Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect - ISAR-CHOICE

Description:

The goal of the trial was to evaluate the effect of different clopidogrel doses (300 mg, 600 mg, or 900 mg) on platelet aggregation among patients with coronary artery disease undergoing coronary angiography.

Study Design

Study Design:

Patients Enrolled: 60
Mean Patient Age: Mean age 65 years
Female: 32

Patient Populations:

Suspected or documented coronary artery disease admitted for coronary angiography.

Exclusions:

Unstable angina, acute myocardial infarction, hemodynamic instability, stroke within 3 months, malignancies, active bleeding and bleeding diatheses, oral anticoagulation therapy with a coumarin derivate, treatment within 30 days with a glycoprotein IIb/IIIa antagonist or other antiplatelet drugs except for aspirin, platelet count <150x109/L, serum creatinine level >2 mg/dL, or liver disease with a bilirubin level >2 mg/dL

Primary Endpoints:

Maximal ADP-induced (5 µmol/L) platelet aggregation 4 hours after clopidogrel administration.

Drug/Procedures Used:

Patients were randomized in a double-blind manner to a clopidogrel loading dose of 300 mg (n=20), 600 mg (n=20), or 900 mg (n=20). For optical aggregometry, blood samples were drawn immediately before and 4 hours after administration of clopidogrel. To assess plasma concentrations of clopidogrel-related compounds, EDTA blood was obtained from the venous catheter before study drug administration and 20, 40, 60, 120, and 240 minutes afterward.

Concomitant Medications:

Aspirin 100 mg

Principal Findings:

Baseline characteristics were well balanced between groups, with 17% diabetics, 10% current smokers, and 62% hypercholesterolemic. Concomitant medications included beta-blockers (65%), ACE inhibitors (55%) and statins (42%).

Plasma concentrations of active metabolite were higher for the 600 mg dose vs 300 mg dose (p=0.03) but did not differ between the 600 mg dose and 900 mg dose (p=0.38). Likewise, plasma concentrations of clopidogrel were higher with 600 mg vs 300 mg (p=0.01) but did not differ between the 600 mg dose and 900 mg dose (p=0.81). Concentrations of carboxyl metabolite were higher for the 600 mg vs 300 mg comparison (p<0.001), and also for the 900 mg vs 600 mg comparison (p=0.03). The primary endpoint of maximal aggregation induced with 5 µmol/L ADP four hours after administration of clopidogrel was 66.5% with 300 mg and 52.7% with 600 mg (p=0.01), but there was no difference between the 600 mg and 900 mg aggregation (49.7% for 900 mg, p=0.59). Likewise, with 20 µmol/L ADP induced maximal aggregation four hours after administration of clopidogrel was 85.1% with 300 mg and 69.8% with 600 mg (p=0.004), but there was no difference between the 600 mg and 900 mg aggregation (64.8% for 900 mg, p=0.39).

Interpretation:

Among patients with coronary artery disease undergoing coronary angiography, use of a 600 mg clopidogrel dose was associated with greater suppression of ADP-induced platelet aggregation compared with a 300 mg dose, with no significant additional suppression with a 900 mg dose over a 600 mg dose.

The results of the present trial are similar to those observed in the ALBION trial, which also evaluate 300 mg, 600 mg and 900 mg doses of clopidogrel and showed increased levels of platelet inhibition with a higher dose of clopidogrel but minimal differences between 600 mg and 900 mg doses. Despite the improvements in platelet aggregation and pharmacokinetic parameters with 600 mg of clopidogrel over 300 mg, neither trial has been powered to evaluate a difference in clinical endpoints. The ARMYDA-2 trial demonstrated a significant reduction in peri-procedural MIs and biomarker release with a 600 mg dose of clopidogrel compared with a 300 mg dose in patients undergoing coronary stenting for acute coronary syndromes. Larger trials are warranted to more fully evaluate the effect of a higher dose of clopidogrel on clinical events, as well as to evaluate safety events such as bleeding.

References:

von Beckerath N, et al. Absorption, Metabolization, and Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel: Results of the ISAR-CHOICE Trial. Circulation. 2005;112:2946-2950.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, ACS and Cardiac Biomarkers, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Biological Markers, Coronary Angiography, Ticlopidine, Blood Platelets, Diabetes Mellitus


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