Mehmet Akif Cacan, Ibrahim Azboy.
Response/Recommendation: Non-steroidal anti-inflammatory drugs (NSAID) used with aspirin (ASA) may reduce the antithrombotic activity of ASA. This effect is greater with the use of non-selective NSAID. Therefore, ASA should be taken at least 2 hours before taking NSAID.
Strength of Recommendation: Moderate.
Rationale: NSAID are often used for postoperative pain control. These drugs are effective in reducing postoperative pain and opioid use. In addition, NSAID for postoperative analgesia may facilitate for early mobilization and rehabilitation1,2. In recent years, the use of ASA for venous thromboembolism (VTE) prophylaxis has increased after orthopaedic surgeries, and ASA may be prescribed in conjunction with NSAID for postoperative pain control3,4.
Nociceptive pain and platelet aggregation are mediated by cyclo-oxygenase (COX) enzymes in the form of COX-1 and COX-2. Platelet aggregation is mediated by COX-1, whereas COX-2 mediates the inflammatory response and pain when tissue damage occurs5. COX inhibiting drugs can be selective or non-selective. Nonselective NSAID inhibit both COX-1 and COX-2. Ibuprofen, naproxen, diclofenac, indomethacin and ASA are in this group. However, Coxibs specifically inhibit COX-2, and examples of coxibs include celecoxib, rofecoxib, etoricoxib. NSAID reversibly inhibit COX enzymes and have a longer half-life compared to ASA. In contrast, ASA irreversibly inhibits COX-1, but circulates only transiently. Consequently, the administration of non-selective NSAID several hours before ASA inhibits the antiplatelet effect of ASA, which is mediated almost entirely by COX-I inhibition6–10.
There are many studies in the literature demonstrating the pharmacodynamic interaction when ASA and NSAID are given together, although the extent of this interaction may differ between agents4,6,11–22. A total of 20 studies evaluating the relationship between ASA and other NSAID since 2001 were reviewed1,4,11–18,21–30. However, almost all of these studies evaluated the relationship between ASA and other NSAID in vitro as opposed to in the clinical setting. In addition, most of these studies were conducted in healthy volunteers. To the best of our knowledge, no clinical studies with a high level of evidence has been performed to investigate the effect of concomitant use of ASA and other NSAID on VTE. Since drug interactions and clinical conditions of patients (age, weight, gender, comorbidity, etc.) are multifactorial, it may be difficult to conduct such studies.
Many studies have claimed that ibuprofen interacts with ASA and interferes with the antiplatelet effects of ASA4,13–22,25. However, Cryer et al., did not find any interaction between ASA and ibuprofen in their study25. Although there is conflicting information about naproxen in the literature, it has been cited as an alternative to ibuprofen in patients with cardiovascular risk31. In addition, several studies have found that naproxen does not interact with ASA15,20,32 (15,20,32), low-dose ASA22 or ASA at ≥ 300mg16,19, and others have reported no interaction when these two drugs were not used simultaneously12,21. In other studies, no interaction was reported for diclofenac19,28, celecoxib14,16,22 and meloxicam4,13.
Catella–Lawson et al., first demonstrated the interaction between ASA and NSAID in vivo11. In the study, it was reported that ibuprofen inhibited the platelet inhibitory effect of ASA clinically, but diclofenac or rofecoxib did not demonstrate this effect. In some subsequent in vivo and in vitro studies, it was found that naproxen and indomethacin were also ASA-blocking agents, but celecoxib and sulindac did not interact with ASA16. MacDonald and Wei evaluated the use of ibuprofen, diclofenac, and other NSAID in patients on low-dose (<325 mg) ASA in a study with 7,107 patients, observing that the mortality risk in ASA and ibuprofen users was statistically and clinically significantly higher than that of patients using ASA alone. No such increase in risk was observed in those using diclofenac, rofecoxib, or acetaminophen together with ASA33, although rofecoxib was subsequently withdrawn from the market.
Several studies have investigated the interaction between naproxen and ASA in the literature. Capone et al., investigated the interaction between the two drugs in vitro and ex vivo in 9 healthy subjects who took 100 mg ASA and 500 mg naproxen twice a day, and found that a single dose of naproxen taken less than 2 hours before ASA interfered with the antiplatelet effect of the latter12. Similarly, the effect of ibuprofen, naproxen, meloxicam, and etoricoxib taken 2 hours before ASA was evaluated in a separate placebo-controlled, ex vivo, serial crossover study by Meek et al., on 30 healthy subjects4. Accordingly, it was stated that although ibuprofen and naproxen inhibited the antiplatelet effect of ASA, meloxicam and etoricoxib did not show this effect. On the other hand, Gurbel et al., noted in their randomized controlled trial (RCT) that there was no interaction within the first 10 days. This study was initiated with 117 healthy subjects, and the pharmacodynamic interaction between ASA 81 mg and naproxen 220 mg was investigated with the data of 80 subjects. After 10 days of treatment, varying degrees of pharmacodynamic interaction were reported30.
