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 Research Support/P.I. Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai EmployeeN/A Consultant Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai Major StockholderN/A Speakers BureauN/A Honoraria Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai, GSK Scientific Advisory Board Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol–Myers Squibb, Eisai N/A = not applicable (no conflicts)

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

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

6. Kakkar V V et al, Lancet. 1975;2:45-51.

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

8. NS = not significant.Kakkar vv et al, Lancet. 1975;2:45-51.

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

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

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

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

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

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

15. 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 Kakkar AK, et al. Thromb Haem 2005. In press All patients (low-dose UFH or LMWH) Cancer (n = 6124) No cancer (n = 16,954) P

16. Enoxaparin 40 mg od* (n = 332) 1 1 Bergqvist D, et al. N Engl J Med. 2002;346:975-80; 2 Rasmussen MS, et al. J Thromb Haemost. 2006 Dalteparin 5000 IU od (n = 198) 2 *od = once daily. Total DVT (%) 19.6 8.8 1 week4 weeks 21/107 P < 0. 04 0 5 10 20 15 Total DVT (%) 1 week 4 weeks 12.0 4.8 20/167 8/165 P = 0.02 0 5 10 20 15 8/91

17. Prevention of VTE in Pts Receiving Chemotherapy Thromboembolic Event (%) 16/76915/381 P= 0.033 RRR = 47.2% NNT = 54 Agnelli G. et al. ASH 2008

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

19. Hip replacement (n=3411) EPHESUS (n=1827) PENTATHLON 2000 (n=1584) –58.9 to –27.4 –72.8 to –37.2 –52.2 to –7.6 Hip fracture PENTHIFRA (n=1250) –73.4 to –45.0 Major knee surgery PENTAMAKS (n=724) –75.5 to –44.8 Common odds reduction (n=5385) –63.1 to –45.8 Exact 95% CI Fondaparinux betterEnoxaparin better –100 –80–60–40–2020 0 406080 100 –45.3% –63.1% –55.2% –61.6% p<0.001 % Odds reduction –58.3% –28.1% Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

20. Fondaparinux (n=3,616) Enoxaparin (n=3,621) Fatal, (n) (0)(1) In a critical organ, (n) (0)(1) Leading to re-operation, % (n) 0.3(12)0.2(8) Overt bleeding with index ≥2, % (n) 2.3(84)1.5 (53). Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

21. MEDENOX 1 63% Placebo Enoxaparin PREVENT 2 49%Placebo Dalteparin ARTEMIS 47%Placebo Fondaparinux 14.9 * 5.5 StudyRRRThromboprophylaxisPatients with VTE (%) 5.0 * 2.8 10.5 † 5.6 * VTE at day 14; † VTE at day 15. 1 Samama MM, et al. N Engl J Med. 1999;341:793-800. 2 Leizorovicz A, et al. Circulation. 2004;110:874-9. 3 Cohen AT, et al. J Thromb Haemost. 2003;1 (Suppl 1):P2046. p < 0.001 p = 0.0015 p = 0.029 RRR = relative risk reduction

22. Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) Placebo n/N 13 / 420 53 / 1850 10 / 114 14 / 371 2755 Anticoagulant n/N 5 / 429 27 / 1856 3 / 109 5 / 367 2761 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] 0.10.20.512510 Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

23. Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) Placebo n/N 25 / 420 103 / 1850 8 / 114 50 / 371 2755 Anticoagulant n/N 14 / 429 107 / 1856 8 / 109 41 / 367 2761 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] 0.10.20.512510 Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

24. 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 10 + 4 Mandatory ultrasonography 0 R Enoxaparin 40 mg sc od* Placebo 38 ± 4 Day Follow-up Enoxaparin 40 mg sc od Open-labelDouble-blind 180 ± 10 *qd = once a day, SC = subcutaneous

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

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

27. Coagulation cascade Initiation Propagation Thrombin activity TF/VIIa VIIIa IXa IX X Xa Va II IIa FibrinogenFibrin TFPI NAPc2 TF: Tissue factor, TFPI: Tissue factor pathway inhibitor. * anti Xa > anti IIa activity. Fondaparinux Idrabiotaparinux Apixaban Rivaroxaban YM-150 AVE 5026* Ximelagatran Dabigatran TTP889

28. 0 10 20 30 40 50 RE-NOVATE Hip †,1 Total VTE and All-cause Mortality (%) 150 mg once daily RE-MODEL Knee †,2 RE-MOBILZE Knee ‡,3 8.6 6.0 6.7 40.5 36.4 37.7 33.7 31.1 25.7 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. Enoxaparin 220 mg once daily

29. Enoxaparin Dabigatran (150 mg) Dabigatran (220 mg) Major VTE, %3.33.8 3.0 Absolute risk difference, % (95% CI) – 0.5 (−0.6−1.6) −0.2 (−1.3−0.9) Major bleeding, %1.41.1 1.4 Caprini J, et al. J Thomb Haemost. 2007;5(suppl 2):AO-W-050.

30. Hip replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days vs. Enoxaparin 40 mg o.d. for 35 ± 4 days N = 4541 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 Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 40 mg o.d. for 12 ± 2 days N = 2531 Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 30 mg b.i.d. for 12 ± 2 days N = 3148 Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.