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Rapid Responses: Rapid Responses published:
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Questioning the scientific validity of the APPROVe study's official interpretation
- Jeffrey Mann (25 February 2005)
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Cardiovascular side effect of selective COX-2 inhibitors: all or nothing.
- Alfredo Tartarone, Gianpiero Romano, Raffaele Ardito, Giuseppina Gallucci, Nicola Di Renzo (25 February 2005)
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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The manufacturer of rofecoxib recently withdrew the drug from the market because the APPROVe study demonstrated that the drug was associated with a significantly increased risk of adverse cardiovascular events, presumably due to the drug's prothrombotic effect. The study investigators' official interpretation of the APPROVe study was that "the study's results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group". I think that this particular conclusion may not be accurate. I personally think that the study's results primarily reflect the fact that the placebo group had an unexpectedly low control event rate during the last 18 months of the trial. During the first 18 months of the study there was little difference in adverse cardiovascular event rates between the placebo and rofecoxib treated patients. The rofecoxib treated patients had an adverse event rate of 1.33/100 patient-years while the placebo patients had an adverse event rate of 1.13/100 patient-years. The relative risk (RR) was only 1.18, which is not clinically significant. During the second half of the 36 month study, the RR increased dramatically to 4.45. However, the main cause of that dramatic increase in RR was not due to a marked increase in the adverse event rate in the rofecoxib treated patients, which only increased from 1.33/100 patient- years to 1.77/100 patient-years. Rather, it was due to a marked decrease in the adverse event rate in the placebo patients during that time period -- the adverse event rate plummeted to 0.38/100 patient-years from a previous level of 1.13/100 patient-years (a ~300% difference). I have analysed all these facts in great detail in a critical essay, called "Questioning the validity of the APPROVe study's official interpretation". The essay is available online at http://www.homestead.com/emguidemaps/files/vioxx-APPROVeCritique.htm. (The essay is situated in the soapbox section of my personal website -- type "Jeff Mann EM guidemaps" in the US-version of Google's search engine to locate my website if the link doesn't work). I concluded that the APPROVE study had a low control event rate, a small signal, and significant noise (presumably due to patient heterogeneity and chance effects that possibly created an imbalance in prognostic variables between the treated and placebo patients during the second half of the trial trial). Under those circumstances, a RCT is deemed to have a low signal/noise ratio, and Sackett [2] states that one cannot be confident in the conclusion of a randomised controlled trial that has a low signal/noise ratio. If the APPROVe study is widely deemed to have a low signal/noise ratio, then public health policy decision makers need to take that fact into full account. Jeff Mann. MD. References: 1. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. NEJM 2005. Online - Feb 15. (due to be published in the print version of the NEJM in late March 2005). 2. Sackett, David L. Why randomized controlled trials fail but needn't: 2. Failure to employ physiological statistics, or the only formula a clinician-trialist is ever likely to need (or understand!) CMAJ 165(9):1226-1237, October 30, 2001. Available online at http://www.cmaj.ca/cgi/content/full/165/9/1226 Competing interests: None declared |
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Alfredo Tartarone, oncologist Division of Medical Oncology and Hematology, Centro di Riferimento Oncologico della Basilicata (C.R., Gianpiero Romano, Raffaele Ardito, Giuseppina Gallucci, Nicola Di Renzo
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On 30 September 2004 on the basis of the APPROVe (Adenomatous Polyp Prevention On Vioxx) trial that showed an adverse cardiovascular side- effect profile, rofecoxib (Vioxx™) was withdrawn from the market. After more than 80 million patients had taken this medicine a relative small trial revealed an already know side effect toxicity of rofecoxib. In fact previously, also the VIGOR (Vioxx Gastrointestinal Outcomes Research) trial revealed a significant increase of cardiovascular events in patients taking rofecoxib compared with those receiving naproxen1. A similar public health concern occurred about another coxib (valdecoxib), which is used by 7 million patients worldwide2. Recently, the National Institutes of Health (NIH) announced that it has suspended the use of COX- 2 inhibitor celecoxib (Celebrex™) for all participants in a large colorectal cancer prevention clinical trial conducted by the National Cancer Institute (NCI)3. The study, called the Adenoma Prevention with Celecoxib (APC) trial, was stopped because analysis by an independent Data Safety and Monitoring Board (DSMB) showed a 2.5-fold increased risk of major fatal and non-fatal cardiovascular events for participants taking the drug compared to those on a placebo. Considering that the rigor of relatively small clinical trials has allowed us to find this problem, several questions remain to be addressed and in particular, how could be improved the efficacy of the post marketing surveillance? Which is the cardiovascular side effect of the other selective COX-2 inhibitors actually available in commerce? REFERENCES 1. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286(8):954-9. Ray WA, Griffin MR, Stein CM. Cardiovascular toxicity of valdecoxib. N Engl J Med 2004;351:2767. Solomon SD, McMurray JJ, Pfeffer MA et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352: Feb 15; [Epub ahead of print]. Competing interests: None declared |
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