There is inconsistency regarding the interaction between celecoxib and ASA in the literature. Li et al., evaluated the interactions of ibuprofen, naproxen, and celecoxib with ASA 325 mg in a study of 61 healthy subjects. In that study, there was a strong interaction between ibuprofen and ASA, and between naproxen and ASA, but no such interaction between celecoxib and ASA was reported22. Renda et al., similarly, evaluated the interaction between celecoxib and ASA in patients with osteoarthritis and stable ischemic heart disease. They found that, unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 by ASA14. Other studies reported contrasting results28,29. Ruzov et al., found that when ASA was added to the treatment of those who received 200 mg of celecoxib daily, the effects of ASA were reduced by 15% in the first few days, and this interaction did not change with the timing of drug intake. No interaction was observed in the chronic concomitant use of these drugs, and the authors concluded that the combination of the two drugs did not increase the risk of cardiovascular and cerebrovascular events29.
The timing of drug administration has been shown to affect the degree of interaction6. In the study by Catella-lawson et al., 400 mg of ibuprofen given 2 hours before 81 mg of ASA negated the effect of ASA, but this interaction was not observed when ASA was taken 2 hours before ibuprofen11. A similar effect was seen with naproxen use. In the study by Anzelotti et al., sequential dosing of 220 mg of naproxen and low-dose ASA twice a day interfered with the irreversible inhibition of platelet COX-1 by ASA, although the interaction was minimal when naproxen was given 2 hours after low-dose ASA21. Capone et al., concluded that ASA should be administered before naproxen to minimize drug interactions12. Gurbel et al., evaluated the co-administrating of 81 mg of ASA and 220 mg of naproxen and reported that when naproxen was used for more than a certain period of time, it could interact with ASA, and this interaction could be reduced by taking ASA at least 30 minutes before naproxen30.
Although more acute myocardial infarctions were observed in patients using ASA and NSAID concurrently in clinical studies, other studies found that there was not enough evidence to prove this relationship33,34. In a clinical study conducted by Krauss et al., patients were routinely given meloxicam or celecoxib in addition to 81 mg ASA twice a day for VTE prophylaxis in a high-volume joint replacement center. A total of 2 cases of VTE were observed within 1 month, after which ASA was administered 2 hours before the NSAID. Following this change in protocol, only 2 cases of VTE were observed within 1 year. Notwithstanding, it was difficult to attribute this reduction to the change in timing of drug administration35.
In light of the available literature, it is likely that NSAID and ASA demonstrate pharmacodynamic interactions when taken together. This interaction differs among different NSAID and is highly dependent on many factors such as the time of administration, the dose of ASA or the NSAID, and its pharmacokinetic properties12,21,35. However, the clinical significance of this pharmacodynamic interaction has not been established in large, RCT studies. Taking ASA 2 hours before an NSAID may minimize the interaction between the two drugs. Nonetheless, further clinical research is needed to confirm this recommendation.
1. Lee SK, Lee JW, Choy WS. Is multimodal analgesia as effective as postoperative patient-controlled analgesia following upper extremity surgery? Orthop Traumatol Surg Res. 2013;99(8):895-901. doi:10.1016/j.otsr.2013.09.005
2. Soffin EM, Wu CL. Regional and Multimodal Analgesia to Reduce Opioid Use After Total Joint Arthroplasty: A Narrative Review. HSS J. 2019;15(1):57-65. doi:10.1007/s11420-018-9652-2
3. Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem. 1990;265(28):16737-16740.
4. Meek IL, Vonkeman HE, Kasemier J, Movig KLL, van de Laar M a. FJ. 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. 2013;69(3):365-371. doi:10.1007/s00228-012-1370-y
5. Van Dorpd null, Beerthuis RK, Nugteren DH, Vonkeman H. THE BIOSYNTHESIS OF PROSTAGLANDINS. Biochim Biophys Acta. 1964;90:204-207. doi:10.1016/0304-4165(64)90144-8
6. Gurbel P, Tantry U, Weisman S. A narrative review of the cardiovascular risks associated with concomitant aspirin and NSAID use. J Thromb Thrombolysis. 2019;47(1):16-30. doi:10.1007/s11239-018-1764-5
