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Dual Antiplatelet Therapy (DAPT) Duration Dilemma: Recent Trials And Guidelines For

Dual Antiplatelet Therapy (DAPT) Duration Dilemma: Recent Trials And Guidelines For Clinical Practice. Dean J. Kereiakes, MD FACC FSCAI Medical Director, The Christ Hospital Heart & Vascular Center and the Lindner Research Center at The Christ Hospital, Cincinnati, Ohio

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Dual Antiplatelet Therapy (DAPT) Duration Dilemma: Recent Trials And Guidelines For

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  1. Dual Antiplatelet Therapy (DAPT) Duration Dilemma: Recent Trials And Guidelines For Clinical Practice Dean J. Kereiakes, MD FACC FSCAI Medical Director, The Christ Hospital Heart & Vascular Center and the Lindner Research Center at The Christ Hospital, Cincinnati, Ohio Professor of Clinical Medicine, Ohio State University

  2. Dean J. Kereiakes, MD – Disclosure Information Consulting fees: • Modest: Medpace, HCRI, Ablative Solutions, Inc. • Significant: Boston Scientific, Abbott Vascular, REVA Medical Inc.

  3. IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III I I I I I I I I I B B B DURATION 2011 ACC/AHA/SCAI Guideline for PCI The duration of P2Y12 inhibitor therapy should generally be as follows: • In patients receiving a stent (BMS or DES) • during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel75 mg daily,prasugrel10 mg daily or ticagrelor90mg twice daily • b. In patients receiving DES for non-ACS indication, clopidogrel should be given for at least 12 months if patients are not at high risk for bleeding. • c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless patient is at increased risk for bleeding;then it should be given for a minimum of 2 weeks) Circulation 2011;124:e574-651 3

  4. Randomized Trials of DAPT Duration *Plus a 3 month washout period ‡Strategy not DAPT duration **2014-2015

  5. Correlation of Clopidogrel Therapy Discontinuation in REAL-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events: REAL-LATE Trial Patients on current dual antiplatelet therapy without MACCE or major bleeding for at least the first 12 months after DES implantation (Total N~2,700) 1:1 randomization Stratified by (1) centers (2) Initial DES types Aspirin Mono-therapy (N=1,000) Aspirin + clopidogrel Dual-therapy (N=1,000) Regular Clinical assessment after randomization Primary end points: The composite of cardiac death or MI

  6. PRODIGY Study: 6 vs 24m DAPT after DES or BMS, randomized at 30 days 2,013 randomly allocated to recieve one of the four study stent types 499 randomized to and received EES 498 randomized to and received PES 500 randomized to and received ZES 502 randomized to and received BMS (1497 DES) 694 Excluded, 353 Not Meeting Inclusion Criteria 232 Refused to Participate, 109 Operator’s choice 1,970 DES and BMS randomized at 30 days Not blinded 983 6 Months DAPT 987 24 Months DAPT BMS 30d treatment allowed and counted as 6m Primary EP Death,MI,CVA 979 2 year follow-up Ff f 984 2 year follow-up Ff f Valgimigli, M., et al., Circulation, 2012.

  7. EXCELLENT Trial Design Prospective, open label, two-arm, randomized multi-center trial 1372 Patients Matching Enrollment Criteria 19 centers in Korea Everolimus-Eluting StentN=1029 Sirolimus-Eluting StentN=343 Randomization 3:1 DAT 6 moN=515 DAT 12 moN=514 DAT 6 moN=171 DAT 12 moN=172 2x2 factorial design Percutaneous Coronary Intervention clinical endpoint evaluation Clinical TVF* 1mo 3mo 9mo 12mo 2yr 3yr 4yr 5yr Angiographic Primary endpoint: In-segment LL Am Heart J 2009 May;157:811-817.e1. Gwon et al. Circ. 2012;125:505-513 *CD,MI,IDTVR 7

  8. OPTIMIZE STUDY 3,120 minimally selected* patients undergoing PCI with E-ZES in 33 sites in Brazil Randomization ** (1:1) DAPT for 3 months DAPT for 12 months N = 1,560 N= 1,560 Clinical FU at 1, 3, 6, 12 and 18 months and yearly up to 3 yrs Primary endpoint: Net Clinical Benefit†at 12-month FU Feres et al. AHJ 2012:164:810 e3 Feres et al. TCT 2013 LBCT * Exclude ACS with + biomarker; prior DES Rx;SVG target ** Stratified by DM and Institution; not blinded † composite endpoint of all-cause death, MI, CVA and major bleeding

