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Gregg W. Stone, MD

ADAPT-DES A ssessment of D ual A nti P latelet T herapy with D rug- E luting S tents A Large-Scale, Prospective, Multicenter Registry Examining the Relationship Between Platelet Responsiveness and Stent Thrombosis After DES Implantation. Gregg W. Stone, MD.

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Gregg W. Stone, MD

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  1. ADAPT-DESAssessment of Dual AntiPlatelet Therapy with Drug-Eluting StentsA Large-Scale, Prospective, Multicenter Registry Examining the Relationship Between Platelet Responsiveness and Stent Thrombosis After DES Implantation Gregg W. Stone, MD Columbia University Medical Center NewYork-Presbyterian Hospital Cardiovascular Research Foundation

  2. Consulting Fees/Honoraria Abbott Vascular, Boston Scientific, Medtronic, Volcano, The Medicines Company, Daiichi Sankyo, Eli Lilly Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company

  3. ADAPT-DES: Background I • Although prior studies have shown a correlation between platelet hyporesponsiveness to ADP antagonists and stent thrombosis, all have been small to moderate in size. As such, several important questions remain unanswered: • What proportion of the risk of ST at different times after stent implantation can be attributed to platelet ADP antagonist response, and how useful is this to reclassify the risk of ST? • What is the optimal cutoff for platelet reactivity to predict stent thrombosis? • Is ADP antagonist hyporesponsiveness important in all pts? (e.g. non-diabetics as well as diabetics; stable CAD vs. ACS)

  4. ADAPT-DES: Background II • Prior studies have emphasized the absolute level of platelet activation/aggregation to ADP antagonists • The role of the baseline level of platelet activation and % platelet inhibition to ADP antagonists have largely been unstudied • The impact of 1) platelet hyporesponsiveness to aspirin, and 2) overall platelet aggregation on DAPT on the risk of ST has been incompletely studied

  5. ADAPT-DES Assessment of Dual AntiPlateletTherapy with Drug-Eluting Stents Up to 11,000 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

  6. ADAPT-DES: DAPT Loading and GPI Washout for VerifyNow Assessment Post-PCI • Aspirin loading: Pre-PCI mandatory: ≥300 mg non EC oral aspirin ≥6 hours prior to PCI or 324 mg chewed or ≥250 mg IV aspirin at least 30 minutes prior to PCI. • Clopidogrel loading: Pre-PCI recommended, but in all cases 600 mg ≥6 hours or 300 mg ≥12 hours prior to VerifyNow, or ≥75 mg for ≥5 days prior to VerifyNow. • GP IIb/IIIa inhibitor washout: GP IIb/IIIa inhibitors may be used per standard of care. If used, eptifibatide or tirofiban must have been discontinued for ≥24 hrs prior to VerifyNow, and abciximab must have been discontinued for ≥10 days prior to VerifyNow.

  7. 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

  8. ADAPT-DES: Sites and enrollment 8,575 pts wereenrolled at 11 sites between 1/7/2008 and 9/16/2010; 2,158 pts wereenrolled in the IVUS substudy Site Principal investigator(s) N enrolled Charité Benjamin Franklin Bernhard Witzenbichler 1,426 Columbia University Medical Center Giora Weisz 1,369 Herz-Zentrum Bad Krozingen Franz-Josef Neumann 1,035 Carolinas Medical Center Mike Rinaldi 1,110 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

  9. ADAPT-DES: Baseline features (n=8,575) Age (years) 63.6 ± 10.9 Female 25.9% Non-caucasian 11.4% 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

  10. ADAPT-DES: Baseline features (n=8,575) 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

  11. ADAPT-DES: Anti-platelet agents (n=8,575) Aspirin - Pre-admission 82.0% - Loading dose pre-PCI 88.7% - Discharge 99.2% Thienopyridine - Pre-admission 42.8% - Loading dose pre-PCI 86.4% - Discharge 99.7% • Ticlopidine n=3 (0.04%) • Clopidogrel n=8,541 (99.7%) • Prasugrel n=26 (0.3%)

  12. ADAPT-DES: PCI procedure (n=8,575) N = 10,091vessels, 12,898 lesions N vessels treated per pt 1.2 ± 0.4 - LM 3.7% - LAD 46.0% - LCX 30.9% - RCA 37.0% - bypass graft 3.3% 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 64.4% / 58.3% - 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%

  13. ADAPT-DES: Platelet function test results (n=8,575) Post-PCI to VerifyNow (hrs) 19.0 [16.3, 21.8] 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

  14. ADAPT-DES: Stent Thrombosis Within 30 Days Stent thrombosis (ARC def/prob) occurred in 39 (0.46%) pts 6 Probable Definite 5 Definite or probable 0.46% (39) - Definite 0.32% (27) - Probable 0.14% (12) 4 Frequency 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Days to definite or probable stent thrombosis

