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Rapid response to:


Life without COX 2 inhibitors

BMJ 2006; 332 doi: (Published 01 June 2006) Cite this as: BMJ 2006;332:1287

Rapid Response:

The death of COX 2 inhibitors is greatly exaggerated

Shaugnessy and Gardener1 are to be commended for emphasising the non-
pharmacological treatment of arthritis – the daily mantra of
rheumatologists. Unfortunately, they misrepresent the data from the meta
–analysis of Kearney and colleagues2 that generated their leading article.
Their introductory statement that COX 2 inhibitors “have been associated
with an increased risk of myocardial infarction with prolonged use
compared with placebo or other NSAIDs” is both misleading and inaccurate,
as it is not supported by published data. The conclusions from Kearney’s
meta-analysis was actually that, with the exception of naproxen, there was
no difference between COX 2 inhibitors and NSAIDs in relation to vascular
events. The only surprise in this study was the apparent reduction in risk
from naproxen as this has not been observed in large population and case
controlled studies. The results from a retrospective observational study
in the Ontario population did not find any reduction in risk of a
myocardial infarction from naproxen compared with COX 2 inhibitors3. A
prospective large population based study conducted by the FDA in
California4 found a significant association between naproxen and
myocardial infarction, in addition to a number of other NSAIDs and
rofecoxib, but not with celecoxib, an observation that led to a black box
warning on all NSAIDs and COX 2 inhibitors in the USA. This finding was
similar to that from a nested case control study from a GP data-base in
the UK5. The important conclusion from all this data is that, with the
exception of high dose rofecoxib, there is no greater risk of myocardial
infarction from COX 2 inhibitors than non-selective NSAIDs. Whether this
observation is from the drugs or the arthritis however is not clear as
there is an established association between arthritis and cardio-vascular

Shaugnessy and Gardner also dismiss the argument for prescribing COX
2 inhibitors: “ The common assumption that COX 2 inhibitors are safer than
other NSAIDs has not been borne out.” This statement is referenced with a
critical review of the CLASS study yet they fail to reference a range of
other studies that demonstrate increased safety from COX 2 inhibitors. It
could be argued that the data from a case control study in a UK based GP
register6 supports their argument as the authors concluded that there was
no strong evidence for any enhanced benefit from COX 2 inhibitors.
However, although the study included symptomatic ulceration in addition to
serious complications, they observed that naproxen had the highest risk
and did not find an association between the use of celecoxib and GI
complications. The VIGOR7 and TARGET8 studies of rofecoxib and lumiracoxib
respectively both found an increased rate of GI complications from non-
selective NSAIDs. This potential benefit of COX 2 inhibitors was an
observation also supported by the Ontario population study9.

The major concern is the significant toxicity from non-selective
NSAIDs. They are arguably the most toxic drugs prescribed in primary care
and their toxicity is a major public health problem. Of course we need
more and better outcome data to determine which group of patients should
be considered for COX 2 inhibitors. Reducing the use of all these drugs is
an important message, but switching patients from a COX 2 inhibitor to a
non-selective NSAID confers no benefit to the patient and may increase the
risk of a serious and potentially life threatening GI complication.

1.Shaugnessy AF Gordon AE Life without COX 2 inhibitors BMJ
2006;332:1287-8 (3 June)

2. Kearney PM Baigent C Godwin J Halls H Emberson JR Patrono C. Do
selective cyclo-oxygenase inhibitors and traditional NSAIDs increase the
risk of atherothrombosis? Meta-analysis of randomised trials. BMJ
2006;332:1302-5(3 June)

3. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, Austin
PC, Laupacis A.Effect of selective cyclooxygenase 2 inhibitors and
naproxen on short-term risk of acute myocardial infarction in the elderly.
Arch Intern Med. 2003;163:481-6

4. Graham DJ,Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray
WA. Risk of acute myocardial infarction and sudden cardiac death in
patients treated with cyclo-oxygenase 2 selective and non-selective non-
steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;

5. Hippisley-Cox J, Coupland C Risk of myocardial infarction in patients
taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-
inflammatory drugs: population based nested case-control analysis. BMJ.

6. Hippisley-Cox J, Coupland C, Logan R Risk of adverse gastrointestinal
outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional
non-steroidal anti-inflammatory drugs: population based nested case-
control analysis BMJ 2005;331:1310-1316

7. Bombardier Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R,
Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ;
VIGOR Study Group Comparison of upper gastrointestinal toxicity of
rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study
Group. N Engl J Med. 2000 Nov 23;343(21):1520-8

8. Hawkey Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M,
Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ;
TARGET Study Group Comparison of lumiracoxib with naproxen and ibuprofen
in the Therapeutic Arthritis Research and Gastrointestinal Event Trial
(TARGET), reduction in ulcer complications: randomised controlled trial.
Lancet 2004;364(9435):665-74

9. Muhammad Mamdani, Paula A Rochon, David N Juurlink, Alex Kopp, Geoffrey
M Anderson, Gary Naglie, Peter C Austin, and Andreas Laupacis
Observational study of upper gastrointestinal haemorrhage in elderly
patients given selective cyclo-oxygenase-2 inhibitors or conventional non-
steroidal anti-inflammatory drugs. BMJ 2002; 325:624-8

Competing interests:
Clinical investigator COX 2 inhibitors and occasional paid lectures.

Competing interests: No competing interests

16 June 2006
Frank McKenna
Consultant Physician and Rheumatologist
Trafford General Hospital Manchester