  9. Ischemic Endpoints By DAPT Duration In Randomized Trials EXCELLENT t PRODIGY ttREAL-LATE/ OPTIMIZE tttt ZEST-LATEttt 6 mos(n=957) 6 mos (n=1546) 12 mos (n=1344) 3 mos (n=1563) 12 mos (n=970) 24 mos (n=1500) 24 mos (n=1357) 12 mos (n=1556) Adapted from tGwon et al. ACC 2011 ttValgimigli et al. ESC 2011 ttt Park et al. NEJM 2010;362:1374 ttttFeres et al. TCT 2013 LBCT *Cardiac death / MI / TVR **Death / MI, CVA, Revasc ***Death/MI/Revasc

  10. Major Bleeding (TIMI or GUSTO/REPLACE 2* ) By DAPT Duration In Randomized Trials EXCELLENT t PRODIGY ttREAL-LATE/ OPTIMIZE tttt* ZEST-LATEttt 6 mos 6 mos 12 mos 3 mos 12 mos 24 mos 24 mos 12 mos P=0.42 P=0.04 P=0.35 P=0.66 Adapted from tGwon et al. ACC 2011 ttValgimigli et al. ESC 2011 ttt Park et al. NEJM 2010;362:1374 ttttFeres et al. TCT 2013 LBCT

  11. Type II, III or V BARC Bleeding: PRODIGY CEC adjudicated P=0.00018 7.4 3.5 Hazard ratio: 0.46 (0.1-0.69) Valgimigli et al. Circulation 2012; 125:2015-2026

  12. PRODIGY BARC Bleeding Categories P=0.001 P=0.075 P=0.029 *BARC 2 “Any overt, actionable sign of hemorrhage that…meets at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation…no change in hemoglobin, blood transfusion or hemodynamic sequelae are required” Mehran et al. Circ 2011;123:2736-2747

  13. OPTIMIZE : NACCE at 1 Year(All-Cause Death, MI, Stroke, Major Bleeding) 15 3M DAPT 12M DAPT Log-Rank P = 0.838 10 Cumulative Incidence of NACCE (%) 6.0 5.8 5 0 0 3 6 9 12 Time After Initial Procedure (Months) Feres et al. TCT 2013 LBCT

  14. Zone of non-inferiority Pre-specified margin = 2.7% Primary Endpoint: NACCE at 1 Year(All-Cause Death, MI, Stroke, Major Bleeding) 3M DAPT (N = 1563) 6.1% 12M DAPT (N = 1556) 5.9% Difference : 0.2% Upper 1-sided 95% CI : 2.0% Non-inferiority P value = 0.002 Non-inferior -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 % Upper one-sided 95% CI Primary Non-Inferiority Endpoint Met

  15. OPTIMIZE :Other Clinical Events at 1 Year* Bleeding / Safety Ischemic / Efficacy 12% 12% 9.4% Events (%) 14% 12.5% *All P=NS Feres et al. TCT 2013 LBCT

  16. OPTIMIZE: Stent Thrombosis* vs. Major Bleeding ARC Def./Prob. Stent Thrombosis Major Bleeding 12M DAPT 3M DAPT 10 3M DAPT 12M DAPT P = 0.64 HR 0.81 (0.34-1.96) P = 0.18 HR 3.97 (0.44-35.49) Cumulative Incidence (%) 5 10 0.26 2x ~4x 0.07 P = 0.79 HR 0.87 (0.32-2.40) P = 0.31 HR 0.50 (0.12-1.99) 0 0.7 0 3 6 9 12 Cumulative Incidence (%) 5 Time After Initial Procedure (months) 0.6 0.4 0.2 0 0 3 6 9 12 Time After Initial Procedure (months) *0.2% absolute difference Feres et al. TCT 2013 LBCT

  17. RESET E-ZES with 3-month DAPT Standard Therapy Other DES with 12-month DAPT Primary Endpoint: CV death, MI, ST, ID-TVR, Bleed (TIMI major & minor) Kim et al. JACC 2012;60:1340-1348

  18. RESET: Clinical Events Through 1 Year Adapted from Kim et al. JACC 2012 Sep 5 (e-Pub ahead of print) % Patients 40 41 8 11 2 3 2 6 *Primary Endpoint: (Assumed 10% with N.I. margin 4% for absolute difference in risk) **SORT OUT III / ENDEAVOR IV / PROTECT / KAMIR

