Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00465322 |
| Other study ID # |
1101 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
April 23, 2007 |
| Last updated |
April 23, 2007 |
Study information
| Verified date |
April 2007 |
| Source |
University Hospital Inselspital, Berne |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Switzerland: Swissmedic |
| Study type |
Observational
|
Clinical Trial 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.
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
