Editorial

NSAIDs and aspirin: friends or foes?

Keywords: NSAID; Aspirin; Platelet aggregation; Thromboxane

Nonsteroidal antiinflammatory drugs (NSAIDs) are backin the spotlight. The controversy about the cardiovascularside effects of specific COX-2 inhibitors was still ongoingwhen an article by Catella-Lawson et al. [1] published lastyear in the New England Journal of Medicine raised a newconcern: when taken immediately before low-dose aspirin,some NSAIDs inhibited the biological effects of low-doseaspirin therapy associated with cardiovascular protection.

Low-dose aspirin (75–150 mg/d [2]) has been convinc-ingly shown to reduce the incidence of myocardial infarctionand stroke in high-risk patients [3]. This protective effect ofaspirin is largely ascribable to the inhibition of platelet aggre-gation, which results from the inhibition of platelet throm-boxane synthesis. Catella-Lawson et al. [1] gave 6 d oflow-dose aspirin treatment (81 mg/d) in the morning 2 hbefore or 2 h after single doses of ibuprofen 400 mg oncedaily, acetaminophen (1000 mg/d), or rofecoxib (25 mg/d).In addition, the same aspirin dose was tested in associationwith ibuprofen 400 mg tid and delayed-release diclofenac75 mg bid. Assays done on the sixth day showed completeinhibition of platelet aggregation and thromboxane synthesisby aspirin even when acetaminophen, rofecoxib, or di-clofenac was also taken. Platelet aggregation and thrombox-ane production remained maximally inhibited when a singledose of ibuprofen was taken 2 h after the aspirin dose.However, a single ibuprofen dose taken before the aspirin oribuprofen tid inhibited the effects of aspirin on platelet aggre-gation and thromboxane formation.

Thromboxane B2 is produced when the enzyme cy-clooxygenase (COX) converts arachidonic acid to thrombox-ane. Data obtained in the early 1990s showed that plateletscontain the COX-1 but not the COX-2 isoform [4]. Thus,platelet thromboxane is produced only by COX-1. Studiesconducted in the 1970s [5] show that aspirin binds to theserine at position 529 of the COX binding site, therebyirreversibly inhibiting the activity of the enzyme. Aspirin hasgreater affinity for COX-1 than for COX-2. Thus, even lowdoses of aspirin cause irreversible and specific inhibition ofplatelet COX-1, leading to complete irreversible inhibition ofthromboxane synthesis. Low-dose aspirin therefore acts as aspecific COX-1 inhibitor. Identification of the inducible

COX-2 isoform produced in inflammatory disorders recentlyled to the development of the specific COX-2 inhibitorscelecoxib and rofecoxib, with the goal of improving thegastric safety profile as compared to nonspecific COX inhibi-tors. COX-2 inhibitors do not inhibit COX-1, the enzyme thatproduces prostaglandins associated with protection of thegastric mucosa. COX-2 inhibitors do not inhibit plateletCOX-1 and, consequently, fail to inhibit platelet aggregation.In theory, all nonspecific NSAIDs are capable of inhibitingplatelet aggregation, and this has been confirmed by experi-mental data. This does not mean, however, that all nonspe-cific NSAIDs, when used on a long-term basis, afford thecardiovascular protection demonstrated with low-dose aspi-rin. Protection is probably dependent on complete and long-lasting thromboxane synthesis inhibition, such as producedwhen aspirin binds irreversibly to the active COX-1 site.When this happens, restoration of circulating thromboxanelevels is mainly related to the release of new platelets fromthe pool of bone marrow megakaryocytes. Platelets have ahalf-life of 10 d, so that the effect of a single aspirin doseshould be long lasting. However, daily dosing is necessarybecause significant production of thromboxane occurs whenonly 10–15% of new platelets are present in the bloodstream[1]. Nonspecific NSAIDs bind reversibly to active COX sites.This explains why thromboxane synthesis inhibition is notlinear during treatment with nonspecific NSAIDs. Thus,there is no firm evidence that NSAIDs other than aspirin offerprotection against cardiovascular events [6]. In a recent trialcomparing the safety profiles of rofecoxib and naproxen [7],myocardial infarction was more common in the rofecoxibarm. This unexpected result has generated heated contro-versy between those who believe that specific COX-2 inhibi-tors disrupt the balance between endothelial vasodilatingprostaglandins (produced by COX-2) and aggregation-inducing platelet thromboxane (produced by COX-1) [8] andthose who contend that the higher myocardial infarction ratein the rofecoxib group is ascribable to a decrease in myocar-dial infarctions in the naproxen group consistent with anaspirin-like effect of this NSAID [9]. Naproxen was nottested in the study by Catella-Lawson et al. [1]. Cautionsuggests that low-dose aspirin should be continued during

