How to Combine Antiplatelet Therapy with Oral Factor Xa Inhibitor in ACS Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine University of Florida College of Medicine - Jacksonville

Dominick J. Angiolillo, MD, PhD Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

Plasma Clotting cascade Thrombus Formation Two key elements: cellular (platelets) and plasmatic (coagulation factors) Platelet activation Platelet aggregation ADP Collagen THROMBUS TXA2 Thrombin Fibrinogen Fibrin Plasma Clotting cascade Tissue Factor Prothrombin

Thrombin Generation in ACS 300 250 200 150 100 50 400 600 800 1200 1000 Time (seconds) Thrombin (nM) Control Acute Coronary Syndromes n=28 Coronary Artery Disease n=25 Adapted from Brummel-Ziedins K, et al. J Thromb Haem 2008;6:104–110

The Role of Thrombin in Coagulation and Platelet Activation Platelet Aggregation Platelet Tissue Factor IIb/IIIa IXa + + Fibrinogen VII Ca ++ IIb/IIIa + X PAR - 1,3,4 Platelet VIII Ia Ib Receptor activation Collagen Vessel Wall Rivaroxaban Factor Xa Inhibitor PAR-1 Xa Platelet Adhesion Prothrombin THROMBIN Fibrinogen Fibrin Formation Coughlin SR, Nature 2000;407:258-264; Perzborn E et al. Nat Rev Drug Discov. 2011;10(1):61-75

ATLAS ACS-TIMI 46 Phase 2 Dose-Finding Study 4 Doses with QD and BID Formulations N=3,491 Placebo 6 HR 0.69 (95% CI, 0.50 – 0.96) P = 0.03 5.5% 4 3.9% Death, MI, or Stroke (%) Rivaroxaban (combined) TIMI Major Bleeding (%) 2 4 QD BID Large N 30 60 90 120 150 180 Placebo 5 mg 10 mg 15 mg 20 mg Rivaroxaban Days In Addition to Aspirin and Thienopyridine (Stratum 2) Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM, Lancet 2009

Low BID Doses: Death, MI, or Stroke Results in pooled 2.5 mg BID and 5 mg BID doses Background: ASA Alone Background: ASA + Thieno 5% 15% HR 0.54 (0.27-1.08) HR 0.55 (0.27-1.11) PLACEBO 11.9% 12% P=0.08 4% P=0.09 PLACEBO 3.8% 3% 9% RIVA 6.6% RIVA 2.0% 6% 2% 3% 1% 0% 0% 90 180 90 180 Days Days Gibson CM, AHA 2009

Trial Design TIMI 51 2.5 mg BID Rivaroxaban 5.0 mg BID Placebo G02-536 w_script.ppt 1/30/2018 2:34:04 AM ATLAS ACS 2 Trial Design TIMI 51 Recent ACS: STEMI, NSTEMI, UA Stabilized 1-7 Days Post-Index Event Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke or TIA if on ASA + thienopyridine N=15,526 ASA 75 to 100 mg/day Stratified by Thienopyridine Use at MD Discretion Rivaroxaban 2.5 mg BID Rivaroxaban 5.0 mg BID Placebo ¼. ½ PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG 9

Primary Efficacy Endpoint: CVD, MI, or Stroke ATLAS ACS 2 Primary Efficacy Endpoint: CVD, MI, or Stroke TIMI 51 2 Yr KM Estimate Placebo 10.7% 8.9% HR 0.84 (0.74-0.96) mITT p = 0.008 ITT p = 0.002 ARR 1.8% NNT = 56 Estimated Cumulative Incidence (%) Rivaroxaban (both doses) Months After Randomization Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, NEJM 2012 10

Components of the Endpoint ATLAS ACS 2 Components of the Endpoint TIMI 51 Myocardial Infarction Cardiovascular Death Placebo Placebo HR 0.85 mITT p=0.047 ITT P=0.011 2 Yr KM HR 0.80 mITT p=0.038 ITT p=0.053 2 Yr KM 6.6% 4.1% 5.5% 3.3% Estimated Cumulative incidence (%) Estimated Cumulative incidence (%) Rivaroxaban (both doses) Rivaroxaban (both doses) 12 24 12 24 Months Months Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, NEJM 2012

Efficacy Endpoints: Very Low Dose 2.5 mg BID ATLAS ACS 2 Efficacy Endpoints: Very Low Dose 2.5 mg BID TIMI 51 CV Death / MI / Stroke Cardiovascular Death All Cause Death 5% 5% 12% HR 0.84 mITT p=0.020 ITT p=0.007 Placebo HR 0.66 mITT p=0.002 ITT p=0.005 Placebo HR 0.68 mITT p=0.002 ITT p=0.004 Placebo 10.7% 4.1% 4.5% 9.1% 2.7% 2.9% Estimated Cumulative incidence (%) Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID NNT = 63 NNT = 71 NNT = 63 12 12 24 24 12 24 Months Months Months Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, NEJM 2012 12

TIMI STENT THROMBOSIS* 51 2.9% Placebo 2.3% HR 0.69 (0.51- 0.93) ATLAS ACS 2 STENT THROMBOSIS* ARC Definite, Probable, Possible TIMI 51 2 Yr KM Estimate 2.9% Placebo 2.3% Estimated Cumulative incidence (%) HR 0.69 (0.51- 0.93) mITT p = 0.016 ITT p = 0.008 Rivaroxaban (both doses) ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012 Months After Randomization * End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

