Prasugrel, similar to clopidogrel, is approved for patients with acute coronary syndromes. The drug is given orally as a 60-mg loading dose and then 10 mg/d in combination with aspirin as outlined for clopidogrel. The Trial to assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI38) compared prasugrel with clopidogrel in a randomized, double-blind trial with aspirin and other standard therapies managed with percutaneous coronary interventions. This trial showed a reduction in the primary composite cardiovascular endpoint (cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) for prasugrel in comparison with clopidogrel. However, the major and minor bleeding risk was increased with prasugrel. Prasugrel is contraindicated in patients with history of TIA or stroke because of increased bleeding risk. In contrast to clopidogrel, cytochrome P450 genotype status is not an important factor in prasugrel pharmacology.
Ticagrelor is a newer type of ADP inhibitor (cyclopentyl triazolopyrimidine) and is also approved for oral use in combination with aspirin in patients with acute coronary syndromes. Cangrelor is a parenteral P2Y12 inhibitor approved for IV use in coronary interventions in patients without previous ADP P2Y12 inhibitor therapy.
The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. In part this variation reflects the definition of resistance (recurrent thrombosis while on antiplatelet therapy versus in vitro testing), methods by which drug response is measured, and patient compliance. Several methods for testing aspirin and clopidogrel resistance in vitro are now FDA-approved. However, the measures of drug resistance vary considerably by testing method. These tests may be useful in selected patients to assess compliance or identify patients at increased risk of recurrent thrombotic events. However, their utility in routine clinical decision-making outside of clinical trials remains controversial. A recent randomized prospective trial found no benefit over standard therapy when information obtained from monitoring antiplatelet drug effect was used to alter therapy.
The platelet GP IIb/IIIa (integrin αIIbβ3) receptor functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the final common pathway for platelet aggregation. Ligands for GP IIb/IIIa contain an Arg-Gly-Asp (RGD) sequence motif important for ligand binding, and thus RGD constitutes a therapeutic target. There are approximately 50,000 copies of this complex on the surface of each platelet. Persons lacking this receptor have a bleeding disorder, Glanzmann’s thrombasthenia.
The GP IIb/IIIa antagonists are used in patients with acute coronary syndromes. These drugs target the platelet GP IIb/IIIa receptor complex shown in Figure 34–1. Abciximab, a chimeric monoclonal antibody directed against the IIb/IIIa complex including the vitronectin receptor, was the first agent approved in this class of drugs. It has been approved for use in percutaneous coronary intervention and in acute coronary syndromes. Eptifibatide is a cyclic peptide derived from rattlesnake venom that contains a variation of the RGD motif (KGD). Tirofiban is a peptidomimetic inhibitor with the RGD sequence motif. Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by their occupancy of the receptor but do not block the vitronectin receptor. Because of their short half-lives, they must be given by continuous infusion. Oral formulations of GP IIb/IIIa antagonists are in various stages of development.