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C. Michael Gibson, M.S., M.D.

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 Antiplatelet Therapy. PCI after hospital discharge. PCI ≥ 48 hrs from rand and during initial hosp . <48 hrs after rand. 0.20. 0.20. 0.20.

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C. Michael Gibson, M.S., M.D.

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

  2. PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy PCI after hospital discharge PCI ≥ 48 hrs from rand and during initial hosp <48 hrs after rand 0.20 0.20 0.20 Denotes median Time to PCI ASA ASA 0.15 0.15 0.15 ASA 0.10 0.10 0.10 Cumulative Hazard Rates Death / MI ASA + Clopidogrel ASA + Clopidogrel 0.05 0.05 0.05 ASA + Clopidogrel RR:0.72 (0.51-1.01) RR:0.53 (0.27-1.06) RR:0.70 (0.48-1.02) 0.0 0.0 0.0 0 100 200 300 0 100 200 300 0 100 200 300 Days of Follow-up Days of Follow-up Days of Follow-up Lewis BS, et al. Am Heart J. 2005;150:1177-1184.

  3. Thrombus & Complex Lesion Remains One Month After STEMI • 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 100% 83% % Thrombus on Angioscopy 79% 80% 71% 70% 60% 40% 20% 0% < 8 Days (n=18) 8 < & < 10 Days (n=10) 10 < & < 15 Days (n=14) > 15 Days (n=14) Days after lysis or medical therapy Van Belle et al. Circulation. 1998;97:26-33.

  4. Edge Body Overlapping Segment Angioscopy Follow-up 6 Months After SES or BMS Implantation Grade 0 No neointima Grade 1 Thin neointima Grade 2 Full neointima Visible Thrombus P=.70 P<.001 >80% P=.63 P=.80 P<.0005 P<.05 100 2.5 * 80 2 P=.031 * 60 Frequency of Persistence of Thrombus (%) 1.5 * Stent Coverage Grade 40 *P<.001 comparedwith the corresponding segment in the BMS. 1 20 0.5 0 0 n=7 SES n=7 BMS n=28 n=33 n=5 BMS n=21 n=33 n=12 SES (N=46, 66 lesions: 33 SES, 33 BMS) Takano M, et al. Eur Heart J. 2006;27:2189-2195.

  5. 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

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

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

  8. ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common 999 Pts within 8 wks of UA or Acute MIRx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg Efficacy Safety 30 Major Bleed Tranfusion 20 Minor Bleed % 15 Death,MI,CVA 8 10 5 2 1 1 1 1 1 0 ASA Coumadin Combo Rate of Discontinuation 10% 19% 20% van Es et al Lancet 360:109,2002

  9. 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 Oral A/C + ASA 15 % Pts 11.9 9 8.9 10 7.8 6.1 5 0 Compliance: Good Bad Good Bad(% on Oral AC) >70 % < 70% > 70% < 70% CVD,MI,CVA CVD, MI, CVA, Rehosp UA OASIS Inv JACC 37:475,2001

  10. ESTEEM: Primary Endpoint Death/MI/Severe Recurrent Ischemia 20% • 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 % Death/MI/Recurrent Ischemia 16.3% p=0.03 15% 12.7% 10% 5% n=1,245 n=638 0% Placebo Pooled Ximelagatran Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMI

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

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

  13. New Antithrombins ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 IX X APC (drotrecoginalfa) sTM (ART-123) RivaroxabanApixabanLY517717YM150 DU-176bPRT-054021 IXa VIIIa Va AT Xa FondaparinuxIdraparinux II DX-9065aOtamixaban XimelagatranDabigatran IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J ThrombHaemost2005

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

  15. Oral Factor Xa Inhibitors In Clinical Development Rivaroxaban (Bayer) Phase IIb Phase III Apixaban (BMS) Phase III YM150 (Astellas) Phase IIb DU-176b (Daiichi) Phase IIb LY517717 (Lilly) Phase IIb 813893 (GSK) Phase I/II PRT054021(Portola) Phase II

  16. Factor Xa Inhibitors in Development *Prevention of VTE after major orthopaedic surgery, unless indicated

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