Correspondence

Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin

N Engl J Med 2002; 346:1589-1590May 16, 2002

Article

To the Editor:

The article by Catella-Lawson et al. (Dec. 20 issue)1 is interesting, particularly in view of the number of patients with cardiac conditions who are candidates for both traditional nonsteroidal antiinflammatory drugs (NSAIDs) and low-dose aspirin.

One result reported by the authors seems to be in conflict with the pharmacokinetics and mechanism of action of ibuprofen and aspirin. In the parallel-group study, aspirin was given two hours before the start of a multiple-dose regimen of ibuprofen. Surprisingly, the protective effect of aspirin was not maintained in these circumstances. If we accept the idea that the mechanism underlying the effect of aspirin is an irreversible acetylation of the serine residue, then antagonism of the effect of the dose of aspirin is unlikely. The subsequent doses of ibuprofen may have modified the benefit of aspirin but should not have eliminated the benefit, since 12 hours after dosing, up to six half-lives may have passed and blood levels of ibuprofen should be minimal.2

Thomas G. Burnakis, Pharm.D.
Baptist Medical Center, Jacksonville, FL 32207
tburnaki@bmcjax.com

2 References

1. 1

   Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-1817
   Full Text | Web of Science | Medline

2. 2

   McEvoy GK, ed. AHFS drug information, 2001. Bethesda, Md.: American Society of Health-System Pharmacists, 2001.
   

To the Editor:

Catella-Lawson and colleagues conclude that treatment with ibuprofen may limit the cardioprotective effects of aspirin in patients with an increased risk of cardiovascular events. However, the extent of ex vivo platelet cyclooxygenase inhibition does not reflect in vivo inhibition of thromboxane biosynthesis and may not be a reliable measure of the potential cardioprotective effects of drugs that target cyclooxygenase. Episodic increases in thromboxane biosynthesis, as reflected by increases in urinary 11-dehydro-thromboxane B₂ excretion,1 have been reported in patients with unstable angina, despite more than 95 percent suppression of platelet cyclooxygenase by aspirin,2 and can be more effectively suppressed by a nonselective inhibitor of cyclooxygenase than by aspirin.3 Despite the lack of a demonstrable effect of rofecoxib on ex vivo thromboxane generation in patients already receiving aspirin, as reported by Catella-Lawson et al., it remains possible that the combination of a selective cyclooxygenase inhibitor and aspirin is more effective than aspirin alone for suppressing in vivo thromboxane generation. Whether greater suppression of in vivo thromboxane biosynthesis reduces the risk of cardiovascular events remains to be determined.

Andrew McQuillan, M.B., B.S.
John W. Eikelboom, M.B., B.S.
Royal Perth Hospital, Perth 6847, Australia
john.eikelboom@health.wa.gov.au

3 References

1. 1

   Perneby C, Granstrom E, Beck O, Fitzgerald D, Harhen B, Hjemdahl P. Optimization of an enzyme immunoassay for 11-dehydro-thromboxane B(2) in urine: comparison with GC-MS. Thromb Res 1999;96:427-436
   CrossRef | Web of Science | Medline

2. 2

   Vejar M, Fragasso G, Hackett D, et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990;63:163-168
   Web of Science | Medline

3. 3

   Cipollone F, Patrignani P, Greco A, et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation 1997;96:1109-1116
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Burnakis believes that interference with the action of aspirin by a multiple-dose daily regimen of ibuprofen is unexpected. However, the evidence that relates plasma NSAID levels to platelet cyclooxygenase-1 inhibition is scant, and the evidence that links drug levels to the likelihood of an interaction with aspirin is nonexistent. We reported that six hours after a single dose of ibuprofen — roughly three half-lives — the inhibition of platelet cyclooxygenase-1, as reflected by serum thromboxane B₂ levels, remains substantial (81±4 percent). Inhibition might be even greater after the administration of ibuprofen three times a day for six days. It also seems plausible that inhibition may be related nonlinearly to the capacity for interference with the access of aspirin to its target serine.

Drs. McQuillan and Eikelboom misinterpret the implications of our description of the nonlinear relation between the inhibition of serum thromboxane B₂ and urinary thromboxane metabolite excretion,1 in questioning the importance of platelet cyclooxygenase-1–derived thromboxane in patients with unstable angina. However, controlled trials have shown that daily doses of 75 mg, 324 mg, and 1300 mg of aspirin have similar effects on cardiovascular outcomes in patients with unstable angina.2 Although such diverse regimens all completely suppress platelet cyclooxygenase-1, they are unlikely to accomplish similar degrees of inhibition of cyclooxygenase-2.

Indeed, it “remains to be determined” whether cyclooxygenase-2 inhibitors augment the efficacy of aspirin in such situations. However, it also remains plausible that they may undermine the efficacy of aspirin in patients with cardiac conditions and renoprival syndromes or may even represent an independent cardiovascular hazard. Drs. McQuillan and Eikelboom also suggest that NSAIDs might afford cardioprotection superior to that of low-dose aspirin. Again, there is no evidence to that effect.3 A recent epidemiologic analysis of 17,000 patients did not show a cardioprotective effect of naproxen.4 Interestingly, the relative risk of a myocardial infarction in patients taking aspirin together with ibuprofen was increased by roughly 30 percent, a finding consistent with the hypothesis advanced in our article.

Francesca Catella-Lawson, M.D.
Muredach P. Reilly, M.D.
Garret A. FitzGerald, M.D.
University of Pennsylvania, Philadelphia, PA 19104
garret@spirit.gcrc.upenn.edu

4 References

1. 1

   Reilly IAG, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987;69:180-186
   Web of Science | Medline

2. 2

   Reilly M, FitzGerald GA. Gathering intelligence on antiplatelet drugs: the view from 30 000 feet: when combined with other information overviews lead to conviction. BMJ 2002;324:59-60
   CrossRef | Web of Science | Medline

3. 3

   Garcia Rodriquez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000;11:382-387
   CrossRef | Web of Science | Medline

4. 4

   Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359:118-123
   CrossRef | Web of Science | Medline

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