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300 PART 3: Cardiovascular Disorders

infarct size, left ventricular function, and survival. 55,56 The ultimate goal absorption and metabolism have been used to assess clopidogrel respon-
is to restore adequate blood flow through the infarct-related artery to siveness. 64,65 Clinical trials have not shown increased efficacy with higher
the infarct zone as well as to limit microvascular damage and reperfusion clopidogrel dosing in nonresponders, however, and testing for clopido-
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injury. The latter is accomplished with adjunctive and ancillary treat- grel resistance has not been shown to change outcome.
ments that will be discussed below. Prasugrel is a recently approved thienopyridine that irreversibly binds
to the P2Y12 component of the ADP receptor with a more rapid onset of
Coronary Stenting: Primary angioplasty for acute myocardial infarc- action. Prasugrel is metabolized more completely to active drug than
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tion results in a significant reduction in mortality but is limited by the clopidogrel, resulting in a higher level of inhibition of platelet aggrega-
possibility of abrupt vessel closure, recurrent in-hospital ischemia, reoc- tion. The onset of inhibition of platelet aggregation is dose dependent
clusion of the infarct related artery, and restenosis. The use of coronary and can be achieved in <30 minutes at a dose of 60 mg, but peak effect
stents has been shown to reduce restenosis and adverse cardiac outcomes occurs in approximately four hours. Prasugrel (given as a loading
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in both routine and high-risk PCI. The PAMI Stent Trial was designed dose of 60 mg followed by maintenance dose of 10 mg) decreased the
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to test the hypothesis that routine implantation of an intracoronary combined end point of death, MI, and stroke compared to clopidogrel
stent in the setting of myocardial infarction would reduce angiographic (300 mg load, followed by 75 mg maintenance) in the randomized,
restenosis and improve clinical outcomes compared to primary balloon double-blind TRITON-TIMI 38 trial of 13,608 ACS patients under-
angioplasty alone. This large, randomized, multicenter trial involving going PCI for ACS (3534 STEMI, 10,074 UA/NSTEMI). The rate of
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900 patients did not show a difference in mortality at 6 months but did major bleeding was higher in the prasugrel group, as was the rate of life-
show improvement in ischemia-driven target vessel revascularization threatening bleeding. A post-hoc analysis of the trial showed harm with
and less angina in the stented patients compared to balloon angioplasty prasugrel patients with a history of TIA or stroke, and no benefit with
alone. Despite the lack of definite data demonstrating mortality ben- patients in which prasugrel was found to be harmful or >75 or body
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efit, virtually all of the trials investigating adjunctive therapy for STEMI weight <60 kg, so caution is warranted in these groups. 69
have employed a strategy of primary stenting, and stenting is becoming Dual antiplatelet therapy with aspirin and thienopyridines is given to all
the default strategy. Whether to use a bare metal stent or a drug eluting patients undergoing PCI, as described above. However, data suggest that
stent in acute MI is a question that has not yet been addressed defini- even patients not undergoing PCI benefit from the addition of clopidogrel
tively by clinical trials; selection is currently based on both patient and to aspirin. In the COMMIT-CCS-2 trial, a broad population of 45,852
angiographic characteristics. unselected patients with ST-elevation MI, only 54% of patients were
■ ADJUNCTIVE THERAPIES TO PRIMARY PCI treated with fibrinolytics, and most of the rest had no revascularization
at all. Clopidogrel added to aspirin decreased all-cause mortality from
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Aspirin: Aspirin is the best known and the most widely used of all 8.1% to 7.5% (p = 0.03), without increased bleeding in the clopidogrel
group. On the basis of these data, patients presenting with MI should be
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the antiplatelet agents because of low cost and relatively low toxicity. considered for a thienopyridine regardless of whether or not they under-
Aspirin has been shown to reduce mortality in acute infarction to the went reperfusion therapy. The optimal duration of thienopyridine use in
same degree as fibrinolytic therapy, and its effects are additive to fibri- this population has yet to be defined.
