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What is the best loading dose of clopidogrel for patients undergoing percutaneous coronary intervention (PCI)? Is the answer "CLEAR"?

Sarah A. Spinler, Pharm.D., FCCP
May, 2005

Previous trials have suggested that a 300 mg loading dose decreases the time to maximal platelet inhibition (as measured by ex vivo platelet aggregation studies) with clopidogrel as compared to lower doses.^1,2 In patients undergoing percutaneous coronary intervention (PCI), the best time to administer clopidogrel is at least 6 or more hours prior to the procedure for maximal platelet inhibition.^3,4,5 Interest in administration of a 600 mg loading dose of clopidogrel was peaked by the publication of the ISAR-REACT (Intracoronary Stenting with Antithrombotic Regimen Rapid Early Action for Coronary Treatment) study which compared the rates of death, myocardial infarction (MI) or need for urgent target vessel revascularization (uTVR) in 2159 patients without an acute coronary syndrome (ACS) undergoing elective PCI. 30-day event rates were low in both groups (4%) and not significantly different. Although underpowered, this study suggested no benefit of adding abciximab to an aspirin/clopidogrel 600 mg antiplatelet regimen.

Two recently published trials further explore the role of a 600 mg clopidogrel loading dose for patients undergoing PCI. In the ARMYDA-2 (Antiplatelet Therapy for the Reduction of Myocardial Damage During Angioplasty Study), 255 patients were randomized to either a 600 mg or a 300 mg loading dose of clopidogrel administered 4 to 8 hours prior to PCI.⁶ Twenty-five % of these patients were hospitalized with non-ST-segment elevation ACS and 75% had stable angina. All patients received aspirin and unfractionated heparin (UFH). The primary end point of the study, 30-day rates of death, MI or TVR, was reduced by 66% in the 600 mg clopidogrel-treated patients (from 12% to 4%, P=0.041). The benefit was observed entirely in peri-procedural MI as defined by elevations in cardiac enzymes. Bleeding was rare and not different between groups. However, all of the aforementioned studies suffer from the same limitation in that the use of glycoprotein IIb/IIIa blockers, was low. Therefore, the question arises, do we need a higher dose of clopidogrel if a GP IIb/IIIa receptor blocker, is co-administered?

This question was addressed in the CLEAR PLATELETS (Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets) study.⁷ In this 2X2 factorial design, 120 non-ACS patients undergoing elective PCI were randomized to one of the following groups

1. clopidogrel 600 mg
2. clopidogrel 300 mg
3. clopidogrel 600 mg plus eptifibatide
4. clopidogrel 300 mg plus eptifibatide.

Clopidogrel was administered immediately after stenting as is the usual common practice in many interventional laboratories across the U.S., and continued at 75 mg once daily. Aspirin and UFH were administered to all patients. The end points of the study were adenosine diphosphate (ADP)-induced ex vivo platelet aggregation, P-selectin expression and release of cardiac markers of necrosis as measured at 3,8, and 18-24 hrs following stenting. When comparing the 300mg and 600mg clopidogrel treated patients who did not receive eptifibatide, the 600 mg group had significantly greater inhibition response to ADP and reduction in P-selectin expression at 18-24 hrs compared to the 300 mg group. However, both eptifibatide-treated groups demonstrated superior platelet inhibition compared to the clopidogrel only groups (P<0.05) with no significant differences observed between the 300mg and 600mg clopidogrel plus eptifibatide groups. The two eptifibatide-treated groups had the lowest release of creatine kinase-MB.

Thus, when using a GP IIb/IIIa receptor blocker (administered for at least 12-18 hrs following PCI), it probably doesn't matter what dose of clopidogrel is administered. Whether or no pre-treatment with clopidogrel impacts outcomes has not been well studied in patients treated with GP IIb/IIIa receptor blockers, however. Also, whether or not significant differences in platelet aggregation which are seen between 300mg and 600mg clopidogrel at 18-24 hrs impact outcomes when the GP IIb/IIIa receptor blocker is discontinued, is unknown. GP IIb/IIIa receptor blockers are still indicated for PCI in high risk patients but may not be necessary in low risk patients who are pretreated with 600 mg of clopidogrel. So is it clear?

References

1. Cadroy Y, Bossavy JP, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000;101:2823-8.
   
   
2. Longstreth K, Wertz J. High-dose clopidogrel loading in percutaneous coronary intervention. Ann Pharmacother 2005;39:918-922.
   
   
3. Chan AW, Moliterno DJ, Berger PB, Stone GW, DiBattiste PM, Yakubov SL, et al. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol 2003;42: 1188-95. DOI 10.1016/S0735-1097(03)00944-6.
   
   
4. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411-20.
   
   
5. Steinhubl SR, Darrah S, Brennan D, McErlean E, Berger PB, Topol EJ. Optimal duration of pretreatment with clopidogrel prior to PCI: data from the CREDO trial (abstract 1742). Circulation 2003;108:IV-374.
   
   
6. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) Study. Circulation 2005; 111: 2099 - 2106.
   
   
7. Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the clopidogrel loading with eptifibatide to arrest the reactivity of platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153-9.

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