Antiplatelet Effects of Anticoagulants Potential of Oral Factor

Antiplatelet Effects of Anticoagulants: Potential of Oral Factor Xa Inhibitors to Prevent Arterial Thrombosis David J. Moliterno, MD Division of Cardiovascular Medicine The University of Kentucky Linda and Jack Gill Heart Institute

David J. Moliterno, MD § Honoraria – Takeda Pharmaceuticals, Inc. – sanofi-aventis – Merck & Co. , Inc. and Company, Inc. – Portola Pharmaceuticals, Inc. – Boston Scientific Corporation

Platelet-Thrombin Interaction n Can drugs or agents targeting platelet function affect the coagulation cascade? n Can drugs or agents targeting the coagulation cascade affect platelet function?

Platelet-Thrombin Interaction n In vitro effect? n In vivo effects? n Circulating effects? n Clot-bound effects? n Additivity? n Synergism? n Biological or clinical relevance?

Platelet-Thrombin Interaction Thrombus Xa+Va+Ca+II Fibrin Thrombin Fibrinogen

Platelet-Xa-Thrombin Interactions Intrinsic Pathway (Surface Contact) Extrinsic Pathway VIIa (Tissue Factor) XIIa a. PTT PT a. PTT/PT XIa IXa Xa Platelet surface P 2 Y 12 IIb/IIIa PAR-1 Heparins Thrombin DTI Fibrin-bound Thrombin

Platelet Receptors Platelet Thrombin (Factor II) ADP TBX A 2 Epinephrine Serotonin Collagen Platelet PAR-1 PAR-4 Fibrinogen GP IIb/IIIa P 2 Y 12 TBXA 2 -R GP IIb/IIIa EPI-R 5 HT 2 A GP VI GP Ia Anionic phospholipid surfaces

Heparin with Abciximab Maximum ACT in Cath Lab Moliterno et al. Am J Cardiol 1995; 75: 559 -562

Heparins: Indirect Thrombin Inhibitors UFH 15, 000 D LMWH 5, 000 D DIIai 2, 500 D DXai 500 D Weitz. N Engl J Med 1997; 337: 688 -698

Factor Xa Inhibitors Pharmacologic Properties of Oral Direct FXa Inhibitors in Advanced Clinical Development Drug Rivaroxaban LY 517717 Otamixaban Apixaban 500 D K for FXa (n. M) Half-life (hours) Time to Cmax (hours) Bioavailability (%) Mode of Excretion Bayer Healthcare Ortho-Mc. Neil 0. 4 5 -9 2. 5 -4 60 -86 Biliary/fecal 28%; Renal 66% Lilly 4. 6 -6. 6 25 -- 25 -82 Primarily GI Sanofi-Aventis 0. 5 1. 5 -2 -- -- Renal 25% Biliary/fecal 75% Bristol-Myers Squibb Pfizer 0. 8 9 -14 -- 34 -88 Manufacturer Modified from Turpie AG. ATVB 2007; 27: 1240 Multiple, including renal and fecal

Factor Xa Inhibitors

Rivaroxaban Laux et al. Semin Thromb Hemost 2007; 33: 516

Platelet-Mediated Thrombin Generation Halfon et al. Blood Coag Fibrinolysis 2002; 13: 715

Factor Xa Inhibitors Otamixaban: no pharmacokinetic interaction between otamixaban and aspirin; the combination had no additive effects on coagulation or platelet parameters; no clinically relevant effect on bleeding Thromb Haemost 2006; 95: 224– 228 Rivaroxiban: No additive effects on platelet aggregation were observed when rivaroxaban was co-administered with aspirin Eur J Clin Pharmacol 2005; 61: 873– 880

Antiplatelet Effects of Anti-Xa Agents Thrombosis and Haemostasis 2010; 104: 302 -310

Antiplatelet Effects via Extrinsic Pathway Wong et al. Thromb Haemost 2010; 104: 302 -310

Antiplatelet Effects of Anti-Xa Agents Wong et al. Thromb Haemost 2010; 104: 302 -310

ATLAS—Death, MI, CVA 12% STRATUM 1 ASA Alone (N=761) 11. 9 P trend = 0. 01 HR 0. 67 8% STRATUM 2 ASA + Clop. (N=2, 730) 8. 0 HR 0. 58 7. 0 4% P trend = 0. 72 HR 0. 37 HR 1. 24 4. 7 3. 8 0 n=253 n=154 n=196 n=158 Plac 5 mg 10 mg 20 mg n=907 Plac Gibson CM, AHA 2008 HR 0. 70 HR O. 71 2. 7 n=154 n=860 5 mg 4. 7 HR 0. 79 3. 0 n=356 n=453 10 mg 15 mg 20 mg

ATLAS—Bleeding 15% Stratum 1: ASA Alone Stratum 2: ASA + Clopidogrel 14. 5 P trend: ASA Alone <0. 001; ASA + Clopidogrel <0. 0001 n/a 10% 10. 0 9. 8 10. 1 9. 6 5% 0 2. 1 n/a 0 0 0 2. 0 0. 2 0. 7 1. 5 1. 7 Plac 5 10 15 20 TIMI Major n/a 0. 6 0. 4 0 0 1. 1 0. 9 0. 2 0. 7 Plac 5 10 15 20 TIMI Minor Gibson CM, AHA 2008 3. 5 4. 1 1. 6 1. 9 Plac 5 10 15 20 Medical Attention

Antiplatelet Effects of Anti-Xa Agents n Small, direct acting, reversible effectors of free and platelet-bound Xa n Limit production of new Factor IIa n Laboratory effects on a. PTT, PT n Limited clinical relevance from antiplatelet effect n Factor Xa inhibitors are in phase III clinical trial development