nolytics. In addition, aspirin reduces the risk of reinfarction. Unless
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contraindicated, all patients with a suspected acute coronary syndrome Glycoprotein IIb/IIIa Receptor Antagonists: Glycoprotein IIb/IIIa receptor
(STEMI, NSTEMI, unstable angina) should be given aspirin as soon antagonists inhibit the final common pathway of platelet aggrega-
as possible. tion, blocking crosslinking of activated platelets, and are often used
in percutaneous intervention. 71-73 Three agents are currently avail-
Thienopyridines: Thienopyridines are oral antiplatelet agents that block able. Abciximab is a chimeric murine-human monoclonal antibody
the platelet adenosine diphosphate (ADP) receptor and thus inhibit Fab fragment with a short plasma half-life (10-30 minutes) but a long
activation and aggregation. Currently used thienopyridines include duration of biologic action. Tirofiban is a small molecule, synthetic
clopidogrel and prasugrel. Clopidogrel is a pro-drug converted in the nonpeptide agent with a half-life of approximately 2.5 hours and a lower
liver to the active thiol metabolite via cytochrome P450 (CYP). This receptor affinity than abciximab. Eptifibatide is a small molecule, cyclic
active metabolite irreversibly binds to the P2Y12 component of the ADP heptapeptide with a 2-hour half-life.
receptor on the platelet surface, which prevents activation of the GPIIb/ In the era of dual antiplatelet therapy using a thienopyridine
IIIa receptor complex and reduces platelet aggregation for the remainder and aspirin, the role of addition of a glycoprotein IIb/IIIa inhibi-
of the platelet’s lifespan, which is approximately 7 to 10 days. Onset of tor in primary angioplasty for STEMI is uncertain. Studies such as
inhibition of platelet aggregation is dose-dependent, with a 300- to 600- the ADMIRAL and CADILLAC trials conducted prior to the use of
mg loading dose achieving inhibition of platelets within 2 hours (peak dual antiplatelet therapy established the efficacy of abciximab in pri-
effect 3-6 hours) whereas a dose of 50 to 100 mg achieves inhibition of mary PCI (with or without stenting) in patients with STEMI. 74,75 The
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platelets in about 24 to 48 hours (peak effect 5-7 days). 61 results of recent clinical trials have raised questions about whether
Clopidogrel in combination with aspirin was shown to reduce the glycoprotein IIb/IIIa antagonists have additional utility when added
composite end point of infarct artery patency or death or recurrent to dual antiplatelet therapy in patients with STEMI. 76-78 When either
MI before angiography when given in conjunction with fibrinolytic abciximab or placebo was added to 600 mg of clopidogrel in 800
therapy, heparin, and aspirin in the 3491 patient CLARITY TIMI-28 patients undergoing primary stenting in the BRAVE-3 trial, there
trial. When the 1863 patients in CLARITY TIMI-28 that underwent was no difference in either infarct size or the secondary composite
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PCI were examined, retreatment with clopidogrel in addition to aspirin end point of death, recurrent myocardial infarction, stroke, or urgent
resulted in a significant reduction in cardiovascular death, MI, or stroke revascularization of the infarct-related artery. Similar findings were
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at 30 days (7.5% vs 12.0%; p = 0.001) without causing excess bleeding, seen in ON-TIME 2, in which tirofiban added to dual antiplatelet ther-
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It is therefore routine practice to administer a loading dose of clopido- apy in 984 patients with STEMI prior to transport for PCI improved
grel 300 mg or 600 mg prior to PCI regardless of the physician’s concern resolution of ST segment elevation, but had no significant difference
that the patient might need coronary artery bypass grafting (CABG) in in the 30-day composite end point of death, recurrent MI, or urgent
the near future. target-vessel revascularization. The current guidelines suggest that
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Some patients are considered clopidogrel nonresponders, usually when a STEMI patient is treated with a thienopyridine and aspirin plus
defined as a reoccurrence of cardiovascular events while on the recom- an anticoagulant such as UFH or bivalirudin, the use of a glycoprotein
mended dose. Both ex vivo assays measuring the degree of inhibition of IIb/IIIa inhibitor at the time of PCI may be beneficial but cannot be
platelet aggregation and genetic tests for alleles that affect clopidogrel recommended as routine. 41

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