Σάββας Σουρμελής Διευθυντής Β Ορθοπαιδικής Κλινικής ΔΘΚΑ «Υγεία»

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1 Σάββας Σουρμελής Διευθυντής Β Ορθοπαιδικής Κλινικής ΔΘΚΑ «Υγεία»

2 193s Heparin 194s 198s Low-molecularweight heparin Vitamin K antagonists 199s Direct thrombin inhibitors 22 Indirect Xa inhibitor 24 Oral direct thrombin inhibitors 28 Oral direct Xa inhibitor Xa ATIII + Xa + IIa II, VII, IX, X (Xa > IIa) (Protein C,S) ATIII + Xa + IIa (1:1 ratio) IIa ATIII + Xa IIa

3 Initiation TF VII a X IX Propagation Xa IXa I I Prothrombin Inactive factor Active factor Transformation Catalysis Direct Rivaroxaban Apixaban DX-965a DU-176b YM-15 II a Thrombin Clot formation Fibrinogen Fibrin Adapted from Spyropoulos AC. Expert Opin Investig Drugs 27;16:431 4.

4 Eriksson et al., N Engl J Med 358: , 28 Kakkar et al., Lancet 372:31 39, 28

5 Lassen et al., N Engl J Med 358: , 28 Turpie et al, The Lancet May 29

6 2 18 ARD 9.2% ( 12.4, 5.9) p <.1 RRR = 49% 18.9% Enoxaparin regimen Rivaroxaban regimen Incidence (%) ARD 2.6% ( 3.7, 1.5) p <.1 RRR = 7% ARD 7.3% ( 9.4, 5.2) p <.1 RRR = 79% 9.3% 9.6% ARD 3.2% (.71, 5.67) p =.16 RRR = 31% 1.1% 6.9% % 1.1% 2.% * *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short- duration (12 ± 2 days) enoxaparin. Data from 1 Eriksson BI et al. N Engl J Med 28;358: ; 2 Kakkar AK et al. Lancet 28;372:31 9; 3 Lassen MR et al. N Engl J Med 28;358: ; 4 Turpie AGG et al. Lancet 29;373: ARD, absolute weighted risk difference (95% CI); RRR, relative risk reduction.

7 Incidence (%) 3 2 Enoxaparin regimen Rivaroxaban regimen 1 p =.18 NS NS.5% p =.77 NS.6% p =.11 NS.7%.1%.3% <.1% <.1% *.3% *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short- duration (12 ± 2 days) enoxaparin. Eriksson BI et al. N Engl J Med 28;358: ; Kakkar AK et al. Lancet 28;372:31 9; Lassen MR et al. N Engl J Med 28;358: ; Turpie AGG et al. Lancet 29;373:

8 Incidence (%) Incidence (%) % 1.5% Enoxaparin 4 mg o.d. 38/2224 Enoxaparin 4 mg o.d. 24/1239 Rivaroxaban 1 mg o.d. 34/229 5 TKR 1.9% 2.% Rivaroxaban 1 mg o.d. 25/122 THR 1.7% 1.6% Short-duration enoxaparin + placebo 21/1229 Enoxaparin 3 mg b.i.d. 22/158 Extended-duration rivaroxaban 2/ % 1.4% Rivaroxaban 1 mg o.d. 21/1526 Eriksson BI et al. N Engl J Med 28;358: ; Kakkar AK et al. Lancet 28;372:31 9; Lassen MR et al. N Engl J Med 28;358: ; Turpie AGG et al. Lancet 2929;373:

9 Enoxaparin regimen % Rivaroxaban regimen %.4.4 * *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. ** Events coded as post-operative wound infections according to the MeDRA classification Eriksson BI et al. N Engl J Med 28;358: ; Kakkar AK et al. Lancet 28;372:31 9; Lassen MR et al. N Engl J Med 28;358: ; Turpie AGG et al. Lancet 29;373:

