Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
The overlooked benefits of aspirin-COX-2 inhibitor combination for patients with cardiovascular risk
- Michal R Pijak, Frantisek Gazdik (27 February 2003)
|
|
|||
|
Michal R Pijak, consultant in allergy and rheumatology Institute of Preventive and Clinical Medicine, 83301 Bratislava,Slovakia, Frantisek Gazdik
Send response to journal:
|
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 complications. 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 Frantisek Gazdik 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 1995;310:827-830. 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 2003;163:481-486. 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- 84. Competing interests: None declared |
|||