ACS/AMI: What is the Standard of Care for Antiplatelet Therapy in the USA? George D. Dangas, MD, PhD Professor of Medicine (Cardiovascular Disease) The Icahn School of Medicine at Mount Sinai, New York, NY Cardiovascular Research Technologies - CRT 2013 February 24, 2013 Washington, DC

George Dangas, MD Consulting: Astra Zeneca Grant Support: SMS/Sanofi, The Medicines Co. Advisory Board: Abbott Vascular, Ortho McNeil, Regado Biosciences

Inhibitors of Platelet Activation Clopidogrel/ticlopidine ADP Dipyridamole P2Y12 PGI2 ADP PDE Gi P2X1 ADP Gs ATP Ca++ AC cAMP PIP2 Ca++ Collagen Thrombin TXA2 ?? GP IIb/IIIa Receptor Gq IP3 COX Ca++ TP/ This is the Sample Column Charts slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Charts page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph. TXA2 Aspirin Schafer AI. Am J Med. 1996;101:199–209 & Schrör K. Vasc Med 1998;3:247-51.

Efficacy of New DAPT Rx: ACS+PCI 3 Active Controlled Trials (vs Standard Clop) P<0.001 P=0.003 P=0.04 P=0.002 P<0.001 P=0.01 Def/Prob NEJM 2007 Def/Prob NEJM 2009 N=17,232 1-month FU D/MI/CVA ESC 2009 N=13,608 15-month FU D/MI/CVA NEJM 2007 N=11,289 1-year FU D/MI/CVA TCT 2009 Def/Prob ESC 2009

Step-wise reloading increased % Inhibition and % responders After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target. Mean ±SD Control VASP-guided p VASP after first LD, % 68 ±11 69 ±10 0.4 VASP after adjustment, %  38 ±14* *<0.001 Log rank p =0.007 MACE: CV death, MI, revascularization Bonello et al. J Am Coll Cardiol 2008

Definite Stent Thrombosis in 4 Groups (Angiographically Proven) C Standard, A Low 0.012 C Standard, A High C Double, A Low 0.008 Cumulative Hazard C Double, A High 0.004 Standard Clop Double Clop HR P Intn High ASA 1.2 0.6 0.49 0.003 Low ASA 0.8 0.058 0.35 0.0 3 6 9 12 15 18 21 24 27 30 Days

PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) P<0.0001 for each P<0.0001 N=201 Prasugrel 60 mg Clopidogrel 600 mg Clopidogrel 150 mg Prasugrel 10 mg Hours 14 Days Wiviott et al Circ 2007 8 8

TIMI-38 STENT ANALYSIS Definite/Probable ST: BMS Only (N=6461) EARLY ST LATE ST HR 0.45 [0.28-0.73] P=0.0009 HR 0.68 [0.35-1.31] P=0.24 CLOPIDOGREL 1.66% PRASUGREL % of Subjects 55% 0.78% 32% 0.75% 0.53% DAYS Wiviott et al, SCAI-ACCi2 2008 9

Inhibition of platelet aggregation after initial doses AZD6140 Ticagrelor Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS Patients (DISPERSE-2) Inhibition of platelet aggregation after initial doses *P<0.05 Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry). Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6

Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 6.9 7 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 Ticagrelor 5 4 4 4.0 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 60 120 180 240 300 360 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364

Optimal Duration of Anti-platelet Therapy Post DES Still Unclear ESC PCI Updated Guidelines 2010 Cypher Stent® Launch 2003 CURE (PCI-CURE) 20011 (6-12 months post PCI) 1 year BMS Era DES Era FDA, ACC/AHA/SCAI Recommendations 2011 (1 year post PCI in pts at low risk of bleeding AHA/ACC Guidelines 2001 TAXUS® Express2TM Stent Launch 2004 AHA/ACC/SCAI Updated Guidelines 2005 (9-12 months post PCI) (TAXUS stent 6 months post PCI) (Cypher stent 3 months post PCI)

Safety of New DAPT Regimens 3 Active Controlled Trials (vs Standard Clop) P<0.001 P=0.32 Non-CABG related bleeding P=0.001 P=0.002 P=0.03 N=25,087 1-month FU CURRENT major bleed NEJM 2009 N=13,608 15-month FU TIMI major+minor bleed NEJM 2007 N=18,864 12-month FU PLATO Major bleed NEJM 2009 TIMI major+minor bleed NEJM 2007 PLATO Major bleed NEJM 2009

Challenging the guidelines One-year dual antiplatelet therapy is: Too long! Not long enough!

