Systematic review of celecoxib for osteoarthritis and rheumatoid arthritisBMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7384.334 (Published 08 February 2003) Cite this as: BMJ 2003;326:334
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The overlooked benefits of aspirin-COX-2 inhibitor combination for patients with cardiovascular risk
To the Editor:
Recognition of the failure of selective COX-2 inhibitors to afford cardio-
protection has led to raised interest in their combination with aspirin.
Meta-analysis by Deeks et al on celecoxib documented that patients
taking celecoxib with aspirin (up to 325mg/day) still showed a significant
reduction (51%) in the incidence of ulcers detected by endoscopy,
compared with other non-steroidal anti-inflammatory drugs (NSAID) at 12
weeks (1). However the reduction was greater (73%) in those not taking
aspirin. The same pattern of results at six months was observed in the
CLASS study. Based on these results the authors concluded: "The present
weight of evidence does not suggest that celecoxib should be withheld
from aspirin users as currently recommended by the National Institute for
Clinical Excelence (NICE), but further research should clarify the
possible reduction in efficacy in this group"(1).
The position taken on this issue by Deeks et al has been strictly
objected to Metcalfe et al who say: "Pending any further information, we
concur with the current precautionary recommendation of the NICE, to
withhold celecoxib from aspirin users"(2). Rationale for this opinion
appears to be based on uncertainties about the effectiveness of celecoxib
beyond six months. We accept the reasoning that aspirin use by reducing
GI benefit may change cost-effectiveness of COX-2 inhibition and, hence,
there is no justification for prescribing a more expensive therapy. To
make such a recommendation, however, would require the examination of
the risk and benefits of less expensive alternative therapies,
especially combination of aspirin and non-aspirin NSAID (NANSAID) or
aspirin and NANSAID alone. This issue, however, was not explored in detail
yet. We would like, therefore, to introduce three points, which,
according to us, might support the benefits of aspirin-COX-2 inhibitor
combination over other alternatives to patients with cardiovascular risk.
Firstly, several studies documented additive risk for GI
complications by concurrent use of prophylactic aspirin and NANSAIDs. It
should be emphasised that this risk is substantially increased by higher
doses of NSAIDs (3). It is possible, that with higher dosages of COX2
inhibitors, the specificity for cyclooxygenase may be lost. These facts
should be taken into account in evaluating data from clinical studies
such as the CLASS, which employed much higher doses of celecoxib than
usual. Therefore it is likely that the smaller risk reduction in
aspirin users in CLASS could be attributable mainly to the supra-
therapeutic dosages of celecoxib. Nevertheless, aspirin users still
showed tendency to relative risk reduction of GI bleeding, based on using
12-15 month data (2). In a view of this, it seems reasonable to assume
that combination of lowest effective doses of both aspirin (30-75mg) and
COX-2 inhibitor may show more significant risk reduction of GI
Secondly, a further potential advantage to combine aspirin with COX-
2 inhibitor instead of NANSAID is based on the assumption that COX-2
inhibitor is less likely to interfere with the antiplatelet effect of
aspirin. In fact, recent evidence suggests that concomitant
administration of certain NANSAIDs antagonizes the irreversible platelet
inhibition induced by aspirin due to competetive interaction with
platelet COX-l (4). This newly identified and unique drug-drug interaction
does not extend to the COX-2-specific inhibitors, as they have no effect
on the platelet COX-1 isoenzyme. Another approach might be to try agents
other than aspirin for platelet inhibition. In any case, more clinical
data on the subject are needed.
Thirdly, the main concern of using NANSAIDs alone relates to the
fact that in most cases the antiplatelet effect does not last
throughout the dosing period (5). This fear is reinforced by the results
of three epidemiological studies that found no evidence of cardoprotective
effects of NANSAIDs. Recently, however, three case control studies
documented reduced rate of acute myocaridal infarction (MI) in naproxen
users. These results, at least in part, help to explain higher incidence
of MI in rofecoxib users in the VIGOR study. However, recent population-
based retrospective cohort study showed no significant difference in MI
risk for new users of celecoxib, naproxen, or nonnaproxen NSAIDs (6).
These results support the notion that brief antiplatelet effect, may
limit the usefulness of using naproxen for cardioprotection in rheumatic
patients, in whom the most frequent pattern of NSAID use is
intermittent. The same drawback relates to all NSAIDs, including aspirin.
Of importance, low doses of aspirin provide more effective
cardioprotection then higher analgesic doses (7).
In summary, the available data indicate that combination of aspirin
and COX-2 inhibitor seems to be, for the moment, the most optimal regimen
for patients requiring cardiovascular prophylaxis as well as chronic
therapy with NSAID. The benefits of aspirin-COX-2 combination over
alternatives mentioned above include not only better gastrointestinal
tolerability but also higher guarantee of sustained inhibition of
platelet aggregation, along with more freedom in the selection of
appropriate dosing regimen. Since COX-2 inhibitors have been so far
reserved only for patients at highest risk of GI toxicity, we assume that
spectrum of their indication should be extended also to those with
cardiovascular risk, who can tolerate low dose aspirin.
Michal R Pijak
consultant in allergy and rheumatology
Department of Clinical Immunology,
Institute of Preventive and Clinical Medicine,
833 01 Bratislava, Slovakia
1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper
gastrointestinal safety of celecoxib for treatment of osteoarthritis and
rheumatoid arthritis: systematic review of randomised controlled trials.
BMJ 2002;325:619-23. (21 September).
2. Metcalfe S, Dougherty S, McNee W. Celecoxib`s relative
gastrointestinal safety is overstated. Electronic response to: Systematic
review of celecoxib for osteoarthritis and rheumatoid arthritis. bmj.
2003. bmj.com/cgi/content/full/326/7384/334 (accessed 8 Feb).
3. Weil J, Colin-Jones D, Langman M, Lawson D, Logan R, Murphy M et
al. Prophylactic aspririn and risk of peptic ulcer bleeding. BMJ
4. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S,
Tournier B et al. Cyclooxygenase inhibitors and the antiplatelet effects
of aspirin. N Engl J Med 2001;345-1809-17.
5. Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M et
al. Platelet-active drugs. The relationships among dose, effectiveness,
and side effects. Chest 2001;119:39S-63S.
6. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G et
al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-
term risk of acute myocardial infarction in the elderly. Arch Intern Med
7. Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe
KE et al. Low-dose and high-dose acetylsalicylic acid for patients
undergoing corotid endarterectomy: a randomised controlled trial. ASA and
Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999;353:2179-
Competing interests: No competing interests