  19. ISAR-SAFEStudy Flowchart Drug- Eluting Stenting • 8thto -5th Continuous Clopidogrel therapy for 5 to 8 months Randomization 0 Primary Analysis 2015 Clopidogrel 75 mg/d for 6 months Placebo for 6 months 1st FU: 1 month after randomization 2nd FU: 6 months after randomization (at least one day after study drug cessation) 3rd FU: 9 months after randomization (at least 3 months after study drug cessation) Follow Up 1st 6th 9th PEP = death,MI,stentthrombosis,stroke,TIMI major bleed

  20. DAPT: Study Design • Eligible for Enrollment after PCI • Any PCI with DES or BMS • >18 years of age • No contradictions to dual antiplatelet therapy • Able and willing to provide written informed consent • Not Eligible for Randomization at 12 m • Death • MI or repeat PCI at > 6 weeks • CABG • Stroke • Major Bleed Primary Analysis 2014 Eligible for Randomization at 12 m Stratified by DES v BMS, drug type, and complexity (ACS or lesion-based) Total 33 month follow-up Primary analysisDES treated subjects, 12-30m Secondary analysispropensity matched BMS to DES subjects 0-30m 2 co-primary endpoints: stent thrombosis and MACCE (death, myocardial infarction or stroke) Powered safety endpoint: major bleeding (GUSTO) 12 m DAPT Arm Aspirin + blinded placebo 30 m DAPT Arm Aspirin + blinded thienopyridine 18 mos Study treatment period 12-30 m Study observation period 30-33m Total 33 month follow-up Mauri, Kereiakes et al AHJ 2010;160:1038-1041 20

  21. Thienopyridine Type: DAPT Study All Randomized Subjects; N = 11,649

  22. Stent Type: DAPT Study All Randomized Subjects N = 11,649 *Some patients received more than one DES type

  23. Complexity Amongst Randomized Subjects: DAPT *clinical =ACS, renal insufficiency LVEF <30% **anatomic=UPLM; >3 vessels; >2 lesions/vessel; LL ≥30mm; bifurcation; DES ISR; SVG; thrombus; VBT

  24. EXCELLENT Trial: Target Vessel Failure 6-mo DAT 12-mo DAT P=0.507 HR = 1.17 (95% CI 0.73-1.89) 4.7% Cumulative incidence rate (%) 4.4% Months after initial procedure Am Heart J 2009 May;157:811-817.e1.

  25. TVF According To Diabetes And DAPT Duration: EXCELLENT Non-diabetics Diabetics 6-mo DAT 12-mo DAT p=0.022 HR = 0.42 (95% CI 0.20-0.88) p=0.005 HR = 3.15 (95% CI 1.41-7.01) 8.8% 5.2% 2.9% 2.2% Gwon et al,ACC 2011 LBCT

  26. 6 vs. 12 months DAPT After DES: EXCELLENT 0.125 0.25 0.5 1 2 4 8 Favors 6 mo DAPT Favors 12 mo DAPT Gwon et al. Circulation 2012;125:505-13

  27. Clopidogrel Duration after PCI in Diabetics*: Death and Non-Fatal Myocardial Infarction < 6 months 6-9 months > 9 months Composite of death & MI Death p <0.001 p < 0.001 Cumulative Incidence (%) 0 90 180 270 360 450 540 630 0 90 180 270 360 450 540 630 Time (days) Time (days) # at risk < 6 mos 261 234 222 174 261 239 231 186 6- 9 mos 117 113 106 83 117 116 111 88 > 9 mos 371 358 356 286 371 362 361 293 *749 consecutive diabetic patients/Kaiser L.A. Brar et al. JACC 2008;51:2220

  28. Stent Type and Clopidogrel Duration After PCI in Diabetics:Death and Non-Fatal Myocardial Infarction w/ clopidogrel w/ clopidogrel w/o clopidogrel w/o clopidogrel DES landmark-left censored P=0.07 BMS landmark-left censored P=0.01 Cumulative Incidence (%) 0 90 180 270 360 450 540 630 0 90 180 270 360 450 540 630 Time (days) Time (days) # at risk # at risk BMS with clop 147 145 139 DES with clop 323 312 220 BMS w/o clop 74 67 64 DES w/o clop 127 125 83 Brar et al. JACC 2008;51:2220

  29. Multivariate Analysis Predictors of BARC Bleeding Events on DAPT* *1,542 patients (clopidogrel 1155; prasugrel 387) Adapted from Cuissett et al. JACC Card Int 2013;6:854-863

  30. Stent Thrombosis Stratified by Clinical Syndrome and Stent Type BMS: SA vs. ACS logrank p=0.01 DES: SA vs. ACS logrank p=0.0007 SA: BMS vs. DES logrank p=0.2 ACS: BMS vs. DES logrank p=0.06 Definite Stent Thrombosis (%) ACS vs SA logrank p<0.0001 DES, ACS BMS, ACS DES, SA BMS, SA ACS SA 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Time (months) Time (months) N=5,816 Kukreja et al. JACC Intv 2009;2:534

