1. ADAPT-DES One-Year Results Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents A Large-Scale, Multicenter, Prospective, Observational Study of the Impact of Clopidogrel and Aspirin Hyporesponsiveness on Patient Outcomes Gregg W. Stone, MD Columbia University Medical Center NewYork-Presbyterian Hospital Cardiovascular Research Foundation

2. Disclosures Gregg W. Stone Gregg W. Stone  Consultant to Eli Lilly, Daiichi Sankyo, AstraZeneca, Medtronic, Boston Scientific, Abbott Vascular, Volcano, The Medicines Company

3. From the large-scale prospective, multicenter ADAPT-DES registry, we previously demonstrated a strong relationship between platelet hyporesponsiveness to clopidogrel, but not to aspirin, and subsequent stent thrombosis to 30 days From the large-scale prospective, multicenter ADAPT-DES registry, we previously demonstrated a strong relationship between platelet hyporesponsiveness to clopidogrel, but not to aspirin, and subsequent stent thrombosis to 30 days With follow-up to 1-year, we now report the overall treatment implications of aspirin and clopidogrel hyporesponsiveness on patient outcomes With follow-up to 1-year, we now report the overall treatment implications of aspirin and clopidogrel hyporesponsiveness on patient outcomes ADAPT-DES: Background

4. ADAPT-DES Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents 11,000 DES pts prospectively enrolled No clinical or anatomic exclusion criteria 11 sites in US and Germany Clinical FU at 30 days, 1 year and 2 years Angio core lab assessment all STs w/1:2 matching controls Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics VerifyNow Aspirin, VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded) PCI with ≥1 non-investigational DES Successful and uncomplicated (IVUS/VH substudy; Up to 3000 pts enrolled) clinicaltrials.gov NCT00638794

5. ADAPT-DES: Study organization Principal investigator:Gregg W. Stone ( & Chuck Simonton prior to joining AVD) Co-principal investigators:Thomas Stuckey, Bruce Brodie, Mike Rinaldi Pharmacology committee:Paul Gurbel and Steve Steinhubl Sponsor (IDE):Cardiovascular Research Foundation Site management & monitoring:R. Stuart Dickson Institute For Health Studies Michael Dulin, director, Sherry Laurent, consultant Data management:R. Stuart Dickson Institute For Health Studies Susan Christopher, project lead Event adjudication:Cardiovascular Research Foundation Roxana Mehran and Ecaterina Cristea, directors Angio and IVUS core labs:Cardiovascular Research Foundation Ecaterina Cristea and Akiko Maehara, directors Biostatistics:Cardiovascular Research Foundation Helen Parise, director Financial support:Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, Accumetrics

6. ADAPT-DES: Sites and enrollment 8,583 pts were enrolled at 11 sites between 1/7/2008 and 9/16/2010; 2,143 pts were enrolled in the IVUS substudy SitePrincipal investigator(s)N enrolled Charité Benjamin FranklinBernhard Witzenbichler1,435 Columbia University Medical CenterGiora Weisz1,365 Herz-Zentrum Bad KrozingenFranz-Josef Neumann1,035 Carolinas Medical CenterMike Rinaldi1,113 Wellmont Holstein ValleyChris Metzger790 Minneapolis Heart InstituteTim Henry and Ivan Chavez788 Lehigh Valley HospitalDavid Cox673 Firsthealth Moore RegionalPeter Duffy544 LeBauer CV ResearchBruce Brodie, Tom Stuckey534 Ohio State UniversityErnest Mazzaferri304 Indiana Heart InstituteJim Hermiller2

7. ADAPT-DES: Baseline features (n=8,583) Age (years)63.6 ± 10.9 Female 25.9% Caucasian 88.6% Diabetes mellitus32.4% - Insulin-treated11.6% Hypertension79.6% Hyperlipidemia74.4% Cigarette smoking, current22.6% Prior MI25.2% Prior PCI42.8% Prior CABG17.1% Prior CHF8.1% Prior PAD10.2% History of renal insufficiency7.7% - Dialysis1.6% BMI29.5 ± 5.7

8. Presentation during PCI - Stable CAD48.3% - ACS51.7% - UA, biomarker negative27.7% - NSTEMI14.5% - STEMI9.5% Extent of CAD - 1 vessel disease38.3% - 2 vessel disease33.0% - 3 vessel disease28.7% - Left main disease3.0% LVEF (%)55.0 ± 14.1 LVEDP (mmHg)16.7 ± 9.3 ADAPT-DES: Baseline features (n=8,583)

