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Increased Risk in Patients with High Platelet Aggregation Receiving Chronic

Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention:

Is the Current Antiplatelet Therapy Adequate?

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; Kevin P. Bliden, BS; Joseph DiChiara, BS; Udaya S. Tantry, PhD; Ashwani K. Bassi, MS; Srivasavi K. Chaganti, MD; Paul A. Gurbel, MDAshwani K. Bassi, MS; Srivasavi K. Chaganti, MD; Paul A. Gurbel, MD

Published in JACCPublished in JACC

February 13, 2007February 13, 2007

Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary

Intervention: Is the Current Antiplatelet Therapy Adequate?

Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary

Intervention: Is the Current Antiplatelet Therapy Adequate?


Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Background (cont.)


• Platelet aggregation can lead to ischemic Platelet aggregation can lead to ischemic complications after percutaneous coronary complications after percutaneous coronary intervention (PCI).intervention (PCI).

• Dual antiplatelet therapy with aspirin and Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet clopidogrel is the gold standard to attenuate platelet function during PCI.function during PCI.

• However, nearly 20% of PCI patients will However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic experience recurrent ischemic or thrombotic events.events.

• Platelet aggregation can lead to ischemic Platelet aggregation can lead to ischemic complications after percutaneous coronary complications after percutaneous coronary intervention (PCI).intervention (PCI).

• Dual antiplatelet therapy with aspirin and Dual antiplatelet therapy with aspirin and clopidogrel is the gold standard to attenuate platelet clopidogrel is the gold standard to attenuate platelet function during PCI.function during PCI.

• However, nearly 20% of PCI patients will However, nearly 20% of PCI patients will experience recurrent ischemic or thrombotic experience recurrent ischemic or thrombotic events.events.

Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.Bliden et al. JACC. 2007 Feb 13; 49 (6): 657-66.




• The goal of this study was to determine whether The goal of this study was to determine whether patients receiving chronic clopidogrel therapy patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display undergoing nonemergent stenting who display high on-treatment preprocedural platelet high on-treatment preprocedural platelet aggregation are at increased risk for poststenting aggregation are at increased risk for poststenting ischemic events.ischemic events.

• The goal of this study was to determine whether The goal of this study was to determine whether patients receiving chronic clopidogrel therapy patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display undergoing nonemergent stenting who display high on-treatment preprocedural platelet high on-treatment preprocedural platelet aggregation are at increased risk for poststenting aggregation are at increased risk for poststenting ischemic events.ischemic events.



Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Study Design

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 Primary Endpoint: Ischemic events defined as: death secondary to any cardiovascular cause, stroke, myocardial infarction, ischemia requiring cardiovascular cause, stroke, myocardial infarction, ischemia requiring a hospital stay, and target vessel revascularization (TVR), nontarget a hospital stay, and target vessel revascularization (TVR), nontarget vessel revascularization (NTVR), or medical management. vessel revascularization (NTVR), or medical management.

Primary Endpoint: Ischemic events defined as: death secondary to any Primary Endpoint: Ischemic events defined as: death secondary to any cardiovascular cause, stroke, myocardial infarction, ischemia requiring cardiovascular cause, stroke, myocardial infarction, ischemia requiring a hospital stay, and target vessel revascularization (TVR), nontarget a hospital stay, and target vessel revascularization (TVR), nontarget vessel revascularization (NTVR), or medical management. 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 < 100,000/mm3, hematocrit <30%, creatinine >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 < 100,000/mm3, hematocrit <30%, creatinine >4.0mg/dl, and glycoprotein (GP) IIb/IIIa use

before the procedure.

1, 6, and 12 mos. follow-up1, 6, and 12 mos. follow-up

LTA and TEG to determine platelet reactivity

LTA and TEG to determine platelet reactivity

*HPR defined as *HPR defined as ≥ 50% ADP-induced aggregation after stimulation ≥ 50% ADP-induced aggregation after stimulation with 5-with 5-μμmol ADP as mol ADP as measured by LTA or measured by LTA or ≥ ≥ 70% ADP-platelet induced aggregation with 2-70% ADP-platelet induced aggregation with 2-μμmol ADP as measured by TEG.mol ADP as measured by TEG.



Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Baseline Characteristics

Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Baseline Characteristics

• Cardiovascular risk factors and multivessel Cardiovascular risk factors and multivessel interventions using drug-eluting stents were interventions using drug-eluting stents were commoncommon..

• No significant differences in age, gender, ethnicity, No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data BMI, baseline medications, or hematological data existed between reactivity groups.existed between reactivity groups.

• Patients with HPR exhibited a higher prevalence of Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium-hypertension, diabetes, and use of calcium-channel blockers.channel blockers.

• Cardiovascular risk factors and multivessel Cardiovascular risk factors and multivessel interventions using drug-eluting stents were interventions using drug-eluting stents were commoncommon..