  15. ADAPT-DES: Relationship between VerifyNow platelet response to DAPT and subsequent definite or probable stent thrombosis VerifyNow test Def/prob ST No def/prob ST P (n=39) (n=8536) Aspirin ARU 425.6 ± 60.1 419.2 ± 55.3 0.46 - ARU ≥550 7.7% 5.6% 0.57 P2Y12 Base 301.7 ± 63.9 309.6 ± 58.1 0.41 P2Y12 PRU 249.4 ± 88.5 187.6 ± 96.7 0.0001 - PRU >208 74.4% 42.6% 0.0002 - PRU ≥230 64.1% 34.9% 0.0003 P2Y12 % Inhibition 19.8 ± 23.7 40.1 ± 28.2 <0.0001 - Inhibition ≤11% 51.3% 19.9% <0.0001 IIb/IIIa PAU 188.2 ± 54.9 192.7 ± 53.4 0.60 Rates are KM estimates (n).

  16. ADAPT-DES: ROC curve analysis of the relationship between VerifyNow assessed platelet response to DAPT and subsequent stent thrombosis VerifyNow test Def/prob ST Definite ST AUCCut-offAUCCut-off Aspirin ARU 0.563 403 0.626 403 P2Y12 Base 0.536 289 0.604 303 P2Y12 PRU 0.679 206 0.716 230 P2Y12 % Inhibition0.720 25% 0.787 11% IIb/IIIa PAU 0.542 195 0.587 181

  17. ADAPT-DES: Relationship Between VerifyNow P2Y12 PRU and Stent Thrombosis within 30 Days Definite or probable stent thrombosis 2.0 P2Y12 PRU Q1 (≤94) (n=1691) P2Y12 PRU Q2 (95-160) (n=1701) 1.8 P2Y12 PRU Q3 (161-216) (n=1705) 1.6 P2Y12 PRU Q4 (217-275) (n=1666) P2Y12 PRU Q5 (≥276) (n=1691) 1.4 1.2 Definite/Probable ST (%) 1.0 0.79% 0.8 0.78% 0.6 0.36% 0.4 0.24% 0.2 0.18% 0.0 0 5 10 15 20 25 30 Days Number at Risk Quintile 1 1691 1665 1663 1640 Quintile 2 1688 1657 1657 1630 Quintile 3 1705 1677 1676 1656 Quintile 4 1666 1633 1631 1607 Quintile 5 1691 1662 1659 1635

  18. ADAPT-DES: Relationship Between VerifyNow P2Y12 PRU and Stent Thrombosis within 30 Days Definite or probable stent thrombosis 2.0 P2Y12 PRU > 208 (n=3607) 1.8 P2Y12 PRU ≤ 208 (n=4834) HR [95% CI]= 1.6 3.89 [1.90, 7.98] 1.4 P <0.001 1.2 Definite/Probable ST (%) 1.0 0.81% 0.8 0.6 0.4 0.21% 0.2 0.0 0 5 10 15 20 25 30 Days Number at risk >208 PRU 3607 3540 3534 3482 ≤208 PRU 4834 4754 4752 4686

  19. ADAPT-DES: Relationship Between VerifyNow P2Y12 % Inhibition and Stent Thrombosis within 30 Days Definite or probable stent thrombosis P2Y12 % Q1 (≤11) (n=1694) 2.0 P2Y12 % Q2 (12-28) (n=1672) 1.8 P2Y12 % Q3 (29-46) (n=1676) P2Y12 % Q4 (47-68) (n=1744) 1.6 P2Y12 % Q5 (≥69) (n=1626) 1.4 1.19% 1.2 Definite/Probable ST (%) 1.0 0.8 0.6 0.42% 0.4 0.42% 0.17% 0.2 0.12% 0.0 0 5 10 15 20 25 30 Days Number at Risk Quintile 1 1694 1667 1663 1637 Quintile 2 1672 1647 1647 1627 Quintile 3 1676 1641 1639 1613 Quintile 4 1744 1712 1712 1692 Quintile 5 1653 1626 1624 1598

  20. ADAPT-DES: Relationship Between VerifyNow P2Y12 % Inhibition and Stent Thrombosis within 30 Days Definite or probable stent thrombosis 2.0 VerifyNow P2Y12 % Lowest Quintile (≤11) (n=1694) 1.8 VerifyNow P2Y12 % Highest 4 Quintiles (>11) (n=6745) 1.6 1.4 1.19% 1.2 Definite/Probable ST (%) 1.0 HR [95% CI]= 0.8 4.18 [2.23, 7.82] 0.6 P<0.001 0.4 0.29% 0.2 0.0 0 5 10 15 20 25 30 Days Number at risk ≤11% 1694 1667 1663 1637 >11% 6745 6626 6622 6530

