Page 2404 - Hematology_ Basic Principles and Practice ( PDFDrive )

2146 Part XII Hemostasis and Thrombosis

platelet activation and aggregation. Like aspirin, the antiplatelet effect and safety of prasugrel in 13,608 ACS patients with or without
of clopidogrel lasts for the lifetime of the platelet. Clopidogrel is an ST-segment elevation who were undergoing PCI, all of whom were
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effective antiplatelet drug for the prevention of MI and death when treated with aspirin (recommended dose: 75–162 mg/day). Com-
used in combination with aspirin, but has a slow onset of action and pared with clopidogrel (300 mg followed by 75 mg once daily there-
a variable antiplatelet effect that may limit its effectiveness. after), prasugrel (60 mg followed by 10 mg once daily thereafter)
The COMMIT trial, which involved 45,582 patients with STEMI, continued for a median of 14.5 months reduced the risk of MI, stroke,
all of whom were treated with aspirin (162 mg/day), demonstrated or cardiovascular death (9.9% vs. 12.1%; p < .001) and stent throm-
that compared with placebo, 30 days of treatment with clopidogrel bosis (1.1% vs. 2.4%; p < .001) but did not reduce mortality and
(75 mg/day) reduced the risk of MI, stroke, or death (9.2% vs. 10.1%; increased noncoronary artery bypass graft (CABG) major bleeding
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p = .002) with no increase in major bleeding (0.58% vs. 0.55%). (2.4% vs. 1.8%; p = .03) as well as intracranial and fatal bleeding.
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There was no age restriction in the COMMIT trial, and clopidogrel The TRILOGY ACS (Targeted Platelet Inhibition to Clarify the
was given without a loading dose. In the CLARITY (Clopidogrel as Optimal Strategy to Medically Manage Acute Coronary Syndromes)
Adjunctive Reperfusion Therapy) trial (n = 3491), which was con- trial evaluated the efficacy and safety of prasugrel in 9326 aspirin-
ducted in parallel with COMMIT, clopidogrel was given as a loading treated patients with NSTE ACS who were managed noninvasively.
dose of 300 mg followed by 75 mg/day for 2–8 days and was com- At a median of 17 months of follow-up, prasugrel (30 mg followed
pared with placebo in patients receiving fibrinolysis. Clopidogrel by 10 mg once daily in patients less than 75 years or 5 mg once daily
reduced the risk of MI or death (15% vs. 21.7%; p < .001). Consistent for those 75 years or older or who weighed less than 60 kg) and
benefits of clopidogrel were demonstrated in the 1863 patients who clopidogrel (300 mg followed by 75 mg once daily) were associated
underwent PCI after mandated angiography. with similar rates of MI, stroke or cardiovascular death (13.9% vs.
The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent 16.0%; p = .21) and similar rates of major bleeding.
Events) trial, which involved 12,562 patients with NSTE ACS, all of
whom were treated with aspirin (recommended dose: 75–325 mg/
day), demonstrated that compared with placebo, a median of 9 Ticagrelor
months of treatment with clopidogrel (300 mg loading dose followed
by 75 mg/day) reduced the risk of MI, stroke, or death (9.3% vs. Ticagrelor is a nonthienopyridine platelet P2Y12 receptor antagonist.
11.4%; p < .001) at the cost of an increase in major bleeding (3.7% Like prasugrel, ticagrelor is more potent and has a more rapid onset
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vs. 2.7%; p = .001). Consistent benefits of clopidogrel were seen in of action than clopidogrel, but unlike both clopidogrel and prasugrel,
the 2658 patients who underwent PCI irrespective of whether or not ticagrelor binds reversibly to the platelet P2Y12 receptor.
they underwent coronary stenting. The PLATO trial evaluated the efficacy and safety of ticagrelor in
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Prompted by concerns that some patients achieve suboptimal 18,624ACS patients with or without ST-segment elevation. Com-
inhibition of platelet function with conventional doses of clopidogrel, pared with clopidogrel (300 or 600 mg loading dose followed by
the CURRENT-OASIS 7 trial compared the efficacy and safety of a 75 mg once daily), ticagrelor (180 mg loading dose followed by
higher loading and maintenance dose of clopidogrel (600-mg loading 90 mg twice daily) reduced the risk of MI, stroke, or vascular death
dose followed by 150 mg/day for 6 days and 75 mg/day for 23 days by 16% (9.8% vs. 11.7%; p < .001) and produced a significant
thereafter) with standard-dose clopidogrel (300-mg loading dose and reduction in vascular death (4.0% vs. 5.1%; p = .001) and stent
75 mg daily thereafter) in 25,086 patients with ACS referred for an thrombosis (1.3% vs. 1.9%; p = .009). There was no increase in major
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invasive management strategy. Both regimens were associated with bleeding (11.6% vs. 11.2%) or in intracranial or fatal bleeding, but
similar rates of the primary outcome, MI, stroke, or vascular death ticagrelor increased non-CABG major bleeding (4.5% vs. 3.8%;
(4.2% vs. 4.4%), but the higher dose regimen was associated with an p = .03).
increase in major bleeding (2.5% vs. 2.0%; p = .01). However, in the
17,263 patients who underwent PCI, the higher dose regimen
reduced MI, stroke, or vascular death (3.9% vs. 4.5%; p = .039) and Intravenous Antiplatelet Drugs
stent thrombosis (0.7% vs. 1.3%; p = .0001) compared with the
lower dose regimen. Glycoprotein IIb/IIIa Inhibitors

Three GP IIb/IIIa inhibitors are available for clinical use (see Table
Prasugrel 146.4). Abciximab is a humanized version of a Fab fragment of a
murine antibody directed against GP IIb/IIIa; tirofiban is a nonpep-
Prasugrel is a third-generation thienopyridine that is more potent and tide tyrosine derivative that selectively binds to GP IIb/IIIa; and
has a more rapid onset of action than clopidogrel. Prasugrel is a eptifibatide is a synthetic disulfide-linked cyclic heptapeptide with
prodrug, but unlike clopidogrel, it requires only single-step biocon- high specificity for GP IIb/IIIa.
version to form the active metabolite that irreversibly blocks the The efficacy and safety of GP IIb/IIIa inhibitors have been exten-
platelet P2Y12 receptor. sively evaluated in patients with ACS. A meta-analysis restricted to
The TRITON-TIMI 38 (Trial to Assess Improvement in Thera- trials (n = 6) involving at least 1000 patients suggests a modest effect
peutic Outcomes by Optimizing Platelet Inhibition With Prasugrel– of these agents for the prevention of MI, urgent revascularization,
Thrombolysis In Myocardial Infarction 38) trial evaluated the efficacy or vascular death in patients with NSTE ACS (10.8% vs. 11.8%;

TABLE Pharmacologic Characteristics of Intravenous Antiplatelet Drugs Used in the Management of Acute Coronary Syndrome
146.4
GP IIb/IIIa inhibitors ADP Receptor Antagonists
Characteristic Abciximab Eptifibatide Tirofiban Cangrelor
Class Fab fragment Nonpeptide Cyclic heptapeptide Nonthienopyridine
Onset Rapid Rapid Rapid Rapid
Drug half-life 10–30 min 2 hours 2.5 hours 3–6 min
Reversibility of platelet inhibition Slow Rapid Rapid Rapid
Excretion Unknown 40%–70% renal 50% renal Dephosphorylation