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Gregg W. Stone, MD

ADAPT-DES One-Year Results A ssessment of D ual A nti P latelet T herapy with D rug- E luting S tents A Large-Scale, Multicenter, Prospective, Observational Study of the Impact of Clopidogrel and Aspirin Hyporesponsiveness on Patient Outcomes.

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Gregg W. Stone, MD

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  1. ADAPT-DES One-Year ResultsAssessment of Dual AntiPlateletTherapy with Drug-Eluting StentsA 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 • 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 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 AntiPlateletTherapy with Drug-Eluting Stents 11,000 DES pts prospectively enrolled No clinical or anatomic exclusion criteria 11 sites in US and Germany PCI with ≥1 non-investigational DES Successful and uncomplicated (IVUS/VH substudy; Up to 3000 pts enrolled) Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics VerifyNow Aspirin, VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded) Clinical FU at 30 days, 1 year and 2 years Angio core lab assessment all STs w/1:2 matching controls 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 wereenrolled at 11 sites between 1/7/2008 and 9/16/2010; 2,143 pts wereenrolled in the IVUS substudy Site Principal investigator(s) N enrolled Charité Benjamin Franklin Bernhard Witzenbichler1,435 Columbia University Medical Center Giora Weisz 1,365 Herz-Zentrum Bad Krozingen Franz-Josef Neumann 1,035 Carolinas Medical Center Mike Rinaldi1,113 Wellmont Holstein Valley Chris Metzger 790 Minneapolis Heart Institute Tim Henry and Ivan Chavez 788 Lehigh Valley Hospital David Cox 673 Firsthealth Moore Regional Peter Duffy 544 LeBauer CV Research Bruce Brodie, Tom Stuckey 534 Ohio State University Ernest Mazzaferri 304 Indiana Heart Institute Jim Hermiller 2

  7. ADAPT-DES: Baseline features (n=8,583) Age (years) 63.6 ± 10.9 Female 25.9% Caucasian 88.6% Diabetes mellitus 32.4% - Insulin-treated 11.6% Hypertension 79.6% Hyperlipidemia 74.4% Cigarette smoking, current 22.6% Prior MI 25.2% Prior PCI 42.8% Prior CABG 17.1% Prior CHF 8.1% Prior PAD 10.2% History of renal insufficiency 7.7% - Dialysis 1.6% BMI 29.5 ± 5.7

  8. ADAPT-DES: Baseline features (n=8,583) Presentation during PCI - Stable CAD 48.3% - ACS 51.7% - UA, biomarker negative 27.7% - NSTEMI 14.5% - STEMI 9.5% Extent of CAD - 1 vessel disease 38.3% - 2 vessel disease 33.0% - 3 vessel disease 28.7% - Left main disease 3.0% LVEF (%) 55.0 ± 14.1 LVEDP (mmHg) 16.7 ± 9.3

  9. ADAPT-DES: PCI procedure (n=8,583) N = 10,106vessels, 12,940 lesions N vessels treated per pt 1.2 ± 0.4 - LM 3.1% - LAD 39.1% - LCX 26.2% - RCA 31.5% - Bypass graft 4.5% N lesions treated per pt 1.8 ± 1.1 N stents per pt 1.7 ± 1.0 Total stent length (mm) 32.4 ± 22.3 DES type used per pt / lesion - Xience V / Promus 64.5% / 58.5% - Taxus (Express, Liberté) 16.5% / 14.4% - Cypher 13.5% / 13.0% - Endeavor 6.2% / 5.2% - Resolute 2.2% / 2.1% - Other 0.2% / 0.2%

  10. ADAPT-DES: Anti-platelet agents (n=8,583) Aspirin Thienopyridine Pre-admission 82.0% 42.9% Loading dose pre-PCI 88.7% 86.4% Discharge 99.2% >99.9% - clopidogrel - 99.7% - ticlopidine - 0.03% - prasugrel - 0.3% Days taken through 1 year 345 ± 120 334 ± 120 Daily through 1 yr w/o any d/c 87.2% 79.6% Taking at 1 year 95.4% 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 PAU 193 ± 53 *Pre-specified cut-off values

