DAPT in Contemporary PCI Risk, Benefit and Much to Still Learn 38 RCTs 18,000 pts DAPT in Contemporary PCI Risk, Benefit and Much to Still Learn David E. Kandzari, MD Director, Interventional Cardiology Research Scripps Clinic La Jolla, California kandzari.david@scrippshealth.org

David E. Kandzari, MD DISCLOSURES Consulting Fees Abbott Vascular, Cordis, a Johnson & Johnson company, Edwards Lifesciences LLC , Medtronic CardioVascular, Inc., Micell Technologies Grants/Contracted Research Abbott Vascular, Cordis, a Johnson & Johnson company, Medtronic CardioVascular, Inc. I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation. I intend to reference drug eluting stents for off-label indications.

Antiplatelet Therapy and DES Revascularization Timeline Perspective Stent thrombosis, irrespective of timing or stent type, is associated with considerable morbidity and mortality January 2006, December 2007 ACC/AHA/SCAI guidelines consensus-opinion based recommendations of 12 months DAPT following DES for pts without apparent contraindications December 2006 FDA Panel concern over annualized ST rates motivate FDA to mandate DES labeling incorporate 12 month DAPT recommendation December 2007 Inter-society Scientific Advisory reiterates 12 month guidelines 1. The principal driver for extended term DAPT is to reduce the risk of ST 2. We need evidence to support long-term DAPT in reducing the ST risk 3. This evidence does not exist, and in fact, multiple studies now report data to the contrary, that long-term DAPT does not reduce the occurrence of late and very late ST and may also in selected populations yield conflicting results regarding D/MI benefit

‘Optimal’ DAPT Duration and DES Revascularization A Less than ‘Optimal’ Evidence Basis RCT and RCT substudies (CREDO, PCI-CURE) Pharma trials evaluating pretreatment and dosing strategies Follow-up limited to ≤12 months Majority of treatment effect within initial 30-90 days Observational studies consistently demonstrate ‘premature’ thienopyridine discontinuation with increased risk of ST Single-center, observational surveys demonstrating reductions in death and MI, but not ST Duke Cardiovascular Database, Eisenstein et al. JAMA 2007 Kaiser Permanente, Brar et al. J Am Coll Cardiol 2008 No estimate of bleeding risk CHARISMA Severe bleeding: 1.7% over ~2 year follow-up ‘Clopidogrel survivor’ theory reflects selection bias Consensus opinion: Emotive, intuitive perception that extended DAPT could reduce ST events No prospective, (randomized) data associating long-term DAPT with reductions in ST There is a time for the art of medicine in the absence of well-founded science, and thus an emotive, seemingly intuitive perception that extended DAPT could reduce ST events

58 cases of ST through 540 Days (1.9%) Rate of ST in Patients On DualAnti-platelet Therapy and in Patients Who Discontinued Thienopyridine Therapy 0.16 0.14 Patients who discontinued thienopyridine therapy 0.12 0.10 58 cases of ST through 540 Days (1.9%) 0.08 Event Rates 0.06 0.04 Patients who on thienopyridine therapy 0.02 0.00 60 120 180 240 300 360 420 480 540 No. of Patients Discontinued Thienopyridine 258 422 560 1,128 1,180 1,680 2,044 2,138 2,251 On Thienopyridine 2,750 2,576 2,411 1,829 1,771 1,245 865 756 634 * Aalen-Nelson estimate of cumulative hazard function Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

Relationship Between Thienopyridine Discontinuation and ST VLST 360 – 540 days (0.2%) LST 180 – 360 days (0.3%) LST 30 – 180 days (0.4%) 58 Patients with Stent Thrombosis SAT (0.9%) 60 120 180 240 300 360 420 480 540 Days post-PCI Median time from clopidogrel discontinuation and ST: - ST within first 6 months: 13.5 days (IQR range, 5.2 to 25.7) - ST after the first 6 months: 90 days (IQR, 30 to 365 days) Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

Temporal Trends in DAPT Compliance and Incidence of ST while On or Off Thienopyridine Therapy Is Thienopyridine Discontinuation a Cause or Epiphenomenon? Thienopyridine Adherence Over Time A common statistical error is to associate 2 parallel occurring events with each other or as causative, but the observation that thienopyridine discontinuation beyond a certain time point does not result in an uptick in events suggests against a strong association or that DAPT is somehow suppressive of late ST events. In fact, in this analysis, beyond 6 months, ST is if anything more common among patients with continued thienopyridine therapy Airoldi F, Colombo A, et al., Circulation 2007;116:745-54

