Meeting The Unmet Needs in Chronic Anticoagulation C

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Meeting The Unmet Needs in Chronic Anticoagulation C. Michael Gibson, M. S. , M.

Meeting The Unmet Needs in Chronic Anticoagulation C. Michael Gibson, M. S. , M. D.

PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual

PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy Cumulative Hazard Rates Death / MI <48 hrs after rand 0. 20 Denotes median Time to PCI ASA 0. 15 PCI after hospital discharge PCI ≥ 48 hrs from rand during initial hosp 0. 20 ASA 0. 15 0. 10 0. 05 ASA 0. 15 0. 10 ASA + Clopidogrel 0. 05 ASA + Clopidogrel RR: 0. 53 (0. 27 -1. 06) 0. 0 0 100 200 300 Days of Follow-up RR: 0. 72 (0. 51 -1. 01) 0. 0 0 100 200 300 Days of Follow-up RR: 0. 70 (0. 48 -1. 02) 0. 0 0 100 200 300 Days of Follow-up Lewis BS, et al. Am Heart J. 2005; 150: 1177 -1184.

Thrombus & Complex Lesion Remains One Month After STEMI % Thrombus on Angioscopy 100%

Thrombus & Complex Lesion Remains One Month After STEMI % Thrombus on Angioscopy 100% 83% 80% 79% 70% 71% 60% 40% • Angioscopic findings suggestive of plaque instability are extremely frequent (75% to 80% of the study population) as is the presence of clot even in the absence of clinical symptoms. • Only 16% of clot seen on angio 20% 0% < 8 Days 8<& 10 < & (n=18) < 10 Days < 15 Days (n=10) (n=14) > 15 Days (n=14) Days after lysis or medical therapy Van Belle et al. Circulation. 1998; 97: 26 -33.

Angioscopy Follow-up 6 Months After SES or BMS Implantation Grade 1 Thin neointima Stent

Angioscopy Follow-up 6 Months After SES or BMS Implantation Grade 1 Thin neointima Stent Coverage Grade 2. 5 2 1. 5 P<. 05 P=. 63 P=. 80 Edge Body Overlapping Segment * * * 1 *P<. 001 compared with the corresponding segment in the BMS. 0. 5 0 Visible Thrombus P=. 70 P<. 001 P<. 0005 Grade 2 Full neointima n=21 n=33 n=12 SES n=28 n=33 n=5 BMS Frequency of Persistence of Thrombus (%) Grade 0 No neointima 100 >80% 80 P=. 031 60 40 20 0 n=7 SES n=7 BMS (N=46, 66 lesions: 33 SES, 33 BMS) Takano M, et al. Eur Heart J. 2006; 27: 2189 -2195.

Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy • Series

Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy • Series from 1997 -2002 • Among first anterior STEMI patients echoed within 72 hours LV clot was seen in 23. 5%. (36/153) * STEMI pts managed with lytic or medical mgt Porter A et al. Coron Artery Dis. 2005 Aug; 16(5): 275 -9

Positive Feedback Loops Thrombin “Amplification” “Burst” “Cascade” “Activation” Confidential. Do Not Distribute. Prasugrel is

Positive Feedback Loops Thrombin “Amplification” “Burst” “Cascade” “Activation” Confidential. Do Not Distribute. Prasugrel is not FDA indicated for use.

Meta Analysis of Anticoagulation Rates of Recurrent MI Rothberg et al. Ann. Int. Med.

Meta Analysis of Anticoagulation Rates of Recurrent MI Rothberg et al. Ann. Int. Med. 2005; 143: 241 -250

ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common 999 Pts within

ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common 999 Pts within 8 wks of UA or Acute MI Rx : ASA 80 mg; Coumadin (INR 3 -4); or Combination: ( INR 2 -2. 5)+ ASA 80 mg Efficacy Safety % Death, MI, CVA 30 Major Bleed Tranfusion Minor Bleed 20 15 8 10 5 1 1 2 1 0 ASA Rate of Discontinuation 10% Coumadin Combo 19% 20% van Es et al Lancet 360: 109, 2002

OASIS 2: Impact of Anticoagulation Discontinuation P=0. 02 P=0. 33 P=0. 005 P=0. 16

