ST elevation myocardial infarction aspirin therapy
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Aspirin
Overview
Aspirin, or acetylsalicylic acid, was first synthesized in 1897 at Friedrich Bayer & Company as a more palatable formulation of salicylic acid—a pain reliever used in some form dating back to ancient Egypt. Aspirin was initially sold to pharmacists in 250-g bottles and was dispensed to patients as a powder. Imitators and adulterated versions of the powder led Bayer to develop an aspirin tablet in 1900. [1]
In the United States, this was sold as a 5 grain (approximately 325-mg) pill, the genesis of the dose commonly used today. The 81-mg/d children's dosage, which is one quarter of the adult dosage and was arbitrarily determined, first became available in 1922.[1] [1]
Mechanism(s) of Benefit
Acetylation of platelet cyclooxygenase-1 (COX-1) begins to occur in the portal circulation prior to any measurable systemic level; thus, the measurement of plasma levels of the inactive form of acetylsalicylic acid may be an incomplete measure of efficacy. Nonetheless, peak plasma levels are achieved rapidly, within approximately 30 minutes, followed by rapid clearance with a half-life of 15-20 minutes. The systemic bioavailability of aspirin is about 50% for single oral doses ranging from 20-1300 mg.[1]
Both the beneficial and detrimental effects of aspirin are believed to be primarily due to inhibition of prostanoid biosynthesis, in particular the inhibition of of thromboxane A2 (TXA2) and prostaglandins (e.g., PGE2 and PGI2).
Aspirin irreversibly inhibits platelet cyclooxygenase 1 (COX-1) through acetylation of the amino acid serine at position 529, thereby preventing arachidonic acid's access to the COX-1 catalytic site through steric hindrance. By inhibiting COX-1, the platelet is unable to synthesize prostaglandin H2, which, under normal circumstances, is then converted to thromboxane A2 (TXA2) via the enzyme Thromboxane synthase. Although anucleate platelets possess some capacity for protein synthesis, they are incapable of overcoming COX-1 inhibition with new protein synthesis, and the aspirin-induced defect spans the 8 to 10 day life span of the platelet. Because of platelet turnover, approximately 10% of platelets with normal COX activity will be recovered daily following cessation of aspirin therapy. Therefore, up to 10 days can be required for complete recovery of platelet COX activity; however, it may require only 20% of normal COX activity to exhibit normal hemostasis.[1] [1] [1] [1]
COX-1 is constitutively expressed in most cells and plays important roles beyond TXA2 production in platelets. Of particular importance is the production of the cytoprotective prostaglandins by gastric mucosa. Unlike platelets, gastric mucosal cells possess the biosynthetic machinery necessary to overcome COX-1 inhibition and, therefore, recover the ability to synthesize prostaglandins within a few hours after exposure to aspirin. COX-2, a second cyclo oxygenase isoenzyme primarily responsible for synthesis of the platelet inhibitor PGI2 by endothelial cells and induced in response to inflammatory stimuli, is less sensitive to the effects of aspirin. Aspirin is 170 fold less effective at inhibiting COX-2 than COX-1.
At higher doses, aspirin suppresses vascular endothelial cell production of prostacyclin, which, if unopposed, results in inhibition of platelet aggregation and induces vasodilatation.
It has been postulated that aspirin’s anti-inflammatory properties may explain at least part of its mechanism of benefit in CVD. However, with aspirin’s much greater selectivity for COX-1 and the central role of COX-2 in inflammation, dosages that achieve measurable anti-inflammatory activity (up to several grams daily) are much higher than those proven clinically effective in the prevention of atherothrombotic events. Consistent with this is the lack of an effect on high sensitivity C-reactive protein levels in most studies.
Currently, there is no gold standard measure of aspirin’s pharmacodynamics.
There has been only 1 randomized study that directly compared aspirin dose in STEMI. The Duke University Clinical Cardiology Group Study-II (DUCCS-II) compared the efficacy of 81 and 325 mg aspirin doses in 162 patients with STEMI treated with front loaded tissue plasminogen activator or an isolated plasminogen streptokinase activator complex. No effect of aspirin dose on clinical outcomes was noted; however, because of its early termination, the study was severely underpowered. The majority of data supporting the use of aspirin in the setting of acute myocardial infarction are from ISIS-2. In this study, 162.5 mg aspirin reduced vascular mortality, re-infarction, and stroke without substantially increasing the risk of major bleeding. Other studies of aspirin in the acute setting of myocardial infarction have been severely underpowered to address the clinical efficacy and safety profile of aspirin in this setting.