9. ADAPT-DES: PCI procedure (n=8,583) N vessels treated per pt1.2 ± 0.4 - LM3.1% - LAD39.1% - LCX26.2% - RCA31.5% - Bypass graft4.5% N lesions treated per pt1.8 ± 1.1 N stents per pt1.7 ± 1.0 Total stent length (mm) 32.4 ± 22.3 DES type used per pt / lesion - Xience V / Promus64.5% / 58.5% - Taxus (Express, Liberté)16.5% / 14.4% - Cypher13.5% / 13.0% - Endeavor6.2% / 5.2% - Resolute2.2% / 2.1% - Other0.2% / 0.2% N = 10,106 vessels, 12,940 lesions

10. ADAPT-DES: Anti-platelet agents (n=8,583) AspirinThienopyridine Pre-admission82.0%42.9% Loading dose pre-PCI88.7%86.4% Discharge99.2%>99.9% - clopidogrel-99.7% - ticlopidine-0.03% - prasugrel-0.3% Days taken through 1 year345 ± 120334 ± 120 Daily through 1 yr w/o any d/c87.2%79.6% Taking at 1 year95.4%83.9%

11. ADAPT-DES: Platelet function test results (n=8,583; 8,527 with ARU, 8,449 with PRU) Post-PCI to VerifyNow (hrs) 20.3 ± 8.3 VerifyNow Aspirin (ARU)419 ± 55 - >550 ARU*5.6% VerifyNow P2Y12 (BASE) 310 ± 58 VerifyNow P2Y12 (PRU)188 ± 97 - >208 PRU*42.7% - ≥230 PRU*35.0% VerifyNow P2Y12 Inhibition (%) 40.0 ± 28.3 VerifyNow IIb/IIIa PAU193 ± 53 *Pre-specified cut-off values

12. Days to definite or probable stent thrombosis Frequency Definite or probable0.84% (70) - Definite0.63% (53) - Probable0.20% (17) 40 (57.1%) of ST events occurred within 30 days 70 patients (0.84%) developed 74 ST events (ARC def/prob) ADAPT-DES: Time to First Stent Thrombosis Definite ST Probable ST N=8,583

13. VerifyNow testDef/prob ST No def/prob ST P (n=70)(n=8,513) Aspirin ARU 426 ± 58 419 ± 550.30 - ARU ≥5507.2%5.6%0.54 P2Y12 Base 305 ± 60310 ± 580.56 P2Y12 PRU234 ± 97188 ± 97<0.0001 - PRU >208 65.2%42.5%0.0002 - PRU ≥230 53.6%34.9%0.001 P2Y12 % Inhibition24.8 ± 27.040.1 ± 28.2<0.0001 - Inhibition ≤11% 44.9%19.9% <0.0001 IIb/IIIa PAU 194 ± 56193 ± 540.92 ADAPT-DES: Relationship between VerifyNow platelet response to DAPT and subsequent 1-year def/prob stent thrombosis (n=8,583)

14. ADAPT-DES: Stent thrombosis (definite or probable) according to post-PCI PRU HR [95%CI] = 2.54 [1.55, 4.16] P=0.0001 PRU >208 (n=3610) PRU ≤208 (n=4839) Stent thrombosis (def/prob) (%) 0 1 2 Months 036912 36103450342033803152 48394688465446314341 Number at risk: PRU > 208 PRU ≤ 208 1.3% 1.3% 0.5% 0.5%

15. ADAPT-DES: MI and major bleeding according to post-PCI PRU PRU >208 (n=3610) PRU ≤208 (n=4839) 0 5 10 Months 0612 6.7% 6.7% 5.6% Major bleeding HR [95%CI] = HR [95%CI] = 0.83 [0.69, 0.99]P=0.04 Myocardial infarction HR [95%CI] = HR [95%CI] = 1.47 [1.15, 1.87]P=0.002 PRU >208 (n=3610) PRU ≤208 (n=4839) 0 5 10 Months 0612 3.9% 3.9% 2.7% 2.7%

