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Prevention of Venous Thromboembolism (VTE) Andrew Nicolaides

Prevention of Venous Thromboembolism (VTE) Andrew Nicolaides Emeritus Professor of Vascular Surgery Imperial College, London UK. VTE mortality per year in 25 EU countries. Deaths due to VTE : 543,454 1 More than double the combined deaths due to: AIDS 5,860 2

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Prevention of Venous Thromboembolism (VTE) Andrew Nicolaides

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  1. Prevention of Venous Thromboembolism (VTE) Andrew Nicolaides Emeritus Professor of Vascular Surgery Imperial College, London UK

  2. VTE mortality per year in 25 EU countries • Deaths due to VTE : 543,4541 • More than double the combined deaths due to: • AIDS 5,8602 • breast cancer 86,8312 • prostate cancer 63,6362 • transport accidents 53,5992 1Cohen AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005. 2Eurostat statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.

  3. Risk by Patient Group in the Absence of Prophylaxis Patient group Studies DVT incidence 95% CI Stroke 8 56% 51-61% THR 17 51% 48-54% Multiple trauma 4 50% 46-55% TKR 7 47% 42-51% Hip fracture 15 44% 40-47% Spinal cord inj. 9 35% 31-39% Retrop. prostatectomy 8 32% 27-37% Patients in ICU 3 25% 19-32% General Surgery 20 25% 24-26% Neurosurgery 5 22% 17-27% Gynecol. (malignancy) 4 22% 17-26% Gynecol. Surgery 4 15% 11-17% General medical 10 8.1% 7-9.1% Knee arthroscopy 7 8% 6-10% Nicolaides A et al Intern Angiol 2013 (In Press)

  4. ENDORSE Survey Multinational, cross-sectional survey of: (a) prevalence of VTE risk and (b) prophylaxis use in hospital

  5. Patient Enrollment Criteria Inclusion Criteria Acute medical patients age 40 or older Surgical patients age 18 or older Exclusion Criteria Admitted for treatment of VTE Not evaluable because of missing data

  6. Criteria for VTE Risk and Recommendations for Prophylaxis 1 Geerts WH, et al. Chest. 2004; 126 (Suppl 3):338S-400S

  7. ENDORSE : A worldwide study 32 countries - 358 hospitals First patient enrolled August 2, 2006 Last patient enrolled January 4, 2007

  8. Patients at risk for VTE in 32 countries N= 68,183 Mean=52%

  9. Patients at risk for VTE receiving recommended prophylaxis in 32 countries N= 35,329 Mean = 50%

  10. 59% receiving ACCP Rec. Px 40% receiving ACCP Rec. Px Surgical Patients at risk for VTE and receiving recommended prophylaxis Overall (N= 68,183) 52 % at Risk for VTE Primary objectives 50 % receiving ACCPRec. Px Medical ( n= 37,356) Secondary objectives Surgical ( n= 30,827) 64% at Risk for VTE 42% at Risk for VTE

  11. Conclusions ENDORSE demonstrates: the high prevalence of patients at risk for VTE and the need to improve the rate of prophylaxis use.

  12. These data reinforce the rationale to : (a) Implement hospital-wide strategies (b) Assess patient risk for VTE routinely (c) Provide appropriate prophylaxis (d) Educate the public to ask for prophylaxis when admitted to hospital

  13. The International Guidelines on Prevention of VTE (2013)

  14. PREVENTION AND TREATMENTOF VENOUS THROMBOEMBOLISMInternational Consensus Statement 2013Guidelines According to Scientific Evidence Developed under the auspices of the: Cardiovascular Disease Educational and Research Trust (UK) European Venous Forum North American Thrombosis Forum International Union of Angiology and Union Internationale du Phlebologie

  15. Prevention and Treatment of Venous Thromboembolism Consensus Statement • Aim • Provide a concise account of the evidence of efficacy or harm for various methods available to prevent and treat venous thromboembolism (VTE) • Provide recommendations based on critical evaluation of the evidence

  16. EDITORIAL COMMITTEE Chairman: AN Nicolaides, Cochairmen: J Fareed, AK Kakkar Members: AJ Comerota, SZ Goldhaber, R Hull, K Myers, M Samama, J Fletcher Editorial Secretary: E Kalodiki

