Current practice and limitations of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention

1. Current practice and limitations of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention Dr Robert F Storey Senior Lecturer and Honorary Consultant in CardiologyUniversity of SheffieldSheffield, UK

2. ESC 2007 Guidelines for NSTE ACS Aspirin: loading dose 160–325mg and maintenance dose 75–100mg Clopidogrel 300mg loading dose and 75mg maintenance dose for 1 year unless excess risk of bleeding 600mg may be given for rapid effect prior to PCI postponing therapy to after angiography not recommended CABG patients: stop clopidogrel 5 days prior if feasible

3. ACC/AHA UA/NSTEMI 2007 Guidelines Aspirin: initial dose 162–325mg then 75–162mg/day (medical therapy) or 162–325mg/day following stent for either 1 month (BMS) or 3–6 months (DES) followed by 75–162mg/day Clopidogrel timing of doses may depend on selection of invasive or conservative strategy – option to delay clopidogrel until post-angiogram unless high-risk features or delay to angiography (GP IIb/IIIa antagonist used pre-angiogram) CABG patients: discontinue 5–7 days prior unless urgent surgery required despite increased bleeding risk

4. CRUSADE registry: adherence to guidelines is associated with better mortality

5. Platelet activation mechanisms

6. Variable response to clopidogrel with incomplete P2Y12 receptor blockade

7. Platelet aggregation before and 4 hours after clopidogrel 600mg in patients undergoing PCI: whole-blood single platelet counting in response to ADP 10uM

8. Causes of clopidogrel variability Much of the variability remains unexplained Further work required to assess effects of age, weight and disease states such as diabetes Baseline platelet reactivity influences post-treatment reactivity Genetic influences polymorphisms of genes for cytochrome P450 enzymes involved in active metabolite generation CYP3A4/5: little or no effect; CYP2C19: mild to moderate effect polymorphisms of platelet receptor genes P2Y12: no effect; other platelet receptor genes: little or no effect Drug interactions statins: appear not to have a significant effect ketoconazole: moderate inhibitory effect on clopidogrel response omeprazole: one group have reported moderate inhibitory effect

9. Effect of clopidogrel 75mg daily on mean (± SEM) bleeding time: prolongation relative to baseline, nine healthy volunteers

10. Conclusions Adherence to ACS guidelines is associated with improved outcomes Dual antiplatelet therapy with aspirin and clopidogrel is recommended for ACS patients unless there is an excess risk of bleeding Standard regimens of clopidogrel achieve partial P2Y12 receptor blockade ? suboptimal protection against arterial thrombosis in some patients Irreversibility of action may be a limitation of thienopyridines for patients requiring urgent CABG surgery