16. ADAPT-DES: Mortality according to post-PCI PRU PRU >208 (n=3610) PRU ≤208 (n=4839) Mortality (%) Months 036912 36103475344734083181 48394696466446454365 Number at risk: PRU > 208 PRU ≤ 208 2.4% 2.4% 1.5% 1.5% HR [95%CI] = 1.62 [1.18, 2.22] P=0.002 0 351 2 4

17. ADAPT-DES: Assessment of Propensity Score Model to Adjust for 87 Baseline Predictors of VerifyNow P2Y12 >208 PRU No variables remain significant in the adjusted model Log Odds Ratio -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Amidorome Through Procedure Intra-aortic balloon pump Anemia Diabetes Diabetes Insulin Retavase Through Procedure BMI>30 IC/IV Nitroprusside During PCI (IV) Killip Class 2-4 History of renal insufficiency Black TNK (rtPA) Through Procedure Diuretic Through Procedure PPI Through Procedure Cox-2 inhibitor Through Procedure IV Pressor Through Procedure STEMI History of CHD Calcium blocker Through Procedure NSAID Through Procedure Age >= Median (64) Amiodarone Through Procedure Coumadin Through Procedure Graft Any Lesion within a graft Platelet Count <15000 Hypertension tPA Through Procedure IC Adenosine During PCI (IV) ACE or ARB Through Procedure Enrolled in Substudy GPIIb/IIIa Through Procedure History of PAD Pre TIMI 0/1 Any dissection Previous CABG Atropine Through Procedure Beta Blocker Through Procedure Hyperlipidemia IVUS used to guide and optimize procedure Xience / Promus Atypical chest pain Closure device used VerifyNow P2Y12 (BASE) Total stent length >= Median (24mm) Previous MI (> 7 Days PCI) LAD Aspirin Pre-hospital admission Max Pre-stenosis >= Median (90%) Positive stress test Max device diameter >= Median (3.25mm) Aspirin Loading dose Any Calcium Cardiopulmonary Support Max balloon pressure >= Median (16atm) Thienopyridine Pre-hospital admission Patients with DES only Caucasian Any Chronic Total Occlusion 3+ vessels treated Current smoking Final TIMI 0/1 Cilostazol Through Procedure Open circles: P<0.05 Solid circles: P=NS History of dialysis Male Bivalirudin Through Procedure Anti Hypertensives Through Procedure CrCl <60 ml/min Non-STEMI Previous Coronary Brachytherapy Heparin though substudy LMWH Through Procedure Any previous brachytherapy Any Ostial Vascular Access Femoral Aysmpomatic CAD Any bifurcation Model c-statistic = 0.744 Includes: Age Diabetes Prior MI NSTEMI STEMI Anemia Etc.

18. ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow PRU >208 for subsequent 1-year adverse events (n=8,583) EventAdj HR [95%CI]P value ST, def/prob 2.49 [1.43, 4.31]0.001 - Definite3.05 [1.62, 5.75]0.0006 MI1.42 [1.09, 1.86]0.01 Major bleeding0.73 [0.61, 0.89]0.002 Death, all-cause1.20 [0.85, 1.70]0.30 Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD, premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)

19. ADAPT-DES: Relationship between adverse events and death at 1 year Event typeEventNo eventHR [95%CI] P value Definite STNo definite ST N538530 Deaths5 (9.6%)156 (1.9%) 5.47 [2.25, 13.31] <0.0001 MI w/o STNo MI w/o ST N2248359 Deaths 21 (9.7%) 140 (1.7%) 5.78 [3.65, 9.14] <0.0001 Major bleedingNo major bleeding N5318052 Deaths 45 (8.6%)116 (1.5%)5.97 [4.23, 8.42] <0.0001 - 161/8583 pts (1.9%) died within 1 year - 1 year event rates (n=8,583) Definite ST: 53 (0.6%); MI w/o def :ST 224 (2.6%); Major bleeding: 531 (6.2%) 1 year event rates (n=8,583) Definite ST: 53 (0.6%); MI w/o def :ST 224 (2.6%); Major bleeding: 531 (6.2%)