OASIS 2: Impact of Anticoagulation Discontinuation P=0. 02 P=0. 33 P=0. 005 P=0. 16 21. 3 20 18. 5 Std Rx 16. 5 % Pts Oral A/C + ASA 15 10 11. 9 8. 9 6. 1 7. 8 9 5 0 Compliance: Good (% on Oral AC) >70 % CVD, MI, CVA OASIS Inv JACC 37: 475, 2001 Bad < 70% Good > 70% Bad < 70% CVD, MI, CVA, Rehosp UA

ESTEEM: Primary Endpoint % D e a th / MI / R e c

ESTEEM: Primary Endpoint % D e a th / MI / R e c u r r e n t I s c h e m i a 20% Death/MI/Severe Recurrent Ischemia 16. 3% 15% p=0. 03 12. 7% 10% 5% 0% • The primary endpoint was lower for pooled ximelagatran compared with placebo (12. 7% vs 16. 3%, HR 0. 76, p=0. 03) • Ximelagatran Dc’d in 7% of pts due to LFT abnormalities n=1, 245 n=638 Placebo Pooled Ximelagatran Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMI

Factor Xa Inhibition: At The Intersection of the Intrinsic and Extrinsic Pathways TF (Tissue

Factor Xa Inhibition: At The Intersection of the Intrinsic and Extrinsic Pathways TF (Tissue Factor) XIa XI Intrinsic Pathway IX IXa VIIa + TF VIIIa X If either the Intrinsic or Extrinsic pathway is activated, Factor Xa inhbitors block the final common coagulation pathway to form thrombin by blocking Factor XA VII Extrinsic Pathway Xa Va II IIa (Thrombin) Fibrinogen Fibrin

Meeting the Unmet Needs in Long Term Anticoagulation in ACS • Safe • Effective

Meeting the Unmet Needs in Long Term Anticoagulation in ACS • Safe • Effective • Ease of use No monitoring Unaffected by diet

New Antithrombins ORAL PARENTERAL TF/VIIa TTP 889 TFPI (tifacogin) IX X Rivaroxaban Apixaban LY

New Antithrombins ORAL PARENTERAL TF/VIIa TTP 889 TFPI (tifacogin) IX X Rivaroxaban Apixaban LY 517717 YM 150 DU-176 b PRT-054021 Ximelagatran Dabigatran Fibrinogen VIIIa APC (drotrecogin alfa) s. TM (ART-123) IXa Va Xa AT II Fondaparinux Idraparinux DX-9065 a Otamixaban IIa Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

Rivaroxaban Inhibits Thrombin Generation • In vitro: platelet-rich human plasma activated by diluted tissue

Rivaroxaban Inhibits Thrombin Generation • In vitro: platelet-rich human plasma activated by diluted tissue factor Thrombin concentration (n. M) 120 Control 5 n. M Rivaroxaban 10 n. M Rivaroxaban 20 n. M Rivaroxaban 50 n. M Rivaroxaban 80 n. M Rivaroxaban 100 80 60 40 20 0 0 10 20 30 40 50 Time (minutes) Gerotziafas & Samama. ICT 2004, Ljubljana, Slovenia, ISTH 2005, Sydney, Australia

Oral Factor Xa Inhibitors In Clinical Development Rivaroxaban (Bayer) Phase IIb Phase III Apixaban

Oral Factor Xa Inhibitors In Clinical Development Rivaroxaban (Bayer) Phase IIb Phase III Apixaban (BMS) Phase III YM 150 (Astellas) Phase IIb DU-176 b (Daiichi) Phase IIb LY 517717 (Lilly) Phase IIb 813893 (GSK) Phase I/II PRT 054021(Portola) Phase II

Factor Xa Inhibitors in Development Indication VTE prevention* VTE treatment Stroke prevention in patients

Factor Xa Inhibitors in Development Indication VTE prevention* VTE treatment Stroke prevention in patients with AF Other? Idraparinux – Phase III results expected soon Phase III halted – Phase III ACS Phase II LY 517717 Phase IIb completed – – – YM 150 Phase IIa completed – Planned – DU-176 b Phase IIa completed – Planned ACS planned Apixaban Phase IIb completed; planned in cancer patients Phase II underway – Post-ACS planned Phase II planned Planned Secondary prevention of stroke and MI planned Rivaroxaban PRT-054021 *Prevention of VTE after major orthopaedic surgery, unless indicated