Recent FDA Warning of the Concomitant Use of Aspirin and Ibuprofen and the Effects on Platelet Aggregation

Abstract

On September 8, 2006, the US Food and Drug Administration (FDA) issued a statement to health professionals to inform them of an interaction between immediate-release, low-dose aspirin and ibuprofen. Taking ibuprofen too close to aspirin may result in the loss of aspirin's antiplatelet effects, which could reduce potential cardioprotective benefits.1 Based on an analysis of published and unpublished ex vivo human studies, the FDA suggests that patients taking immediate-release, low-dose aspirin should do so at least 30 minutes before or 8 hours after taking ibuprofen to prevent any possible interaction. This applies to individuals who use ibuprofen routinely, but does not apply to people who use the enteric-coated aspirin formulation. This new warning is in response to published and unpublished ex vivo studies describing the potential interaction between ibuprofen and low-dose (81 mg, nonenteric coated) aspirin that has existed for several years.1 The statement emphasizes that no specific clinical end point studies have been conducted to evaluate the potential consequences of such an interaction. Low-dose aspirin is a relatively inexpensive, readily available antiplatelet agent that has been associated with reductions in all-cause mortality, cardiac death, and nonfatal myocardial infarction.1 Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are popular over-the-counter medications that are commonly used daily for a variety of indications ranging from headaches to arthritis. It seems very likely that patients taking low-dose aspirin for its cardioprotective benefits may take the 2 medications concomitantly, unaware of the potential consequences. According to the 2006 American Heart Association Heart Disease and Stroke Statistics, each year about 700,000 people experience a new or recurrent stroke or a new coronary attack, costing an estimated $142.5 billion in direct and indirect costs.2 It is therefore important for health care professionals to educate their patients of the potential interaction to ensure that they receive the greatest benefits from these agents. Aspirin irreversibly inhibits both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. COX-1 is an enzyme that catalyzes arachidonic acid to produce various prostaglandins, among them thromboxane A2 (TXA2), a potent vasodilator and promoter of platelet aggregation. Aspirin's interaction with COX-1 results in inhibiting antiplatelet function by irreversible acetylation of a serine residue at position 530 on the COX-1 enzyme.3 This reaction prevents the COX-1 enzyme in platelets from producing TXA2 by preventing access to the catalytic site.4 The inhibition of the COX-1 enzyme by aspirin lasts the lifetime of the platelet, approximately 10 days. Once COX-1 has been inhibited, synthesis of TXA2 now requires production of new platelets, which occurs at a rate of approximately 10% per day.5 Daily low-dose aspirin is able to effectively suppress TXA2 production by newly synthesized platelets.4 NSAIDs bind and inhibit the COX-1 enzyme at the Arginine-120 residue within the same narrow hydrophobic channel where aspirin exhibits its effects.6 This temporary binding causes only reversible inhibition, but may prevent the acetylation of the serine residue by aspirin. Studies have shown that the resulting inhibition of TXA2 synthesis only occurs transiently during the administration of the NSAID.7 It is thought that the possible mechanism of inhibition between aspirin and ibuprofen is due to steric hindrance. The temporary binding of ibuprofen to the active site of the COX-1 enzyme prevents the irreversible binding of aspirin. Once ibuprofen is released from the binding site, a percentage of aspirin has already been eliminated due to its short half-life of 20 minutes. This results in a reduced amount of aspirin at the site of action, resulting in a diminished effect on platelet aggregation. The optimal dose of aspirin has been the subject of many randomized trials.6 These studies have evaluated the clinical effectiveness, antithrombotic effects, and incidence of gastrointestinal side effects of a range of doses. The most widely evaluated doses shown to be effective range between 75 and 325 mg. Doses higher than this have been studied and are associated with a higher incidence of side effects.8 Based on these studies, use of the lowest effective dose of aspirin is recommended to ensure maximum efficacy and a decreased risk of side effects. The FDA currently recommends the use of low-dose aspirin (50 to 325 mg/d) for secondary prevention of myocardial infarction and stroke.9 The interaction between aspirin and various NSAIDs in addition to acetaminophen has been previously studied. In one crossover study by Catella-Lawson and colleagues,7 patients received 81 mg of immediate-release aspirin followed by ibuprofen, diclofenac, rofecoxib (COX-2 inhibitor), or acetaminophen 2 hours later for 