  21. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles Definite or probable stent thrombosis VerifyNow test N N Adj. HR* P Attributable Attributable P2Y12 at risk events [95%CI] value events percent P2Y12 PRU >208† 8439 39 3.00 0.005 19.3 49.6% [1.39, 6.49] [8.1, 24.5] [20.7%, 62.9%] P2Y12 PRU ≥230† 8439 39 2.75 0.005 15.9 40.8% [1.35, 5.60] [6.4, 20.5] [16.5%, 52.7%] Inhibition ≤11%† 8437 39 2.78 0.003 12.8 32.8% [1.43, 5.40] [6.0, 16.3] [15.4%, 41.8%] *Adjusted for non-ACS vs NSTEMI vs STEMI, diabetes vs no diabetes, and stent length Model c-statistics = 0.609, 0.591, 0.623 †Pre-specified measures

  22. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles Definite or probable stent thrombosis VerifyNow test N N HR P Attributable Attributable at risk events [95%CI] value events percent P2Y12PRU >208 8439 39 3.00 0.005 19.3 49.6% [1.39, 6.49] [8.1, 24.5] [20.7%, 62.9%] P2Y12PRU ≥230 8439 39 2.75 0.005 15.9 40.8% [1.35, 5.60] [6.4, 20.5] [16.5%, 52.7%] Inhibition ≤11% 8437 39 2.78 0.003 12.8 32.8% [1.43, 5.40] [6.0, 16.3] [15.4%, 41.8%] ARU ≥550 8517 39 1.69 0.39 1.2 3.1% [0.51, 5.61] [-2.9, 2.5] [-7.4%, 6.3%] P2Y12 Base ≥360 8436 39 1.18 0.70 1.4 3.6% [0.50, 2.80] [-9.0, 5.8] [-23.0%, 14.8%] GPIIb/IIIa ≥238 8265 38 0.66 0.37 -3.1 -8.1% [0.27, 1.64] [-16.5, 2.3] [-43.5%, 6.1%]

  23. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles Definite stent thrombosis VerifyNow test N N Adj. HR* P Attributable Attributable P2Y12 at risk events [95%CI] value events percent P2Y12 PRU >208† 8439 27 5.36 0.002 17.9 66.3% [1.89, 15.21] [10.4, 20.6] [38.3%, 76.1%] P2Y12 PRU ≥230† 8439 27 4.46 0.001 14.7 54.6% [1.80, 11.03] [8.5, 17.3] [31.4%, 64.0%] Inhibition ≤11%† 8437 27 4.60 0.0003 13.3 49.3% [2.01, 10.55] [8.5, 15.4] [31.6%, 57.0%] *Adjusted for non-ACS vs NSTEMI vs STEMI, diabetes vs no diabetes, and stent length Model c-statistics = 0.753, 0.721, 0.722 †Pre-specified measures

  24. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles Definite stent thrombosis VerifyNow test N N HR P Attributable Attributable at risk events [95%CI] value events percent P2Y12PRU >208 8439 27 5.36 0.002 17.9 66.3% [1.89, 15.21] [10.4, 20.6] [38.3%, 76.1%] P2Y12PRU ≥230 8439 27 4.46 0.001 14.7 54.6% [1.80, 11.03] [8.5, 17.3] [31.4%, 64.0%] Inhibition ≤11% 8437 27 4.60 0.0003 13.3 49.3% [2.01, 10.55] [8.5, 15.4] [31.6%, 57.0%] ARU ≥550 8517 27 2.87 0.09 2.0 7.2% [0.84, 9.82] [-0.6, 2.7] [-2.1%, 10.0%] P2Y12 Base ≥360 8436 27 0.99 0.99 0.0 -0.1% [0.33, 2.99] [-10.2, 3.3] [-37.7%, 12.3%] GPIIb/IIIa ≥238 8265 27 0.43 0.18 -3.9 -14.5% [0.13, 1.49] [-20.8, 1.0] [-77.0%, 3.7%]

  25. ADAPT-DES: Predictive accuracy of VerifyNow testing – all pts (n=8,575) Definite or probable stent thrombosis by 30 days (n=39) Definite stent thrombosis by 30 days (n=27)

  26. ADAPT-DES: ADP Platelet Responsiveness in Pts with and without Definite/Probable Stent Thrombosis within 30 Days 100 600 P=0.0001 P<0.0001 500 75 400 Median [IQR] 252 [206, 311] VerifyNow P2Y12 PERCENT (%) 50 VerifyNow P2Y12 (PRU) 300 Median [IQR] 188 [112, 260] 200 25 Median [IQR] 38 [16, 62] 100 Median [IQR] 11 [0, 36] 0 0 No Stent Thrombosis Stent Thrombosis No Stent Thrombosis Stent Thrombosis N=8400 N=39 N=8402 N=39

