Page 2433 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 149 Antithrombotic Drugs 2171

aggregation within 6 hours. Prasugrel is given as a loading dose of Dosing
60 mg followed by 10 mg once daily. Partial inhibition of ADP- Ticagrelor is given as a 180-mg oral loading dose followed by 90 mg
induced platelet aggregation is evident within 1 hour of prasugrel twice daily. Although the trial comparing ticagrelor with clopidogrel
administration. was not powered to compare outcomes in different geographical
regions, patients enrolled in North America did not have the same
Side Effects benefit as those from other countries. On the basis of post hoc analy-
Gastrointestinal and hematologic side effects, other than bleeding, sis, the only baseline covariate associated with this difference was the
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are rare with clopidogrel and prasugrel. higher dose of aspirin used in the United States. Consequently, it
is recommended that when ticagrelor is combined with aspirin, the
Clopidogrel Resistance daily aspirin dose should be less than 100 mg.
There is considerable between patient variability in the capacity of
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clopidogrel to inhibit ADP-induced platelet aggregation. Nonre- Side Effects
sponsiveness to clopidogrel is termed clopidogrel resistance, and Ticagrelor produces dyspnea, which is usually mild and dose related,
platelets from patients with this phenomenon exhibit high reactivity asymptomatic bradycardia with ventricular pauses, and a modest
to ADP. Reduced responsiveness to clopidogrel reflects, at least in increase in the levels of uric acid. The mechanisms responsible for
part, genetic polymorphisms in CYP2C19, which is critical for meta- these side effects are unclear. One possible explanation relates to the
bolic activation of clopidogrel in the liver. Thus loss-of-function capacity of ticagrelor to inhibit adenosine reuptake by erythrocytes,
CYP2C19*2 and CYP2C19*3 alleles are found in 2% of white thereby increasing circulating levels of adenosine. In addition to
individuals, 4% of black individuals, and 14% of Asian individuals, explaining the dyspnea and the bradycardia, the resultant adenosine-
and the levels of the active metabolite of clopidogrel are reported to induced vasodilation and increased myocardial perfusion could also
be up to 33% lower in carriers of either of these alleles than in those endow ticagrelor with beneficial effects that are independent of P2Y 12
with healthy alleles. Patients with clopidogrel resistance are reported blockade.
to have a higher risk of ischemic complications after PCI, including
myocardial infarction and stent thrombosis. On the basis of these
findings, some experts recommend pharmacogenetic testing and Cangrelor
point-of-care assessment of platelet reactivity to predict or assess
clopidogrel responsiveness. However, attempts to manage such Cangrelor is the only available parenteral inhibitor of P2Y 12 .
patients with higher doses of clopidogrel or with additional antiplate-
let drugs have not resulted in improved outcomes. Instead, patients Mechanism of Action
with clopidogrel resistance may benefit from a switch to prasugrel, Cangrelor is a rapidly acting reversible inhibitor of P2Y 12 . It has an
which produces more uniform inhibition of ADP-induced platelet immediate onset of action after intravenous administration, a half-life
aggregation, or to ticagrelor. of 3 to 5 minutes, and an offset of action within 1 hour.
Indications
Ticagrelor Cangrelor is licensed for use in patients undergoing PCI, in whom
it produces rapid ADP receptor blockade in those who have not
An orally active agent belonging to the cyclopentyl-triazolopyrimidine received pretreatment with clopidogrel, prasugrel, or ticagrelor and
class, ticagrelor acts as a direct inhibitor of P2Y 12 . are not receiving a GPIIb/IIIa inhibitor.
Mechanism of Action Dosing
Ticagrelor reversibly binds to P2Y 12 at a location distinct from Cangrelor is administered as a 30 µg/kg intravenous bolus before PCI
the ADP binding site and blocks ADP-mediated receptor activa- followed by an infusion of 4 µg/kg/min for at least 2 hours or for
tion in a noncompetitive fashion, likely through an allosteric the duration of PCI, whichever is longer. When transitioning to oral
mechanism. Because it does not require metabolic activation, P2Y 12 inhibitor therapy, ticagrelor can be given at a loading dose of
ticagrelor has a more rapid onset of action than clopidogrel or 180 mg at any time during the cangrelor infusion or immediately
prasugrel. after discontinuation. In contrast, loading doses of prasugrel or
clopidogrel (60 and 600 mg, respectively) should be given only after
Indications cangrelor is stopped, because cangrelor blocks the interaction of their
When compared with clopidogrel in 18,624 patients with acute coro- active metabolites with P2Y 12 .
nary syndromes, ticagrelor reduced the rate of cardiovascular death,
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myocardial infarction, or stroke from 11.7% to 9.8%. All-cause Side Effects
mortality was also reduced with ticagrelor compared with clopidogrel The major side effect of cangrelor is bleeding.
(4.5% and 5.9%, respectively; p < .001), but ticagrelor produced
more major bleeding not related to bypass surgery (2.8% and 2.2%,
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respectively). An invasive strategy was planned for 72% of the Dipyridamole
patients entered in the trial. In this subset, the primary composite
endpoint occurred in 9.0% of patients randomized to ticagrelor and Dipyridamole is a relatively weak antiplatelet agent on its own. An
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in 10.7% of those given clopidogrel, a 16% relative risk reduction. extended-release formulation of dipyridamole combined with low-
Rates of major bleeding were similar with ticagrelor and clopidogrel dose aspirin, a preparation known as Aggrenox, is used for prevention
(11.6% and 16.5%, respectively; p = .88). Therefore ticagrelor of stroke in patients with transient ischemic attacks.
also was superior to clopidogrel in patients undergoing coronary
interventions.
If cost is not an issue and patients are compliant with twice-daily Mechanism of Action
dosing, ticagrelor is a reasonable alternative to clopidogrel in patients
with acute coronary syndrome, regardless of whether they are By inhibiting phosphodiesterase, dipyridamole blocks the breakdown
managed medically or undergo PCI with stent implantation. For of cyclic AMP (cAMP). Increased levels of cAMP reduce intracellular
these indications, ticagrelor should be given for at least 1 year. It also calcium and inhibit platelet activation. Dipyridamole also blocks the
is reasonable to use ticagrelor in place of clopidogrel in patients with uptake of adenosine by platelets and other cells. This produces a
clopidogrel resistance or in those who develop in-stent thrombosis further increase in local cAMP levels because the platelet adenosine
despite clopidogrel therapy. A 2 receptor is coupled to adenylate cyclase (Fig. 149.3).