Findings from COX 2 studies are releasedBMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7488.381-a (Published 17 February 2005) Cite this as: BMJ 2005;330:381
All rapid responses
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effect profile, rofecoxib (Vioxx™) was withdrawn from the market.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?
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: No competing interests
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
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  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.
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: No competing interests