Venous thromboembolism – Primary prevention after major orthopaedic surgery

Effect of prophylaxis on total DVT rates after total hip replacement Venous thromboembolism Effect of prophylaxis on total DVT rates after total hip replacement No of n Prevalence trials % (95%Cl) RRR % Placebo/control 12 626 54 (50-58) - Elastic stockings 4 290 42 (36-48) 23 Aspirin 6 473 40 (35-45) 26 Low-dose UFH 11 1016 30 (27-33) 45 Warfarin 13 1828 22 (20-24) 59 IPC 7 423 20 (17-24) 63 LMWH 30 6216 16 (15-17) 70 R-hirudin 3 1172 16 (14-19) 70 Patients undergoing orthopaedic surgery have a particulary high risk of VTE, as multiple risk factors are present. Both physical and pharmacological approaches to the prevention of VTE have been developed. The total DVT relative risk reduction (RRR) by using different methods in connection to the total hip replacement has been shown in the slide. Reference: Geerts WH, Heit JA, Clagett GP, Pireo GF, Colwell CW, Andersson FA et al. Prevention of venous thromboembolism. The Sixth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2001;119:132S-75S. Geerts WH et al. Chest 2001;119:132S–175S November 2005

Venous thromboembolism 7th ACCP recommendations Total hip, knee replacement or hip fracture surgery Thromboprophylaxis for at least 10 days [Grade 1A] with: LMWH (high-risk dose) Fondaparinux (2.5 mg daily) Vitamin K antagonist (VKA, target INR 2.5 [INR range 2–3]) For TKR, intermittent pneumatic compression is an alternative [Grade 2B] Reference: Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S. Geerts WH et al. Chest 2004;126:338S–400S November 2005

Venous thromboembolism 7th ACCP recommendations Total hip, knee replacement or hip fracture surgery Prophylaxis should be extended until 28–35 days after surgery THR: LMWH, VKA or fondaparinux [all Grade 1A)] HFS: Fondaparinux (Grade 1A), LMWH or VKA [both Grade 1C+] TKR: Benefits remain unclear Geerts WH et al. Chest 2004; 126:338S–400S November 2005

Timing of anticoagulant therapy in orthopaedic surgery Venous thromboembolism In Europe, the first dose of LMWH is commonly administered the evening (10-12 hours) before surgery The timing of initiation of anticoagulant therapy is an important issue in orthopaedic surgery patients as it affects the delicate balance between efficacy and risk of bleeding. Currently, geographic differences in clinical practice exist with regards to the time that prophylaxis is first administered. In Europe, the first dose of LMWH is commonly administered the evening (10-12 hours) before surgery, while in North America the initial dose of LMWH or warfarin is not administered until 12-24 hours after surgery. A third, more recently introduced option for time of initiation of anticoagulant therapy is perioperative administration, which involves either a late preoperative (<2 hours prior to surgery, knife to skin) or an early postoperative (4-6 hours after surgery) first dose. It is now recognised that there is little difference between efficacy with preoperative (10-12 hours before surgery) and postoperative (12-14 hours after surgery) initiation of heparin or LMWH. Perioperative administration offers a greater risk reduction in the incidence of VTE, but also carries a greater risk of bleeding. In addition to the risk of bleeding, the decision regarding the time of initiation of prophylaxis is influenced by the risk of spinal haematoma, a complication of spinal or epidural anaesthesia that can lead to permanent spinal nerve injury. November 2005

Timing of anticoagulant therapy in orthopaedic surgery Venous thromboembolism In North America the initial dose of warfarin, or less common, LMWH is not administered until 12-24 hours after surgery The timing of initiation of anticoagulant therapy is an important issue in orthopaedic surgery patients as it affects the delicate balance between efficacy and risk of bleeding. Currently, geographic differences in clinical practice exist with regards to the time that prophylaxis is first administered. In Europe, the first dose of LMWH is commonly administered the evening (10-12 hours) before surgery, while in North America the initial dose of LMWH or warfarin is not administered until 12-24 hours after surgery. A third, more recently introduced option for time of initiation of anticoagulant therapy is perioperative administration, which involves either a late preoperative (<2 hours prior to surgery, knife to skin) or an early postoperative (4-6 hours after surgery) first dose. It is now recognised that there is little difference between efficacy with preoperative (10-12 hours before surgery) and postoperative (12-14 hours after surgery) initiation of heparin or LMWH. Perioperative administration offers a greater risk reduction in the incidence of VTE, but also carries a greater risk of bleeding. In addition to the risk of bleeding, the decision regarding the time of initiation of prophylaxis is influenced by the risk of spinal haematoma, a complication of spinal or epidural anaesthesia that can lead to permanent spinal nerve injury. November 2005

