Effect of Fluvastatin on Top of Clopidogrel and Aspirin in Patients After DES Implantation on Platelet Aggregation
Condition: Drug-Interactions
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      1. 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.

        2. Aim

           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 .

        3. 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.

      Measured variables:

        1. 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).

        2. Blood analysis: Blood smear, coagulation parameters, lipid profile, liver enzyme,
           creatinkinase, homocysteine, hs-CRP, BNP

      Sample size justification: It is estimated that 50 patients per treatment group will provide
      99% power to achieve a 10% difference in platelet aggregation (± 10 standard deviation).

      4. Study Design and Duration

      Duration: 12 months, 2.5 months for assessment of platelet aggregation Primary endpoint:
      platelet aggregation after 2.5 months Secondary endpoint: MACE after 12 month

      5. Inclusion Criteria

        -  all patients with stent implantation followed by treatment with aspirin and clopidogrel

        -  routinely treated with acetylsalicylic 100 mg/day

           6. Exclusion Criteria

        -  acute coronary syndrome

        -  use of a GPIIb/IIIa inhibitor

        -  allergy to acetylsalicylic acid, clopidogrel, statins

        -  elevated liver enzymes (> 3 x norm value)

        -  muscle myopathy

        -  active liver disease

        -  recent gastrointestinal bleeding (< 3 months)

        -  known platelet dysfunction or abnormal platelet count

        -  pregnancy

        -  indication for treatment with non-steroidal drugs

        -  indication for long-term treatment with a drug metabolized by cytochrome p450 3A4 or 2C9

           7. Literature

             1. Berger, P.B., et al., Clopidogrel versus ticlopidine after intracoronary stent
                placement. J Am Coll Cardiol, 1999. 34(7): p. 1891-4.

             2. Lau, W. C., L. A. Waskell, et al. (2003). "Atorvastatin reduces the ability of
                clopidogrel to inhibit platelet aggregation: a new drug-drug interaction."
                Circulation 107(1): 32-7.

             3. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human
                cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos
                2003;31(1):53-9

             4. Wenaweser P., et al. Do Statins Interfere With the Antiaggregatory Effect of
                Clopidogrel in Patients With Stent Thrombosis ? Abstract presentation Swiss Cardiac
                Society, June 2005, Lausanne

             5. McKenzie ME, Gurbel PA, Levine DJ, Serebruany VL. Clinical utility of available
                methods for determining platelet function. Cardiology. 1999;92(4):240-7. Review
    

Intervention name(s): fluvastatin
Intervention type(s): Drug
Time perspective: Prospective