20. ADAPT-DES: Multivariable propensity score Cox model for all-cause mortality (n=8,583), including events during FU as time-adjusted covariates Baseline featuresAdj HR [95%CI]P value Age (years)1.03 [1.01, 1.05]0.001 Male gender1.95 [1.32, 2.87]0.0008 Diabetes mellitus1.84 [1.30, 2.62]0.0007 Current smoking1.48 [0.96, 2.29]0.08 Hyperlipidemia0.59 [0.41, 0.85]0.005 Creatinine clearance0.99 [0.98, 1.00]0.004 Hemoglobin (g/dL)0.74 [0.66, 0.83]<0.0001 WBC (x10 3 /mL)1.03 [1.01, 1.05]0.003 STEMI/NSTEMI (vs stable CAD)1.38 [0.96, 2.00]0.08 Premature DAPT D/C w/i 1 year4.30 [2.96, 6.26]<0.0001 Adverse events (time-adjusted) Definite stent thrombosis3.43 [1.48, 7.98]0.004 MI (w/o definite ST)4.52 [2.84, 7.17]<0.0001 Major bleeding4.17 [2.84, 6.13]<0.0001 VerifyNow P2Y12 > 208 PRU and VerifyNow Aspirin > 550 ARU Other variables in model: prior MI, NSTEMI/STEMI, hypertension, platelet count, creatinine clearance, MVD, VerifyNow P2Y12 > 208 PRU and VerifyNow Aspirin > 550 ARU

21. Hypothetically Increasing Clopidogrel Response in Pts with >208 PRU → Incremental Decrease in Stent Thrombosis (from 1.3%) vs. Increase in Bleeding (from 5.5%) Safety treatment effect: Major bleeding increase (from MV HR 0.76) NNT/NNH (# of ↑ Bleeding to Prevent One ST) ↑ 10% (to 6.1%) 0 2 4 6 8 10 12 14 16 18 ↑ 20% (to 6.6%) ↑ 30% (to 7.2%) ↑ 50% (to 8.2%) ↑ 60% (to 8.8%) ↑ 40% (to 7.7%) ST ↓ 15% (to 1.1%) ST ↓ 20% (to 1.0%) ST ↓ 25% (to 1.0%) ST ↓ 30% (to 0.9%) ST ↓ 35% (to 0.8%) ST ↓ 40% (to 0.8%) ST ↓ 45% (to 0.7%) ST ↓ 50% (to 0.7%) ST ↓ 55% (to 0.6%) ST ↓ 60% (to 0.6%) ST ↓ 65% (to 0.5%) ST ↓ 70% (to 0.4%) Efficacy treatment effect (from MV HR 2.51) If max effect on ST and bleeding: ~4 bleeds caused for each ST prevented

22. ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow ARU >550 for subsequent 1-year adverse events (n=8,583) EventAdj HR[95%CI]P value ST, def/prob 1.46 [0.58, 3.64]0.42 - Definite1.60 [0.57, 4.48]0.37 MI0.81 [0.46, 1.42]0.46 Major bleeding0.65 [0.43, 0.99]0.04 Death, all-cause1.42 [0.83, 2.43]0.20 Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD, premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)

23. ADAPT-DES: Conclusions and Implications I In the large-scale, prospective ADAPT-DES study, on-treatment hyporesponsiveness to clopidogrel after DES was an independent predictor of 1-year ST and MI, but was also protective against major bleeding, both of which were strongly related to mortality In the large-scale, prospective ADAPT-DES study, on-treatment hyporesponsiveness to clopidogrel after DES was an independent predictor of 1-year ST and MI, but was also protective against major bleeding, both of which were strongly related to mortality As a result, on-treatment clopidogrel hypo- responsiveness was not independently predictive of 1-year mortality As a result, on-treatment clopidogrel hypo- responsiveness was not independently predictive of 1-year mortality

24. ADAPT-DES: Conclusions and Implications II Overcoming clopidogrel hyporesponsiveness with more potent antiplatelet agents is therefore unlikely to improve survival unless the beneficial effects of reducing ST and MI can be uncoupled from the likely increase in bleeding with greater platelet inhibition Overcoming clopidogrel hyporesponsiveness with more potent antiplatelet agents is therefore unlikely to improve survival unless the beneficial effects of reducing ST and MI can be uncoupled from the likely increase in bleeding with greater platelet inhibition Hyporesponsiveness to aspirin was unrelated to ST, MI or death, but may be related to bleeding, questioning the utility of aspirin in pts treated with DES Hyporesponsiveness to aspirin was unrelated to ST, MI or death, but may be related to bleeding, questioning the utility of aspirin in pts treated with DES