Prophylaxis most effective when initiated in close relation to surgery Venous thromboembolism Odds ratio 1.4 Quadratic fit for study odds ratio for DVT vs. the number of hours from surgery for the first dose of LMWH 1.0 0.6 0.2 Thromboprophylaxis is most effective when initiated in close temporal relation to surgery. The closer to surgery, the smaller the dose to obtain adequate anticoagulation. Reference: Hull R. Timing of initial administration of low molecular weight heparin prophylaxis against deep vein thrombosis in patients following elective arthroplasty. Arch Intern Med 2001;161:1952-60. -10 10 20 Hours from surgery Upper and lower dashed lines indicate the 95% confidence interval for the estimated odds ratio Hull R et al. Arch Intern Med 2001;160:2208-15 November 2005

Thrombin activation at bone traumatisation during THR surgery Venous thromboembolism Thrombin-antithrombin (TAT) (ng/mL) Prothrombin F1 + 2 (nmol/L) 100 80 60 40 20 5 * 4 *p=0.0001 Bone trauma Bone trauma 3 * 2 The activation of the coagulation cascade leading to deep venous thrombosis (DVT) begins during total hip arthroplasty. A better understanding of thrombogenesis during total hip arthroplasty (THR) may provide a more rational basis for treatment. In 3 separate studies, the following observations were made. Circulating indicators of thrombosis and fibrinolysis: prothrombin F1+2, thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer rose significantly during insertion of the femoral component. A significant decline in central venous oxygen tension was observed after relocation of the hip joint and after insertions of cemented and noncemented femoral components, providing evidence of femoral venous occlusion during insertion of the femoral component. Administration of 1000 units of unfractionated heparin (UFH) before insertion of a cemented femoral component blunted the rise of fibrinopeptide A. With increasing doses of heparin it was possible to control thrombin activity, but there was almost no influence on thrombin generation. The results of these studies suggest that (1) the greatest risk of activation of the coagulation cascade during THR occurs during insertion of the femoral component; (2) femoral venous occlusion and use of cemented components are factors in thrombogenesis during total hip arthroplasty; and (3) measures to prevent DVT during total hip arthroplasty (such as intraoperative anticoagulation) should begin during surgery rather than during the postoperative period and be applied during insertion of the femoral component. Reference: Sharrock NE. Go G. Harpel PC. Ranawat CS. Sculco TP. Salvati EA. The John Charnley Award. Thrombogenesis during total hip arthroplasty. Clin Orthop & Related Res 1995;319:16-27. * * 1 0.5 1.0 1.5 2.0 2.5 0.5 1.0 1.5 2.0 2.5 Time (h) (h) Time (h) Saline UFH 10 units/kg UFH 20 units/kg Sharrock NE et al. Clin Orthop 1995;319:16-27 November 2005