  17. Faculty • D Bergqvist (Sweden) • J Bonnar (Ireland) • JA Caprini (USA) • C Carter (USA) • AJ Comerota (USA) • J Conard (France) • B Eklof (Sweden) • I Elalamy (France) • J Fareed (USA) • J Fletcher (Australia) • G Gerotziafas (France) • G Geroulakos (UK) • A Giannoukas (Greece) • SZ Goldhaber (USA) • I Greer (UK) • M Griffin (UK) • R Hull (USA) • A K Kakkar (UK) • S Kakkos (Greece) • E Kalodiki (UK) • MR Lassen (Denmark) • GDO Lowe (UK) • A Markel (Israel) • K Myers (Australia) • A Nicolaides (Cyprus) • P Prandoni (Italy) • G Raskob (USA) • M Samama (France) • AC Spyropoulos (USA) • AG Turpie (Canada) • JM Walenga (USA) • D Warwick (UK)

  18. Corresponding Faculty C Allegra (Italy) J Arcelus (Spain) N Baekgaard (Denmark) G Belcaro (Italy) H Bjarnason (USA) MA Cairols (Spain) M Catalano (Italy) D Christopoulos (Greece) D Clement (Belgium) F Corvalán (Chile) E Diamantopoulos (Greece) J Fernandes e Fernandes (Portugal) C Fisher (Australia) A Gasparis (USA) H Gibbs (Australia) V Hadjianastassiou (Cyprus) K Ivancev (UK) CP Hsien (Thaiwan) JT Hobbs (UK) D Hoppenstead (USA) EA Hussein (Egypt) O Iqbal (USA) K Ivancev (Russia) R Kistner (USA) TK Kim (Korea) M Kurtoglou (Turkey) T Kölbel (Germany) N Labropoulos (USA) LH Lee (Singapore) BB Lee (USA) Y-J Li (China) NC Liew (Malaysia) A Llinas (Colombia) M Nakamura (Japan) P Neglen (Cyprus) L Norgren (Sweden) H Partsch (Austria) N Ramakrishnan (India) G Rao (USA) J-B. Ricco (France) N Rich (USA) P Robless (Singapore) W Schobersberger (Austria) M Seed (UK) S Schellong (Germany) A Scuderi (Brazil) R Sexana (India) E Shaydakov (Russia) A Shevela (Russia) R Simkin (Argentina) W Toff (UK) JM Trabal (Puerto Rico) M Vandendriessche (Belgium) M Veller (South Africa) L Villavincencio (USA) R Wahi (USA) C Wittens (TheNetherlands) R Wong (Hong Kong)

  19. Levels of Evidence • High level of evidence was considered to be provided by • RCTs with consistent results, or • systematic reviews that were directly applicable to the target population • also, by single randomized trials which have been rigorously performed, methodologically reliable, and sufficiently large to give clear results that are applicable to most patients in most circumstances

  20. Levels of Evidence • Moderate level of evidence was considered to be provided by • RCT with less consistent results, limited power or other methodological problems, which were directly applicable to the target population • Also, by RCT extrapolated to the target population from a different group of patients.

  21. Levels of Evidence • Low level of evidence was considered to be provided by • well-conducted observational studies with consistent results that were directly applicable to the target population. • Lack of evidence ? • Lack of evidence or low level evidence resulted in a number of key questions that require to be addressed by future studies • These key questions are stated throughout the document and are summarised in the final section (Chapter 24).

  22. Outcomes • Evidence is presented for the following outcomes • asymptomatic DVT at screening • symptomatic DVT or PE, • fatal PE, • overall mortality and • development of the post-thrombotic syndrome (PTS) when available

  23. Recommendations Low risk patients (minor general surgery, no risk factors) Graduated elastic compression Avoid dehydration Level of evidence (LE): low (extrapolation from moderate risk)

  24. Effect of GEC (8 studies: moderate risk general surgery) 68% Reduction in DVT Incidence p < 0.001

  25. Effect of LDUH: 32 Studies in General Surgery 68% Reduction in DVT Incidence p < 0.001

  26. LMWH vs Placebo in General Surgery (1 study) 74% Reduction in DVT Incidence p < 0.025

  27. LMWH vs LDUH in General Surgery (17 Studies) 21% Reduction in DVT Incidence p < 0.025

  28. LMWH vs LDUH in General Surgery (14 Studies) 56% Reduction in PE Incidence p < 0.001

  29. LMWH vs LDUH in General Surgery LMWH is more effective in preventing PE has a lower risk of HIT than LDUH requires one injection per day

