Meeting New Challenges with Antiplatelet Therapy in Primary Care

Introduction

The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.¹ Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.² Among the several classes of antiplatelet agents currently available, the thromboxane A₂ inhibitor (ie, aspirin) and P2Y₁₂ inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.³

Antiplatelet Agents

It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y₁₂, and ADP-A₂ pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y₁₂ inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.

P2Y₁₂ Inhibitors

Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y₁₂ receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y₁₂ receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.^2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.

In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y₁₂ inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.^2,4,5

Prasugrel

Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.⁶

The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).^7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).⁷ Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.