Antiplatelet Therapy Clopidogrel

Antiplatelet therapy has also proved to be valuable in the context of ACS and coronary atherosclerosis. In the context of PCI, antiplatelet therapy has become a mainstay for its ability to reduce stent thrombosis and ischemic events. The Clopidogrel for the Reduction of Events During Observation (CREDO) study demonstrated the benefit of using clopidogrel before elective PCI with respect to ischemic events over a 1-year period.67 In the setting of PCI for ACS (non-ST-elevation myocardial infarction [NSTEMI] or unstable angina), pretreatment with clopidogrel was noted to reduce the risk of MI, cardiovascular death, and need for revascularization.68 The use of clopido-grel in the setting of rescue PCI led to a significant reduction in MI and death from cardiovascular causes.69

Platelets provide a vital link between inflammation and thrombosis, and clopidogrel may have anti-inflammatory actions by way of its effects on platelet function, albeit separate from its inhibition of the adenosine diphosphatase (ADP) receptor. Platelet function has been shown to be highly variable after clopidogrel loading. The fact that clopidogrel can affect platelet activity through other pathways, including via inhibition of thrombin receptor agonist peptide (TRAP) stimulation of the protease-activated receptors (PAR), has important implications for understanding the mechanism of clopidogrel— specifically the potential for clopidogrel to alter TRAP-induced platelet-leukocyte aggregation, suggesting a possible anti-inflammatory effect.70 Others have noted the ability of clopidogrel to reduce platelet-leukocyte aggregates and P-selectin expression.71

The benefits of clopidogrel may extend well beyond its antiplatelet and antithrombotic effects. In 833

patients undergoing PCI, pretreatment with clopido-grel (median duration, 5 days) was associated with a reduction in the postprocedural rise in CRP (Fig. 1-12) and, in some, a postprocedural decline in CRP level.72 Other makers of inflammation, such as platelet expression of CD40L and P-selectin, were reduced after pretreatment with clopidogrel (median, 5 days).73 Although these studies were nonrandom-ized, the data remain provocative regarding the anti-inflammatory effects of clopidogrel when pretreat-ment is initiated before PCI.

Although the potential benefits of pretreatment with clopidogrel in the setting of PCI are established, the optimal duration of pretreatment remains controversial. The PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) study demonstrated benefits of pretreatment given a median of 6 days before PCI in a relatively high-risk NSTEMI population. Among those undergoing elective PCI (Table 1-4), data from CREDO has shown fewer adverse cardiovascular events with greater than 15 hours of pretreatment (Fig. 1-13). However, the Plavix Reduction Of New Thrombus Occurrence (PRONTO) study suggested that the duration of pretreatment before elective PCI has no bearing on platelet function, and that even 3 hours of pretreatment will achieve significant platelet inhibition. In that study, 300 mg of clopidogrel, regardless of the duration of pretreat-ment, resulted in a peak in platelet activity both at 2 hours and 2 days after PCI. Whereas the PRONTO analysis suggested that duration of pretreatment is of little consequence to platelet inhibition, post-PCI peaks in platelet activity and improved outcomes with longer duration of pretreatment imply an alternative benefit to clopidogrel loading. That benefit may come in the form of anti-inflammatory properties, as described earlier. Anti-inflammatory effects may be responsible for avoiding post-PCI rises in cardiac troponins.74 Higher loading doses may help achieve a more rapid benefit while improving clinical outcomes, as was noted in the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-2) study,75 and in such circumstances the duration of pretreatment may not be relevant.76 It is unclear whether the benefit of a 600-mg loading dose is related to a more potent anti-inflammatory effect.

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