Glycoprotein IIbIIIa Inhibitors

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Glycoprotein IIb/IIIa inhibitors have established a niche in the adjuvant treatment of ACS and in elective PCI. The benefits of these medications have been demonstrated in many large-scale clinical trials, both in the context of elective PCI and in PCI for ACS. Their potent antithrombotic actions are most likely responsible for their effects, but the advantages of their use probably involve anti-inflammatory action as well. Although the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) study demonstrated no benefit to the addition of abciximab in patients

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1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Preprocedural CRP (mg/dL)

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1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Preprocedural CRP (mg/dL)

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1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Preprocedural CRP (mg/dL)

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1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Preprocedural CRP (mg/dL)

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Preprocedural CRP (mg/dL)

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1st Quartile 2nd Quartile 3rd Quartile 4th Quartile

D Preprocedural CRP (mg/dL)

Figure 1-11. A through D, Major adverse cardiac events within the first year after percutaneous coronary intervention (PCI), stratified by statin pretreatment before PCI and preprocedural C-reactive protein (CRP) level. MI, myocardial infarction. (Redrawn from Chan AW, Bhatt DL, Chew DP, et al: Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750-1756.)

Pretreatment No pretreatment

Figure 1-12. Mean change in high-sensitivity CRP (hs-CRP) according to clopidogrel pretreatment. Averaged data are shown as means + standard error of the mean (SEM). (Redrawn from Vivekananthan DP, Bhatt DL, Chew DP, et al: Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol 2004;94:358-360.)

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Figure 1-13. Kaplan-Meier curve of the occurrence of the combined end point of death, myocardial infarction (MI), and urgent target vessel revascularization (UTVR) in patients randomly assigned to receive placebo, clopidogrel (300-mg loading dose) less than 15 hours before percutaneous coronary intervention (PCI), or the same dose of clopidogrel 15 hours or longer before PCI. (Redrawn from Steinhubl SR, Berger PB, Brennan DM, Topol EJ: Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939-943.)

Days

Figure 1-13. Kaplan-Meier curve of the occurrence of the combined end point of death, myocardial infarction (MI), and urgent target vessel revascularization (UTVR) in patients randomly assigned to receive placebo, clopidogrel (300-mg loading dose) less than 15 hours before percutaneous coronary intervention (PCI), or the same dose of clopidogrel 15 hours or longer before PCI. (Redrawn from Steinhubl SR, Berger PB, Brennan DM, Topol EJ: Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939-943.)

Table 1-4.

Duration of Pretreatment with Clopidogrel before Percutaneous Coronary Intervention

Duration of

Study

N

Primary End Point

Pretreatment

Outcome

Comments

Steinhubl

1 762 to undergo

28-day combined end

Randomized to 300 mg

Longer duration of

At least 15 hr of

et al107

elective PCI

point of death, MI,

of clopidogrel or

pretreatment (>15 hr)

pretreatment is required

or urgent TVR

placebo at 3 hr

was associated

to see benefit of

(minimum) to 24 hr

with a significant

clopidogrel over

(maximum) before

reduction in the

placebo before PCI

PCI

primary end point

Kandzari

2159 to undergo

30-day combined end

600 mg of clopidogrel

No benefit of

Authors suggested rapid

et al76

elective PCI

point of death, MI,

given at 2-3 hr, 3-6 hr,

treatment noted

and maximal platelet

or urgent TVR

6-12 hr, or >12 hr

beyond 2-3 hr of

inhibition is the result

before PCI

pretreatment

of a higher dose

Hochholzer

1001 patients

30-day composite of

Pretreatment with

For those undergoing

Degree of platelet

et al108

undergoing

MACE; other end

600 mg of

PCI, no significant

inhibition was time

diagnostic

points included

clopidogrel at

differences in

dependent during first

catheterization,

platelet aggregation/

intervals from 1 to

MACE if pretreatment

2 hr

428 of whom

function

6 hr before PCI

was <2 vs. >2 hr

underwent PCI

Gurbel

100 patients

Multiple markers of

Pretreatment with

Pretreatment at all

Authors suggested that

et al109

undergoing

platelet function

300 mg of

time points was

platelet inhibition is not

elective PCI

clopidogrel at 24,

associated with

time dependent

12, or 3-6 hr before

platelet inhibition

PCI or with 75 mg at

the time of PCI

Patti et al75

255 patients

30-day combined end

300 mg or 600 mg of

End point occurred

End point driven primarily

undergoing PCI

point of death, MI,

clopidogrel 4-8 hr

in 4% of high-dose

by occurrence of

randomized to

or TVR

before PCI

group vs. 12% of

periprocedural MI,

600 or 300 mg of

lower-dose group

although end point was

clopidogrel (25%

measured only out to

had NSTEMI/ACS)

30 days

ACS, acute coronary syndrome; MACE, major adverse cardiac event; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; TVR, target vessel revascularization.

ACS, acute coronary syndrome; MACE, major adverse cardiac event; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; TVR, target vessel revascularization.

pretreated with 600 mg of clopidogrel before elective PCI,77 ISAR-REACT-2 noted reduction in a 30-day composite end point of death, MI, or urgent target vessel revascularization in high-risk ACS patients with an elevated troponin I who were randomized to abciximab versus placebo after pretreatment with clopidogrel.78

The use of glycoprotein IIb/IIIa inhibitors, particularly abciximab, appears to affect the degree of circulating markers of inflammation such as sCD40L and platelet-leukocyte aggregates79 and affects the rise of inflammatory markers such as IL-6, TNF-a, and CRP after angioplasty, suggesting a potent anti-inflammatory effect. The Chimeric c7E3 Fab Anti-Platelet Therapy in Unstable REfractory angina (CAPTURE) investigators noted the importance of inflammation when they stratified an ACS population as high risk defined by a heightened state of inflammation (elevated sCD40L). Abciximab therapy, they observed, was particularly of benefit for those with higher sCD40L.12 Although abciximab has been shown to be of particular value in those with elevated troponin levels, the benefit may come from preventing distal microembolization and myonecrosis.

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