1. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention: Is the Current Antiplatelet Therapy Adequate? Kevin P. Bliden, BS; Joseph DiChiara, BS; Udaya S. Tantry, PhD; Ashwani K. Bassi, MS; Srivasavi K. Chaganti, MD; Paul A. Gurbel, MD Published in JACC February 13, 2007 Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention: Is the Current Antiplatelet Therapy Adequate?

2. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Background (cont.) Platelet aggregation can lead to ischemic complications after percutaneous coronary intervention (PCI).Platelet aggregation can lead to ischemic complications after percutaneous coronary intervention (PCI). Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet function during PCI.Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet function during PCI. However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic events.However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic events. Platelet aggregation can lead to ischemic complications after percutaneous coronary intervention (PCI).Platelet aggregation can lead to ischemic complications after percutaneous coronary intervention (PCI). Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet function during PCI.Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet function during PCI. However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic events.However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic events. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

3. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Background (cont.) The goal of this study was to determine whether patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display high on-treatment preprocedural platelet aggregation are at increased risk for poststenting ischemic events.The goal of this study was to determine whether patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display high on-treatment preprocedural platelet aggregation are at increased risk for poststenting ischemic events. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

4. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Study Design  Primary Endpoint: Ischemic events defined as: death secondary to any cardiovascular cause, stroke, myocardial infarction, ischemia requiring a hospital stay, and target vessel revascularization (TVR), nontarget vessel revascularization (NTVR), or medical management. Hi On-treatment Platelet Reactivity* (HPR) n=22 Hi On-treatment Platelet Reactivity* (HPR) n=22 Normal On-Treatment Platelet Reactivity (NPR) n=78 Normal On-Treatment Platelet Reactivity (NPR) n=78 100 patients > 18 yrs receiving clopidogrel for ≥1month before non-emergent PCI. Exclusion criteria: history of bleeding diathesis, acute MI within 48 h, elevated cardiac markers, cerebrovascular event within 3 months, illicit drug or alcohol abuse, prothrombin time >1.5times control, platelet count 4.0mg/dl, and glycoprotein (GP) IIb/IIIa use before the procedure. 100 patients > 18 yrs receiving clopidogrel for ≥1month before non-emergent PCI. Exclusion criteria: history of bleeding diathesis, acute MI within 48 h, elevated cardiac markers, cerebrovascular event within 3 months, illicit drug or alcohol abuse, prothrombin time >1.5times control, platelet count 4.0mg/dl, and glycoprotein (GP) IIb/IIIa use before the procedure. 1, 6, and 12 mos. follow-up LTA and TEG to determine platelet reactivity *HPR defined as ≥ 50% ADP-induced aggregation after stimulation with 5-μmol ADP as measured by LTA or ≥ 70% ADP-platelet induced aggregation with 2-μmol ADP as measured by TEG. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

5. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Baseline Characteristics Cardiovascular risk factors and multivessel interventions using drug-eluting stents were common.Cardiovascular risk factors and multivessel interventions using drug-eluting stents were common. No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data existed between reactivity groups.No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data existed between reactivity groups. Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium- channel blockers.Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium- channel blockers. Cardiovascular risk factors and multivessel interventions using drug-eluting stents were common.Cardiovascular risk factors and multivessel interventions using drug-eluting stents were common. No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data existed between reactivity groups.No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data existed between reactivity groups. Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium- channel blockers.Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium- channel blockers. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

6. Clinical Trial Results. org Baseline on-treatment aggregation With Events p < 0.0001 Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results Baseline on-treatment aggregation p < 0.0001 n = 77 50±13% 31±13% 76±13% 49±13% Without Events With Events Without Events Baseline on-treatment Aggregation in Patients with and without Ischemic Events As measured by LTA As measured by TEG n = 23 n = 77 n = 23 Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

7. Clinical Trial Results. org Displaying HPR (%) With Events Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results (cont.) Displaying HPR (%) n = 77 70% 8%8%8%8% 87% 17% Without Events With Events Without Events Percentage of Patients with and without Ischemic Events Displaying HPR at Baseline As measured by LTA As measured by TEG n = 23 n = 77 n = 23 Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

8. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results (cont.) These results yielded positive predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG.These results yielded positive predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG. The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG).The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG). These results yielded positive predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG.These results yielded positive predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG. The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG).The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG). Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

9. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results (cont.) High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 for both assays).High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events. High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 for both assays).High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

10. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Limitations The results are limited by a small sample size.The results are limited by a small sample size. Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose remains unclear.Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose remains unclear. Inherent differences within the study population by virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity.Inherent differences within the study population by virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity. The results are limited by a small sample size.The results are limited by a small sample size. Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose remains unclear.Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose remains unclear. Inherent differences within the study population by virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity.Inherent differences within the study population by virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.

11. Clinical Trial Results. org Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Summary Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for postprocedural ischemic events.Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for postprocedural ischemic events. The results of the study have potential implications for clinicians who do not administer additional clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy.The results of the study have potential implications for clinicians who do not administer additional clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy. Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for postprocedural ischemic events.Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for postprocedural ischemic events. The results of the study have potential implications for clinicians who do not administer additional clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy.The results of the study have potential implications for clinicians who do not administer additional clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy. Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.