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

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)

postoperative patients normal Kakkar VV, et al. Lancet. 1969;2:

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 Kakkar et al. Lancet 1972;2:101–6

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

Number of patients with fatal PE P < ControlUFH Low-dose UFH saves 7 lives for every 1000 operated patients. Kakkar VV et al, Lancet. 1975;2:45-51.

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

Prevalence of Proximal DVT (%) Asymptomatic DVT RR=67 % Fatal PE Frequency of PE (%) RR=68% Control UFH Collins R, et al. N Engl J Med. 1988;318:

LMWH UFH DVTPE*Major bleeding RR 0.68 RR 0.43 RR 0.75 Proportion of Patients Experiencing Outcome Nurmohamed MT, et al. Lancet. 1992;340: / /622 10/590 24/582 6/672 8/622

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] Eikelboom JW, et al. Lancet. 2001;358:9-15. Placebo/ No treatment LMWH

OR = 0.33 [0.19–0.56] OR = 0.74 [0.26–2.15] 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

Clinical thromboembolismCancer 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

Autopsy confirmed fatal PE (%) Control (n=2,076) Low-dose heparin t.i.d. (n=2,045) P< Kakkar VV, et al. Lancet. 1975;2:45-51; Haas S, et al. Thromb Haem. 2005;94: Autopsy proven fatal PE (%) 0.15 P=NS Low-dose heparin t.i.d (n=11,536) LMWH o.d. (n=11,542)

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

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 Dalteparin 5000 IU od (n = 198) 2 *od = once daily. Total DVT (%) week4 weeks 21/107 P < Total DVT (%) 1 week 4 weeks /167 8/165 P = /91

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

Geerts et al. Chest 2001; Turpie et al. Arch Intern Med Placebo/controlASAWarfarinLMWHFondaparinux Total DVT incidence (%) Total knee replacement Total hip replacement Hip fracture surgery

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– –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:

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:

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

Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) Placebo n/N 13 / / / / Anticoagulant n/N 5 / / / / RR (random) 95% CI Weight % 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] Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

Study or subcategory Cohen 2006 Leizorovicz 2004 Fraisse 2000 Samama 1999 Total (95% CI) Placebo n/N 25 / / / / Anticoagulant n/N 14 / / / / RR (random) 95% CI Weight % 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] Favors Anticoagulant Favors Placebo Lloyd NS, et al. J Thromb Haemost. 2008;6:405–414

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 days of initial treatment with enoxaparin 40 mg sc qd 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

VTE Efficacy – VTE Events Proximal DVT Symptomatic VTE Placebo Enoxaparin Incidence (%) RRR - 44% RRR -34% RRR -73% PE Fatal PE p = p = p = p = p =

Total Bleeding Safety – Bleeding Major Bleeding Minor Bleeding Placebo Enoxaparin p = p = p = Incidence (%)

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

RE-NOVATE Hip †,1 Total VTE and All-cause Mortality (%) 150 mg once daily RE-MODEL Knee †,2 RE-MOBILZE Knee ‡, Eriksson BI, et al. Lancet. 2007;370: Eriksson BI, et al. J Thromb Haemost. 2007;5: The RE-MOBILIZE Writing Committee. J Arthroplasty Enoxaparin 220 mg once daily

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

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.