Emergent aspirin use in cardiovascular disease in the emergency department: oral dosing versus rectal suppositories.

M ore than 50 million people in the United States regularly take aspirin, primarily for cardiovascular disease prevention—translating into over 10 billion tablets taken yearly. In the emergency department (ED), aspirin is used emergently in two settings: 1) for the secondary prevention of noncardioembolic ischemic stroke and transient ischemic attack (TIA), aspirin at a dose of 50 to 325 mg ⁄ daily within 48 hours of an event is currently recommended; and 2) for the management of acute coronary syndrome (ACS), treatment with 162 to 325 mg of a chewed non–enteric-coated aspirin is indicated immediately. Chewing is important because inhibition of platelet thromboxane A2 (TXA2) formation is detected within 3 minutes of ingestion when chewed and 7.5 minutes from ingestion when swallowed without chewing. At least 162 mg of aspirin chewed is needed for ACS because maximal inhibition of TXA2 occurs at 15 minutes in all subjects using this dose, compared to only some subjects using the 81-mg dose, albeit all subjects at both doses have maximal inhibition within 30 minutes. Enteric-coated aspirin may delay platelet TXA2 inhibition by hours and should not be used in ACS unless chewed; chewing a 325-mg enteric-coated tablet has been shown to almost completely suppress TXA2 within 15 minutes. The primary mechanism of action of aspirin, also known as acetylsalicylic acid, is to bind irreversibly to the cyclooxygenase I (COX-I) enzyme through acetylation of the amino acid serine at position 529. COX-I enzymes are constitutively expressed in most normal cells and tissues including the gastric epithelial mucosa, but not the platelet. The platelet, being anucleate, cannot regenerate COX-I, resulting in the inability to synthesize TXA2 for the life of the platelet. TXA2, a potent platelet activator, is not synthesized and regeneration of new platelets occurs at about 10% per day, resulting in at least partial reduction in platelet aggregation for 10 days. By 72 hours, however, some COX-I activity is present due to new platelets, requiring intermittent aspirin dosing. COX-I enzymes in gastric mucosa maintain the production of cytoprotective prostaglandins. Low doses of aspirin at 30 mg ⁄ day result in 50% inhibition of gastric COX-I with maximal inhibition occurring at 1300 mg ⁄ day. Gastric mucosal cells regenerate COX-I enzymes within hours, preventing irreversible loss of COX-I activity in these cells. In addition, it has been suggested that aspirin at 1200 mg ⁄ day has a higher risk of gastrointestinal (GI) bleeding than aspirin at 300 mg ⁄ day. Multiple other studies have shown that aspirin doses ranging from 30 to 325 mg show a differential increase in GI bleeding as aspirin dose is increased. The differential GI bleeding with dose is consistent with the differential suppression of COX-I with dose. This does not include the slight increased risk of hemorrhagic stroke of 0.2 events per 1,000 patient-years of aspirin therapy. Therefore, the therapeutic goal has been to find the lowest dose of aspirin that would maximize therapeutic benefit and minimize bleeding. In contrast to aspirin, the other nonsteroidal antiinflammatory medications reversibly inhibit platelet COX-I, with the transient inhibition related to the pharmacokinetics of the drugs. Only indomethacin reversibly inhibits platelet COX-I TXA2 synthesis greater than 95%, a degree similar to that of aspirin. Salicylic acid, the product of aspirin metabolism by tissue and plasma esterases, is not an inhibitor of COX-I, although it has been mistaken to be an inhibitor. In this issue of Academic Emergency Medicine, we have a study by Maalouf et al. comparing salicylic acid levels in normal subjects after rectal vs. oral dosing. Theoretically, the counterfactual study design is the ideal. Turning the study by Maalouf et al. into a hypothetical counterfactual example, all 24 subjects would undergo treatment with oral aspirin therapy with salicylic acid levels drawn at baseline, 30, 60, and 90 minutes. Then, going back in time, the same subjects take aspirin suppositories over the same (previous) time frame and with the same salicylic acid levels drawn. A comparison would be made and the ‘‘only difference’’ between treatments would be the intervention. Because this perfect design is counter-to-fact, albeit a thought experiment that helps one conceptualize theoretical weaknesses in other designs, a compromise design using patients as their own control best approximates the ideal as in the current study. This crossover design eliminates age, gender, and pharmacogenetics as confounders, an attractive feature in drug studies with a reduced number of participants where pharmacogenetic variation would be beyond what any