Japan Cypher 2-Year Relationship Between ST Events and APT, N=10,778 Kimura, T. et al. Circulation 2009;119:987-995

Japan Cypher 6-Month Landmark Analysis Based on Thienopyridine Use OFF Thienopyridine, N=2,628 P value Death 3.4 0.90 Myocardial Infarction 0.6 0.8 0.42 Death/ Myocardial Infarction 4.1 0.99 Death, MI or Stroke 4.0 0.79 Kimura, T. et al. Circulation 2009;119:987-995

Korean Stent Thrombosis Registry Multicenter Observational Cohort Study 7,221 PCI patients (48.3% DES) DES associated with significantly higher risk of ST beyond 1 year Adjusted risks of D, D/MI and TLR significantly lower with DES Despite increased risk of VLST with DES, thienopyridine continuation beyond 1 year not associated with reduced risk of D, D/MI or ST Park DW, et al. J Am Coll Cardiol Interv 2008

Korean Stent Thrombosis Registry Multicenter Observational Cohort Study Aalen-Nelson Estimate Curves of Cumulative Hazard Function for Definite ST Park DW, et al. J Am Coll Cardiol Interv 2008

ISAR Relationship Between DAPT and ST over 4 year Follow-up, N=6,816 2 3 4 Cumulative incidence of stent thrombosis (%) 5 10 15 Years after procedure 5,181 1,074 398 116 6,816 1,277 3,934 2,539 1,373 No. of patients Discont. clopidogrel On clopidogrel Patients who discontinued clopidogrel therapy Patients on clopidogrel therapy 6 months Schulz S, Kastrati A, et al. Eur Heart J 2009

ISAR Relationship Between DAPT and ST over 4 year Follow-up, N=6,816 Schulz S, Kastrati A, et al. Eur Heart J 2009

van Werkum, J. W. et al. J Am Coll Cardiol 2009;53:1399-1409 Dutch Stent Thrombosis Registry Independent Risk Factors for ST, N=21,009 van Werkum, J. W. et al. J Am Coll Cardiol 2009;53:1399-1409

ENDEAVOR IV Very Late Stent Thrombosis to 3-Years ARC Definite/Probable ST 12–36 Months (VLST) 2 Endeavor DES Taxus DES 1.5% Definite/Probable Thrombosis (%) Cumulative Incidence of 1 93% RRR p = 0.004 (1–3 years) 0.1% 360 450 540 630 720 810 900 990 1080 Time After Initial Procedure (days) Endeavor 732 719 716 710 699 688 684 680 Taxus 734 721 718 714 701 690 681 674

ENDEAVOR IV Timing of ARC Def/Prob VLST 413 495 619 645 689 697 835 838 878 949 1024 Taxus VLST ( n=11) 5/11 On ASA or Plavix 4/11 on ASA 2/11 No DAPT 9/11 Result in MI Taxus 369 Endeavor VLST ( n=1) 1/1 No DAPT 1/1 Result in MI Endeavor 360 480 600 720 840 960 1080 Days

SYNTAX Trial Graft Occlusion and Stent Thrombosis Medication Status at Time of ST/GO Per Patient Patients Patients Aspirin DAPT Single Thienopyridine Neither/ Unknown Aspirin DAPT Single Thienopyridine Neither/ Unknown CABG Arm (n=27) PCI Arm (n=28) Presented by Dr. Ted Feldman, EuroPCR, 2009 See Glossary for prescribing information outside the US

What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration? DAPT durations, inclusion of BMS, landmarking and ‘event-free’ patients Inclusion Group, N DAPT Duration DES Type 1° Endpoint 2° Endpoint(s) DAPT 20,645 12-month event free 12 vs 30 months All DES, BMS D/MI/Stroke at 33 mos Def/prob ST at 33 mos GUSTO Bleeding ISAR-SAFE 6,000 6-month event free 6 vs 12 months All DES D/MI/Stroke/TIMI major bleed at 15 mos Individual component endpoints REAL-LATE 2,000 12-month event free 12 vs 24 months 2-yr Cardiac D/MI ARC ST, Bleeding ZEST-LATE SES, PES, ZES 2-yr D/MI DATE 823 non-ACS 3 months ZES 1y cardiac D/MI/ST Individual component endpoints, TLR OPTIMIZE 3,120 non-STEMI 3 vs. 12 months 1-yr D/MI/Stroke/TIMI major bleed ARC ST SEASIDE 900 non-ACS 6 months 1-yr D/MI/Stroke CYP2C19 Kandzari et al. JACC Int 2009; www.clinicaltrials.gov