6 days. This was followed by a washout period of 14 days, after which the same 2 medications were administered in reverse order for the remaining 6 days. The inhibition of COX-1 was assessed by measurements of serum thromboxane B2 (TXB2), platelet aggregation induced by arachidonic acid was measured in platelet-rich plasma ex vivo, and COX-2 activity was determined by the measurement of the formation of lipopolysaccharide-stimulated prostaglandin E2 in whole blood ex vivo. No changes in the platelet aggregation or COX-1 inhibition were seen when acetaminophen, rofecoxib, or diclofenac was administered before aspirin following 6 days of treatment. However, patients taking single-dose ibuprofen (400 mg) 2 hours before aspirin experienced a 53% inhibition of thromboxane B2 vs a 99% inhibition when aspirin was administered before ibuprofen following 6 days of treatment (P<.001). Single-dose ibuprofen administered 2 hours after low-dose aspirin showed no effect on aspirin's COX-1 inhibition ability. When patients followed this dosing regimen, at least a 98% inhibition of serum thromboxane B2 was measured after dosing on day 6. A parallel-group of the study showed a 67% inhibition of thromboxane B2 on day 6 when multiple-dosed ibuprofen (400 mg tid) was given 2, 7, and 12 hours after a single daily 81-mg enteric-coated aspirin (P<.05). The FDA recommendation was also supported by an analysis of multiple-dosed ibuprofen 400 mg administered 3 times daily for 10 days (the maximum dose allowed per over-the-counter package insert) on the antiplatelet effects of nonenteric-coated aspirin 81 mg at 1, 3, 7, and 10 days vs placebo. Subjects were pretreated with 81 mg of nonenteric-coated aspirin alone for 8 days. Following 10 days of treatment with ibuprofen 400 mg tid or placebo at the specified time intervals following aspirin administration, patients continued to show a >90% inhibition of TXB2 suggesting no loss in platelet aggregation is found when nonenteric-coated aspirin is administered before multiple-dose ibuprofen. Separately, an unpublished analysis of single-dose ibuprofen 400 mg demonstrated inhibition of aspirin's anti-platelet effects when taken within 30 minutes before or within 8 hours after immediate-release aspirin administration.1 Naproxen has also been shown to affect platelet aggregation in the same reversible manner as ibuprofen.10 Capone et al6 examined the interaction both in vivo and ex vivo between naproxen (500 mg orally bid) and aspirin (100 mg orally daily) on platelet aggregation and TXB2 synthesis. Results suggested that the inhibition of platelet aggregation by aspirin was not significantly effected by naproxen when given either 2 hours before or 2 hours after. The in vitro analysis suggested that a potential interaction between the two existed, but it is unclear whether experimental conditions represented physiologic conditions.7 Studies evaluating the effects of over-the-counter strength naproxen and aspirin are currently not available. It is not yet clear as to how the inhibition of platelet aggregation by the concomitant dosing of low-dose aspirin and ibuprofen translates into clinical outcomes. Currently, there are no prospective, randomized clinical trials evaluating the cardiovascular effects that concomitant dosing may produce. Any recommendations regarding the possible impact of this interaction would be based purely on observational studies. The currently published observational studies evaluating the risk of cardiovascular effects with concomitant use of low-dose aspirin and NSAIDs suffer from various limitations such as: use of patient populations not applicable to the general population, failure to assess over-the-counter NSAID use, the use of surveys that may promote recall bias, the inability to accurately record medication compliance, and inconstancies in results among studies.11-15 The recent recommendation made by the FDA is not based on any of these existing studies. It is on this information that the FDA has based its current recommendation of administering immediate release, low-dose aspirin at least 30 minutes before or 8 hours after taking ibuprofen. This recommendation is based on data evaluating the drug mechanism of action of aspirin and ibuprofen and not on clinical outcome data. At this point, it is unclear as to the possible clinical effect of concomitant administration of the 2 agents due to a lack of sufficient data. One recommendation may be to have patients completely avoid the 2 agents altogether, but this may not be an option in individuals who rely on the anti-inflammatory effects of ibuprofen. Acetaminophen doesn't appear to have an effect on the antiplatelet effects of aspirin, but this may not be a reasonable alternative for everyone. Until definitive clinical trials are performed to effectively evaluate the potential outcomes regarding the interaction's effect on the cardioprotective effects of aspirin, the best recommendation may be to have patients follow the FDA's dose-staggering recommendation.