The Landscape of Oral Antiplatelet Agents 2009 George D. Dangas, MD, PhD, FSCAI, FACC Associate Professor of Medicine Columbia University Medical Center

Disclosures Advisory Board: Accumetrics, Astra- Zeneca Advisory Board: Accumetrics, Astra- Zeneca Consultant: Lilly, Daichi-Sankyo Consultant: Lilly, Daichi-Sankyo Speaker honoraria: Sanofi-Aventis, BMS Speaker honoraria: Sanofi-Aventis, BMS

EPISTENT: IV vs po Anti-Platelet Rx IV placebo/abciximab & po ticlopidine preRx/no-preRx Steinhubl SR, Circulation 1998;98:I-573 % MACE (Death, MI, Urgent Revasc) Placebo/ No PreRx N=343 Abciximab/ N=328Abciximab/ PreRx PreRxN=466Placebo/ PreRx N= %  P= %  P=0.028 Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC

Proportion Event-Free Benefit of Clopidogrel Therapy at Early and Late Time Intervals Months Weeks Proportion Event-Free RRR 21% P= % CI 0.67– 0.92 P=0.003 Clopidogrel + ASA Placebo + ASA MI, stroke, CV Death: 0–30 days Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107: MI, stroke, CV Death: 31 d - 1 y RRR 18% P= % CI 0.70– 0.95 P=0.009 Clopidogrel + ASA Placebo + ASA CURE ACS pts

CLARITY trial of APT in STEMI: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P= P= Odds Ratio 0.64 (95% CI ) Clopidogrelbetter Placebobetter n=1752n= % Odds Reduction 36% Odds Reduction

Safety of Long-Term Clopidogrel 3 Placebo Controlled Trials P=0.001 NEJM 2006;354: N=15, year FU GUSTO major + moderate bleed N=12,563 1 year FU CURE major bleed NEJM 2001;345; N=2,116 1 year FU TIMI major bleed JAMA 2002;288: P=0.07 P<0.001

Placebo + ASA* Clopidogrel + ASA* Major Bleeding by ASA Dose <100 mg 2.6%2.0% 100–200 mg 3.5% 2.3% >200 mg 4.9% 4.0% ASA Dose CURE

Mean ±SDControlVASP-guidedp VASP after first LD, %68 ±1169 ±100.4 VASP after adjustment, %  38 ±14**<0.001 Bonello et al. J Am Coll Cardiol 2008 MACE: CV death, MI, revascularization Log rank p =0.007 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.

Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Compliance:

Days Cumulative Hazard Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CV Death, MI or Stroke

Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standar d N= 8684 Double N=8548 Hazard Ratio 95% CIP TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion ≥ 2U CABG-related Major ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard C Standard, A Low C Standard, A High C Double, A Low C Double, A High Standar d Clop Double Clop HRP P Int n High ASA Low ASA

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

Balance of Efficacy and Safety P= HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) P=0.03 HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH =

TIMI-38 STENT ANALYSIS Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.29 [ ]P= HR 0.46 [ ]P=0.04 DAYS EARLY STLATE ST 1.44% 0.42% 71% 0.91% 0.42% 54% CLOPIDOGREL PRASUGREL Wiviott et al, SCAI-ACCi2 2008

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

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

PLATO study design Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 5,096 5,161 4,047 4, Cumulative incidence (%) ,219 HR 0.84 (95% CI 0.77–0.92), p= Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177 Days after randomisation 6,703 6,796 5,136 5,210 4,109 4, Cumulative incidence (%) Clopidogrel Ticagrelor ,279 HR 0.84 (95% CI 0.75–0.95), p= Clopidogrel Ticagrelor HR 0.79 (95% CI 0.69–0.91), p= ,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation ,441 5,482 4,364 4,4198,626 Myocardial infarction Cardiovascular death Cumulative incidence (%) Secondary efficacy endpoints over time

Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Ticagrelor Clopidogrel

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

Efficacy of New DAPT Rx in ACS 3 Active Controlled Trials (vs Standard Clop) P=0.37N=25,087 1-month FU D/MI/CVA ESC 2009 P=0.02N=13, month FU D/MI/CVA NEJM 2007 Def/Prob ESC 2009 Def/Prob NEJM 2007 Def/Prob NEJM 2009 P= P=0.002 P<0.001 P<0.001N=18, Year FU D/MI/CVA NEJM 2009

Efficacy of New DAPT Rx: ACS+PCI 3 Active Controlled Trials (vs Standard Clop) P=0.04N=17,232 1-month FU D/MI/CVA ESC 2009 P<0.001 P=0.02N=13, month FU D/MI/CVA NEJM 2007 Def/Prob ESC 2009 Def/Prob NEJM 2007 Def/Prob NEJM 2009 P=0.0 P=0.002 P<0.001N=11,289 1-year FU D/MI/CVA TCT 2009

ACC/AHA/SCAI Guideline Update for PCI Oral Antiplatelet Adjunctive Therapies In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. IIIaIIbIII C

Antiplatelet Therapy Summary Major recent advances in clinical research have established the value of early + sustained therapy with combination oral antiplatelet agents for CAD Major recent advances in clinical research have established the value of early + sustained therapy with combination oral antiplatelet agents for CAD More complex combination regimens are under investigations that address the different clinical situations More complex combination regimens are under investigations that address the different clinical situations Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk stratification Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk stratification Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG bleeding. Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG bleeding. Cilostazol Cilostazol  3ple combination therapy investigational