Page 2432 - Hematology_ Basic Principles and Practice ( PDFDrive )

2170 Part XII Hemostasis and Thrombosis

death, myocardial infarction, or stroke in these patients. There is Thienopyridines
mounting evidence that aspirin is of limited benefit for primary
prevention in subjects without clinical evidence of cardiovascular The thienopyridines include clopidogrel and prasugrel, as well as
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disease. Although metaanalyses demonstrate a reduction in nonfatal ticlopidine, which is rarely used.
myocardial infarction with daily aspirin use, this benefit is partially
offset by an increase in gastrointestinal bleeding. Nonetheless, there Mechanism of Action
also is evidence that aspirin reduces cancer mortality. If used for The thienopyridines are structurally related drugs that selectively
primary prevention, aspirin should be restricted to those at moderate inhibit ADP-induced platelet aggregation by irreversibly blocking
to high risk of cardiovascular events. 2 P2Y 12 (see Fig. 149.2). Clopidogrel and prasugrel are prodrugs that
must be metabolized by the hepatic cytochrome P450 (CYP) enzyme
system to acquire activity. Consequently, their onset of action is
Dosages delayed unless loading doses are given. The metabolic activation of
prasugrel is more efficient than that of clopidogrel. Consequently,
Aspirin is usually administered at doses of 75 to 325 mg once daily. prasugrel produces more rapid, higher, and more uniform P2Y 12
There is no evidence that higher-dose aspirin is more effective than blockade than clopidogrel.
lower aspirin doses, and some analyses suggest reduced efficacy with
higher doses. Because the side effects of aspirin are dose-related, daily Indications
aspirin doses of 75 to 150 mg are recommended for most indications. When compared with aspirin in patients with recent ischemic stroke,
When rapid platelet inhibition is required, an initial aspirin dose of myocardial infarction, or peripheral arterial disease, clopidogrel
at least 160 mg should be given. reduced the risk of cardiovascular death, myocardial infarction,
and stroke by 8.7%. Therefore clopidogrel is more effective than
aspirin, but it also is more expensive. In some patients, clopidogrel
Side Effects and aspirin are combined to capitalize on their capacity to block
complementary pathways of platelet activation. For example, the
Most common side effects are gastrointestinal and range from dys- combination of aspirin plus clopidogrel is recommended for at least 4
pepsia to erosive gastritis or peptic ulcers with associated bleeding. weeks after implanting a bare metal stent in a coronary artery and for
These side effects are, at least to some extent, dose related. Use of at least 1 year in those with a drug-eluting stent. Concerns about late
enteric-coated or buffered aspirin in place of plain aspirin does not in-stent thrombosis with drug-eluting stents have led some experts
eliminate the prostaglandin-mediated gastrointestinal side effects. to recommend long-term use of clopidogrel plus aspirin for this
The risk of major bleeding with aspirin ranges from 1% to 3% per indication.
year and is higher when aspirin is used in conjunction with antico- The combination of clopidogrel and aspirin also is effective in
agulants, such as warfarin. When dual therapy is used, low-dose patients with unstable angina. Thus in 12,562 such patients, the risk
aspirin should be given (75 to 100 mg daily). Eradication of Helico- of cardiovascular death, myocardial infarction, or stroke was 9.3% in
bacter pylori infection and concomitant administration of proton those randomized to the combination of clopidogrel and aspirin and
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pump inhibitors may reduce the risk of upper gastrointestinal bleed- 11.4% in those given aspirin alone, a 20% relative risk reduction.
ing, particularly in patients with a history of peptic ulcer disease. However, combining clopidogrel with aspirin increases the risk of
Aspirin should not be administered to patients with aspirin allergy major bleeding to about 2% per year. This bleeding risk persists even
characterized by bronchospasm. This problem occurs in about 0.3% if the daily dose of aspirin is 100 mg or less. Therefore the combina-
of the general population, but it is more common in those with tion of clopidogrel and aspirin should be used only when there is a
chronic urticaria or asthma, particularly in subjects with coexisting clear benefit. For example, this combination has not proven to be
nasal polyps or chronic rhinitis. Hepatic and renal toxicity are superior to clopidogrel alone in patients with acute ischemic stroke
observed with aspirin overdose. or to aspirin alone for primary prevention in those at risk for cardio-
vascular events.
When compared with clopidogrel in 13,608 patients with acute
Aspirin Resistance coronary syndromes undergoing percutaneous coronary interventions
(PCIs), prasugrel reduced the combined rate of cardiovascular death,
The term aspirin resistance has been used to describe both clinical and myocardial infarction, or stroke from 12.1% to 9.9%, a decrease
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laboratory phenomena. Clinical aspirin resistance is defined as the driven mainly by a reduction in nonfatal myocardial infarction.
failure of aspirin to protect patients from ischemic vascular events. However, prasugrel increased the rate of major bleeding and fatal
This is not a helpful definition, because it is made after the event bleeding, particularly in patients over the age of 65 years, in those
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occurs. Furthermore, it is not realistic to expect aspirin, which blocks weighing less than 60 kg, and in those with a history of stroke.
only thromboxane A 2 –induced platelet activation, to prevent all Therefore prasugrel should not be used in patients with these
vascular events. characteristics. Prasugrel was compared with clopidogrel in 7243
Aspirin resistance also has been described biochemically as failure aspirin-treated patients under the age of 75 years with unstable
of the drug to produce its expected inhibitory effects on tests of angina or myocardial infarction without ST-segment elevation.
platelet function, such as thromboxane A 2 synthesis or arachidonic At a median follow-up of 17 months, the primary endpoint, the
acid–induced platelet aggregation. However, the tests used for the composite of cardiovascular death, myocardial infarction, and stroke
diagnosis of aspirin resistance are not well standardized. Furthermore, had occurred in 13.9% of the prasugrel group and in 16.0% of the
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there is no definitive evidence that these tests identify patients at risk clopidogrel group, a difference that was not statistically significant.
of recurrent vascular events, or that resistance can be reversed either Rates of major bleeding and intracranial bleeding were similar with
by giving higher doses of aspirin or by adding other antiplatelet drugs. the two treatment regimens. Therefore prasugrel has no advantage
Until such information is available, testing for aspirin resistance over clopidogrel in medically managed patients with acute coronary
remains a research tool. syndrome.
Dosing
ADP Receptor Antagonists Clopidogrel is given once daily at a dose of 75 mg. Because its onset
of action is delayed for several days, loading doses of clopidogrel are
P2Y 12 is the major ADP receptor on platelets. Agents that inhibit given when rapid ADP receptor blockade is desired. For example,
P2Y 12 include oral agents such as the thienopyridines as well as patients undergoing coronary artery stenting are often given a loading
ticagrelor, and cangrelor, which is a parenteral inhibitor. dose of 600 mg, which produces inhibition of ADP-induced platelet