Unplanned DAPT Interruption Following ZES Revascularization SENS Trial Outcomes within 30 days of Non-cardiac Surgery and DAPT Discontinuation Characteristics N=3,099 (%) Patients with brief interruption of DAP 194 (6.2) Age (yrs)/Male 63.5/54.9 Comorbid illness Diabetes illness 88 (46.4) Hypertension 123 (64/1) Hyperlipidemia 56 (29.1) Smoking 49 (25.6) EF (%) 60.1 ± 11.1 ACS at stenting 122 (63.5) Type of procedure(s) Orthopedic/Head and neck 34 (18) Abdominal 27 (14) Gynecological/Uro 15 (8) Vascular 7 (3) Dental 44 (23) Ophthalmic 13 (7) Endoscopy, GI/Broncho 54 (28), 43/11, (23/5) Kim JW, et al. ACC 2009

Aortic-femoral bypass Unplanned DAPT Interruption Following ZES Revascularization SENS Trial Outcomes within 30 days of Non-cardiac Surgery and DAPT Discontinuation Early Surgery Late Surgery Op Name Tracheostomy Wound debridement Aortic-femoral bypass HNR Days from stenting to events 28 86 13 334 DAP withdrawal days 7 14 5 3 MACE Death MI (LCX) MI (LCX Os) Procedural Characteristics Stented vessel LAD RCA LAD, LCX Main to LAD Stent diameter (mm) 2.75 4.0, 3.5 2.75, 2.5 3.5, 3.3 Stent number 1 2 Stent length (mm) 24 mm 48 mm 35 mm Post-events management POBA Medication Kim JW, et al. ACC 2009 Kim JW, et al. ACC 2009

Antiplatelet Therapy and DES 2010 What We Still Don’t Know What is the ‘optimal’ duration of DAPT? What is ‘premature’ discontinuation? Is the ‘optimal’ duration same for all DES? What are the consequences of brief DAPT interruption? Is there a rebound phenomenon with thienopyridine discontinuation? Will there be differences between different APT agents in real world practice? Is there a role for platelet and/or genomic testing to individualize therapy?

TRITON TIMI 38 Stent Thrombosis (ARC Definite + Probable) Any Stent at Index PCI N= 12,844 2.4 (142) Clopidogrel 2 Endpoint (%) >30 days: 0.49 vs 0.82, P=0.03 DM: 3.6 vs 2.0, P=0.007 No DM: 0.9 vs. 2.0, P<0.001 1.1 (68) 1 Among the 12,844 patients receiving a stent at the index PCI, PRASUGREL REDUCED the rate of stent thrombosis from 2.4% in the clopidogrel group to 1.1% . The prevention of 74 stent thromboses with prasugrel represented a highly significant 52% reduction in the HR. Although not shown on the slide, there was a significant reduction of about 50% in stent thrombosis in both BMS and DES-treated patients. Prasugrel HR 0.48 P <0.0001 NNT= 77 30 60 90 180 270 360 450 Wiviott et al. NEJM 2007 Days 22

Influence of Trial Conduct and Definitions What is Meaningful to a Doctor May Differ to a Trial Committee Definite Stent Thrombosis Prasugrel Clopidogrel RR P Value CEC adjudicated 52 122 0.42 <0.001 Site reported 139 204 0.68 2.7x  1.7x  http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_MedR_P23.pdf

DAPT in Contemporary PCI Summary Given that ST is uniformly associated with MI and 30% mortality, any measure that may reduce events is clinically meaningful but must be proven and without excessive risk! Role of DAPT in reducing early ST is firmly established Issue is not that thienopyridine should be discontinued for all pts at a predetermined timepoint but whether it is safe to discontinue (ST risk) and if there is acceptable benefit to maintain (D, MI, stroke) While extended DAPT may decrease late death or MI proportionate to risk, the benefit is most likely associated with reduction of events independent of stent territory Available evidence predominantly demonstrates that in all-comer, broad PCI populations, extended DAPT (eg, >6-12 months) likely does not reduce ST risk

DAPT in Contemporary PCI Summary Whether patient variable responsiveness may be overcome by increased clopidogrel dose vs prasugrel is issue of ongoing study Role of APT responsiveness point of care assays Evolution of genomic assays Studies are underway to identify the ‘optimal’ DAPT duration, but must consider: Variability in DAPT durations studied Potential differences in DES, thienopyridine therapy, individual patients Bleeding risk Intention to treat vs as treated, “clear” patients vs. those with events