In 1999, the pharmaceutical company Merck introduced the drug Vioxx (Rofecoxib) to be used as an anti-inflammatory treatment for pain associated with osteoarthritis. It was claimed to be effective and safer than other treatments already available. Subsequently it was found to increase the risks and deaths due to cardiovascular disease and was withdrawn from the market. Harlan Krumholtz and colleagues were involved in the legislation that resulted, which gave them access to company documents that provided valuable insight into the relevant background. Their conclusions were summarised in a paper published in the BMJ (1).

The Merck studies

Studies conducted during 1996/7 raised the possibility that the drug increased the risk of thrombus formation. Despite this the company failed to explore this aspect in greater depth. In fact it cobbled together results from a range of limited studies to prepare marketing material used to promote the cardiovascular safety of the drug to the medical profession. This “cardiovascular card” was criticised by US Congressman Henry Waxman because it falsely minimised the cardiovascular risks and had never been approved by the FDA.

In January 1999, the VIGOR study was started. This was designed to show that Vioxx would have fewer gastrointestinal side effects than a competitor drug, naproxen, for the treatment of rheumatoid arthritis. However it was clear that the study was initiated without any proper procedures for collecting information on cardiovascular events and there was no cardiologist on the data safety monitoring board.

At the first examination of safety in November 1999, it was found that there was a 79% increase in the risk of death or serious cardiovascular event in one treatment group compared with the other. Similar results were noted in December that year and so it was recommended that an analysis plan be developed to examine serious cardiovascular events and that the study continue until it reached its gastrointestinal endpoint target, expected in March 2000.

Conflicts of interest

Although the members of the board responsible for the conduct of the trial are supposed to be totally independent without any financial involvement, the head of the VIGOR board was awarded a two-year consulting contract two weeks before the trial ended. It was also disclosed that his family had shares in Merck valued at $70,000. This information was in the public record at the time.

The results

The VIGOR showed that Vioxx was not more effective than naproxen in relieving symptoms of rheumatoid arthritis but did halve the risk of gastrointestinal events. However there was also evidence of an increased risk of myocardial infarction. The relative risk was 5.00, which is very high.

The Merck chief scientist commented on this in an email to a colleague:

“It is a shame but it is a low incidence…”

So it was clear that there were staff within the company who were concerned about the cardiovascular implications.

Playing down the risks

When the report of the ViGOR study was published, the cardiovascular risks were certainly not emphasised. According to Krumholz:

  • “The report contained data from an interim analysis that had different termination dates for cardiovascular and gastrointestinal events (gastrointestinal events were counted for one month longer than the cardiovascular events). This highly irregular procedure was not described in the publication and had the effect of favouring the drug’s effect on gastrointestinal events while understating the risk of cardiovascular events.
  • The published cardiovascular risk was not accurate because three additional myocardial infarctions occurred in the Vioxx group in the month after the researchers stopped counting cardiovascular events (none had occurred in the naproxen group).
  • The potential harm was further minimised by a post hoc subgroup analysis based on “indication for aspirin prophylaxis”; had Merck included the three cases, the subgroup analysis would have shown an increased cardiovascular risk in both groups.
  • The publication concealed the cardiovascular risk even further by presenting the hazard of myocardial infarction as if naproxen was the intervention group (relative risk 0.2, 0.1 to 0.7) and without reporting the absolute number of cardiovascular events, even though all other results were presented appropriately with Vioxx as the intervention group.
  • Finally, the authors proposed a naproxen hypothesis, suggesting that rofecoxib had not been harmful but that naproxen had been protective, despite there being no accepted evidence that naproxen had a strong cardioprotective effect.”

