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Pharmacological thromboprophylaxis

Pharmacological thromboprophylaxis. Professor Ajay Kakkar Barts and the London School of Medicine Thrombosis Research Institute, London, UK. Register of interests for Ajay Kakkar. N/A = not applicable (no conflicts). My talk today. Rationale for prophylaxis

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Pharmacological thromboprophylaxis

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  1. Pharmacological thromboprophylaxis Professor Ajay Kakkar Barts and the London School of Medicine Thrombosis Research Institute, London, UK

  2. Register of interests for Ajay Kakkar N/A = not applicable (no conflicts)

  3. My talk today Rationale for prophylaxis Established pharmacological methods New agents

  4. Natural history of postoperative DVT 4 92 normal 9 132 postoperative patients 40 26 Kakkar VV, et al. Lancet. 1969;2:230-232.

  5. Pharmacological Prevention of Thrombosis • Efficacy of low-dose unfractionated heparin (UFH) in prevention of DVT after major surgery 45 42 • s.c. low-dose UFH: pre-operative and b.i.d.post-operative • 78 ‘high-risk’ patients 40 35 30 25 Patients with DVT (%) 20 15 8 10 5 0 Control Low-dose UFH Kakkar et al. Lancet 1972;2:101–6 s.c., subcutaneous; b.i.d., twice a day .

  6. Prophylaxis of fatal, postoperative PE with low-dose UFH International multicenter trial 4121 patients undergoing major surgery Primary end point: fatal PE Randomized: control or UFH (5000 IU 2 hours before surgery and every 8 hours postoperativelyfor 7 days) 180 patients died during the postoperative period: 100 in the control group and 80 in the UFH group Rate of autopsy: 70% Kakkar V V et al, Lancet. 1975;2:45-51.

  7. Prophylaxis of fatal, postoperative PE with low-dose UFH P < 0.005 18 16 16 14 12 Number of patientswith fatal PE 10 8 6 4 2 2 0 Control UFH Low-dose UFH saves 7 lives for every 1000 operated patients. Kakkar VV et al, Lancet. 1975;2:45-51.

  8. Bleeding complications Control Heparin Excessive blood loss 126182NS Wound hematoma 117158 < 0.01 Mean transfusion requirements (mL) 1285 1316 0.34 Mean Hb fall (g/dl) 0.7 1.0 0.23 NS = not significant. Kakkar vv et al, Lancet. 1975;2:45-51.

  9. Reduction in Asymptomatic DVT and Fatal PE RR=67% RR=68% 60.5 1.9 Control Frequency of PE (%) UFH Prevalence of Proximal DVT (%) 20.3 0.6 Collins R, et al. N Engl J Med. 1988;318:1162-1173. Asymptomatic DVT Fatal PE

  10. LMWH and UFH in Major OrthopaedicSurgery 25 RR 0.68 LMWH 20 132/622 UFH 15 93/672 Proportion of Patients Experiencing Outcome 10 5 RR 0.43 RR 0.75 24/582 0 10/590 8/622 6/672 DVT PE* Major bleeding Nurmohamed MT,et al.Lancet. 1992;340:152-156.

  11. Extended–duration Prophylaxis and Asymptomatic DVT Placebo/ No treatment LMWH OR = 0.82 [0.49–1.40] OR=0.39 [0.28–0.54] 24.0 25 20.5 18.6 20 Prevalence of DVT (%) 15 7.7 10 5 0 THR (NNT=9) TKR (NNT=29) Eikelboom JW, et al. Lancet. 2001;358:9-15.

  12. Extended-duration Prophylaxis and Symptomatic VTE Placebo/ No treatment LMWH In-hospital prophylaxis followed by: OR = 0.33 [0.19–0.56] 5.0 4.3 4.0 Prevalence of VTE (%) 3.0 OR = 0.74 [0.26–2.15] 2.0 1.4 1.4 1.0 1.0 0.0 THR (NNT=34) TKR (NNT=250) Eikelboom JW, et al. Lancet. 2001;358:9-15.