  27. ADAPT-DES: Relationship between ACS and stent thrombosis P=0.002 9/4140 30/4435 10/2377 7/1246 13/812

  28. ADAPT-DES: Relationship between ACS and VerifyNow response to DAPT VerifyNow test ACS No ACS P (n=4435) (n=4140) Aspirin ARU 419.5 ± 54.4 419.0 ± 56.4 0.66 - ARU ≥550 5.4% 5.8% 0.43 P2Y12 Base 304.6 ± 57.6 314.8 ± 58.1 <0.0001 P2Y12 PRU 193.8 ± 96.2 181.7 ± 97.0 <0.0001 - PRU >208 45.6% 39.7% <0.0001 - PRU ≥230 37.6% 32.3% <0.0001 P2Y12 % Inhibition 37.3 ± 28.2 42.9 ± 28.1 <0.0001 - Inhibition ≤11% 23.3% 16.6% <0.0001 IIb/IIIa PAU 187.9 ± 52.3 197.8 ± 54.1 <0.0001

  29. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles ACS: Definite or probable stent thrombosis VerifyNow test N N Adj. HR* P Attributable Attributable P2Y12 at risk events [95%CI] value events percent PRU >208† 4347 30 3.91 0.005 17.9 59.5% [1.51, 10.11] [8.1, 21.6] [27.0%, 72.1%] PRU ≥230† 4347 30 2.95 0.01 13.2 44.1% [1.29, 6.77] [4.5, 17.0] [14.9%, 56.8%] Inhibition ≤11%† 4346 30 3.53 0.001 12.2 40.6% [1.66, 7.52] [6.8, 14.7] [22.6%, 49.1%] *Adjusted for diabetes vs no diabetes and stent length Model c-statistics = 0.541, 0.464, 0.524 †Pre-specified measures

  30. ADAPT-DES: Multivariable (Cox PHR) models of 30-day stent thrombosis stratified by propensity quintiles No ACS: Definite or probable stent thrombosis VerifyNow test N N Adj. HR* P Attributable Attributable P2Y12 at risk events [95%CI] value events percent PRU >208† 4092 9 1.49 0.59 1.6 18.3% [0.35, 6.36] [-9.3, 4.2] [-103.0%, 46.8%] PRU ≥230† 4092 9 2.02 0.35 2.5 28.0% [0.46, 8.74] [-5.8, 4.4] [-64.0%, 49.2%] Inhibition ≤11%† 4091 9 2.22 0.28 1.6 18.3% [0.53, 9.28] [-2.7, 2.7] [-29.6%, 29.7%] *Adjusted for diabetes vs no diabetes and stent length Model c-statistics = 0.704, 0.705, 0.760 †Pre-specified measures

  31. ADAPT-DES: Conclusions and Implications • The absolute and relative levels of platelet inhibition to ADP antagonists as assessed by the VerifyNow P2Y12 test are powerful independent predictors of stent thrombosis within 30 days, with a significant proportion of events independently attributable to clopidogrel hyporesponsiveness. • In contrast, the Base level of platelet P2Y12 response, as well as aspirin and overall platelet responsiveness after DAPT loading as assessed by VerifyNow were not shown to be related to the 30-day rate of stent thrombosis.

  32. ADAPT-DES: Conclusions and Implications • These data suggest that agents which more effectively inhibit ADP-induced platelet activation should reduce 30-day stent thrombosis when applied to large patient populations (underlying the positive findings of TRITON-TIMI 38 and PLATO). • However, the modest sensitivity and specificity of platelet function testing, coupled with the low prevalence of events, implies that testing of platelet ADP antagonist responsiveness is unlikely to provide useful information to guide clinical decision-making in most individual patients for the prevention of stent thrombosis at 30 days.

  33. ADAPT-DES: Conclusions and Implications • The degree of platelet responsiveness to ADP antagonist loading is useful to predict 30-day stent thrombosis in diabetic and non-diabetic patients, as well as those with ACS, but may have less clinical utility in patients with stable CAD. • The very low stent thrombosis rate in pts with stable CAD, coupled with the poor prognostic utility of platelet function testing in this setting suggests that assessing DAPT response in pts without ACS undergoing PCI is unlikely to provide incremental clinical utility, and may explain the negative results of trials such as GRAVITAS and TRIGGER-PCI.

  34. ADAPT-DES: Conclusions and Implications • The relationship between platelet responsiveness testing and the occurrence of late and very late stent thrombosis (in patients who have maintained and discontinued DAPT) will be assessed during the 2-year clinical follow-up phase of the ADAPT-DES study.

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