Clopidogrel therapy in CS is associated with increased platelet inhibition and lower aggregation as compared with NS. The mechanism of the smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.

Background: High on-treatment platelet reactivity to adenosine diphosphate (HPR-ADP) may be a risk factor for ischemic events after percutaneous coronary intervention (PCI). We determined whether a cutpoint of HPR-ADP, similar to the INR used to guide anticoagulant therapy, could predict ischemic event occurrence after PCI. Methods : Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 352 consecutive patients undergoing non-emergent PCI followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements. Results: Eighty-two patients (23%) suffered ischemic events and had higher 5 and 20 μM ADP-induced aggregation compared to patients without ischemic events (46 ± 14% and 60 ± 13% versus 30 ± 17% and 43 ± 19%, respectively, p<0.0001 for both measurements). Using a combined receiver operator curve analysis, HPR-ADP cutpoints of 46% aggregation following 5μM ADP stimulation and 59% aggregation following 20μM ADP stimulation were associated with 63% and 74% of ischemic events, respectively. Multivariate Cox regression demonstrated significance between events and post-procedural HPR-ADP cutpoints (20μM ADP, OR=8.6, p<0.0001; and 5μM ADP, OR=2.9, p=0.01). Conclusions: High on-treatment platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data are the first to support a therapeutic target for antiplatelet therapy based on an ex vivo platelet function test, similar to the INR used for anticoagulant therapy. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.

Background: Wide response variability to clopidogrel therapy has been reported. Clopidogrel is a prodrug that requires metabolic activation by hepatic cytochromes (CYP). Cigarette smoking is an inducer of CYP1A2 and may, therefore, enhance the metabolism of clopidogrel. We sought to examine the effect of cigarette smoking on the platelet response to clopidogrel. Methods: Three hundred thirteen consecutive patients undergoing elective coronary stenting were studied. Platelet aggregation (PA) was assessed by light transmittance aggregometry (LTA) stimulated by 5 and 20μ M adenosine diphosphate. One hundred fourteen patients were on chronic clopidogrel therapy, were not reloaded, and had pre-stenting PA measurements. Pre-and post-stenting PA was measured in 199 patients: 60 were loaded with 300mg and 139 were loaded with 600mg. There were 120 current smokers (smoking within 2 weeks of PCI) and 193 non-smokers (no prior history of smoking). Low PA was defined as the lowest two quartiles of 5μM ADP-induced platelet aggregation (≤ 40%). Results: PA was significantly lower (p ≤ 0.008) in smokers on long term chronic clopidogrel treatment (Table ). Relative platelet inhibition (RPI) was higher in smokers treated with either 300mg or 600mg clopidogrel measured by 5 and 20μM ADP-induced PA. In a multivariate analysis, cigarette smoking was an independent predictor of low PA in patients on chronic clopidogrel therapy and in patients loaded with clopidogrel (r=0.3, p=0.0001). Conclusion: Clopidogrel therapy in smokers is associated with increased platelet inhibition and lower aggregation as compared to non-smokers. The mechanism of the smoking effect deserves further study and may be another cause of response variability to clopidogrel. RPI = 100 x ((baseline aggregation-post-treatment aggregation)/(baseline aggregation))