  13. Thromboprophylaxis: general surgery LMWH betterUFH better Asymptomatic DVT Clinical PE Clinical thromboembolism Cancer Death Non-cancer Major hemorrhage Total hemorrhage Wound hematoma Transfusion 0 1.0 2.0 3.0 4.0 Mismetti P et al. Br J Surg 2001;88:913–30.

  14. Prevention of fatal PE in surgical patients P< 0.005 0.16 0.8 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Autopsy confirmed fatal PE (%) P=NS 0.5 0.5 Autopsy proven fatal PE (%) 0.4 0.4 0.3 0.3 0.16 0.1 0.2 0.15 0.2 0.1 0.1 0 0 Low-dose heparin t.i.d. (n=2,045) Low-dose heparin t.i.d (n=11,536) LMWH o.d. (n=11,542) Control (n=2,076) Kakkar VV, et al. Lancet. 1975;2:45-51;Haas S, et al. Thromb Haem. 2005;94:814-9.

  15. PE and death: cancer vs no cancer All patients (low-dose UFH or LMWH) Cancer (n = 6124) No cancer (n = 16,954) P Death (%) Fatal PE (%) Non-fatal PE (%) 192 (3.1) 20 (0.31) 5 (0.08) 120 (0.7) 15 (0.09) 4 (0.02) 0.0001 0.0001 Kakkar AK, et al. Thromb Haem 2005. In press

  16. Prolonged thromboprophylaxis after cancer operations 20 15 P =0.02 12.0 20/167 Total DVT (%) 10 4.8 5 8/165 0 1 week 4 weeks Enoxaparin 40 mg od*(n=332)1 Dalteparin 5000 IU od(n=198)2 20 19.6 15 P < 0. 04 21/107 Total DVT (%) 10 8.8 8/91 5 0 1 week 4 weeks 1Bergqvist D, et al.N Engl J Med. 2002;346:975-80; 2Rasmussen MS, et al. J Thromb Haemost. 2006 *od = once daily.

  17. Prevention of VTE in Pts Receiving Chemotherapy P= 0.033 RRR = 47.2% NNT = 54 Thromboembolic Event (%) 16/769 15/381 Agnelli G. et al. ASH 2008

  18. Efficacy of Current Anticoagulants 70 64.3 Total knee replacement Total hip replacement 60 56.0 54.2 Hip fracture surgery 48.0 50 46.8 40.2 40 34.0 Total DVT incidence (%) 30.6 27.0 30 24.0 22.1 20 16.1 12.5 7.9 10 4.8 0 Placebo/control ASA Warfarin LMWH Fondaparinux Geerts et al. Chest 2001; Turpie et al. Arch Intern Med 2002

  19. Fondaparinux: Efficacy Fondaparinux better Enoxaparin better Exact 95% CI –45.3% –58.3% –28.1% –61.6% –63.1% –55.2% p<0.001 0 100 –80 –60 –40 –20 20 40 60 80 –100 % Odds reduction Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

  20. Fondaparinux: Safety .Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

  21. Thromboprophylaxis in medical patients Study RRR Thromboprophylaxis Patients with VTE (%) 14.9* MEDENOX1 63% Placebo Enoxaparin PREVENT2 49% Placebo Dalteparin ARTEMIS 47% Placebo Fondaparinux p< 0.001 5.5 5.0* p = 0.0015 2.8 10.5† 5.6 p = 0.029 *VTE at day 14; †VTE at day 15. 1Samama MM, et al. N Engl J Med. 1999;341:793-800.2Leizorovicz A, et al. Circulation. 2004;110:874-9. 3Cohen AT, et al. J Thromb Haemost. 2003;1 (Suppl 1):P2046. RRR = relative risk reduction

  22. Thromboprophylaxis: proximal DVT Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) Anticoagulant n/N 5 / 429 27 / 1856 3 / 109 5 / 367 2761 Placebo n/N 13 / 420 53 / 1850 10 / 114 14 / 371 2755 RR (random) 95% CI Weight % 13.08 64.96 8.57 13.39 100.00 RR (random) 95% CI 0.38 [0.14, 1.05] 0.51 [0.32, 0.80] 0.31 [0.09, 1.11] 0.36 [0.13, 0.99] 0.45 [0.31, 0.65] 0.1 0.2 0.5 1 2 5 10 Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

