx were without risk 鈥� contrary to the previous suggestion that heart attack risk increased only with long-term use.
鈥淗ealth catastrophes鈥�
Furthermore, Egger suggests that many participants in Vioxx trials were at much lower risk of cardiovascular disease than the elderly population who generally uses arthritis medication. Given a representative population鈥檚 profile, Vioxx could raise the risk of heart attacks by up to eight times, they suggest.
But Merck says the study鈥檚 conclusions are 鈥渂ased on an analysis that violates the basic principle of meta-analyses to combine 聭like with like'鈥�. It asserts that the 鈥渋nappropriate combining鈥� of data by the team 鈥渋nvalidates the results and conclusions鈥� of their analysis.
In a commentary accompanying The Lancet article, editor Richard Horton calls the licensing and use of Vioxx 鈥減ublic health catastrophes鈥�, and called for further investigations.
鈥淲hy clinical investigators studying Vioxx did not do more to raise concerns is a fair question that needs to be answered,鈥� he writes. 鈥淏ut in doing so, we must not diminish the importance of the covenant of trust that society has established with powerful commercial and governmental institutions. For with Vioxx, Merck and the FDA acted out of ruthless, short-sighted, and irresponsible self-interest.鈥�
Journal reference: The Lancet (early online publication)