Increasing thrombin generation and thrombus growth after one week Venous thromboembolism F1+2* 20 Venography shows DVT ~1 week after surgery Arterial blood Scanning electron microscopy shows DVT ~1 hour after THR surgery 15 10 6 3 1 Days after Surgery 5 Mixed venous blood Hip replacement surgery, using acrylic cement for prosthesis fixation, is associated with intraoperative cardiorespiratory dysfunction, and a high frequency of postoperative proximal DVT. Levels of prothrombin fragments 1+2 (F1+2), tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor 1 activity (PAI-1), D-dimer and interleukin 6 (IL-6) were measured in arterial and mixed venous blood in five patients during and after total hip replacement operation with acrylic cement prosthesis fixation. Sequential peaks of F1+2, t-PA, PAI-1 and IL-6 appeared, starting with activation of coagulation during preparation of bone, closely followed by activation of fibrinolysis. Later, this was counteracted by an antifibrinolytic response and increase of IL-6. After a fibrinolytic shutdown on the third postoperative day as evidenced by a drop in t-PA and D-dimer concentrations, a second wave of coagulation was seen at the end of the first week (Dahl et al 1993). Levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity were determined in femoral vein blood from both limbs during and after surgery in 18 pigs that had undergone hemiarthroplasty. On the operated side, TAT increased during bone traumatization followed by a substantial rise in t-PA activity and a gradual decline in PAI-1 activity. This indicates a local pre- and post-operative sequential activation of coagulation and fibrinolysis followed by a fibrinolytic shutdown, all reflected in femoral vein blood on the operated side. Postoperative scanning electron microscopic (SEM) examination of the femoral veins showed thrombi on the operated side in 62% of the animals in the cement group and 25% in the non-cement group. In an additional study with eight animals undergoing cement-anchored hip prosthesis operations significantly higher levels of TAT, t-PA and PAI-I were found in femoral vein blood compared with mixed venous blood while no significant change was found in arterial blood compared with mixed venous blood. These studies indicate that traumatisation of bone marrow during hip surgery induce a marked local activation of coagulation and a high incidence of deep vein thrombosis in proximal veins, in particular if bone cement is used for prosthesis fixation (Dahl et al 1995). References: Dahl OE, Pedersen T, Kierulf P, Westvik AB, Lund P, Arnesen H et al. Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery. Thromb Res 1993;70:451-8. Dahl OE, Aspelin T, Lyberg T. The role of bone traumatization in the initiation of proximal deep vein thrombosis during cemented hip replacement surgery in pigs. Blood Coagulation & Fibrinolysis 1995;6:709-17. 1 2 3 4 5 6 7 8 Intraoperatively (h) Dahl OE et al. Thromb Res 1993;70:451-8 Dahl OE et al. Blood Coagul Fibrinolysis 1995;6:709-17 * Thrombin generation factors November 2005

Onset of VTE after THR / TKR - cumulated risk within 3 months Venous thromboembolism All VTE PE Thromboembolic events (%) Pulmonary embolism (%) 3.5 1.3 Primary hip Primary hip Primary knee Primary knee 3.0 1.0 2.5 0.8 2.0 1.5 0.5 1.0 Although routine prophylaxis in patients undergoing THR and TKR has become a widely accepted practice over the past decade, VTE remains an important problem. While the majority of patients receive prophylaxis in the hospital, 50% to 75% of thromboembolic events are diagnosed after discharge. White et al (1998) performed an analysis of the incidence and time course of objectively diagnosed VTE events following 19,586 primary unilateral THR and 24,059 unilateral TKR procedures performed in California during a 2 year period (1991-1993). The cumulative incidence of DVT and/or PE within 3 months of surgery was 2.8% after THR and 2.1% after TKR. The diagnosis of VTE was made after hospital discharge in 76% of THR patients and in 47% of TKR patients (P<0.001), with a median time of diagnosis of 17 days in THR patients and 7 days in TKR patients (P<0.001). 95% of patients had received thromboprophylaxis, mainly with warfarin or UFH, with or without intermittent pneumatic compression (IPC). Approximately 32% received warfarin after hospital discharge for an average duration of 4 weeks. The authors concluded that earlier, more intense prophylaxis may be needed in TKR, and more prolonged prophylaxis may be required after THR. Reference: White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998;158:1525-31. 0.3 0.5 0.0 0.0 14 28 42 56 70 84 14 28 42 56 70 84 Days Days White RH et al. Arch Intern Med. 1998;158:1525-1531 November 2005

