Biological Efficacy of Clopidogrel After Implantation of Drug-eluting Stents (SPACE)

Study Overview
=================
Brief Summary
-----------------
The risk of thrombotic complications after implantation of drug-eluting stents (DES) may be increased in patients with diabetes mellitus (DM) or metabolic syndrome (MS). It is recommended that all patients take an association of aspirin and clopidogrel for several months after DES implantation to reduce this risk. However, the biological efficacy of current antiplatelet therapies has not been studied prospectively and specifically in DM or MS patients. Our aim is to study the biological efficacy of an association of aspirin and clopidogrel (600 mg loading dose followed by 75 mg maintenance dose) using an assay measuring ex vivo shear-induced platelet aggregation (SIPA), along with other assays measuring platelet activation and aggregation, in patients with DM, MS, or no DM/MS. Patients with stable coronary artery disease and successful DES implantation in native coronary arteries will be eligible. They will be stratified at entry according to their metabolic status (DM, MS, or no DM/MS). Measurements will be performed 6-24 hours after clopidogrel loading dose (acute effects) and 4 months later under clopidogrel maintenance dose (chronic effects). Study end-points: A. Primary biological end-point: To compare SIPA levels in DM vs. MS vs. no DM/MS patients. B. Secondary biological end-points: To compare the results of other tests of platelet aggregation/activation in DM vs. MS vs. no DM/MS patients. To compare the acute (6-24 hours after clopidogrel loading dose) and chronic (4 months later) results of the above mentioned tests. These comparisons will be performed in the overall population and in each group (DM, MS, no DM/MS). C. Secondary clinical end-points: To study the relationship between SIPA levels (and the other tests of platelet aggregation/activation) and the occurrence of: Periprocedural myocardial infarctions Major adverse cardiac events (cardiovascular death, myocardial infarction or ischaemia-driven target vessel revascularization) at 4 and 12 months after stent implantation. We, the researchers at Assistance PUBLIQUE - HOPITAUX de Paris, anticipate our study may help improve our knowledge of the efficacy of current antiplatelet therapies in DM and MS patients treated with DES.

Detailed Description
-----------------
The risk of thrombotic complications after implantation of drug-eluting stents (DES) in coronary arteries may be increased in patients with diabetes mellitus (DM) or metabolic syndrome (MS). It is recommended that all patients take an association of aspirin and clopidogrel for several months after DES implantation to reduce this risk. However, the biological efficacy of current antiplatelet therapies has not been studied prospectively and specifically in DM or MS patients. In the present study, we will study the biological efficacy of an association of aspirin and clopidogrel (600 mg loading dose followed by 75 mg maintenance dose) using an assay measuring ex vivo shear-induced platelet aggregation (SIPA), along with other assays measuring platelet activation and aggregation, in order to better describe the heterogeneity of response to antiplatelet agents in patients with DM, MS or no DM/MS. All patients with stable coronary artery disease and successful DES implantation in native coronary arteries (including high risk features, eg, left main stenosis, bifurcations or in-stent restenosis) will be eligible. They will be stratified at entry according to their metabolic status (DM, MS, or no DM/MS). Measurements will be performed both 6-24 hours after clopidogrel loading dose (acute effects) and 4 months later under clopidogrel maintenance dose (chronic effects). Study end-points: A. Primary biological end-point: To compare SIPA levels in DM vs. MS vs. no DM/MS patients. B. Secondary biological end-points: To compare the results of other tests of platelet aggregation/activation (light transmittance aggregometry in response to ADP and arachidonic acid; flow cytometry measurements of VASP phosphorylation, platelet expression of P-selectin and GPIIbIIIa, and circulating levels of platelet microparticles and leukocyte-platelet aggregates; PFA-100 occlusion time; circulating levels of thromboxane B2) and circulating levels of other markers of atherosclerosis (CRPhs, von Willebrand factor, PAI-1, fibrinogen, and soluble CD40L) in DM vs. MS vs. no DM/MS patients. To compare the acute (6-24 hours after clopidogrel loading dose) and chronic (4 months later) results of all the above mentioned tests. These comparisons will be performed in the overall population and in each group (DM, MS, no DM/MS). C. Secondary clinical end-points: To study the relationship between SIPA levels (and the other tests of platelet aggregation/activation) and the occurrence of: Periprocedural myocardial infarctions Major adverse cardiac events (cardiovascular death, myocardial infarction or ischaemia-driven target vessel revascularization) at 4 and 12 months after stent implantation. We anticipate our study may help improve our knowledge of the efficacy of current antiplatelet therapies in DM and MS patients treated with DES.

Official Title
-----------------
Biological Efficacy of Clopidogrel 600 mg Loading Dose Followed by 75 mg Maintenance Dose After Implantation of Drug-eluting Stents in Patients With Diabetes Mellitus or Metabolic Syndrome (SPACE)

Conditions
-----------------
Coronary Artery Disease, Atherosclerosis, Diabetes Mellitus, Metabolic Syndrome X

Intervention / Treatment
-----------------
* Procedure: blood samples


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years Documented myocardial ischaemia (stable angina with positive stress ECG or stress myocardial scintigraphy, silent ischemia with positive stress ECG or stress myocardial scintigraphy, non-ST elevation acute coronary syndrome) Treatment with at least 100 mg/day of aspirin for ≥ 6 hours before percutaneous coronary intervention 600 mg clopidogrel loading-dose given ≥ 6 hours and < 24 hours before coronary angiography Presence of one or several stenosis in native coronary arteries requiring percutaneous coronary intervention and implantation of one or several drug-eluting stents Exclusion Criteria: ST-elevation acute coronary syndrome Pregnancy or breast feeding Severe disease with life expectancy lower than 1 year High bleeding risk (blood coagulation disorders, uncontrolled severe hypertension, active bleeding, history of severe bleeding) Intolerance or contraindication to aspirin or clopidogrel Current treatment (or stopped < 10 days) with vitamin K antagonist Current treatment (or stopped < 10 days) with clopidogrel (except for the clopidogrel loading-dose given prior to percutaneous coronary intervention), ticlopidine, dipyridamole, non-steroidal antiinflammatory agent, GPIIB-IIIA blocker One-year follow-up impossible Refusal to sign the information and consent form

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: SPACE group<br> | Procedure: blood samples<br>* blood samples before percutaneous coronary intervention (PCI) and at 4 months<br>* Other names: blood samples before percutaneous coronary intervention;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary biological end-point: To compare SIPA levels in DM vs. MS vs. no DM/MS patients |  | 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stent, percutaneous coronary intervention, platelet aggregation, clopidogrel, shear, metabolic syndrome