Review
Aspirin, Clopidogrel, and Ticagrelor in Acute Coronary Syndromes

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Dual antiplatelet therapy is the cornerstone in the management of patients with acute coronary syndromes (ACS). Ticagrelor, an oral, direct, reversibly binding, P2Y12 receptor antagonist, is approved for the prevention of atherothrombotic events in adult patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with significant reductions in cardiovascular events, cardiovascular mortality, and all-cause mortality compared with clopidogrel. A subanalysis of PLATO trial data identified a geographic region interaction (p = 0.045), indicating reduced efficacy of ticagrelor versus clopidogrel in North American patients. This effect could be due to chance, but may be explained by an interaction of ticagrelor with high aspirin doses, which are commonly used in the United States. In patients taking low-dose maintenance aspirin, ticagrelor was more effective than clopidogrel in decreasing cardiovascular events regardless of the geographic region. A proposed hypothetical mechanism for the interaction between ticagrelor and higher aspirin dose is linked to the level of P2Y12 inhibition and the potential prothrombotic effects of high-dose aspirin through the suppression of prostacyclin. A review of data regarding aspirin use for secondary prevention of events in ACS demonstrated that low aspirin doses (75 to 160 mg/day) are consistently favored for short- and long-term use because of the lack of a dose-response relationship between increasing aspirin dose and improved efficacy, and a higher incidence of gastrointestinal bleeding with increasing aspirin dose. The use of low aspirin doses reflects good clinical practice and is encouraged in current guidelines.

Section snippets

Aspirin

Aspirin mediates its cardioprotective effects through the irreversible inhibition of cyclooxygenase (COX)-1 in the arachidonic acid pathway, subsequently blocking the production of thromboxane A2, a platelet agonist, thereby reducing thrombus formation.11, 12

The use of aspirin has been shown unequivocally to reduce vascular morbidity and mortality in patients with ACS both in the acute13 and long-term clinical settings.14 In a meta-analysis of 16 secondary prevention trials comparing long-term

Thienopyridines

The thienopyridines, clopidogrel and prasugrel, selectively inhibit the P2Y12 purinoreceptor and block platelet activation for the lifespan of the platelet because of their irreversible binding to the receptor.19, 20 Both compounds are prodrugs, requiring biotransformation into their active form by hepatic cytochrome P450 (CYP) enzymes, particularly the CYP3A4 isozyme.20, 21

The Evolution of Aspirin Dosing for Secondary Prevention of Events in ACS

The use of aspirin for the prevention of vascular morbidity and mortality has evolved over many years. The original tablet version of aspirin was developed in 1900 and sold in the United States as a 5-grain pill (∼325 mg)—the genesis of the “higher cardiovascular” dose commonly used today.17 An 81-mg tablet for children was arbitrarily selected as a quarter of the adult dose and became available in 1922.17 Given the long-term use of aspirin as an antiplatelet therapy and its inclusion in many

Clopidogrel and Aspirin

An overview of real-world treatment practice showed that high aspirin doses were commonly used in North America.50 Furthermore, a cross-country evaluation of CURE also demonstrated that use of high aspirin doses was common in North America, with 86% of patients receiving ≥200 mg, whereas low aspirin doses were commonly used in Europe (>50% of patients in both Western and Eastern Europe received doses of ≤100 mg/day). In addition to the previously mentioned analysis by aspirin dose of the CURE

Ticagrelor and Aspirin

In the PLATO trial investigating ticagrelor plus aspirin versus clopidogrel plus aspirin for the prevention of cardiovascular events in patients with ACS, it was recommended that all patients receive a maintenance aspirin dose of 75 to 100 mg/day (325 mg for 6 months was permitted in those who received a stent).36 As mentioned above, prespecified subgroup analyses from the PLATO trial indicated that the efficacy of ticagrelor plus aspirin was less compared with clopidogrel with aspirin for 3 of

Acknowledgment

The author acknowledges the assistance of Josh Collis and Jackie Phillipson, PhD, of Gardiner-Caldwell Communications in drafting the review article. Views expressed in this review represent those of the author.

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    The author did not receive any financial compensation for authoring this article. Medical writing support was funded by AstraZeneca.

    See page 743 for disclosure information.

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