• No significant differences in age, gender, ethnicity, No significant differences in age, gender, ethnicity, BMI, baseline medications, or hematological data BMI, baseline medications, or hematological data existed between reactivity groups.existed between reactivity groups.

• Patients with HPR exhibited a higher prevalence of Patients with HPR exhibited a higher prevalence of hypertension, diabetes, and use of calcium-hypertension, diabetes, and use of calcium-channel blockers.channel blockers.



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Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results

Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results

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5050±13%±13%

3131±13%±13%

7676±13%±13%

4949±13%±13%

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Baseline on-treatment Aggregation in Baseline on-treatment Aggregation in Patients with and without Ischemic EventsPatients with and without Ischemic Events

As measured by LTAAs measured by LTA As measured by TEGAs measured by TEG

n = 23n = 23n = 77n = 77n = 23n = 23



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Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Results (cont.)


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7070%%

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EventsWithout Events

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Percentage of Patients with and without Percentage of Patients with and without Ischemic Events Displaying HPR at BaselineIschemic Events Displaying HPR at Baseline

As measured by LTAAs measured by LTA As measured by TEGAs measured by TEG

n = 23n = 23n = 77n = 77n = 23n = 23





• These results yielded positive predictive values of These results yielded positive predictive values of 73% and 67% and negative predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG.LTA and 85% test efficiency with the TEG.

• The area under the combined receiver-operating The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG).LTA, area=0.881, p=0.0001 for TEG).

• These results yielded positive predictive values of These results yielded positive predictive values of 73% and 67% and negative predictive values of 73% and 67% and negative predictive values of 91% and 94%, respectively, for the LTA and TEG, 91% and 94%, respectively, for the LTA and TEG, and demonstrating 87% test efficiency with the and demonstrating 87% test efficiency with the LTA and 85% test efficiency with the TEG.LTA and 85% test efficiency with the TEG.

• The area under the combined receiver-operating The area under the combined receiver-operating characteristic (ROC) curve showed that LTA and characteristic (ROC) curve showed that LTA and TEG can distinguish between ischemic and TEG can distinguish between ischemic and nonischemic groups (area=0.862, p=0.0001 for nonischemic groups (area=0.862, p=0.0001 for LTA, area=0.881, p=0.0001 for TEG).LTA, area=0.881, p=0.0001 for TEG).





• High on-treatment platelet reactivity as measured High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 significantly related to ischemic events (p<0.0001 for both assays)for both assays)..

• The administration of eptifibatide reduced The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.no significant differences in bleeding events.

• High on-treatment platelet reactivity as measured High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables by aggregometry and TEG were the only variables significantly related to ischemic events (p<0.0001 significantly related to ischemic events (p<0.0001 for both assays)for both assays)..

• The administration of eptifibatide reduced The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.no significant differences in bleeding events.



Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Limitations

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 Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose therapy with a further 300- or 600-mg dose remains unclear.remains unclear.

• Inherent differences within the study population by Inherent differences within the study population by virtue of their need for repeat PCI could have virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity.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 Patients were not given an additional loading does of clopidogrel. The clinical benefit of reloading of clopidogrel. The clinical benefit of reloading patients already treated with chronic clopidogrel patients already treated with chronic clopidogrel therapy with a further 300- or 600-mg dose therapy with a further 300- or 600-mg dose remains unclear.remains unclear.

• Inherent differences within the study population by Inherent differences within the study population by virtue of their need for repeat PCI could have virtue of their need for repeat PCI could have impacted the prevalence of high platelet reactivity.impacted the prevalence of high platelet reactivity.



Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Summary

Increased Risk in Patients with High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing PCI: Summary

• Patients receiving chronic clopidogrel therapy Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for LTA or TEG, are at increased risk for postprocedural ischemic events.postprocedural ischemic events.

• The results of the study have potential implications The results of the study have potential implications for clinicians who do not administer additional for clinicians who do not administer additional clopidogrel (before or after PCI) to patients clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy.receiving chronic clopidogrel therapy.

• Patients receiving chronic clopidogrel therapy Patients receiving chronic clopidogrel therapy undergoing nonemergent PCI, who exhibit high on-undergoing nonemergent PCI, who exhibit high on-treatment ADP-induced platelet aggregation by treatment ADP-induced platelet aggregation by LTA or TEG, are at increased risk for LTA or TEG, are at increased risk for postprocedural ischemic events.postprocedural ischemic events.

• The results of the study have potential implications The results of the study have potential implications for clinicians who do not administer additional for clinicians who do not administer additional clopidogrel (before or after PCI) to patients clopidogrel (before or after PCI) to patients receiving chronic clopidogrel therapy.receiving chronic clopidogrel therapy.


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