7. Hawkey CJ. COX-2 inhibitors. Lancet. 1999;353(9149):307-314. doi:10.1016/s0140-6736(98)12154-2
8. Van Hecken A, Schwartz JI, Depré M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000;40(10):1109-1120.
9. Vonkeman HE, van de Laar MAFJ. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum. 2010;39(4):294-312. doi:10.1016/j.semarthrit.2008.08.001
10. Azboy I, Barrack R, Thomas AM, Haddad FS, Parvizi J. Aspirin and the prevention of venous thromboembolism following total joint arthroplasty: commonly asked questions. Bone Joint J. 2017;99-B(11):1420-1430. doi:10.1302/0301-620X.99B11.BJJ-2017-0337.R2
11. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345(25):1809-1817. doi:10.1056/NEJMoa003199
12. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005;45(8):1295-1301. doi:10.1016/j.jacc.2005.01.045
13. Joanne VR, Monika K-E, Ingrid K, et al. Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers. Journal of clinical pharmacology. 2004;44(7). doi:10.1177/0091270004266623
14. Renda G, Tacconelli S, Capone ML, et al. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease. Clin Pharmacol Ther. 2006;80(3):264-274. doi:10.1016/j.clpt.2006.05.004
15. Gengo FM, Rubin L, Robson M, 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(1):117-122. doi:10.1177/0091270007310379
16. Gladding PA, Webster MWI, Farrell HB, Zeng ISL, Park R, Ruijne N. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. Am J Cardiol. 2008;101(7):1060-1063. doi:10.1016/j.amjcard.2007.11.054
17. Hong Y, Gengo FM, Rainka MM, Bates VE, Mager DE. Population pharmacodynamic modelling of aspirin- and Ibuprofen-induced inhibition of platelet aggregation in healthy subjects. Clin Pharmacokinet. 2008;47(2):129-137. doi:10.2165/00003088-200847020-00006
18. Galliard-Grigioni KS, Reinhart WH. A randomized, controlled study on the influence of acetaminophen, diclofenac, or naproxen on aspirin-induced inhibition of platelet aggregation. Eur J Pharmacol. 2009;609(1-3):96-99. doi:10.1016/j.ejphar.2009.02.042
19. Schuijt MP, Huntjens-Fleuren HWHA, de Metz M, Vollaard EJ. The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers. Br J Pharmacol. 2009;157(6):931-934. doi:10.1111/j.1476-5381.2009.00243.x
20. Angiolillo DJ, Hwang C, Datto C, Desai B, Sostek M. Impact of a fixed-dose combination of naproxen and esomeprazole magnesium on serum thromboxane B2 inhibition by low-dose aspirin over 5 days in healthy adults: a phase I, randomized, double-blind, placebo-controlled, noninferiority trial. Clin Ther. 2011;33(12):1883-1893. doi:10.1016/j.clinthera.2011.10.009
21. Anzellotti P, Capone ML, Jeyam A, et al. Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences. Arthritis Rheum. 2011;63(3):850-859. doi:10.1002/art.30175
22. Li X, Fries S, Li R, et al. Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2014;111(47):16830-16835. doi:10.1073/pnas.1406997111
23. Wilner KD, Rushing M, Walden C, et al. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J Clin Pharmacol. 2002;42(9):1027-1030.
24. Capone ML, Tacconelli S, Sciulli MG, et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation. 2004;109(12):1468-1471. doi:10.1161/01.CIR.0000124715.27937.78
25. Cryer B, Berlin RG, Cooper SA, Hsu C, Wason S. Double-blind, randomized, parallel, placebo-controlled study of ibuprofen effects on thromboxane B2 concentrations in aspirin-treated healthy adult volunteers. Clin Ther. 2005;27(2):185-191. doi:10.1016/j.clinthera.2005.01.011
26. Schiff M, Hochberg MC, Oldenhof J, Brune K. Platelet inhibitory effects of OTC doses of naproxen sodium compared with prescription dose naproxen sodium and low-dose aspirin. Curr Med Res Opin. 2009;25(10):2471-2477. doi:10.1185/03007990903185706
27. Lomakin NV, Gruzdev AK. [Cyclooxygenase inhibitors and antiplatelet effect of acetylsalicylic acid. selective approach to nonsteroidal anti-inflammatory drugs in cardiological practice]. Kardiologiia. 2011;51(7):47-52.
28. Saxena A, Balaramnavar VM, Hohlfeld T, Saxena AK. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol. 2013;721(1-3):215-224. doi:10.1016/j.ejphar.2013.09.032
29. Ruzov M, Rimon G, Pikovsky O, Stepensky D. Celecoxib interferes to a limited extent with aspirin-mediated inhibition of platelets aggregation. Br J Clin Pharmacol. 2016;81(2):316-326. doi:10.1111/bcp.12801
30. Gurbel PA, Bliden KP, Zhu J, et al. Thromboxane inhibition during concurrent therapy with low-dose aspirin and over-the-counter naproxen sodium. J Thromb Thrombolysis. 2018;45(1):18-26. doi:10.1007/s11239-017-1593-y
31. Scheiman JM, Fendrick AM. Summing the risk of NSAID therapy. Lancet. 2007;369(9573):1580-1581. doi:10.1016/S0140-6736(07)60722-3
32. Oldenhof J, Hochberg M, Schiff M, Brune K. Effect of maximum OTC doses of naproxen sodium or acetaminophen on low-dose aspirin inhibition of serum thromboxane B2. Curr Med Res Opin. 2010;26(6):1497-1504. doi:10.1185/03007995.2010.481249
33. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361(9357):573-574. doi:10.1016/s0140-6736(03)12509-3
34. Kurth T, Glynn RJ, Walker AM, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation. 2003;108(10):1191-1195. doi:10.1161/01.CIR.0000087593.07533.9B
35. Krauss E, Cronin M, Dengler N, Segal A. Interaction Between Low-Dose Aspirin and Nonsteroidal Anti-Inflammatory Drugs Can Compromise Aspirin’s Efficacy in Preventing Venous Thrombosis Following Total Joint Arthroplasty. Clin Appl Thromb Hemost. 2020;26:1076029620920373. doi:10.1177/1076029620920373