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404 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 405

the secondary prevention of noncardioembolic stroke. Recent system- reduce variability in response; the safety and efficacy of such doses are
112
atic reviews have also suggested that the combination of dipyridamole being compared in ongoing studies. 124
and aspirin is superior to aspirin alone for the prevention of cerebrovas- Prasugrel is a “third-generation” P2Y12 blocking agent. Unlike
cular events. 113 clopidogrel it can be converted to its active metabolite via esterases pres-
The other two phosphodiesterase inhibitors (pentoxifylline and ent in either the liver or the gut. Like clopidogrel it irreversibly blocks
144
cilostazol) are used primarily in patients with peripheral vascular dis- the P2Y12 receptor. Evidence for the use of prasugrel comes predom-
ease. In addition to their inhibitory effect on platelets they may exert a inately from one large study of prasugrel compared with clopidogrel.
beneficial effect on blood rheology and the microcirculation by increas- This study randomized 13,608 patients with moderate-to-high-risk
ing red cell deformability, thereby reducing blood viscosity. Cilostazol acute coronary syndromes and who were scheduled to undergo per-
increases vascular endothelial growth factor levels, which may lead to cutaneous coronary intervention to receive prasugrel (a 60-mg loading
an increase in collateral circulation. It has been shown to reduce risk dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg load-
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of stroke in Asian populations, 114,115 and increases walking distance in ing dose and a 75-mg daily maintenance dose) for up to 15 months.
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patients with peripheral vascular disease. Pentoxifylline inhibits vas- Although prasugrel significantly reduced death from cardiovascular
cular smooth-muscle cell proliferation and collagen synthesis, which causes, nonfatal MI, and nonfatal stroke, it significantly increased all
may enhance vasodilation. Pentoxifylline probably is an effective treat- forms of bleeding, including major and fatal hemorrhage.
ment for ulcers associated with peripheral vascular disease; however, it Ticagrelor is a member of the cyclopentyltriazolopyrimidines
is only modestly effective for treatment of peripheral vascular disease. 117 chemical class, a group of agents that reversibly inhibit the P2Y12 plate-
let receptor. Ticagrelor does not require hepatic activation and has a
ADENOSINE DIPHOSPHATE RECEPTOR more rapid onset of action than clopidogrel. The PLATO trial was a
large phase III randomized study comparing ticagrelor and aspirin (180
BLOCKERS mg loading dose followed by 90 mg twice daily) to clopidogrel (300
The third class of platelet inhibitors is the ADP receptor blockers, which to 600 mg dose followed by 75 mg daily) and aspirin for treatment of
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include thienopyridines (ticlopidine, clopidogrel, and prasugrel) and acute coronary syndrome. Patients receiving ticagrelor experienced
nonthienopyridines (ticagrelor and cangrelor). There are three ADP the composite primary end point (death from vascular causes, MI, or
receptors on platelet membranes (Chap. 112), with the thienopyridines stroke) less often than patients receiving clopidogrel (9.8 percent vs.
inhibiting one of them, the P2Y12 receptor. The inhibition of binding 11.7 percent, hazard ratio [HR] 0.84) without a significant difference in
of ADP to the P2Y12 receptor results in inhibition of adenylate cyclase. the rates of major bleeding (11.6 percent vs. 11.2 percent).
Ticlopidine was available for clinical use before clopidogrel. The Cangrelor, the first parenteral ADP receptor blocker, is not cur-
Canadian American Ticlopidine Study was a randomized, placebo- rently available for clinical use, but has been tested in three large ran-
controlled, double-blind study showing a 30 percent risk reduction for domized clinical trials of patients undergoing intracoronary stent
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recurrent cardiovascular events with ticlopidine. A review of four tri- implantation procedures. Advantages of this agent include parenteral
als of ticlopidine plus aspirin versus oral anticoagulants for coronary administration, very rapid onset, and short half-life. The CHAMPION
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127
129
stenting showed benefit to the combination in terms of reduced risk studies (PLATFORM, PCI, and PHOENIX ) compared cangrelor
of nonfatal myocardial infarction and revascularization at 30 days, to clopidogrel or placebo in patients undergoing coronary interven-
combined negative events (mortality, myocardial infarction, revas- tions. Although only the PHOENIX trial showed a significant reduction
cularization at 30 days), and major bleeding, but increased the risk of (4.7 percent vs. 5.9 percent) in the 48-hour composite end point (death,
thrombocytopenia and neutropenia. 119 MI, ischemia-driven revascularization, or stent thrombosis), in a pooled
In clinical practice fear of toxicity has largely led ticlopidine to be analysis of patient level data from the three CHAMPION trials cangrelor
abandoned in favor of clopidogrel. In a direct comparison of ticlopidine use was associated with a significant reduction in the primary efficacy
and clopidogrel in patients undergoing coronary stenting (CLASSICS end point compared to control (3.8 percent vs. 4.7 percent, OR 0.81). 130
trial), clopidogrel was associated with a significantly lower rate of major
120
adverse events (4.6 percent vs. 9.1 percent). The first clinical trial of
clopidogrel was the Clopidogrel Versus Aspirin in Patients at Risk of a β BLOCKERS
IIB 3
Ischemic Events (CAPRIE) trial, a large randomized, blinded trial of Fibrinogen binds specifically and saturably to the surface of activated
121
clopidogrel versus aspirin in 19,000 patients at risk of ischemic events. platelets, and the α β complex is the fibrinogen receptor. This com-
IIb 3
Patients were enrolled after recent myocardial infarction (MI) or stroke, plex mediates platelet aggregation induced by all physiologic agonists.
or if they had symptomatic peripheral arterial disease. The primary Fibrinogen binds only to the activated conformation of the receptor
outcome was the occurrence of ischemic stroke, MI, or vascular death. α β . Monoclonal antibodies have been developed against α β com-
IIb 3
IIb 3
With a mean followup of 1.91 years, there was a relative risk reduction plex on resting or activated platelets, which prevent aggregation by
of 8.7 percent in the clopidogrel group (p = 0.043). No major differ- blocking ligand binding. Abciximab, is the Fab′ fragment of a chimeric
2
ences were noted in terms of safety. Clopidogrel is also used in acute mouse–human antibody. Initial human pharmacodynamic studies were
coronary syndromes, based on studies like the Clopidogrel in Unsta- performed in patients with unstable angina and in patients undergoing
ble Angina to Prevent Recurrent Events (CURE) study, which showed high-risk coronary angioplasty, and dose-related inhibition of platelet
a significant reduction in the combined end point of cardiovascular function was found. No spontaneous bleeding was observed, despite
death, nonfatal MI, or stroke with clopidogrel and aspirin versus aspirin prolongation of the template bleeding time. Because of the mouse com-
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alone. Several studies have demonstrated the effectiveness of clopi- ponent of abciximab, it may induce antimouse antibodies, preventing
dogrel in patients undergoing percutaneous coronary intervention, and repeated use in patients.
a recent meta-analysis of several large studies showed that clopidogrel The first large clinical trial of abciximab was the Evaluation of c7E3
treatment prior to intervention is associated with decreased incidence for the Prevention of Ischemic Complications (EPIC) trial, published
131
of major cardiac events (MI, stroke, urgent revascularization) compared in 1994, in which the drug was used in patients with high-risk coro-
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to treatment after intervention. The degree of platelet inhibition after nary angioplasty. Abciximab reduced ischemic events after angioplasty
clopidogrel therapy varies. Larger loading doses of clopidogrel appear to when given together with heparin and aspirin, but it also increased the

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