Antiplatelet Effects of Aspirin: Which NSAIDs Interact?

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD
Published Online: Friday, May 17, 2013
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Proceed with caution: Some NSAIDs do reduce the efficacy of aspirin.
Low-dose aspirin is widely used as prevention for myocardial infarction and other cardiovascular diseases, but there is evidence that concurrent use of NSAIDs may inhibit the antiplatelet effect of aspirin.1 There appear to be differences, however, in the relative likelihood of the various NSAIDs to interact with aspirin.

Mechanism

Aspirin acts by acetylating platelet COX-1, thus irreversibly inhibiting platelet function. Ibuprofen appears to block the access of aspirin to the active site on the platelet, although other mechanisms may also be involved.1,2 Other NSAIDs may or may not interact similarly, as described below.

Platelet Studies

In healthy subjects on aspirin 81 mg/day for 6 days, ibuprofen 400 mg given 2 hours before each aspirin dose blocked the antiplatelet effect of aspirin, as did multiple daily ibuprofen given 2, 7, and 12 hours after the aspirin. But a single daily dose of ibuprofen given 2 hours after each dose of aspirin did not interact.2 Aspirin has a very short half-life (~15-20 minutes) so it makes sense that giving ibuprofen 2 hours after the aspirin would avoid the interaction.

Other studies in healthy subjects also found ibuprofen to inhibit the antiplatelet effects of aspirin.3,4 Naproxen and indomethacin may also inhibit the antiplatelet effects of aspirin, but acetaminophen, diclofenac, meloxicam, and sulindac may not.2-7 One study found celecoxib to have no effect on the antiplatelet effect of aspirin,4 while another suggested an interaction.8

Patient Studies

In 18 patients on ibuprofen or naproxen who were also receiving aspirin to prevent stroke, platelet function was found to be similar to patients not taking aspirin. When the NSAID was stopped or given in a dosing schedule to avoid the aspirin, repeat testing in 2 to 4 weeks found the expected antiplatelet effect of aspirin.9

Most large outcome trials of patients taking aspirin for cardioprotection suggest that concurrent ibuprofen reduces aspirin efficacy.10-13

These outcome trials also found that diclofenac, naproxen, and a COX-2 inhibitor (lumiracoxib) may not interact.10,13 Not all studies have found reduced aspirin efficacy with NSAIDs,14,15 but the bulk of the evidence suggests that an interaction does exist.


Recommendations

Given the substantial evidence of interaction, and the potential severity of reduced aspirin efficacy (eg, myocardial infarction, stroke), it would be prudent to err on the side of caution in dealing with these interactions. Thus, one should assume that ibuprofen can reduce aspirin efficacy, and either avoid ibuprofen altogether or give it 2 hours after the aspirin. It may not be possible to avoid the interaction if ibuprofen is taken more than once daily. Naproxen and celecoxib are probably less likely than ibuprofen to interact with aspirin, but there is some evidence of interaction. So pending additional information, it would be prudent to avoid them as well. Drugs least likely to interact with aspirin appear to be acetaminophen and diclofenac, but the evidence suggests that meloxicam and sulindac may also avoid the aspirin interaction (see Table). The effect of NSAIDs on the efficacy of other antiplatelet drugs (eg, clopidogrel, prasugrel) is not established, but combining NSAIDs with such antiplatelet drugs may increase the risk of gastrointestinal bleeding.


Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy. For an electronic version of this article, including references if any, visit www.hanstenandhorn.com.

References
  1. Hohlfeld T, et al. High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs—pharmacological mechanisms and clinical relevance. Thromb Haemost. 2013;109. doi:10.1160/TH12-07-532.
  2. Catella-Lawson F, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-1817.
  3. Meek IL, et al. Interference of NSAIDs with the thrombocyte inhibitory effect of aspirin: a placebo-controlled, ex vivo, serial placebo-controlled serial crossover study. Eur J Clin Pharmacol. 2012. doi:10.1007/s00228-012-1370-y.
  4. Gladding PA, et al. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. Am J Cardiol. 2008;101:1060-1063.
  5. Capone MI, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. JACC. 2005:45:1295-1301.
  6. Anzellotti P, et al. Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences. Arthritis Thrum. 2011;63:850-859.
  7. Livio M, et al. Indomethacin prevents the long-lasting effects of aspirin on human platelet cyclo-oxygenase activity. Prostaglandins. 1982;23:787-796.
  8. Rimon G, et al. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci USA. 2009;107:28-33.
  9. Gengo FM, et al. Effects of ibuprofen on the magnitude and duration of aspirin’s inhibition of platelet aggregation: clinical consequences in stroke prophylaxis. J Clin Pharmacol. 2008;48:117-122.
  10. Farkouh ME, et al. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 2007;66:764-770.
  11. Kimmel SE, et al. The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol. 2004;43:985-990.
  12. Ridker PM, et al. Low-dose aspirin therapy for chronic stable angina: a randomized, placebo-controlled clinical trial. Ann Intern Med. 1991;114:835-839.
  13. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361:573-574.
  14. Fischer LM, et al. Current use of nonsteroidal anti-inflammatory drugs and the risk of acute myocardial infarction. Pharmacotherapy. 2005;25:503-510.
  15. Garcia Rodriguez LA, et al. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 2004;109:3000-3006.
     


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