ST elevation myocardial infarction aspirin therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Antiplatelet therapy with aspirin is a mainstay of pharmacotherapy in STEMI. In the International Study of Infarct Survival 2 (ISIS 2), aspirin reduced mortality in STEMI as much as streptokinase (by approximately 25%) when compared to the administration of neither agent. Full doses of non-enteric coated aspirin should be administered as soon as possible to patients with STEMI if there are no contraindications.

Indications

All STEMI patients should receive a full dose of non-enteric coated or intravenous aspirin (162 to 325 mg) within the first 24 hours of presentation. Aspirin should be administered irrespective of the reperfusion strategy selected (either primary PCI, fibrinolytic administration, or no reperfusion therapy).

Contraindications

• Aspirin allergy
• Anaphylaxis to aspirin
• In patients with true aspirin allergy (hives, nasal polyps, bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be substituted.

It should be noted that prior to hospital discharge, these patients with hypersensitivity can be treated with aspirin desensitization.

• Active major bleeding at a non compressible site is another contraindication.

Clinical Trial Data Supporting the Administration of Aspirin in STEMI

ISIS 2 was a landmark trial which randomized a total of 17,187 patients from 417 hospitals who presented within 24 hours (median 5 h) of STEMI symptom onset to one of 4 strategies:

1. Streptokinase (1.5 million units) administered via the intravenous route over 1 hour or
2. Aspirin (enteric coated at a dose of 160 mg/day) for one month or
3. Both streptokinase and aspirin treatments or
4. Neither treatemnt

Both streptokinase alone and aspirin alone were associated with a similar significant reduction in 5 week cardiovascular mortality:

9.2% (791/8592) incidence of cardiovascular deaths among streptokinase versus 12.0% (1029/8595) among placebo infusion patients (odds reduction: 25% +/- 4; p < 0.00001)

9.4% (804/8587) incidence of cardiovascular deaths among aspirin versus 11.8% (1016/8600) among placebo tablet patients (odds reduction: 23% +/- 4; p < 0.00001)

The combination of streptokinase and aspirin was associated with a significant reduction in cardiovascular mortality when compared to the administration of either agent alone (p < 0.0001). Furthermore, the effect of SK and ASA appeared to be additive as the mortality was only 8.0% (343/4292) among patients treated with both SK and ASA vs 13.2% (568/4300) among those treated with neither agent (42% +/- 5 relative risk reduction; 95% confidence limits 34% to 50%).

Streptokinase was associated with an increased risk of bleeding requiring transfusion (0.5% versus 0.2%) and intracranial hemmorhage (ICH) (0.1% versus 0.0%). Streptokinase was, however, assocaited with fewer non-ICH strokes (0.6% versus 0.8%).

Aspirin was associated with a significant reduction in nonfatal reinfarction (1.0% versus 2.0%) as well as nonfatal stroke (0.3% versus 0.6%). In contrast to streptokinase, aspirin was not associated with a significant increase in intracranial hemorrhage or bleeding requiring transfusion. Furthermore, while streptokinase alone was associated with an increased risk of reinfarction, the addition of aspirin to streptokinase reduced the increased risk of reinfarction associated with streptokinase administration.

Mechanism(s) of Action

Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. It should be noted that NSAIDs compete with aspirin to bind to this sreine residue, and this is the mechanism by which a prior dose of a NSAID inhibits the efficacy of aspirin. While inhibition of thromboxane inhibits platelet aggregation, inhibition of prostaglandins may increase the risk of vasoconstriction. Given the potential for vasoconstriction with increasing doses, higher doses of aspirin (325 mg and greater) may not be more effective than doses of 162 to 75 mg.

COX-1 and COX-2 inhibition

There are at least two different types of cyclooxygenase (COX): COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side-effects.

However, several of the new COX-2 selective inhibitors, such as Vioxx, have been withdrawn recently, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors. Utilization of NSAIDs is contraindicated in STEMI, and NSAIDs therapy should be withdrawn in patients with STEMI because of a heightened risk of recurrent MI and congestive heart failure.

Aspirin Dosing

Full dose aspirin should be administered as soon as possible in the setting of STEMI, including in the pre-hospital setting if there are no contraindications. There are studies that suggest enteric coating may delay aspirin absorption. Therefore, non-enteric coated aspirin is recommended in the setting of ST elevation MI. It should also be noted that aspirin can also be administered via the intravenous route.

Efficacy and safety of low dose (162 mg) aspirin versus high dose (325 mg) aspirin in STEMI patients

Large, prospective, randomized trials randomizing STEMI patients to either low vs high doses of aspirin in STEMI are lacking. The 30 day mortality and bleeding risks associated with the administration of 162 mg versus 325 mg aspirin among patients with STEMI treated with thrombolytic therapy has been compared in a non-randomized retrospective analysis. Data for the largest analysis was drawn from a total of 48,422 patients with acute ST segment elevation myocardial infarction in the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). 24.4% of patients (n=11 828) were treated in a non-randomized fashio with an initial aspirin dose of 325 mg, and 75.6% (n=36 594) were treated with 162 mg. 24-hour mortality did not differ between the two doses: 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. 7 and 30 day mortality rates 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 multivariate adjustment for imbalances in baseline characteristics, the initial aspirin dose was not associated with 24-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 reinfarction or the composite of death or reinfarction between the two aspirin dose 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 for imbalances in baseline characteristics, 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 non-randomized data from trials conducted many years ago with a substantial use of streptokinase 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. These findings require confirmation in large randomized trials of fibrin specific agents before a firm recommendation can be made regarding the optimal initial dose of aspirin in STEMI patients.

ACC / AHA Guidelines (DO NOT EDIT)

“

Class I 1. For all post Percutaneous Coronary Interventions (PCI) stented STEMI patients without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after bare metal stent (BMS) implantation, 3 months after Sirolimus eluting stent implantation (SES), and 6 months after Paclitaxel eluting stent implantation (PES), after which long term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily. (Level of Evidence: B) Class IIa 1. In patients for whom the physician is concerned about risk of bleeding lower-dose 75 mg to 162 mg of aspirin is reasonable during the initial period after stent implantation. (Level of Evidence: C)

”

See Also

• The STEMI Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

• The 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction

• The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction

References

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