1. Brar et al, JACC 2011 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 Somjot Brar, MD George D. Dangas, MD PhD Kaiser Permanente Mount Sinai Medical Center Los Angeles, CA New York, NY Somjot Brar, MD George D. Dangas, MD PhD Kaiser Permanente Mount Sinai Medical Center Los Angeles, CA New York, NY

2. Brar et al, JACC 2011 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. Brar et al, JACC 2011 Co-Investigators Matthew PriceLa Jolla, CA, USA Rosella MarcucciFlorence, Italy Giuseppe PattiRome, Italy Thomas CuissetMarseille, France Somjot S. BrarLos Angeles, CA, USA Jurrien M. ten Bergthe Netherlands Hyo-Soo KimSouth Korea Marco ValgimigliFerrara, Italy Nicoline Breetthe Netherlands Germano DiSciascioRome, Italy Brar et al, JACC 2011 George DangasNew York, NY, USA

4. Brar et al, JACC 2011 Quantifying Clopidogrel Responsiveness Various Methods Platelet Activity P2Y12 LTA VASP VerifyNow

5. Brar et al, JACC 2011 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. Brar et al, JACC 2011 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 VerifyNow Assay P2Y12 Reaction Units (PRU) Brar et al, JACC 2011

7. 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? Meta-Analysis Objectives Primary Secondary - Stent thrombosis - Myocardial infarction - Mortality 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 » I 2 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. *P-values adjusted for multiple comparisons Mortality by PRU Quartile Kaplan-Meier Curves for Mortality @ 2-years 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 Methods - Logistic regression - Bootstrap sampling with replacement Outcome - Death, myocardial infarction, and stent thrombosis 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 ReactivityOutcomeHR 95% CI P Death / MI / Stent thrombosis 2.131.64 - 2.77<0.001 Death1.681.04 - 2.720.03 MI2.071.53 - 2.80<0.001 Stent Thrombosis 2.501.31 - 4.790.005 High (≥ 230) vs. Low (< 230) On-treatment Platelet Reactivity Brar et al, JACC 2011

20. Sensitivity Analysis of PRU Threshold Results from Derivation & Validation datasets The entire cohort was randomly divided into derivation & validation subsets Bootstrap sampling w/ replacement was used to identify the best average PRU cutoff in the derivation subset The performance of the PRU threshold was then evaluated in the validation subset Brar et al, JACC 2011

21. Death/MI/ST rates by High Vs. Low On-Treatment Platelet Reactivity PRU threshold identified =231 Derivation CohortValidation Cohort High on-treatment platelet reactivity Low on-treatment platelet reactivity Log-rank P = 0.0001 Brar et al, JACC 2011 High on-treatment platelet reactivity Low on-treatment platelet reactivity Log-rank P = 0.002

22. Brar et al, JACC 2011 Death/MI/ST Rates Within Selected Subgroups Death / MI / ST PRU ≥ 230 PRU < 230 HR 95% CI P P interaction Male16.2%7.1%2.371.73 - 3.24< 0.0001 0.27 Female12.1%6.4%1.73 1.08 - 2.780.02 Age, > 65 yrs. 14.6%8.4%1.84 1.32 - 2.560.0003 0.20 Age, ≤ 65 yrs. 14.7%5.5%2.56 1.69 - 4.00< 0.0001 Diabetes, yes 13.1%10.9%1.30 0.79 - 2.150.32 0.03 Diabetes, no 15.3%6.2%2.49 1.84-3.39< 0.0001 ACS, yes 11.1%4.3%2.97 1.37 - 6.450.006 0.64 ACS, no 12.4%5.2%2.47 1.79 - 3.40< 0.0001 HighLow Brar et al, JACC 2011

23. 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 Summary Brar et al, JACC 2011

24. 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