  30. Effect of IPC in General Surgery (11 studies) 69% Reduction in DVT Incidence p < 0.001

  31. Recommendations Moderate risk patients (major general surgery, age >40, no additional risk factors) (LDUH) or LMWH LE: high IPC + GEC LE: high

  32. Fondaparinux (Arixtra) in prevention of VTE in General Surgery(n= 2858) Relative Risk Reduction= 25% p = 0.14 7 6 5 6.1% % VTE 4 4.6% 62/1021 3 47/1027 2 1 0 Fondaparinux (Arixtra) Dalteparin British Journal of Surgery 2005, G Agnelliet al

  33. Cancer Surgery (n= 1941) Relative Risk Reduction= 39% (95 %CI : 59.6; 6.7%) p = 0.02 9 8 7 6 % VTE 5 7.7% 4 55/712 4.7% 3 33/696 2 1 0 Fondaparinux (ARIXTRA) Dalteparin British Journal of Surgery 2005, G Agnelliet al

  34. Recommendations High risk patients (major general surgery, age > 60 or age > 40 with at least one additional risk factor) (LDUH) LMWH LE: high IPC + GEC LE: high Fondaparinux (one study) LE: moderate IPC + GEC with LMWH LE: high

  35. Orthopedics

  36. Efficacy in Elective Hip Replacement(Historical progression) Control vs LDUH 50% reduction in DVT (20 sudies) Control vs IPC 52% reduction in DVT (4 studies) LDUH vs LMWH 54% further red. in DVT (10 studies) LMWH vs Fondaparinux 24% further red. In DVT (2 studies) 50% further red. In PE (2 studies) LMWH vs LMWH+IPC 28% vs 0% DVT (1 study)

  37. Efficacy of Fondaparinux vs Enoxaparin Fondaparinux better Enoxaparin better 95% CI Hip replacement n=3,411 (2 studies) -45.3% [-58.9; -27.4] Hip fracture n=1,250 -61.6% [-73.4; -45.0] Knee replacement n=724 [-75.5; -44.8] -63.1% Overall odds reduction p=10-17 -55.2% [-63.1; -45.8] 0 100 -100 -80 -60 -40 -20 20 40 60 80 Odds reduction (%) Homogeneity test: ns Turpie et al. Arch Intern Med 2002;162:1833-40

  38. New Oral Anticoagulants

  39. Figure 1: Site of Actions for Conventional and Newer Oral Anticoagulants

  40. Recommendationsfor Elective Hip Replacement (2013) Fondaparinux LE: high (Most effective) LMWH LE: high IPC + GEC LE: high (Equivalent to LMWH) IPC+GEC+LMWH LE: high (More effective than either) Rivaroxaban, Dabigatran LE: high Initiation LMWH: before or after operation LE: high Fondaparinux: at least 6 hours after operation

  41. Recommendations Neurosurgery IPC + GEC LE: High Acutely ill medical patients (LDUH) or LMWH LE: High IPC + GEC LE: Moderate Fondaparinux LE: Moderate

  42. Duration of thromboprophylaxis Total hip replacement patients (Hull et al1) • 4-5 weeks vs 1-2 weeks LMWH – 64% RRR for symptomatic VTE Cancer surgery (ENOXACAN II) 2 • 4 weeks vs 1 week LMWH – 60% RRR for VTE Major abdominal surgery (Rasmussen et al3) • 4 weeks vs 1 week LMWH –55% RRR for VTE Medical patients ? 1 Hull RD, et al. Ann Intern Med. 2001; 135:858-69.2 Bergqvist D, et al. NEJM. 2002; 346:975-980. 3Rasmussen MS, et al. J Thromb Haemost. 2006; 4:2384-2390.

  43. Study design • 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 Day 180±10 38±4 0 10+4 Mandatory ultrasonography qd = once a day, SC = subcutaneous

  44. Australia/NZ Spain U.K. Poland Germany Canada 4.6% Russia 3.7% 6.5% 4.0% 7.4% 4.1% 3.1% Colombia South Africa 2.8% 7.5% Italy 2.7% Mexico Tunisia 7.9% India 2.6% 2.2% Brazil 1.6% Israel 1.1% France 8.7% Belgium Austria 0.6% Argentina USA 0.3% 0.5% 28.2% Enrolment per country

  45. Baseline: Primary enrolment diagnosis

  46. Placebo Enoxaparin - 44% - 42% Efficacy – all VTE until Day 90 p = 0.0011 p = 0.0115 5.2 RRR 4.9 RRR 3.0 Incidence (%) 2.8 Day 38 Day 90

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

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