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 OPTIMIZE 3,120 non-STEMI 3 vs. 12 months Endeavor ZES 1-yr D/MI/Stroke/TIMI major bleed ARC ST SEASIDE 900 non-ACS 6 months 1-yr D/MI/Stroke CYP2C19

Dual Antiplatelet Therapy (DAPT) Study 12 mo 18 mo DES n=15,245 BMS n=5400 All patients on aspirin + open-label thienopyridine therapy for 12 months 50% of patients continue on dual antiplatelet therapy (clopidogrel or prasugrel) 50% of patients receive aspirin + placebo 1:1 Randomization at month 12 Total 33-month patient evaluation including additional 3-month follow-up PI: Laura Mauri, Co-PI: Dean Kereiakes 16

Should we consider shorter Duration of DAPT with new generation DES?

Impact of the Everolimus-Eluting Drug Eluting Stent on Stent Thrombosis: A Meta-Analysis of 13 Randomized Trials involving 17,097 Patients Usman Baber MD MS, et al   aMount Sinai Medical Center, New York, NY bKaiser Permanente, Pasadena, CA cCardiovascular Research Foundation, New York, NY dSeoul National University Hospital, Seoul, Korea eAsan Medical Center, Seoul, Korea fDeutsches Herzzentrum, Technische Universität, Munich, Germany 18

Stent Thrombosis

PRODIGY Study Flow Chart Intent-to-stent 1:1:1:1 Balancing Randomization Xience V® Taxus® Endeavor® BMS High Late Loss Inhibition Moderate Late Loss Inhibition Mild Late Loss Inhibition No late Loss Inhibition 30-Days 2° Gen 1° Gen 2° Gen 1:1 1° Endpoint Randomization Short DAPT Prologned DAPT Aspirin Clopidogrel Aspirin Clopidogrel 6 mos 6 mos 6 mos 6 Mos* 12 mos 12 mos 12 mos 18 mos 18 mos 18 mos 24 mos 24 mos Valgimigli et al, 2011 24 Mos *: <6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI

Overall Death, MI or CVA Primary Endpoint CEC adjudicated 24 mo DAPT 10.1 10.0 P=0.91 % Hazard Ratio: 0.98 (0.74-1.29) No. at Risk 24-Month Clopidogrel 987 925 884 6-Month Clopidogrel 983 919 881

Type II, III or V BARC bleeding Key Safety Endpoint Type II, III or V BARC bleeding CEC adjudicated 24 mo DAPT 6 mo DAPT P=0.00018 7.4 % 3.5 Hazard Ratio: 0.46 (0.1-0.69) No. at Risk 24-Month Clopidogrel 987 925 884 6-Month Clopidogrel 983 919 881

Most recent data: RESET Trial 2,148 patients enrolled and randomized E-ZES + 3-month DAPT Standard Therapy: Other DES with 12-month DAPT E-ZES + 3-month DAPT (n=1059) Standard therapy (n=1058) Diabetes mellitus subset (N=292) Acute coronary syndrome subset (N=601) Short-length DES Subset (N=681) Long-length DES Subset (N=543) E-ZES (n=301) R-ZES (n=300) E-ZES (n=341) SES (n=340) E-ZES (n=271) E-ZES (n=146) R-ZES (n=146)

(Cardiovascular Death, MI, ST, TVR, or bleeding at 1 year) Primary Endpoint (Cardiovascular Death, MI, ST, TVR, or bleeding at 1 year) 8 Standard therapy E-ZES + 3-month DAPT 6 Difference = 0.0% 95% CI, -2.5 to 2.5; p = 0.84 4.7% Cumulative event rate (%) 4 4.7% p-value for non-inferiority < 0.01 2 6 12 Months

In ACS/AMI, the DAPT Stardard of Care in the US 2nd Generation DES (ZES, EES) With or without potent antiplatelet agents (prasugrel, ticagrelor) Short term DAPT Favors the stronger antiplatelet agents/regimens Is Closely related to type of stent & adherence