Effect of Fluvastatin on Top of Clopidogrel and Aspirin in Patients After DES Implantation on Platelet Aggregation (EFA-1)
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The purpose of the study was to determine the influence of fluvastatin and atorvastatin on platelet aggregation in patients treated with aspirin and plavix after coronary stenting. We hypothezied a positive effect of fluvastatin on platelet aggregation levels.
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Introduction Coronary stent implantation is performed in more than 80 % of all coronary interventions. The use of stents has significantly reduced re-stenosis rate in revascularization in comparison with conventional balloon angioplasty. To prevent stent thrombosis dual antiplatelet therapy with acetylsalicylic acid and clopidogrel (ADP-receptor antagonist) is routinely used (1).
Previous studies reported a drug interaction between clopidogrel and several statins (e.g. atorvastatin, simvastatin) and described a dose-dependent inhibition of the effect of clopidogrel on platelet aggregation. This drug interaction is thought to be due to the fact that both drugs (clopidogrel and atorvastatin/simvastatin) are metabolized by cytochrome P450 3A4 (2, 3). In contrast to atorvastatin and simvastatin, fluvastatin is mainly metabolized by cytochrome P450 2C9. Metabolization of clopidogrel is mandatory for effective platelet inhibition. Since all patients after coronary stent implantation are treated with clopidogrel and over 80 % of patients with coronary heart disease receive a statin the question whether there is a drug-drug interaction is of great importance.
In a previous trial we observed a beneficial effect of fluvastatin on platelet inhibition on top of aspirin and Clopidogrel (4). There was a further reduction of platelet aggregation of approximately 10%, whereas atorvastatin or pravastatin had no effect or even slightly increased platelet aggregation.
The purpose of the present study is 1) to determine a beneficial effect of fluvastatin on platelet aggregation in comparison with atorvastatin in patients with stable coronary artery 2) to assess a potential drug-drug interaction of Clopidogrel and atorvastatin .
Patients and Methods Approximately 100 patients are included in the present study. All patients undergo coronary stent implantation with a drug eluting stent. The first measurement of platelet aggregation under aspirin and clopidogrel treatment (loading dose 600mg) is set to be between 12 and 24 hours after the administration of the loading dose of clopidogrel. Any statin treatment will be stopped for 2 weeks (washout phase for statin treatment before study inclusion) after the PCI. After 2 weeks second platelet aggregation under the treatment with ASA and clopidogrel and randomization to fluvastatin 80mg and atorvastatin 40mg per day in addition to the dual antiplatelet therapy. Third measurement 1 month later and crossover of statin treatment for another month. End of the study with a forth measurement of platelet aggregation.
Clinical follow-up (MACE) 2.5, 6 and 12 months after inclusion.
Platelet aggregation will be assessed by the following method:
· APACT-4 aggregometer (Endothell, Switzerland, induced by 5, 20 µmol ADP and 0.5mg/ml arachidonic acid) (5).
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Layout table for eligibility information
Ages Eligible for Study:
18 Years to 95 Years (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
all patients with stent implantation followed by treatment with aspirin and clopidogrel
routinely treated with acetylsalicylic 100 mg/day
acute coronary syndrome
use of a GPIIb/IIIa inhibitor
allergy to acetylsalicylic acid, clopidogrel, statins
elevated liver enzymes (> 3 x norm value)
active liver disease
recent gastrointestinal bleeding (< 3 months)
known platelet dysfunction or abnormal platelet count
indication for treatment with non-steroidal drugs
indication for long-term treatment with a drug metabolized by cytochrome p450 3A4 or 2C9