Anyone who does a simple literature search will encounter a plethora of articles discussing, debating, and even arguing over this topic. The reasons for all of these issues, in our opinion, has to do with numerous inconsistencies among studies in the doses and duration of ibuprofen used, the timing of ibuprofen dosing in relation to the administration of aspirin, the dose and formulation (enteric or non-enteric coated) of aspirin used, the patient population studied (healthy volunteers vs. patients with known cardiovascular disease (CVD)), whether surrogate laboratory markers were used versus tests that actually assess platelet aggregation, and lastly the study design used by the investigators to generate their findings.1-6  As such, it is very difficult, to nearly impossible, to extrapolate the current data from each of these studies, all of which have limitations or inconsistencies among each other, and generate a definitive answer that can actually translate into clinically meaningful endpoints that are applicable to the general population. Some of the discrepancies in the literature may be due to the ability of platelets to aggregate at times when the concentrations of the non-steroidal anti-inflammatory drugs (NSAIDs) are low versus early on after administration when concentrations are higher.7  By the time the ibuprofen is freed from the binding site in COX-1, some of the aspirin will already have been eliminated from the body. 

The Food & Drug Administration (FDA) warning to healthcare professionals recently stated, "Patients who use immediate release aspirin (not enteric coated) and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion, or more than 8 hours before aspirin ingestion to avoid attenuation of aspirin's effect.  In addition, there are a number of studies with conflicting findings."8  Based on this recommendation, the purpose of this issue is not to critique every single study published on this subject, but rather to explain the proposed mechanism for the drug interaction and then to highlight some of the issues with its interpretation in relation to the medical literature. 

What happens during normal platelet aggregation?

• The process of increased platelet aggregation begins with the release of arachidonic acid (AA) from the cell membrane of a platelet.6 
  
• The AA can then goes down one of two metabolic pathways, the lipoxygenase pathway, which will generate leukotrienes (LT), or the cyclooxygenase (COX)-1 pathway to form prostaglandin (PG) H2.9  Prostaglandin H2 can then be metabolized by prostaglandin synthetase to form other PGs or it can be metabolized by thromboxane (TX) synthetase to form TXA2. 
  
• If TXA2 is formed then platelet aggregation will be facilitated or encouraged.10  This specifically occurs when AA is able to travel through a hydrophobic channel where it can make contact with catalytic site within the COX-1 enzyme.  If this channel or the area surrounding the catalytic site is blocked, the AA will be unable to be metabolized to PGH2 and then onto TXA2, thereby reducing the likelihood for platelet aggregation.6,9,11 

How does aspirin then interfere with platelet aggregation?

• Upon administration of aspirin, it will irreversibly acetylate a serine residue at position 529 within the hydrophobic channel, which is in close proximity to the catalytic site where AA can be metabolize to platelet derived TXA2 by COX-1 enzyme.6,9,11  The acetylation of this area creates a blockade where AA will not be able to gain access to the catalytic site within COX-1. 
  
• Since aspirin does this irreversibly, the ability of that catalytic site within COX-1 enzyme to metabolize AA is blocked or inhibited for the life of that platelet (usually around 7-12 days).  This is one of the main reasons aspirin confers a cardioprotective benefit against cardiovascular events when primarily being used for secondary prevention. 
  
• Therefore, if anything else competes or blocks aspirin's access to acetylate this serine residue within the COX-1 enzyme, the cardioprotective benefits may be diminished. 

How does ibuprofen interfere with the pharmacologic activity of aspirin?

• As with all of the NSAIDs, ibuprofen is a reversible, competitive inhibitor of the catalytic site for AA metabolism within the hydrophobic channel of the COX-1 enzyme.7,12 
  
• The presence of ibuprofen within this hydrophobic channel competitively blocks the access of aspirin to acetylate the serine residue that is in close proximity to the catalytic site for AA.7,12,13 
  
• The degree of inhibition of aspirin's access to exert its pharmacologic effect by ibuprofen is going to be influenced by a number of factors.
  

The first and most obvious factor has to do with the order with which aspirin and ibuprofen are administered in relation to each other.  If the aspirin is given first, it will gain access to irreversibly acetylate the serine residue within the COX-1 enzyme.  Remember, once aspirin has irreversibly inhibited the COX-1 enzyme, the antiplatelet effect will continue to exist for the life for that platelet.  The next factor is the concentration of ibuprofen present in relation to the time of co-administration of aspirin.  Since ibuprofen's inhibition is competitive, platelet aggregation is not only influenced by the concentration of ibuprofen present, but is also reversible in nature.  Therefore, as the drug levels decrease through elimination pathways, the amount of ibuprofen able to block aspirin's access to its active site also decreases, especially given its short half-life of 2-4 hours.14  This pharmacokinetic characteristic of ibuprofen is the reason why it must re-dosed multiple times throughout the day, whereas aspirin is only dosed once a day.  Therefore, one can see why there is variation in the findings from multiple studies published in the medical literature.  Thus the clinical impact of this drug interaction is influenced by the order in which the two medications are administered, the dose and formulation of aspirin used, the dose and frequency of administration of ibuprofen used, the patient population studied, and the type of endpoint from that study. 

In the end, the real question is whether this interaction translates into a clinically relevant pre-defined patient oriented cardiovascular defined outcome.  To our knowledge no such prospective, appropriately designed clinical trial has been done to answer this question with convincing data in the population of patients in question.

References:

1. 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;48:117-22. 
2. Gladding PA, Webster MWI, Farrell HB et al.  The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interactions with aspirin in healthy volunteers.  Am J Cardiol  2008;101:1060-1063. 
3. Cryer B, Berlin RG, Copper SA et al.  Double-blind, randomized, parallel, placebo-controlled study of ibuprofen effects on thromboxane B2 concentrations in aspirin-treated healthy adult volunteers.  Clin Ther 2005;27:185-191.  
4. MacDonald TM, Wei L et al.  Effect of ibuprofen on cardioprotective effect of aspirin.  Lancet 2003;361:573-74.  
5. Kurth T, Glynn RJ, Walker AM et al.  Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs.  Circulation  2003;108:1191-1195.  
6. Catella-Lawson F, Reilly MP, Kapoor SC et al.  Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.  N Engl J Med  2001;345:1809-17. 
7. Evans AM.  Pharmacodynamics and pharmacokinetics of the profens: enantioselectivity, clinical implications, and special reference to S(+)-ibuprofen.  J Clin Pharmacol  1996;36:7S-15S.  
8. Food & Drug Administration.  Information for healthcare professionals: concomitant use of ibuprofen and aspirin.  U.S. Department of Health & Human Services.  Last accessed: 09-19-2011.  
9. Funk CD, Funk LB, Kennedy ME et al.  Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment.  FASEB J  1991;5:2304-12.  
10. Fitzgerald GA.  Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists.  Am J Cardiol  1991;68:11B-15B. 
11. Loll PJ, Picot D, Garavito RM.  The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.  Nat Struct Biol  1995;2:637-43.  
12. Loll PJ, Picot D, Ekabo O et al.  Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site.  Biochemistry  1996;35:7330-40. 
13. Rao GH, Johnson GG, Reddy KR et al.  Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin.  Arteriosclerosis  1983;3:383-8.

• Clinical Trial Summary:  ISIS-2 Trial - Second International Study of Infarct Survival 
• Anatomy:  Heart Anatomy (External)

Ibuprofen, Advil, Motrin, Aspirin, ASA, NSAID and Aspirin Drug Interaction