Publication of the results

The results were published in the New England Journal of Medicine (NEJM) (2). The company purchased almost one million copies to use as promotional material for the medical profession. Several years later in editorial in the journal, expressed devastating criticisms of the VIGOR paper (3). Here are some extracts:

  • The VIGOR study was designed primarily to compare gastrointestinal events in patients with rheumatoid arthritis randomly assigned to treatment with rofecoxib (Vioxx) or naproxen (Naprosyn), but data on cardiovascular events were also monitored. Three myocardial infarctions, all in the rofecoxib group, were not included in the data submitted to the Journal. The editors first became aware of the additional myocardial infarctions in 2001 when updated data were made public by the Food and Drug Administration.
  • Until the end of November 2005, we believed that these were late events that were not known to the authors in time to be included in the article published in the Journal on November 23, 2000. It now appears, however, from a memorandum dated July 5, 2000, that was obtained by subpoena in the Vioxx litigation and made available to the Journal, that at least two of the authors knew about the three additional myocardial infarctions at least two weeks before the authors submitted the first of two revisions and 4 1/2 months before publication of the article. Given this memorandum, it appears that there was ample time to include the data on these three additional infarctions in the article.
  • The fact that these three myocardial infarctions were not included made certain calculations and conclusions in the article incorrect.
  • Lack of inclusion of the three events resulted in an understatement of the difference in risk of myocardial infarction between the rofecoxib and naproxen groups (presented in the article as a reduction in the risk with naproxen but shown here as an increase in the risk with rofecoxib).

 

The plot thickens

As a result of a further study in 2004, the APPROVE trial, Merck accepted that the use of Vioxx was linked to an increase in cardiovascular risk. However the crucial factor was the period of usage. Obviously if there were problems associated with short term use, then the company could continue to promote the drug.

The paper reporting this work was also published in the NEJM. Five of the authors were Merck employees and the other involved were paid consultants. Rather significantly, it concluded the increased cardiovascular risk only occurred after 18 months of use. Subsequently it emerged that this conclusion was based on a flawed methodological approach to the statistical analysis and the NEJM had to issue a correction indicating that statements regarding an increase became apparent after 18 months of use should be removed. It is clear from this that the process of refereeing and reviewing papers prior to acceptance for publication has failed dismally. The NEJM was not alone in this and several other leading journals were equally guilty. As Krumholz comments:

“With billions of dollars at stake, Merck conducted the trials, stored and analysed the data internally, paid academic researchers as consultants to the investigative teams and the safety monitoring boards, and maintained heavy involvement in the writing and presentation of findings. The journals published the studies, and the academic community accepted the findings without expressing much concern.”

The consequences

Between 1999 and 1004, over 100 million prescriptions were dispensed in the USA. An FDA investigation indicated that the drug was responsible for at least 55,000 deaths although the actual number may have been as high as 500,000 (4). A class-action lawsuit resulted in Merck settling for $4.85 billion in 2007. However individuals who claimed were not so fortunate as the Merck challenged them and most were dismissed on the grounds that it was impossible to link a specific case directly to the use of Vioxx.

Conclusion

This a most valuable case history, which very clearly demonstrates the unethical, irresponsible and possibly even worse behaviour exhibited by one particular drug company. Furthermore it also illustrates the failure of mainstream medicine and the associated journals to fulfil their role in protecting the public. The FDA does not exactly cover itself with glory but almost certainly it was subject to political pressures and, of course, it was hamstrung by the failure of Merck to supply all the relevant information. It is only because of the court case that the full story has emerged. Because of the revelations that have appeared the regulations have been tightened up. However the fact remains, there are still lots of drugs on the market which were approved prior to this. Can we absolutely certain that the same approach to the evaluation and approval processes do not apply?

References

  1. H M Krumholz et al (2007). http://www.bmj.com/content/334/7585/120
  2. C Bombardier et al (2000). http://www.nejm.org/doi/pdf/10.1056/NEJM200011233432103
  3. G D Curfman et al (2005). http://www.nejm.org/doi/full/10.1056/NEJMe058314
  4. http://www.theweek.co.uk/us/46535/when-half-million-americans-died-and-nobody-noticed