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Vasodilator-Stimulated Phosphoprotein-02 - VASP-02
Description:
Several platelet response studies have demonstrated a significant variability in the dose-response to regular doses of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). Further, some studies have also suggested that a higher loading dose (LD) of clopidogrel (600 mg) may help overcome some of this resistance. There are, however, limited data with regard to the use of a higher maintenance dose (MD) for overcoming clopidogrel resistance. The VASP-02 trial sought to investigate the antiplatelet effects of using 150 mg/day versus 75 mg/day MD in patients undergoing elective PCI. Furthermore, in patients who were deemed non- or hypo-responders to the standard MD of clopidogrel, they sought to study if the higher dose (150 mg/day) would result in improved antiplatelet efficacy.
Hypothesis:
Higher MD would be associated with an enhancement in the antiplatelet action of clopidogrel, including in those who are deemed nonresponders to the standard dose.
Study Design
Study Design:
Patients Enrolled: 153
Mean Follow Up: 4 weeks
Mean Patient Age: 65 years
Female: 18
Patient Populations:
- Elective PCI
- Age ≥18 years
Exclusions:
- Acute coronary syndrome
- Thienopyridine use prior to enrollment
- Contraindication to aspirin or clopidogrel
- Presence of disease condition requiring anticoagulation
Primary Endpoints:
- PRI at 2 and 4 weeks
Secondary Endpoints:
- Clinical events including death, myocardial infarction, and major bleeding
Drug/Procedures Used:
Clopidogrel orally 300-600 mg as an LD 10-12 hours prior to PCI. Following PCI, patients were randomized in a 2:3 fashion to either clopidogrel 150 mg/day or 75 mg/day as MD. After 2 weeks, patients who were nonresponders in the 75 mg/day arm received 150 mg/day of clopidogrel for an additional 2 weeks.
Concomitant Medications:
Aspirin 75 mg/day (100%), statins (78%), beta-blockers (70%), proton pump inhibitor (27%)
Principal Findings:
A total of 153 patients undergoing elective PCI were included, 58 to the 150 mg/day (high-dose) arm, and 95 to the 75 mg/day (standard-dose) arm. Baseline characteristics were fairly similar between the two groups. Diabetes was present in about 24% of the patients, and about 15% had undergone prior PCI. About 48% of the stents were implanted in the left anterior descending artery, with one or more bare-metal stents being utilized in 41% of the patients. The platelet reactivity index (PRI), measured using a VASP assay, was similar between the two groups at baseline (86.1% vs. 86.2%, p = 0.72).
After 2 weeks, the mean PRI was significantly lower in the high-dose group, compared with the standard-dose group (43.9% vs. 58.6%, p < 0.0001). Similarly, the mean change in PRI was lower in the high-dose group (p < 0.0001). The incidence of non- or hypo-responders to clopidogrel (defined as a PRI ≥69%) was significantly lower in the high-dose clopidogrel group (8.6% vs. 33.7%, p = 0.0004).
In the low-dose arm, 32 patients were considered non- or hypo-responders. By increasing the MD to 150 mg/day, the PRI in 31 of these patients was significantly lowered from 76.2% to 61.5% (p < 0.0001).
Clinical events were extremely infrequent. Only one patient had new ischemia requiring adjustment in medical therapy. No major bleeding episodes were noted in either arm.
Interpretation:
The results of the VASP-02 study indicate that 150 mg/day of clopidogrel as an MD is associated with a greater reduction in PRI (measured using a VASP assay) than 75 mg/day in patients undergoing elective PCI. The incidence of clinical events was extremely low, and the clinical implications of these findings are eagerly awaited.
There are multiple reasons for clopidogrel resistance, including variable intestinal absorption, differential kinetics, and metabolism, including the effect of polymorphisms in genes encoding cytochrome P450 enzymes, such as CYP2C19, as well as drug-drug interactions. The notion that a higher MD of clopidogrel can overcome some or most of this resistance is therefore appealing, but needs careful evaluation for risks and benefits in a large clinical study, before it can be recommended in clinical practice. Moreover, none of the platelet assays (including VASP) are utilized in routine decision making regarding dosing of clopidogrel, and further studies are necessary to evaluate their role in routine practice as well.
Further, the recent PRINCIPLE-TIMI 44 trial demonstrated significantly better platelet inhibition with prasugrel 60 mg LD and 10 mg/day MD, compared with 300 mg LD and 150 mg/day MD of clopidogrel, with a significantly reduced incidence in thienopyridine non- or hypo-responders. Its role in routine practice also needs to be evaluated.
Last, while no major bleeding was noted in this small study, it is unknown if minor and nuisance bleeding were more common in the high-dose group. The risk-benefit and cost-effectiveness of these various strategies need to be systematically evaluated as well.
References:
Aleil B, Jacquemin L, De Poli F, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. J Am Coll Cardiol Intv 2008;1:631-8.
Keywords: Intestinal Absorption, Platelet Aggregation Inhibitors, Decision Making, Thiophenes, Coronary Disease, Ticlopidine, Blood Platelets, Piperazines, Purinergic P2Y Receptor Antagonists, Stents, Percutaneous Coronary Intervention, Drug Interactions, Risk Assessment, Kinetics, Diabetes Mellitus
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