Duration of thrombin generation in THR Venous thromboembolism Thrombin activity (TAT; ng/mL) D-dimer (ng/mL) 30 6000 TAT complexes 25 D-dimer – LMWH 20 4000 15 10 2000 5 1 6 14 20 35 Days after surgery Hip replacement surgery is associated with a high frequency of DVT. At the same time there is a substantial systemic and local activation of coagulation. Discontinuation of thromboprophylaxis one week after surgery may allow a second wave of coagulation and fibrinolysis activation to occur. An almost parallel increase in plasma TAT and D-dimer levels between the 6th and the 35th postoperative day may indicate late DVT formation (Dahl et al 1995). Discontinuation of thromboprophylaxis a few days after surgery may unmask delayed hypercoagulability and contribute to late formation of deep venous thrombosis (DVT). To investigate whether thromboprophylaxis should be prolonged beyond the hospital stay, a prospective, double-blind randomised study was conducted in 308 patients. All patients received initial thromboprophylaxis with dalteparin. On day 7, patients were randomised to receive dalteparin (Fragmin) 5000 IU once daily, or placebo, for 4 weeks. All patients were subjected to bilateral venography, perfusion ventilation scintigraphy and chest X-ray on days 7 and 35. The overall prevalence of DVT on day 7 was 15.9%. On day 35, the prevalence of DVT was 31.7% in placebo-treated patients compared with 19.3% in dalteparin-treated patients (p = 0.034). The incidence of DVT from day 7 to day 35 was 25.8% in the placebo-treated group versus 11.8% in the dalteparin-treated group (p = 0.017). The incidence of symptomatic pulmonary embolism (PE) from day 7 to day 35 was 2.8% in the placebo-treated group compared with zero in the dalteparin-treated group. This included one patient who died from PE. This study shows that prolonged thromboprophylaxis with dalteparin. 5000 IU, once daily for 35 days significantly reduces the frequency of DVT and should be recommended for 5 weeks after hip replacement surgery (Dahl et al 1997). References: Dahl OE, Aspelin T, Arnesen H, Seljeflot I, Kierulf P, Ruyter R, Lyberg T. Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery. Thromb Res 1995;80:299-306. Dahl OE. Andreassen G. Aspelin T. Muller C. Mathiesen P. Nyhus S. Abdelnoor M. Solhaug JH. Arnesen H. Prolonged thromboprophylaxis following hip replacement surgery--results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin).Thrombosis & Haemostasis 1997;77:26-31. 32% DVT at venography 16% Dahl OE et al. Thromb Res 1995;80:299-306 Dahl OE et al. Thromb Haemost 1997;77:26-31 November 2005

Effect of continuing prophylaxis on asymptomatic DVT Venous thromboembolism DVT % 30 7 days Proximal DVT 25 35 days 20 15 10 5 40 Total DVT 30 References: Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlundh U, Nicolas S et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against thromboembolism after total hip replacement. N Engl J Med 1996;335:696-700. Planes A; Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: Double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996;348:224-8. Dahl OE, Anderassen G, Aspelin T, Muller C, Mathiesen P, Nyhus S et al. Prolonged thromboprophylaxis following hip replacement surgery – results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997;77:26-31. Spiro T, Group TECT. A double blind multicenter clinical trial comparing long term enoxaparin and placebo treatments in the prevention of venous thromboembolic disease after hip and knee replacement surgery (abstract) Blood 1997:90 Suppl 1:295a Lassen MR, Borris LC, Anderson BS, Jensen HP, Skejo Bro HP, Anderson G et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasy – the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998;89:281-7. Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K et al. Low molecular weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomised comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2208-15. 20 10 Bergqvist 1996 Planes 1996 Dahl 1997 Spiro 1997 Lassen 1998 Hull 2000 November 2005

Extended LMWH reduces symptomatic VTE Venous thromboembolism Extended Control OR (95% CI) n (N) n (N) Bergqvist 2 (131) 10 (131) 0.25 (0.08, 0.79) Dahl 4 (117) 6 (110) 0.62 (0.17, 2.19) Heit 7 (607) 10 (588) 0.68 (0.26, 1.76) Hull 4 (291) 3 (133) 0.58 (0.12, 2.91) Lassen 2 (140) 3 (141) 0.67 (0.11, 3.92) Planes 3 (90) 7 (89) 0.43 (0.12, 1.52) Total 22 (1376) 39 (1192) 0.50 (0.30, 0.83) Meta-analysis of six published studies that examined the issue of prolongation of thromboprophylaxis post-discharge in patients undergoing lower limb arthroplasty. These studies have consistently shown a 50-60% reduction in venographic DVT when prolonged LMWH prophylaxis for 4-5 weeks is compared to conventional prophylaxis for 7-15 days. However, the relevance of these venographic endpoints for clinical trials in VTE is debated. All six studies were randomised, double-blind and placebo controlled. A meta-analysis was performed using the Cochrane Collaboration´s RevMan to examine the relationship between the clinical VTE events and prolonged prophylaxis. All randomised patients were considered at risk of developing clinical events and only objectively confirmed VTE events were included in the analysis. The overall frequency of clinical VTE events in the six studies was 1.6% (22 events in 1376 patients) in the extended treatment group and 3.3% (39 events in 1192 patients) in the placebo control group. This represented a significant 51% reduction in the risk of symptomatic clinical VTE (RR 0.49, 95% CI 0.29-0.82; p=0.008). The meta-analysis revealed very similar results with a significant 50% reduction in the odds of developing clinical VTE (OR 0.50, 95% CI 0.30-0.83; p=0.009). In conclusion, this analysis has shown that extended thromboprophylaxis with LMWH following lower limb arthroplasty results in a significant 50% reduction in the odds of developing clinical VTE events. It has also shown that the overall reduction in venographic events was very similar to the reduction in clinical events. Reference: Cohen AT, Bailey CS, Alikhan R, Cooper DJ. Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty – a meta-analysis. Thromb Haemost 2001:85;940-1. Cohen A et al. Thromb Haemost 2001;85:940-1 November 2005

