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2076 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2077

Thienopyridines differ from aspirin in their mechanism of anti- moderate or severe bleeding events. Furthermore, a meta-analysis of
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platelet activity and their toxicity profile. All three thienopyridines seven randomized controlled trials involving more than 39,000 patients
are prodrugs that depend on oxidation by cytochrome P450 (CYP) confirmed that intracranial hemorrhage was more frequent in patients
enzymes in the liver (ticlopidine and clopidogrel) or in liver and intes- who received both clopidogrel plus aspirin compared to clopidogrel
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tine (prasugrel) to form the active metabolites that irreversibly inhibit alone. Thus, except for special circumstances such as coronary artery
the platelet P2Y ADP receptor. 58–61 Ticlopidine at 250 mg twice a day, stenting, it appears that the added benefit of dual antiplatelet therapy is
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clopidogrel at 75 mg once per day, and prasugrel at 10 mg once a day small and has the added risk of increased bleeding. 83
inhibit platelet aggregation ex vivo in humans. The extent of this effect
is equivalent to or greater than that of aspirin and the effect of thieno- OTHER ADENOSINE DIPHOSPHATE RECEPTOR
pyridines and aspirin appears additive. 62,63 When given at their usual
oral doses, the effect of thienopyridines on platelet aggregation and ANTAGONISTS
the bleeding time can be seen within hours of the first dose, but are Ticagrelor, cangrelor, and elinogrel are oral, reversible, nonthienopyri-
not maximal for 4 to 6 days. A 300-mg loading dose of clopidogrel or dine P2Y receptor antagonists. Because they are not prodrugs and do
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60 mg of prasugrel, followed by their usual daily doses, shortens the not require metabolic activation, the onset of their inhibitory activity is
time required for their maximal antiplatelet effect to a few hours. 64,65 more rapid than that of the thienopyridines. A novel, and as yet unex-
The common CYP polymorphism CYP2C19 results in lower levels of plained, side effect of treatment with this class of the P2Y antagonists
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active clopidogrel and ticlopidine metabolites and has been reported to is the occurrence of dyspnea which can complicate the management of
be associated with decreased platelet inhibition and an elevated risk for patients with coronary artery disease. 84
major adverse cardiovascular events. 55,66,67 Because the enzyme CYP3A Ticagrelor, the first drug of the class, has been approved for use in
is present in the intestine and can oxidize prasugrel to its pharmacologi- acute coronary syndromes. Its efficacy versus clopidogrel was tested in
cally active metabolite, intestinal metabolism may account for the rapid the PLATO trial in which patients with an acute coronary syndrome
appearance and higher levels of the active metabolite in plasma after were randomized to treatment with either ticagrelor or clopidogrel. 85–87
an oral dose. 61,68–70 Furthermore, prasugrel metabolism and inhibition At 1 year, the combined end point of death, myocardial infarction,
of platelet function are not affected by CYP2C19 polymorphisms. 61,68–70 and stroke was 9.8 percent in patients treated with ticagrelor com-
The clinical efficacy of prasugrel has been compared to clopido- pared to 11.7 percent in patients treated with clopidogrel. Although
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grel in patients with acute coronary syndrome scheduled for percuta- stent thrombosis was also decreased in the ticagrelor-treated group,
neous coronary intervention in the Triton-TIMI 38 trial. Patients who major bleeding not associated with coronary artery bypass surgery was
received prasugrel had a significantly decreased incidence of ischemic increased in this group. The incidence of fatal intracranial hemorrhage
events compared to patients who received clopidogrel (9.9 percent vs. was also greater in the ticagrelor-treated patients, but it was a rare event
12.1 percent, p <0.001). However, major bleeding was also signifi- (0.1 percent of treated patients). In the ATLANTIC trial, patients suf-
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cantly increased in patients receiving prasugrel compared to clopidogrel fering from an ST-segment elevation myocardial infarction were ran-
(2.4 percent vs. 1.8 percent, p <0.03). Thus, although prasugrel appeared domized to receive ticagrelor in the ambulance or in the catheterization
to be more efficacious than clopidogrel, this benefit was partially offset laboratory. Although initiating therapy before hospitalization was safe
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by a higher rate of hemorrhage. 69 and lowered the incidence of stent thrombosis, there was no overall
The platelet inhibitory effects of thienopyridines persist for 4 to improvement in preventing major cardiovascular adverse events. Thus,
10 days after the drugs have been discontinued, either because of their ticagrelor, like prasugrel appears to be more efficacious than clopido-
extended half-life after multiple dosing or their irreversible effect on grel at preventing adverse cardiovascular events, but with more hemor-
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platelets. Ticlopidine administration is associated with potentially rhagic complications.
serious hematologic complications, including neutropenia (neutrophils
<1200 × 10 /L in 2.4 percent of individuals) 58,71,72 and, less commonly,
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aplastic anemia, and thrombocytopenia. 73,74 In addition, at least one THROMBIN RECEPTOR ANTAGONISTS
in 5000 patients develop a thrombotic thrombocytopenic purpura Thrombin is the most potent physiologic platelet agonist. Three G-
(TTP)-like syndrome. 75–77 Results from a large clinical trial suggest that protein–coupled thrombin receptors have been identified in humans
hematologic complications may be less common with clopidogrel or (protease-activated receptors [PARs] 1, 3, and 4). Although human
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prasugrel. Clopidogrel may also be rarely associated with a TTP-like platelets express both PAR-1 and PAR-4, the major platelet thrombin
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syndrome (one in 270,000), although this rate is close to the TTP inci- receptor is PAR-1 and can be activated by nanomolar concentrations
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dence in the general population. Because of its toxicity profile, ticlopi- of thrombin. PAR-4 signaling appears to be unnecessary for platelet
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dine has been replaced by the other thienopyridines in the United States. activation if PAR-1 signaling is intact. Vorapaxar is a potent, selective,
Because aspirin and the thienopyridines inhibit platelet function long-acting, oral PAR-1 inhibitor generated from the naturally occur-
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by different mechanisms, their antithrombotic effects may be additive. ring muscarinic receptor antagonist himbacine. A high-resolution
In theory, this would be beneficial in the treatment of diseases asso- crystal structure of vorapaxar bound to PAR-1 revealed that the binding
ciated with platelet activation such as ischemic heart disease, periph- pocket for the drug is unusual for a peptide-activated G-protein–cou-
eral vascular disease, and ischemic strokes. 62,79,80 This hypothesis was pled receptor in that it consists of a superficial tunnel with little of the
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tested in the CURE trial of patients with acute coronary syndromes. bound drug surface exposed to aqueous solvent, perhaps accounting for
Although clopidogrel plus aspirin decreased the combined incidence the very slow dissociation rate of vorapaxar from PAR-1. 92
of cardiovascular deaths, myocardial infarctions, and strokes from 11.4 The efficacy of vorapaxar for the secondary prevention of arte-
percent to 9.3 percent, the benefit was partially offset by an increase in rial thrombosis was examined in the phase III TRA 2P–TIMI 50 trial
severe bleeding from 2.7 to 3.7 percent. Similarly, in the CHARISMA in which patients with a history of myocardial infarction, stroke, or
trial of a broad population of patients at risk for cardiovascular events, peripheral arterial disease were randomized between vorapaxar and pla-
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there were 94 fewer ischemic events in patients treated with both cebo. Most patients were also taking either aspirin or a thienopyridine.
clopidogrel and aspirin, but this occurred at the expense of 93 more Because of a high incidence of intracranial bleeding in the first years of

Kaushansky_chapter 121_p2073-2096.indd 2076 9/18/15 10:28 AM