10 Cumulative event rate (%) Symptomatic VTE and all-cause mortality (during treatment and follow-up) Day 12 Day 1 = day of surgery Enoxaparin Rivaroxaban events HR=.49 (95% CI.35.69) p<.1 5 events Time-to-event relative to surgery (days) Safety population, n=12,383 Number of subjects at risk Rivaroxaban 6,183 5,98 5,843 5,819 5,572 3,319 3, Enoxaparin 6,2 5,941 5,84 5,765 5,535 3,284 3,92 765

11 Number of subjects at risk Rivaroxaban 6,183 5,99 5,859 5,836 5,587 3,326 3, Enoxaparin 6,2 5,966 5,835 5,795 5,57 3,34 3, Cumulative event rate (%) Day 1 = day of surgery Enoxaparin Rivaroxaban events HR=.61 (95% CI.39.98) p= events Time-to-event relative to surgery (days) Safety population, n=12,383 *Post hoc analysis

12 International, non-interventional, observational, open-label study Decisions about type, duration, and dose of drug used for venous thromboembolism (VTE) prophylaxis were made by the attending physician XArelto in the prophylaxis of post-surgical venous thromboembolism after elective Major Orthopaedic Surgery of hip or knee SOC, standard of care Turpie AGG et al. 212, NCT831714

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14 Total study duration pool Symptomatic VTE * Safety population Symptomatic VTE * n=12,383 *Different treatment duration in RECORD and XAMOS 1. Turpie AGG et al, 211; 2. Turpie AGG et al, 212 n=17,413 (rivaroxaban vs SOC) n=15,833 (rivaroxaban vs LMWH)

15 Incidence (%) Total treatment duration pool 1,* Rivaroxaban Enoxaparin SOC LMWH,4,2 Major bleeding (RECORD) 2,2 1,8 Major bleeding (EMA) 7, 6,5 Any bleeding,4,3,3 Major bleeding (RECORD) Safety Population * 1,4 1,4 1,3 Major bleeding (EMA) 4,7 3,3 3,2 Any bleeding *Different treatment duration in RECORD and XAMOS, all events treatment emergent 1. Turpie AGG et al, 211; 2. Turpie AGG et al, 212

16 Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery Findings from the ORTHO-TEP registry Jan Beyer-Westendorf; Jörg Lützner; Lars Donath; Luise Tittl; Holger Knoth; Oliver C. Radke; Eberhard Kuhlisch; Thoralf Stange5; Albrecht Hartmann2; Klaus-Peter Günther; Norbert Weiss; Sebastian Werth Thrombosis and Haemostasis Jan;19(1):154-63, 213 Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry J. BEYER-WESTENDORF,* J. LU TZNER, L. DONATH, * O. C. RADKE, E. KUHLISCH, A. HARTMANN, N. WEISS* and S. WERTH J Thromb Haemost, 1: , 212

17 Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery Findings from the ORTHO-TEP registry J.Westendorf, J.Lützner et al Thrombosis and Haemostasis Jan;19(1):154-63, 213

18 Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery Findings from the ORTHO-TEP registry J.Westendorf, J.Lützner et al Thrombosis and Haemostasis Jan;19(1):154-63, 213

19 Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry J.Westendorf, J.Lützner et al Journal of Thrombosis and Haemostasis, 1: , 212

20 Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry J.Westendorf, J.Lützner et al Journal of Thrombosis and Haemostasis, 1: , 212

21 Epidural anaesthesia

22 Types of neuraxial anaesthesia in the RECORD studies (n=8,176) % Patients in RECORD programme receiving neuraxial anaesthesia 28% 28% 8% 77.3% 61% 6% Patient demographics similar between neuraxial or GA More allogeneic transfusion in neuraxial group 25% 26% Epidural anaesthesia Indwelling epidural Spinal anaesthesia Spinal anaesthesia catheter only + other types Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin) N. Rosencher, J. V. Llau, et alacta Anaesthesiol Scand. May;57(5):565-72, 213

23 Use of neuraxial anaesthesia in the RECORD studies 12,729 pts randomised 12,383 pts safety population 66% neuraxial anaesthesia (n=8,176) 33% no neuraxial anaesthesia Rivaroxaban n=4,86 Enoxaparin n=4,9 8.6% + GA 9% + GA Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin) N. Rosencher, J. V. Llau, et alacta Anaesthesiol Scand., May;57(5):565-72, 213