TIMI Stent Thrombosis 51 2 yr KM rates HR (95% CI) Riva Placebo ATLAS ACS 2 Stent Thrombosis TIMI 51 2 yr KM rates HR (95% CI) Riva Placebo 0.65 (0.46 - 0.93) mITT p=0.017 ITT p=0.012 Definite/Probable 1.5% 1.9% 0.69 (0.51 - 0.93) mITT p=0.016 ITT p=0.008 Definite/Probable/Possible 2.3% 2.9% HR 0.5 1.0 2.0 Favors Rivaroxaban Favors Placebo Gibson CM, TCT 2012

Rivaroxaban ASA + clopidogrel Stent Thrombosis 79% 86% 98% Thrombus mass (mg) *** *** *** Abstract: Effects of rivaroxaban, ASA and clopidogrel alone and in combination in a porcine model of stent thrombosis Authors: Eva Maria Becker, Elisabeth Perzborn, Alexandra Klipp, Caroline Luecker, Ulf Bütehorn, Raimund Kast, Volker Laux, Cardiovascular Research, Bayer Schering Pharma, Wuppertal – Germany Purpose: Stent thrombosis incidence with standard dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel, remains at 1.4% after stent placement for acute coronary syndrome (ACS). New oral anticoagulants are in late stage clinical studies for secondary prevention after acute coronary syndrome and may be beneficial for prevention of stent thrombosis. The aim of this study is to evaluate the efficacy of rivaroxaban, a novel oral Factor Xa inhibitor, alone and in combination with ASA and clopidogrel in inhibiting high-shear induced stent thrombosis in a porcine ex vivo model. Methods: Stents (Cordis) (12 stents, 3 per treatment) were continuously deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood at a shear rate of 1,500 s-1. Stent thrombus formation was analysed under different treatments: vehicle (n=7); rivaroxaban 0.11, 0.33 and 1.1 μg/kg/h i.v (n=8); rivaroxaban + ASA (1 mg/kg i.v.) (n=6); rivaroxaban + ASA (1 mg/kg i.v.) + clopidogrel (0.5 mg/kg i.v.) (n=7); and ASA (1 mg/kg i.v.) + clopidogrel (0.5 mg/kg i.v.). Thrombus weight is displayed as mean ± SEM. Results: Rivaroxaban alone dose-dependently reduced stent thrombus by 33, 48 and 66%, respectively. Dual antiplatelet therapy with ASA + clopidogrel decreased thrombus weight by 79%. Rivaroxaban in combination with ASA was similar or even more effective in inhibiting stent thrombosis (48, 72 and 86%). Finally, the combination of rivaroxaban with ASA + clopidogrel inhibited stent thrombus formation under these experimental conditions to a nearly undetectable limit of 98%. Conclusions: Rivaroxaban, alone or in combination with antiplatelets, effectively inhibits stent thrombosis in an ex vivo model. These data provide additional support for further clinical studies. Vehicle control ASA + clopidogrel Rivaroxaban + ASA Rivaroxaban ASA + clopidogrel n=7 n=6 n=6 n=7 Rivaroxaban dose: 1 µg/kg/min. Error bars are the standard error of the mean. ***P<0.001 (unpaired t-test vs representative vehicle group). Becker, et al. Eur Heart J (2010) 31 doi:10.1093/eurheartj/ehq290 Porcine Model 15

Safety Endpoints TIMI 51 Placebo Rivaroxaban 2.5 mg BID 5 mg BID ATLAS ACS 2 Safety Endpoints TIMI 51 Placebo Rivaroxaban 2.5 mg BID 5 mg BID Non-CABG TIMI Major 0.6% 1.8% (P<0.001) 2.4% ICH 0.2% 0.4% (P=0.04) 0.7% (P=0.005) Fatal 0.1% (P=NS) Fatal ICH 2-yr KM event rates Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, NEJM 2012

The Role of Thrombin in Coagulation and Platelet Activation Platelet Aggregation Platelet Tissue Factor IIb/IIIa IXa + + Fibrinogen VII Ca ++ IIb/IIIa + X PAR - 1,3,4 Platelet VIII Ia Ib Receptor activation Collagen Vessel Wall Apixaban Factor Xa Inhibitor PAR-1 Xa Platelet Adhesion Prothrombin THROMBIN Fibrinogen Fibrin Formation Coughlin SR, Nature 2000;407:258-264; Perzborn E et al. Nat Rev Drug Discov. 2011;10(1):61-75

APPRAISE-2 Primary Efficacy Outcome N=7,392 Considerations: Dosing APPRAISE 2 and ARISTOTLE used the same dose Dose not tested in the APPRAISE 1 Patient Population Very high risk (vs APPRAISE 1 and other studies) Possibly competing risks not modified by an anticoagulant Stroke and TIA patients (No: HR 0.89, 95% CI 0.74-1.06) n/N: 7.5% apixaban vs 7.9% placebo Alexander JH et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1105819

Antithrombotic Therapies CV Endpoints Prasugrel Aspirin + TRITON TIMI 38 COMPARATOR Ticagrelor Aspirin + PLATO Aspirin Clopidogrel Standard Dose + Rivaroxaban (Very Low Dose 2.5 mg BID)* ATLAS ACS 2 TIMI 51 Aspirin + Clopidogrel Standard Dose Antithrombotic Therapy Emp not Riva, P, and T Cross trial challenge, timing * Not approved for ACS in US

Targeting Antithrombotic Therapies High risk of ischemic events High risk of bleeding events Target Antithrombotic Therapy Ischemic risk Bleeding risk Adapted from Ferreiro, Sibbing, and Angiolillo. Thromb Haemost 2010;103(6):1128-35.