A wide range of aspirin doses, preparations, and methods of ingestion have been evaluated to determine the best way to achieve maximal antiplatelet activity in the acute setting. In a study that evaluated the acute antiplatelet effects of 40 mg, 100 mg, 300 mg, and 500 mg doses of aspirin, the 300 mg and 500 mg doses were found to achieve equal levels of platelet inhibition 2 hours following ingestion, suggesting that there is no added benefit for doses of more than 300 mg. However, at very low doses (0.45 mg/kg, corresponding to about 30 mg in an adult), it may take 10 days to effectively suppress TXA2 production. [1]
Aspirin absorption and the onset of antiplatelet activity are significantly shortened by chewing or drinking soluble aspirin, with maximal inhibition of serum Thromboxane B2 (TXB2) production achieved within 20 to 30 minutes compared with swallowing a whole pill that required approximately 60 minutes.
In another study of 18 volunteers, chewing an 81 mg, 162 mg, or 324 mg aspirin pill led to equivalent reduction in TXB2 production, but maximal inhibition by 15 minutes after ingestion was achieved only with the 162 mg and 324 mg doses. The results of these and other studies suggest that to rapidly (within 15 minutes) achieve the maximal effects of aspirin, at least 162 mg should be chewed or dissolved, then swallowed.[1] [1]
The major risk of aspirin, as with other non steroidal anti inflammatory drugs (NSAIDs), is the risk of bleeding. Although the antiplatelet effects of aspirin likely contribute to an increase in the risk of bleeding, as highlighted by an increased risk of hemorrhagic stroke of 0.2 events per 1000 patient years, the majority of the increased bleeding has a gastrointestinal tract etiology.
Although this increased risk of gastrointestinal bleeding is more commonly attributed to non aspirin NSAIDs, a recent evaluation of patients hospitalized for ulcer bleeding found that low-dose aspirin therapy was responsible for as much ulcer bleeding as all other NSAIDs combined. In another prospective evaluation of 18 820 hospitalized patients, 1225 were admitted as a result of adverse drug reactions, and low-dose aspirin was identified as one of the most common causal agents, with 18% of the hospitalizations and 61% of the fatal cases associated with aspirin.[1] [1] [1] [1]
An analysis of aspirin-treated patients from the UKTIA trial found almost double the risk of gastrointestinal bleeding among patients randomized to 1200 mg/day of aspirin compared with 300 mg/day. In the Dutch-TIA trial, where the higher aspirin dose was more reflective of contemporary dosing, a trend toward less bleeding was noted in the 30 mg group (2.6%) than the 283 mg group (3.2%).
Observational data from the BRAVO (Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trials also demonstrated an increased risk of bleeding with higher doses of aspirin, even when doses no greater than 325 mg were used.[1] [1]
Dosing
If not given prior to hospital admission, Aspirin should be administered to all patients at a dose of 162 to 325 mg to chew and swallow, unless there is a compelling contraindication (e.g., history of anaphylactic reaction). Aspirin is generally administered orally and is rapidly absorbed in the stomach and upper intestine. Enteric coating may delay the absorption, and it is for this reason that not enteric coated aspirin is often administered in the setting of ST elevation MI. It should also be noted that aspirin can also be administered via the intravenous route.[1]
162 mg versus 325 mg
A recent study from Duke University compared the acute mortality and bleeding risks associated with the initial use of 162 mg versus 325 mg aspirin among patients with STEMI treated with thrombolytic therapy. A total of 48,422 patients with acute ST segment elevation myocardial infarction from the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) were studied. The association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding was compared. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% for those receiving an initial aspirin dose of 325 mg versus 2.8% (P=0.894) for those receiving an initial aspirin dose 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin respectively. After adjustment, aspirin dose was not associated with 2]]4-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). However, after adjustment, an initial dose of 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003) compared to an initial does of 162 mg.
This study demonstrates two major findings on the dose of aspirin. First, in the acute setting of STEMI, there is no significant association between initial aspirin dose (162 mg versus 325 mg) and risk of death, myocardial infarction, or stroke. [1] [1]
Second, the initial dose of 325 mg aspirin is associated with a significant increase in the risk of moderate or severe bleeding compared with 162 mg in the initial treatment of STEMI.
This study demonstrates that the initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST elevation myocardial infarction.
Side Effects and Contraindications
The use of aspirin is contraindicated in those with a hypersensitivity to salicylate.
Aspirin suppositories (300 mg) can be used safely and are the recommended route of administration for patients with severe nausea and vomiting or known upper-gastrointestinal disorders.
In patients with true aspirin allergy (hives, nasal polyps, bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be substituted.[1]
Guidelines (DO NOT EDIT)
Class I
Aspirin should be chewed by patients who have not taken aspirin before presentation with STEMI. The initial dose should be: 162 mg (Level of Evidence: A) to 325 mg (Level of Evidence: C). Although some trials have used enteric-coated aspirin for initial dosing, more rapid buccal absorption occurs with non–enteric-coated aspirin formulations.[1]
References
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