  12. ADAPT-DES: Time to First Stent Thrombosis 70 patients (0.84%) developed 74 ST events (ARC def/prob) N=8,583 Definite ST Probable ST Definite or probable 0.84% (70) - Definite 0.63% (53) - Probable 0.20% (17) Frequency 40 (57.1%) of ST events occurred within 30 days Days to definite or probable stent thrombosis

  13. ADAPT-DES: Relationship between VerifyNow platelet response to DAPT and subsequent 1-year def/prob stent thrombosis (n=8,583) VerifyNow test Def/prob ST No def/prob ST P (n=70) (n=8,513) Aspirin ARU 426 ± 58419 ± 55 0.30 - ARU ≥550 7.2% 5.6% 0.54 P2Y12 Base 305 ± 60310 ± 58 0.56 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 PAU194 ± 56193 ± 54 0.92

  14. ADAPT-DES: Stent thrombosis (definite or probable) according to post-PCI PRU 2 PRU >208 (n=3610) HR [95%CI] = 2.54 [1.55, 4.16] P=0.0001 PRU ≤208 (n=4839) 1.3% Stent thrombosis (def/prob) (%) 1 0.5% 0 0 3 6 9 12 Months Number at risk: PRU > 208 3610 3450 3420 3380 3152 PRU ≤ 208 4839 4688 4654 4631 4341

  15. ADAPT-DES: MI and major bleeding according to post-PCI PRU Myocardial infarction HR [95%CI] = 1.47 [1.15, 1.87] P=0.002 Major bleeding HR [95%CI] = 0.83 [0.69, 0.99] P=0.04 PRU >208 (n=3610) PRU >208 (n=3610) PRU ≤208 (n=4839) PRU ≤208 (n=4839) 10 10 6.7% 5.6% 5 5 3.9% 2.7% 0 0 0 6 12 0 6 12 Months Months

  16. ADAPT-DES: Mortality according to post-PCI PRU 5 4 HR [95%CI] = 1.62 [1.18, 2.22] P=0.002 PRU >208 (n=3610) PRU ≤208 (n=4839) Mortality (%) 2.4% 3 2 1.5% 1 0 0 3 6 9 12 Months Number at risk: PRU > 208 3610 3475 3447 3408 3181 PRU ≤ 208 4839 4696 4664 4645 4365

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

  18. ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow PRU >208 for subsequent 1-year adverse events (n=8,583) Event Adj HR [95%CI] P value ST, def/prob 2.49 [1.43, 4.31]0.001 - Definite 3.05 [1.62, 5.75]0.0006 MI1.42 [1.09, 1.86]0.01 Major bleeding 0.73 [0.61, 0.89]0.002 Death, all-cause 1.20 [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 - 161/8583 pts (1.9%) died within 1 year - Event type Event No event HR [95%CI] P value Definite ST No definite ST N 53 8530 Deaths 5 (9.6%) 156 (1.9%) 5.47 [2.25, 13.31] <0.0001 MI w/o ST No MI w/o ST N 224 8359 Deaths 21 (9.7%) 140 (1.7%) 5.78 [3.65, 9.14] <0.0001 Major bleeding No major bleeding N 531 8052 Deaths 45 (8.6%) 116 (1.5%) 5.97 [4.23, 8.42] <0.0001 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 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%) Efficacy treatment effect (from MV HR 2.51) 18 16 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%) 14 12 10 NNT/NNH (# of ↑ Bleeding to Prevent One ST) 8 6 4 If max effect on ST and bleeding: ~4 bleeds caused for each ST prevented 2 0 ↑ 30% (to 7.2%) ↑ 40% (to 7.7%) ↑ 50% (to 8.2%) ↑ 60% (to 8.8%) ↑ 10% (to 6.1%) ↑ 20% (to 6.6%) Safety treatment effect: Major bleeding increase (from MV HR 0.76)

  22. ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow ARU >550 for subsequent 1-year adverse events (n=8,583) Event Adj HR[95%CI] P value ST, def/prob 1.46 [0.58, 3.64]0.42 - Definite 1.60 [0.57, 4.48]0.37 MI0.81 [0.46, 1.42]0.46 Major bleeding 0.65 [0.43, 0.99]0.04 Death, all-cause 1.42 [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. 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 ADAPT-DES: Conclusions and Implications I

  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 • 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

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