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Letters to the Editor
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Adverse effects
Should etolodac be NSAID of first choice?
From Mr A. D. Hutchinson, MRPharmS
I would like to comment on the letter from Paul Jerram (PJ, 8
October, p440 PDF (120K)) and the surprising news that etodolac is the
non-steroidal anti-inflammatory
drug of choice in the Isle of Wight.
Etodolac appears to have been included in the National Institute for Clinical
Excellence’s evaluation of COX-2 selective drugs in 20011, on account
of its in vitro COX-2 selectivity, which is greater than that for a number
of other NSAIDs, including meloxicam and celecoxib.2 However, in
vitro selectivity is no guide to in vivo gastrointestinal (GI) toxicity: piroxicam
has greater COX-2 selectivity in vitro than ibuprofen.2 Etodolac has no
randomised controlled trial (RCT) evidence of superior GI safety compared
with usual reference NSAIDs such as ibuprofen, naproxen or diclofenac.1
Inhibition of endothelial prostacyclin formation in the absence of platelet
thromboxane production is one possible mechanism by which selective COX-2
inhibitors might increase thrombotic risk.3 A risk might therefore be seen
with all selective COX-2 inhibitors. Earlier this year, the Medicines and
Healthcare products Regulatory Agency advised that: “The evidence
suggests that selective COX-2 inhibitors, as a class, may cause an increased
risk of thrombotic events (eg, myocardial infarction and stroke) compared
with placebo and some NSAIDs, and the risk may increase with dose and duration
of exposure.”4 Its letter implies that this statement concerned celecoxib,
etoricoxib, parecoxib and valdecoxib. Given the in vitro COX-2 selectivity
of etodolac, should it have included this drug as well?
Clearly, as in the case of ibuprofen or piroxicam, factors other than COX-2
selectivity affect GI toxicity. But if, in the absence of RCT data, we
were to accept the argument that etodolac must have a lower GI risk than
many other NSAIDs simply because it is much more COX-2 selective, we must
also accept that it might carry an increased risk of thrombotic events.
An increased cardiovascular risk from etodolac has not been demonstrated,
but neither has its cardiovascular safety. Absence of evidence is not evidence
of absence.
We must come back to the four aims proposed by Nicholas Barber as necessary
to hold in the balance when considering what makes good prescribing: maximising
effectiveness, minimising risks, minimising costs and respecting patient
choices.5 The first three help us make decisions and recommendations at
a population or public health level. The fourth does not negate the importance
of the first three, but helps us tailor treatment to the needs and wishes
of individual patients.
There is no reason to believe that, at a population level, one NSAID is
any more effective than any other in managing the symptoms of musculoskeletal
disease6, so that consideration does not support the recommendation of
etodolac as first choice drug. Nor can we accept that using etodolac as
first choice NSAID could be relied upon to minimise risk, given the lack
of RCT evidence on GI safety and the issues relating to cardiovascular
safety referred to above. At current MIMS and Drug Tariff prices, Eccoxolac
600mg per day is more than three times the cost of generic diclofenac tablets
150 mg per day or generic ibuprofen 1.2g per day, and nearly double the
cost of generic ibuprofen 1.8g per day.
It may be that a few patients might, idiosyncratically, respond considerably
better to etodolac than more usual first choice NSAIDs such as ibuprofen
or diclofenac. For such patients, a careful exploration with them of the
use of etodolac in the context of all four of the above aims might lead
to the decision that etodolac is the best drug for them. But, at a population
level, and considering efficacy, safety and cost, I am surprised that the
Isle of Wight Primary Care Trust has made the decision it has.
Andy Hutchinson
Head of Medicines Management
South Leeds Primary Care Trust
References
1. National Institute for Clinical Excellence. Technology appraisal document
27. London: NICE, 2001
2. Department of Pharmacology and Therapeutics, University of British
Columbia. Therapeutics letter 43. Vancouver: University of British Columbia,
2001
3. Medicines and Healthcare Products Regulatory Agency. Cardiovascular
safety of non-steroidal anti-inflammatory drugs, overview of key data.
London: MHRA, August 2005
4. Duff G. Updated advice on the safety of selective cox-2 inhibitors.
London: MHRA, February 2005
5. Barber N. What constitutes good prescribing? BMJ 1995;310:923–5
6. Gøtzsche P. Non-steroidal anti-inflammatory drugs. Clinical Evidence.
Available at: www.clinicalevidence.com. Accessed 20 October 2005. |
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