  31. Analysis of DAPT Duration Beyond 1 Year Following PCI for AMI*: COREA-AMI Registry *2293 consecutive patients MACCE + major bleed free at 1 year post-MI Koh et al. JACC 2013;61:A40 (abstract E161; presentation 1255M-178)

  32. Mortality Following PCI for ACS by Clopidogrel Use: Veterans Administration 2003-2004* Cumulative mortality rate Off clopidogrel On clopidogrel Follow-up time, days *n=1455 (66% BMS, 34% DES) HR BMS 2.65; DES 2.0 Ho et al. Am Heart J 2007;154:846

  33. Target And Non-target Lesion MACE* After Stenting In 1,057 Patients (Sirius Trial) Target Vessel Non-target Vessel % % 74.3% 74.2% 72.3% 57.1% Freedom from Cardiac Death, M I and Revasc SES BMS Log-Rank p<0.001 SES BMS Log-Rank p=0.096 0 360 720 1080 1440 1880 0 360 720 1080 1440 1880 Time after Initial Procedure (days) Time after Initial Procedure (days) *CV Death, M I, Revasc Chacko, Cutlip et al. JACC Intv 2009;2:498

  34. CHARISMA: Dual Therapy Vs. ASA MonotherapyIn Symptomatic* Patients CD / MI / Stroke *Prior MI, CVA or symptomatic PAD Bhatt et al. JACC 2007;49:1982-1988

  35. Death / MI Events Following Clopidogrel Discontinuation After SVG PCI Failure rate Failure rate Sachdeva et al. JACC 2012; Oct 25 [Epub ahead of print]

  36. Stenting for ISR: PRODIGY Substudy short DAPT regimen (n=114) long DAPT regimen (n=110) 0.85 0.90 0.95 1.00 Cumulative incidence of D / MI / CVA (%) P=0.034 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (days) Campo et al. JACC 2013 prepub

  37. Definite Stent Thrombosis Through 3 Years In 18,334 Patients (28,739 Lesions) By Stent Type 3-Year Incidence of Stent Thrombosis 1-Year Landmark Analysis BMS 1G-DES 2G-DES BMS 1G-DES 2G-DES Stent Thrombosis (%) Stent thrombosis (%) Tada, Kastratiet al. JACC INTV 2013; 6:1267-74

  38. Clinical Outcomes By Statistical Model, Duration of DAPT And Follow-Up: Meta Analysis of 13 RCCT Involving 17,097 Patients .1 1 10 0.4 4 0.4 4 EES Non-EES EES Non-EES EES Non-EES Favors Baber et al. JACC 2011;58:569-77

  39. Long-term Risk Of Def/Prob Stent Thrombosis: Network Meta-Analysis Of 76 RCCT* 0.10 1.0 10.0 Bangalore et al. Circ 2012;125:2873-91 * >86% probability that EES has lowest rate of “any” stent thrombosis

  40. Network Meta-Analysis of 49 Trials Involving 50,844 Patients Favors stent 1 Favors stent 2 Palmerini et al. Lancet 2012;379:1393-1402

  41. DAPT Duration: Conclusions • “One size shoe” approach for DAPT duration is unlikely to fit all patients • ACS • Diabetes • CABG-SVG / ISR • We treat symptomatic patients and non-target lesions with objective to reduce events (D/MI/CVA) which may not be stent (target lesion) related • Stent platforms differ with respect to risk for early , late and/or very late stent thrombosis events (“All DES not created equal”) • Conclusions regarding “optimal” DAPT duration should be based on adequately powered RCCT

  42. Stent Thrombosis and DAPT Interruption Through 2 Years: Pooled Analysis of SPIRIT II-V; WOMEN; XV USA/India Analysis population 11,219 / 13,259 (84.6%) ptscomplete DAPT data to 2 years 85 events in 83 pts (0.74%) through 2 years 45 ST events occurred in 44 pts with no DAPT interruption from day 1 through 2 yrs 40 ST events occurred in 39 pts with some DAPT interruption from day 1 though 2 yrs 45 events occurred “On” DAPT* 23 events occurred “On” DAPT 17 events occurred “Off” DAPT ►68/85 ST events (80.0%) occurred “On” DAPT *One patient did not receive loading lose and was off DAPT at ST event (day 0) but started day 1 and never interrupted through 730 days. Stone et al. JACC 2011;58(Suppl B):78

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