  23. Thromboprophylaxis: all-causemortality Anticoagulant n/N 14 / 429 107 / 1856 8 / 109 41 / 367 2761 Placebo n/N 25 / 420 103 / 1850 8 / 114 50 / 371 2755 RR (random) 95% CI Weight % 12.80 51.06 6.22 29.91 100.00 RR (random) 95% CI 0.55 [0.29, 1.04] 1.04 [0.80, 1.35] 1.05 [0.41, 2.69] 0.83 [0.56, 1.22] 0.89 [0.70, 1.14] Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) 0.1 0.2 0.5 1 2 5 10 Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

  24. Exclaim study Multicenter, Prospective, Randomized, Double-blind, Placebo-controlled study to demonstrate superiority of enoxaparin 40 mg sc qd for 28 days + 4 days compared with placebo both following 10 + 4 days of initial treatment with enoxaparin 40 mg sc qd Enoxaparin 40 mg sc od* Enoxaparin 40 mg sc od R Placebo Open-label Double-blind Follow-up 0 Day 180±10 38±4 10+4 Mandatory ultrasonography *qd = once a day, SC = subcutaneous

  25. - 44% -73% -34% Efficacy – VTE Events Placebo Enoxaparin p = 0.0044 p = 0.0011 p = 0.0319 p = 1.0000 p = 0.2498 RRR 4.9 RRR Incidence (%) 3.7 RRR 2.8 2.5 1.1 0.3 0.2 0.1 0.0 0.0 Proximal DVT PE Fatal PE Symptomatic VTE VTE

  26. Safety – Bleeding Placebo Enoxaparin p = 0.007 p = 0.019 p = 0.024 5.70 Incidence (%) 5.20 3.80 3.70 0.60 0.15 Total Bleeding Major Bleeding Minor Bleeding

  27. New anticoagulants Coagulation cascade Initiation TF/VIIa TFPINAPc2 IX X TTP889 Fondaparinux Idrabiotaparinux Apixaban Rivaroxaban YM-150 AVE 5026* IXa Xa VIIIa Propagation Va II Thrombin activity IIa Ximelagatran Dabigatran Fibrinogen Fibrin TF: Tissue factor, TFPI: Tissue factor pathway inhibitor. * anti Xa > anti IIaactivity.

  28. Dabigatran for VTE Prevention 50 Enoxaparin 150 mg once daily 40.5 37.7 40 36.4 220 mg once daily 33.7 31.1 30 25.7 Total VTE and All-cause Mortality (%) 20 8.6 10 6.7 6.0 0 RE-NOVATEHip†,1 RE-MODELKnee†,2 RE-MOBILZEKnee‡,3 1. Eriksson BI, et al. Lancet. 2007;370:949-956. 2. Eriksson BI, et al. J Thromb Haemost. 2007;5:2178-2185. 3. The RE-MOBILIZE Writing Committee. J Arthroplasty. 2008.

  29. Pooled analysis from the phase 3 programme of dabigatran etexilate (RE-MODEL, RE-MOBILIZE, and RE-NOVATE studies) Dabigatran for Prevention of Major VTE : Pooled Analysis Caprini J, et al. J Thomb Haemost. 2007;5(suppl 2):AO-W-050.

  30. RECORD: phase III programme for VTE prevention Rivaroxaban 10 mg o.d. compared with enoxaparin Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 30 mg b.i.d. for 12 ± 2 days N = 3148 Hip replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days vs. Enoxaparin 40 mg o.d. for 12 ± 2 days then placebo N = 2509 Hip replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days vs. Enoxaparin 40 mg o.d. for 35 ± 4 days N = 4541 Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 40 mg o.d. for 12 ± 2 days N = 2531 Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; LassenMR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.

  31. Conclusion LMWH validated for efficacy and safety Orthopaedic General surgical Cancer surgery Medical patients Duration of prophylaxis remains controversial Medical patients New agents available for VTE prevention hip and knee arthroplasty

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