Ignite Creation Date:
2024-05-05 @ 5:29 PM
Last Modification Date:
2024-10-26 @ 9:32 AM
Study NCT ID:
NCT00465322
Status:
COMPLETED
Last Update Posted:
2007-04-25
First Post:
2007-04-23
Brief Title:
Effect of Fluvastatin on Top of Clopidogrel and Aspirin in Patients After DES Implantation on Platelet Aggregation
Sponsor:
Insel Gruppe AG University Hospital Bern
Organization:
Insel Gruppe AG University Hospital Bern
Study Overview
Official Title:
Effect of Fluvastatin on Top of Clopidogrel and Aspirin in Patients After DES Implantation on Platelet Aggregation
Status:
COMPLETED
Status Verified Date:
2007-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EFA-1
Brief 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 eg 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 atorvastatinsimvastatin 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 25 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 05mgml 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 25 months for assessment of platelet aggregation Primary endpoint platelet aggregation after 25 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 mgday
6 Exclusion Criteria
acute coronary syndrome
use of a GPIIbIIIa 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 PB et al Clopidogrel versus ticlopidine after intracoronary stent placement J Am Coll Cardiol 1999 347 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 1071 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 200331153-9
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 1999924240-7 Review
Previous studies reported a drug interaction between clopidogrel and several statins eg 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 atorvastatinsimvastatin 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 25 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 05mgml 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 25 months for assessment of platelet aggregation Primary endpoint platelet aggregation after 25 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 mgday
6 Exclusion Criteria
acute coronary syndrome
use of a GPIIbIIIa 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 PB et al Clopidogrel versus ticlopidine after intracoronary stent placement J Am Coll Cardiol 1999 347 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 1071 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 200331153-9
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 1999924240-7 Review
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None