Relative risk for DVT out-of-hospital Venous thromboembolism No. patients with events Relative risk Study Year LMWH group Control group Weight (95% CI fixed) p value n/n (%) (%) Bergqvist et al 1996 21/117 (17.9) 45/116 (38.8) 28.6 0.46 (0.30–0.73) 0.001 Planes et al 1996 6/85 (7.1) 17/88 (19.3) 10.6 0.37 (0.15–0.88) 0.025 Dahl et al 1997 11/93 (11.8) 23/89 (25.8) 14.9 0.46 (0.24–0.88) 0.020 Lassen et al 1998 5/113 (4.4) 12/102 (11.8) 8.0 0.38 (0.14–1.03) 0.057 Hull et al 2000 14/291 (4.8) 14/133 (10.5) 12.2 0.46 (0.22–0.93) 0.031 Comp et al 2001 15/152 (9.9) 39/138 (28.2) 25.9 0.35 (0.20–0.60) <0.001 Total 72/911 (7.9) 150/666 (22.5) 100.0 0.41 (0.32–0.54) <0.001 Slide: Individual and total outcomes with respect to all venographically detected DVT. Study selection: randomised, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of DVT (placebo rate, 150 of 666 patients, 22.5%); relative risk, 0.41 (95% CI, 0.32 to 0.54; p<0.001); proximal venous thrombosis (placebo rate, 76 of 678 patients, 11.2%; relative risk, 0.31 (CI, 0.20 to 0.47; p<0.001 and symptomatic VTE (placebo rate, 36 of 862 patients (4.2%); relative risk, 0.36 (CI, 0.20 to 0.67; p=0.001). Major bleeding was rare, occuring in only one patient in the placebo group. Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic DVT and symptomatic VTE. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery. Reference: Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001;135:858-869. Hull RD et al. Ann Intern Med 2001;135:858-69 November 2005

Relative risk for symptomatic VTE out-of-hospital Venous thromboembolism Relative risk for symptomatic VTE out-of-hospital No. patients with events Relative risk Study Year LMWH group Control group Weight (95% CI fixed) p value n/n (%) (%) Bergqvist et al 1996 2/131 (1.5) 10/131 (7.6) 26.3 0.20 (0.04–0.90) 0.035 Planes et al 1996 3/90 (3.3) 7/89 (7.9) 18.5 0.42 (0.11–1.59) 0.2 Dahl et al 1997 4/117 (3.4) 6/110 (5.5) 16.3 0.63 (0.18–2.16) >0.2 Lassen et al 1998 2/140 (1.4) 3/141 (2.1) 7.9 0.67 (0.11–3.96) >0.2 Hull et al 2000 4/389 (1.0) 3/180 (1.7) 10.8 0.62 (0.14–2.73) >0.2 Comp et al 2001 0/224 (0.0) 7/211 (3.3) 20.3 0.06 (0.00–1.09) 0.058 Total 15/1,091 (1.4) 36/862 (4.2) 100.0 0.36 (0.02–0.67) <0.001 Slide: findings for symptomatic VTE only. Again a consistent reduction in VTE was shown, underlying the relationship between venographically confirmed DVT and symptomatic DVT. Study selection: randomised, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of DVT (placebo rate, 150 of 666 patients, 22.5%); relative risk, 0.41 (95% CI, 0.32 to 0.54; p<0.001); proximal venous thrombosis (placebo rate, 76 of 678 patients, 11.2%; relative risk, 0.31 (CI, 0.20 to 0.47; p<0.001 and symptomatic VTE (placebo rate, 36 of 862 patients (4.2%); relative risk, 0.36 (CI, 0.20 to 0.67; p=0.001). Major bleeding was rare, occuring in only one patient in the placebo group. Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic DVT and symptomatic VTE. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery. Reference: Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001;135:858-869. Hull RD et al. Ann Intern Med 2001;135:858-69 November 2005