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Impact of Platelet Reactivity When On-treatment With Clopidogrel on Mortality, MI or Stent Thrombosis After PCI

Impact of Platelet Reactivity When On-treatment With Clopidogrel on Mortality, MI or Stent Thrombosis After PCI. A Collaborative Meta-Analysis of Individual Patient Data.

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Impact of Platelet Reactivity When On-treatment With Clopidogrel on Mortality, MI or Stent Thrombosis After PCI

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  1. Impact of Platelet Reactivity When On-treatment With Clopidogrel on Mortality, MI or Stent Thrombosis After PCI A Collaborative Meta-Analysis of Individual Patient Data Somjot Brar, MD George D. Dangas, MD PhD Kaiser Permanente Mount Sinai Medical Center Los Angeles, CA New York, NY

  2. Disclosure • Accumetrics had provided a grant towards Columbia University Interventional Cardiology Fellowship Program • Dr Dangas institution (Mt Sinai) has received research grants from Sanofi-Aventis, BMS, Eli Lilly and Daichi Sankyo and he received Advisory Board consultant honoraria from Astra-Zeneca (modest level). • Dr Brar is a consultant and received speaker honoraria from Accumetrics (modest level)

  3. Co-Investigators Somjot S. Brar Los Angeles, CA, USA Jurrien M. ten Berg the Netherlands Rosella Marcucci Florence, Italy Giuseppe Patti Rome, Italy Matthew Price La Jolla, CA, USA Marco Valgimigli Ferrara, Italy Hyo-Soo Kim South Korea Nicoline Breet the Netherlands Germano DiSciascio Rome, Italy Thomas Cuisset Marseille, France George Dangas New York, NY, USA Brar et al, JACC 2011

  4. Quantifying Clopidogrel Responsiveness Various Methods VerifyNow LTA P2Y12 Platelet Activity VASP

  5. VerifyNow Assay • Measures inhibitory effects of clopidogrel on the P2Y12 receptor • Cartridge based assay • 20 µmol ADP + 22 nmol prostaglandin E1 (to reduce activation of ADP binding to P2Y1 receptors)

  6. VerifyNow Assay P2Y12 Reaction Units (PRU) • Results reported as PRU (P2Y12 Reaction Units) • Higher PRU values reflect an increase in light transmittance • Higher PRU values reflect greater ADP mediated platelet reactivity (i.e. hyporesponsiveness to clopidogrel) • Despite existing variability, this method had the best correlation with LTA from several methods tested in the POPULAR trial Brar et al, JACC 2011

  7. Meta-Analysis Objectives • Is clopidogrel on-treatment platelet reactivity associated with increased adverse cardiovascular events? • What is the best numerical definition of high clopidogrel on-treatment platelet reactivity? Primary - Stent thrombosis - Myocardial infarction - Mortality Secondary Brar et al, JACC 2011

  8. Statistical Methods • Heterogeneity Assessment • Survival Analysis • MACE • Components of MACE (including stent thrombosis) • Threshold Analysis • Logistic regression • Bootstrap analysis Brar et al, JACC 2011

  9. 6 Studies Identified; n=3,059 Individual Patients Brar et al, JACC 2011

  10. Heterogeneity & Small Study Effects • There was no evidence of heterogeneity or a small study effect (publication bias): • Cochrane Q statistic: P=0.56 • I2 statistic = 0% • Egger’s regression test: P=0.62 Brar et al, JACC 2011

  11. Distribution of PRU by Study Brar et al, JACC 2011

  12. MACE Rate by PRU Quartile Probability of Death, MI, & Stent Thrombosis @ 2-y *P-values adjusted for multiple comparisons Brar et al, JACC 2011

  13. Mortality by PRU Quartile Kaplan-Meier Curves for Mortality @ 2-years *P-values adjusted for multiple comparisons Brar et al, JACC 2011

  14. Myocardial Infarction by PRU Quartile Kaplan-Meier Curves for MI at 2-years *P-values adjusted for multiple comparisons Brar et al, JACC 2011

  15. Stent Thrombosis by PRU Quartile Probability of Stent Thrombosis @ 2-years *P-values adjusted for multiple comparisons Brar et al, JACC 2011

  16. PRU Threshold Analysis Outcome - Death, myocardial infarction, and stent thrombosis Methods - Logistic regression - Bootstrap sampling with replacement Brar et al, JACC 2011

  17. PRU Threshold Analysis Kaplan-Meier Curves for High (≥ 230) vs. Low (< 230) On-treatment Platelet Reactivity 2.1 X increase Brar et al, JACC 2011

  18. Landmark Analysis (4 day post-PCI) High (≥ 230) vs. Low (< 230) On-treatment Platelet Reactivity Excluding peri-procedural events 2 X increase Brar et al, JACC 2011

  19. Event Rates & Platelet Reactivity High (≥ 230) vs. Low (< 230) On-treatment Platelet Reactivity Brar et al, JACC 2011

  20. Death/MI/ST Rates Within Selected Subgroups High Low Brar et al, JACC 2011

  21. Summary • In this pooled analysis of 6 prospective studies with 3,059 patients we observed: • In quartile analyses, high clopidogrel on-treatment platelet reactivity is associated with an increase in: • Composite of Death / MI / Stent thrombosis • MI • Stent thrombosis Brar et al, JACC 2011

  22. Summary • The optimal cut point for defining high on-treatment clopidogrel responsiveness in this analysis was: • 230 using logistic regression • 231 using bootstrap sampling with replacement in derivation & validation cohorts • High on-treatment platelet reactivity (PRU ≥ 230) was associated with an increase in: • Death (p = 0.03) • Myocardial Infarction (p<0.001) • Stent thrombosis (p=0.005) Brar et al, JACC 2011

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