Clopidogrel 600-Mg Double Loading Dose Achieves Stronger Platelet Inhibition Than Conventional Regimens - PREPAIR

Description:

The goal of this trial was to compare the degree of platelet inhibition achieved by three different clopidogrel loading regimens, including a double 600 mg loading dose in patients undergoing elective angiography and percutaneous coronary intervention (PCI) when appropriate.

Hypothesis:

A larger loading dose of clopidogrel (two doses of 600 mg) would accelerate and enhance the antiaggregatory effects of clopidogrel in patients undergoing elective angiography and PCI, compared with other conventional dosing regimens.

Study Design

Study Design:

Patients Enrolled: 148
Mean Follow Up: 12-24 hours
Mean Patient Age: 61.7
Female: 22
Mean Ejection Fraction: 61.3%

Patient Populations:

Patients with suspected or documented coronary artery disease admitted for elective coronary angiography and PCI

Exclusions:

• Unstable angina
• Acute or recent myocardial infarction (within 14 days)
• Patients receiving glycoprotein (GP) IIb/IIIa inhibitors
• Stroke within 3 months
• Overt malignancy
• Active bleeding or bleeding diathesis
• Oral anticoagulation with a coumarin derivate with international normalized ratio >1.5
• Recent treatment (within 30 days) with a GP IIb/IIIa antagonist or thienopyridine
• Thrombocytopenia (platelet count <100,000/mm3)
• Serum creatinine >1.8 mg/dl
• Severe liver disease resulting in abnormal bilirubin levels
• Known allergy to thienopyridines
• Concomitant investigational drug use within 1 month

Primary Endpoints:

Percent inhibition of platelet aggregation at 1-2 minutes (peak) after stimulation with ADP at the time of angiography

Secondary Endpoints:

• Percent inhibition of platelet aggregation at 6 minutes after stimulation with ADP at the time of angiography
• Percent inhibition of peak platelet aggregation after stimulation with ADP 12-24 hours after PCI
• Prevalence of nonresponders/resistance
• Occurrence of death, myocardial infarction, or target vessel revascularization up to 30 days after the procedure
• Occurrence of vascular or hemorrhagic complications

Drug/Procedures Used:

Patients were randomly assigned to one of three loading dose regimens: Group A, clopidogrel 300 mg the day before (≥15 hours) + 75 mg the morning of the interventional procedure; Group B, clopidogrel 600 mg the morning of (≥2 hours before) the interventional procedure; and Group C, clopidogrel 600 mg the day before (≥15 hours) and 600 mg the morning of (≥2 hours before) the interventional procedure. These doses were administered in an open-label fashion. In addition, all stented patients received 75 mg of clopidogrel daily for at least 30 days, as clinically indicated after implantation.

Concomitant Medications:

Aspirin (97.3%), statins (79.7%), beta-blockers (58.8%), and angiotensin-converting enzyme inhibitors (52.0%)

Principal Findings:

A total of 148 patients were randomized, 49 each to Groups A and B, and 50 to Group C. The baseline characteristics were similar between the two arms, except for the prevalence of diabetes, which was significantly lower in Group C. The mean age was 61.7 years. Only 27% of patients actually underwent PCI.

Inhibition of platelet aggregation was consistently better in the clopidogrel 600 mg double bolus group (Group C) as compared with the other two regimens. At the time of angiography, percent inhibition of platelet aggregation at 1-2 minutes (peak) after stimulation with adenosine diphosphate (ADP) was 31.4% in Group A, 29.0% in Group B, and 49.5% in Group C (p < 0.0001), with 5 µmol/L ADP and 22.4%, 22.3%, and 39.8%, respectively, with 20 µmol/L ADP (p < 0.0001). There was no difference between groups A and B with both concentrations of ADP.

Percent inhibition of platelet aggregation at 6 minutes after stimulation with ADP was also stronger in Group C, compared with the other two groups (p < 0.0001). Similarly, the peak percent inhibition with 20 µmol/L ADP 12-24 hours after PCI was significantly better in group C, compared with groups A and B (p < 0.001). The incidence of thienopyridine hypo- or non-responsiveness, as defined by a <20% decrease in peak percent inhibition of platelets with both 5 and 20 µmol/L ADP was significantly lower in Group C, compared with Groups A and B (p < 0.001).

There was no death, rehospitalization for myocardial infarction, or repeat target vessel revascularization up to 30 days in this study. Similarly, there was no episode of major bleeding during this period. The incidence of minor bleeding was low and similar in the three groups (three in Group A, eight in Group B, and four in Group C, p = 0.19).

Interpretation:

This study demonstrates that a double bolus of 600 mg of clopidogrel achieves more potent platelet inhibition than either clopidogrel 600 mg single bolus or 300 mg single bolus ≥15 hours before plus 75 mg the morning of an elective interventional procedure, as measured by percent inhibition of platelet aggregation with ADP at the time of angiography, and 12-24 hours following PCI. Moreover, clopidogrel 300 mg single bolus given ≥15 hours before plus 75 mg the morning of an interventional procedure seems to provide similar platelet inhibition as a larger 600 mg single bolus given the morning of the procedure (≥2 hours).

Although limited to patients undergoing elective PCI only, the findings of this study are important for several reasons. First, the double bolus regimen of clopidogrel studied here is different from current recommendations and practice. If these findings can be replicated to show not only sustained and more profound platelet inhibition, but also better patient outcomes, a revision in current guidelines will be necessary. Second, although not noted in this study, it will be interesting to see if other larger studies can demonstrate lower periprocedural myocardial infarctions and stent thrombosis rates with the double bolus of 600 mg of clopidogrel, as compared with conventional dosing regimens. Finally, the recent PRINCIPLE-TIMI 44 study demonstrated superior platelet inhibition with prasugrel compared with a single 600 mg loading dose and 150 mg/day maintenance dose of clopidogrel, although there were more instances of bleeding with prasugrel. It will be interesting to see how this modified clopidogrel loading regimen will compare with prasugrel in future head-to-head studies.

References:

L’Allier PL, Ducrocq G, Pranno N, et al. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: Results from the PREPAIR randomized study. J Am Coll Cardiol 2008;51:1066-72.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Coronary Artery Disease, Myocardial Infarction, Platelet Aggregation Inhibitors, Thiophenes, Ticlopidine, Blood Platelets, Piperazines, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Stents, Coronary Angiography, Thrombosis, Diabetes Mellitus


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