THROMBOPROFYLAXIE BIJ MAJEURE ORTHOPEDISCHE CHIRURGIE

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1 Lok ortho

2 THROMBOPROFYLAXIE BIJ MAJEURE ORTHOPEDISCHE CHIRURGIE Maart 2011 Dr P.Verstraeten

3 alle 3 componenten van de Virchow- triade betrokken bij Orthopedische chirurgie! Hypercoagulabele status Endotheliale lesies Circulatoire stase

4 Major orthopaedic surgery is an important risk factor for DVT Group Prevalence of DVT (%) Medical patients Major gynaecological/ urological/ genital surgery Neurosurgery Stroke Hip/knee replacement surgery/ hip fracture surgery Major trauma Spinal cord injury Adapted from Geerts WH et al. Chest 2008;133:381S 453S, with permission from the American College of Chest Physicians.

5 Bekende gevolgen van VTE Fatale longembolie Verhoogde kans op recidief Chronisch post-thrombotisch syndroom Chronische thromboembolische pulmonale hypertensie (2 à 4 %) Verhoogde morbiditeit en QOL Hoge kosten i.v.m.investigaties en behandeling van symptomatische patients Geerts WH et al. Chest 2008;133:381S 453S.

6 Cave Mogelijks onderschatting van het probleem door de orthopedisch chirurg : Pten met SS VTE ( vnl.longembolie!) komen op Urgentie afdeling terecht, of bij de longarts!!

7 VTE (= DVT en /of LONGEMBOLIE) IN MOS VTE is de meest frekwente oorzaakvan re-hospitalisatie na THR ingreep. De meeste symptomatische VTE s gebeuren na ontslag!! VTE incidentie In-hospital prophylaxis Discharge Most DVTs and PEs occur after discharge Increased risk without prophylaxis Geerts WH et al. Chest 2008;133:381S 453S; Cohen AT et al. Thromb Haemost 2007;98: tijd

8 Cumulative incidence of symptomatic VTE after THR or TKR 2.5 Cumulative VTE incidence (%) TKR (n = 8236) THR (n = 6639) Time after surgery (days) Adapted from Warwick D et al. J Bone Joint Surg Br 2007;89: , with permission and copyright of the British Editorial Society of Bone and Joint Surgery.

9 Timing of VTE events after THR or TKR 50 Median time to discharge Mean time to events Time after surgery (days) Total hip replacement Total knee replacement Data from Warwick D et al. J Bone Joint Surg Br 2007;89:

10 The time course of thromboprophylaxis versus the cumulative incidence of VTE Patients receiving prophylaxis (%) THR Cumulative VTE incidence Prophylaxis (any type) Time after surgery (days) Cumulative VTE incidence (%) Patients receiving prophylaxis (%) TKR Cumulative VTE incidence Prophylaxis (any type) Time after surgery (days) Cumulative VTE incidence (%) Adapted from Warwick D et al. J Bone Joint Surg Br 2007;89: ,, with permission and copyright of the British Editorial Society of Bone and Joint Surgery.

11 THROMBOPROFYLAXE : bij totale heup / knie prothese (THP / TKP) UNDERUSED Ondanks de aanbevelingen krijgt een aanzienlijk aandeel van de patiënten geen adequate tromboprofylaxe na een THP/TKP 1995: enquête van de British Orthopaedic Association: 13 tot 15% en 18 tot 33% van de chirurgen gebruikten geen enkele tromboprofylaxe na respectievelijk een THP en TKP 2007: analyse van de HealthFacts-database: slechts 13.3% van de artsen volgden correct de aanbevelingen voor VTE profylaxe 2007: Global Orthopaedic Registry: profylaxe na een THP/TKP wordt niet voor de juiste tijdsduur voorgeschreven

12 Anticoagulantia bij MOS-pten De anticoagulantia die momenteel beschikbaar zijn voor de preventie van VTE na een THP en TKP zijn : niet-gefractioneerde heparines (UFH) heparines met laag moleculair gewicht (LMWH) fondaparinux vitamine K-antagonisten (VKA) Zij inhiberen onrechtstreeks de vorming en/of de werking van trombine (factor IIa)

13 Aanbevelingen bij totale heup / knie prothese (THP / TKP) Er bestaan geen nationale Belgische aanbevelingen voor de preventie van VTE Folia farmacotherapeutica 1 : Bij majeure orthopedische operaties wordt een behandeling met antitrombotica aanbevolen; LMWH zijn de referentiebehandeling. Fondaparinux is een alternatief, maar is geen voorkeursmiddel omdat er minder ervaring is met langdurig gebruik in vergelijking met heparines de kosten hoger liggen. 1.

