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| Journal of the New Zealand Medical Association,
11-March-2005, Vol 118 No 1211
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COX-2 inhibitors—first, do no harm
Mark Weatherall, Sarah Aldington, Philippa Shirtcliffe,
Brent Caldwell, Richard Beasley
On 22 February 2005, Medsafe advised that the increased
cardiovascular risk of cyclooxygenase-2 (COX-2) inhibitors outweighs their
benefit for the general population and recommended that people at high risk of
cardiovascular events should see their doctor to stop treatment with COX-2
inhibitors immediately.1 This recommendation
followed a review of available research data for all currently marketed COX-2
inhibitors. In response to the Medsafe advice, there was widespread public
criticism from representatives of the pharmaceutical industry and medical
profession.
The main criticisms appeared to be that the finding of an
increased cardiovascular risk with the use of COX-2 inhibitors was somehow
unexpected; that it was specific to rofecoxib (Vioxx) and was not a class
effect; that the magnitude of the risk was very small; that there had been a
comprehensive research programme that had demonstrated their safety; and that
the New Zealand regulatory authority was ‘out of step’ with the rest
of the world.2
We briefly examine the evidence relating to each of these
issues:
Plausible biological mechanismThere is a widely accepted
biologically plausible mechanism whereby COX-2 inhibitors would increase the
cardiovascular risk through shifting the functional balance of the vaso-active
prostanoids towards the promotion of thrombosis and
atherogenesis.3,4 Thromboxane
A2, a major COX-1 mediated product causes
platelet aggregation, vasoconstriction, and smooth muscle proliferation. In
contrast, prostacyclin is a major COX-2 mediated product which essentially has
the opposite effects of thromboxane A2,
inhibiting platelet aggregation and having antiproliferative and vasodilatory
actions.
As a result, by suppressing production of prostacyclin
without affecting the synthesis of thromboxane
A2, COX-2 inhibitors have the potential to
increase the risk of cardiovascular thromboembolic events.
Increased cardiovascular risk is a class effect of COX-2 inhibitors.Increased cardiovascular risk has
now been demonstrated for rofecoxib,5,6
celecoxib,7 valdecoxib, and its pro-drug
parecoxib,8,9 with insufficient data available
concerning etoricoxib, lumiracoxib, and meloxicam. The magnitude and nature of
the risks associated with COX-2 inhibitors are illustrated by the three studies
published in the New England Journal of
Medicine on 21 February, a day prior to the Medsafe
recommendations.7,9,10
The ‘Colorectal Adenoma Chemoprevention Trial’
reported a 1.9-fold increased risk of major cardiovascular thrombotic event with
rofecoxib when compared with placebo,10 similar
to the 2.2-fold risk identified in the previous cumulative meta-analysis of 18
randomised controlled trials of rofecoxib.5 A
similar magnitude of risk was identified from the comparable Colorectal Adenoma
Prevention Trial with celecoxib in which a 2.3- and 3.4-fold increased risk of
cardiovascular events was observed with 400 and 800 mg daily doses of celecoxib
respectively.7
In the third placebo-controlled study investigating the use
of valdecoxib and its pro-drug parecoxib after cardiac surgery, a 3.7-fold
increased risk of major cardiovascular events was
observed.9 As illustrated by these studies, the
currently available evidence indicates a class effect of COX-2 inhibitors
consistent with the biological mechanism discussed above.
The magnitude of the cardiovascular risk with COX-2 inhibitors is considerableMost of the large clinical trials of
COX-2 inhibitors have excluded patients at high risk of cardiovascular events,
despite the fact that a sizeable proportion of patients taking these drugs are
at significant cardiovascular risk. For example, in the VIGOR Study, patients
were excluded if they had received treatment with aspirin or if they had a
history of myocardial infarction or coronary bypass in the year before the
study.6 These criteria led to an incidence of
myocardial infarction in the control group of 0.1 per 100 patient years,
compared with 0.4 with rofecoxib.
However if the four-fold relative risk of myocardial
infarction associated with rofecoxib is applied to a patient at ‘mild to
moderate’ baseline cardiovascular risk (1-2% per year), then one could
estimate that the patient would move into the ‘very high’
cardiovascular risk group (4–8% per year) if taking
rofecoxib.11 This calculation is based on the
finding that the magnitude of the relative risk of myocardial infarction with
COX-2 inhibitors is similar for patients of different baseline
risk.7
As a result, the absolute risk is substantial in the elderly
population in whom this class of drugs is most commonly prescribed. Indeed the
United States’ Food and Drug Agency (FDA) itself has estimated that
between 88,000 and 140,000 excess cases of serious coronary heart disease might
have resulted from rofecoxib rather than other non-steroidal anti-inflammatory
drugs (NSAIDs) in the United States
alone.12
Inadequate research programme of cardiovascular risk.Clinical trials of COX-2 inhibitors
have generally been short-term studies designed to assess their efficacy and to
evaluate adverse gastrointestinal effects. Most studies were neither designed
nor powered to assess the risk of cardiovascular effects and excluded patients
at high risk of cardiovascular
events.5,13,14
The use of NSAIDs (rather than placebo) as control
medication in many of the studies also made the findings difficult to interpret.
As a result, one can draw the conclusion that there has been inadequate research
into the cardiovascular effects of COX-2 inhibitors; in particular, there has
been a paucity of long-term studies in high-risk populations.
Medsafe recommendations similar to those from other regulatory authoritiesThe strong warning issued by Medsafe
was similar to that made by other regulatory authorities. For example, the
European Medicines Agency has also stated that there was an increased risk
cardiovascular adverse events for COX-2 inhibitors as a class, and that these
medicines should not be used in patients with a history of ischaemic heart
disease or stroke.15
To conclude, we refer to the recent
New England Journal of Medicine
editorial which suggested that due to well-established options for treatment of
all approved indications for COX-2 inhibitor drugs, it is reasonable to ask
whether the use of these drugs can now be
justified.16 The editorial went on to comment
that ‘as we apply new science to develop new medicines we must not forget
that our first job is to do no harm.’
Author information:
Mark Weatherall, Senior Lecturer, Rehabilitation Research and Teaching Unit,
Department of Medicine, Wellington School of Medicine and Health Sciences, Otago
University, Wellington; Sarah Aldington, Senior
Medical Research Fellow; Philippa Shirtcliffe, Senior Medical Research Fellow;
Brent Caldwell, Medical Research Fellow; Richard
Beasley, Director, Medical Research
Institute of New Zealand, Wellington
Correspondence:
Professor Richard Beasley, Medical Research Institute of New Zealand, PO Box
10055, Wellington 6001. Fax: (04) 472 9224; email: richard.beasley@mrinz.ac.nz
References:
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