24 1.76% Incidence of total VTE (%) 4.35% 9.13% 5.12% 9.85% 4.77% 9.11% 6.95% 3.17% 9.81% Spinal (+GA) Epidural (total) Epidural with indwelling catheter General or General alone spinal with femoral block Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin) N. Rosencher, J. V. Llau, et al, Acta Anaesthesiol Scand. May;57(5):565-72, 213

25 Two half lifes When can I remove an epidural catheter safely? --Remove it at least two ½ lives time for R has elapsed: after 18-2 hours When do I restart? hours after catheter removal Anaesthesia, 27 Tmax=2h Catheter removal 8 hours for thrombus stabilization

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29 1. Μόνο Ορθοπαιδική(1mgr x 1) 2.Μόνο μετεγχειρητικά 3.Μόνο ολικές αρθροπλαστικές ισχίου & γόνατος 4.Η χρήση στα κατάγματα ισχίου ή άλλες ορθοπαιδικές επεμβάσεις: off label 5.Προτιμότερα από πλευράς κόστους/ όφελος

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32 7 6 ARD, 4.5% ( 6., 3.) p <.1 RRR = 88% Enoxaparin regimen Rivaroxaban regimen Incidence (%) ARD, 1.7 ( 2.5, 1.) p <.1 RRR = 88% 2.% 5.1% ARD, 1.6% ( 2.8,.4) p =.2 RRR = 62% 2.6% ARD.8% ( 1.82,.22) p=.16 NS 2.% 1.2%.6% * 1.% 1.2% *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short- duration (12 ± 2 days) enoxaparin. Data from 1 Eriksson BI et al. N Engl J Med 28;358: ; 2 Kakkar AK et al. Lancet 28;372:31 9; 3 Lassen MR et al. N Engl J Med 28;358: ; 4 Turpie AGG et al. Lancet 29;373: ARD, absolute weighted risk difference (95% CI); RRR, relative risk reduction.

33 Enoxaparin regimen 16 Rivaroxaban regimen Incidence (%) % 5.8% 5.5% 6.5% 4.4% 4.3% 9.2% 1.2% 2 * *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short- duration (12 ± 2 days) enoxaparin. Eriksson BI et al. N Engl J Med 28;358: ; Kakkar AK et al. Lancet 28;372:31 9; Lassen MR et al. N Engl J Med 28;358: ; Turpie AGG et al. Lancet 29;373:

34 ΠΡΟΦΥΛΑΞΗ ΦΘΕ στην ΟΡΘΟΠΑΙΔΙΚΗ ANTΙΠΗΚΤΙΚΗ ΘΕΡΑΠΕΙΑ ΚΟΣΤΟΣ ΗΜΕΡΗΣΙΑΣ ΘΕΡΑΠΕΙΑΣ XARELTO (rivaroxaban) 1,78 CLEXANE (enoxaparin) 1,79 PRADAXA (dabigatran) 2,2 +14% ELIQUIS (apixaban) 2,16 21% INNOHEP (tinzaparin) 2,55 43% IVOR (bemiparin) 2,59 45% ARIXTRA (fondaparinux) 2,99 68% THROMBOPARIN (parnaparin) 3,6 7% Διορθωτικό Δελτίο Τιμών Φαρμάκων Ανθρώπινης Χρήσης (Ορθή Επανάληψη) - Υπουργείο Υγείας

35 ΚΟΛΠΙΚΗ ΜΑΡΜΑΡYΓ Η ΠΡΟΦΥΛΑΞΗ ΟΡΘΟΠΑΙΔΙΚΗ ΘΕΡΑΠΕΙΑ ΦΘΕ ΠΝΕΥΜΟΝΙΚ Η ΕΜΒΟΛΗ ΟΞΥ ΣΤΕΦΑΝΙΑΙΟ ΣΥΝΔΡΟΜΟ ΕΜΑ Apixaban Eliquis Dabigatran Pradaxa Rivaroxaban Xarelto FDA Apixaban Eliquis X Dabigatran Pradaxa X Rivaroxaban Xarelto