Dual Antiplatelet Therapy for Prevention of Recurrent Ischemic Events

Jean Nappi, PharmD, Fccp, Bcps; Robert Talbert, PharmD, Fccp, Bcps

Disclosures

Am J Health Syst Pharm. 2002;59(18) 

In This Article

Rationale for Combination Therapy

Antiplatelet agents target a variety of steps in thrombus formation wherein the platelets play a central role. The ability of any one antiplatelet agent to optimally inhibit platelet aggregation through one predominant mechanism of action may be overcome when multiple aggregation agonists are released from platelets and endothelial cells.[11,66]

Aspirin resistance is one limitation of aspirin monotherapy. Studies of aspirin resistance in patients with ischemic stroke have shown that the antiplatelet effect of aspirin is not constant over time and may place patients at risk for breakthrough vascular events.[67] Despite dose escalation, the antiplatelet effect of aspirin fluctuates between complete inhibition, partial inhibition, and resistance in about one third of individuals.[42,67] A follow-up study of 180 patients treated for two years following ischemic stroke found that major vascular endpoints occurred in 40% of aspirin nonresponders (platelet reactivity index [PRI] of >1.25 based on the ratio of platelets in the supernatants of mixtures of edetic acid [EDTA] buffer alone or EDTA plus formalin) but in only 4.4% of aspirin responders (PRI of <1.25) (p < 0.0001).[68] Aspirin is beneficial in preventing and treating cardiovascular events, but patients who have ischemic events while taking aspirin may have worse outcomes than those not receiving aspirin.[69] The association between aspirin use and clinical outcomes was assessed in 9461 patients with NSTEMI enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial.[69] The results of this trial showed that patients taking aspirin before enrollment were more likely to experience death (p = 0.003) or MI (p = 0.001) after 30 days and the composite of death and MI at 4 days (p = 0.001), 30 days (p = 0.001), and six months (p = 0.001) than nonaspirin users. Thus, a rational approach for patients who develop ischemic events, such as stroke or MI, while using aspirin is to enhance aspirin's relatively weak inhibitory effects[69] by combining it with an anti-platelet agent with a different mechanism of action.[5] Combinations of aspirin with other oral antiplatelet agents, such as clopidogrel, ticlopidine, or dipyridamole, may provide enhanced antiplatelet effects for preventing recurrent events in different vascular beds. Data from ex vivo animal[70,71,72,73] and human studies[74,75,76,77] of platelet aggregation indicate that combination antiplatelet therapy is synergistic with efficacy. Table 3 summarizes the outcomes of selected MI and stroke trials using combination oral antiplatelet therapy.

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