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COX-2 inhibitor treatment, although this may affect theprofile of gastric side effects [10]. Concomitant use of ibu-profen is problematic. The study by Catella-Lawson et al. isconsistent with competition between ibuprofen and aspirinfor the active COX-1 site. Ibuprofen given before aspirin mayoccupy the binding sites, making them inaccessible to aspi-rin. After a few hours, aspirin is excreted from the body andibuprofen detaches from the binding sites. This may leave theCOX-1 sites available for arachidonic acid, which may thenbe converted to thromboxane. Conversely, aspirin given be-fore ibuprofen binds permanently to the COX-1 sites, therebyirreversibly inhibiting thromboxane formation by the plate-lets. In the study by Catella-Lawson et al., repeated doses ofibuprofen (but not diclofenac) prevent aspirin from com-pletely inhibiting platelet aggregation and thromboxane pro-duction, even when the aspirin is taken first. Here, the expla-nation seems more complicated than that for single doses.Two hypotheses can be put forward. One stems from the factthat ibuprofen used alone causes prolonged inhibition ofthromboxane B2 formation that does not, however, uni-formly cover the 24-h cycle. The second hypothesis rests onthe differences between the pharmacological effects of ibu-profen and diclofenac on COX-1 [11]. Aspirin may bind toserine 529 at the active COX-1 site even in the presence ofdiclofenac, which binds to a residue located at a distancefrom serine 529. The bulky ibuprofen molecule, in contrast,may prevent aspirin from accessing serine 529.

Clearly, much work remains to be done to unravel theinteractions between aspirin and NSAIDs. Other interactionshave been found recently. For example, low-dose aspirin andnonspecific NSAID therapy have been shown to act synergis-tically in increasing the risk of gastroduodenal complica-tions. The relative risk of serious gastric events was 2.7(2.2–2.9) with low-dose aspirin alone and 5.6 (4.4–7.0) withlow-dose aspirin and a nonspecific NSAID [12]. Thus, thewell-established benefits of COX-2 inhibitors in terms ofgastric safety may be lost in patients who also takelow-dose aspirin [10].

In conclusion, these new data warrant new precautions. Inpatients taking both ibuprofen and low-dose aspirin, aspirinshould be taken first and a 2-h interval left before the ibupro-fen dose. Since ibuprofen is available over the counter, phar-macists should be made aware of this requirement, whichprobably applies also to other nonspecific NSAIDs.

References

[1] Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenaseinhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809–17.

[2] Antithrombotic Trialists’ Collaboration. Collaborative meta-analysisof randomised trials of antiplatelet therapy for prevention of death,myocardial infarction, and stroke in high risk patients. BMJ 12 Jan2002;324(7329):71–86.

[3] Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94.

[4] Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van DePutte LB, et al. Cyclooxygenase in biology and disease. FASEB J1998;12:1063–73.

[5] Vane JR. Inhibition of prostaglandin synthesis as a mechanism ofaction for aspirin-like drugs. Nat New Biol 1971;231:232–5.

[6] Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidalanti-inflammatory drugs and risk of serious coronary heart disease: anobservational cohort study. Lancet 2002;359:118–23.

[7] Bombardier C, Laine L, Reicin A, et al. Comparison of upper gas-trointestinal toxicity of rofecoxib and naproxen in patients with rheu-matoid arthritis. N Engl J Med 2000;343:1520–8.

[8] Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM,Grosser T, et al. Role of prostacyclin in the cardiovascular response tothromboxane A2. Science 2002;296:539–41.

[9] Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS,Barr E, et al. Cardiovascular thrombotic events in controlled, clinicaltrials of rofecoxib. Circulation 2001;104:2280–8.

[10] Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whel-ton A, et al. Gastrointestinal toxicity with celecoxib vs. nonsteroidalanti-inflammatory drugs for osteoarthritis and rheumatoid arthritis:the CLASS study: A randomized controlled trial. Celecoxib long-termarthritis safety study. JAMA 2000;284:1247–55.

[11] Mancini JA, Riendeau D, Falgueyret J-P, Vickers PJ, O’Neill GP.Arginine 120 of prostaglandin G/H synthase-1 is required for theinhibition by nonsteroidal anti-inflammatory drugs containing a car-boxylic acid moiety. J Biol Chem 1995;270:29372–7.

[12] Sorensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH,McLaughlin JK, et al. Risk of upper gastrointestinal bleeding associ-ated with use of low-dose aspirin. Am J Gastroenterol 2000;95:2218–24.

Francis Berenbaum *Saint-Antoine Teaching and Research Center, Pierre and

Marie Curie University, Paris VI, Paris, FranceE-mail address: francis.berenbaum@sat.ap-hop-paris.fr

Received 6 June 2002; accepted 27 November 2002

* Hôpital Saint-Antoine, service de rhumatologie,184, rue du Faubourg Saint-Antoine, 75012 Paris, France

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