14 VTE prevention : GUIDELINES Evidence-based clinical practice guidelines: American College of Chest Physicians (ACCP) 1 International Consensus Statement 2 AAOS 1 Geerts WH et al. Chest 2008;133: S; 2 Nicolaides AN et al. Int Angiol 2006;25:

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16 ACCP guidelines for VTE prevention after major orthopaedic surgery Eighth ACCP Conference on Antithrombotic Therapy Procedure Recommendation Duration Level of evidence Elective total hip replacement LMWH, fondaparinux, or adjusted-dose VKA At least 10 days, up to 35 days 1A 1A Elective total knee replacement LMWH, fondaparinux, or adjusted-dose VKA At least 10 days, up to 35 days 1A 2B Acetylsalicylic acid is not recommended by the ACCP as sole prophylaxis in any of these patients. Intermittent pneumatic compression is not recommended as sole method of thromboprophylaxis in patients undergoing THR. Data from Geerts WH et al. Chest 2008;133:381S 453S. LMWH, low molecular weight heparin; VKA, vitamin K antagonist.

17 Onbeantwoorde behoeften Verschillende doeltreffende therapeutische modaliteiten zijn momenteel beschikbaar voor de preventie van VTE na een THP/TKP. Ze hebben echter allemaal nadelen, hoofdzakelijk wat betreft toedieningswijze en/of de noodzaak voor biologische monitoring Therapie LMWH Fondaparinux VKA Belangrijkste nadelen Uitstekend evenwicht doeltreffendheidveiligheid / MAAR : - Subcutane injectie - Risico op HIT (controle van de bloedplaatjes) - Subcutane injectie - Meer bloedingen in vergelijking met LMWH - Minder doeltreffend dan LMWH - Frequente controle met INR 17

18 Onbeantwoorde behoeften voor de preventie van VTE Onbeantwoorde : behoeften IDEAAL ANTICOAGULANS : AC met een doeltreffendheids- en veiligheidsprofiel vergelijkbaar met LMWH Orale toediening Zonder monitoring 18

19 Nieuwe anticoagulantia

20 New anticoagulants ORAL PARENTERAL TTP889 TF/VIIa TFPI (tifacogin) X IX Rivaroxaban Apixaban LY YM150 DU-176b PRT Ximelagatran Dabigatran IXa VIIIa Va Xa II IIa AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a Otamixaban Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

21 DABIGATRAN ( PRADAXA) Boehringer Ingelheim

22 Orthopaedic VTE Prevention Re-novate:THR-prolonged Re-model:TKR (EU) Re-mobilize:TKR (USA) Re-novate II : THR VTE Treatment Re-cover: treatment of VTE Re-medy: Long-term treatment status : ongoing (Recover ) Status: completed! Status:Completed Stroke Prevention Atrial fibrillation Pethro Re-ly Status: completed study

23 Dabigatran etexilate (PRADAXA ) Oraal Prodrug! Directe thrombine (FIIa) inhibitor : - snel en krachtig - reversiebele binding Dosis : mgr/dd ( profylaxie) pradaxa

24 Eerste 3 grote Fase III orthopedie-studies Total VTE and all cause mortality ENOXA DABI 150 mgr/d. DABI 220 mgr/d. REMOBILIZE 25.3(2.2) 33.7 (3.0) 31.3(3.4) (THR ; USA) 2x30 mgr REMODEL 37.7(3.5) 40.5(3.8) 36.4(2.6) ( TKR ; EU) RENOVATE 6.7 (3.9) 8.6 (4.3) 6.0 (3.1) ( THR ; UE) ( ) = major VTE

25 MAJEURE BLOEDINGEN (%) ENOXA DABI 150 DABI 220 REMOBILIZE (USA) REMODEL RENOVATE Pooled analysis : major en clin sign.non-major bleed : %

26 RIVAROXABAN XARELTO Bayer

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28 RECORD: phase III programme for VTE prevention Rivaroxaban 10 mg o.d. administered 6 8 hours post surgery compared with enoxaparin Same efficacy and safety outcomes Same independent, blinded adjudication committees Hip replacement Hip replacement Knee replacement Knee replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days Rivaroxaban 10 mg o.d. for 35 ± 4 days Rivaroxaban 10 mg o.d. for 12 ± 2 days Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. vs. vs. vs. Enoxaparin 40 mg o.d. for 35 ± 4 days Enoxaparin 40 mg o.d. for 12 ± 2 days followed by placebo Enoxaparin 40 mg o.d. for 12 ± 2 days Enoxaparin 30 mg b.i.d. for 12 ± 2 days N = 4541 N = 2509 N = 2531 N = 3148 Data from Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358: ; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.

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30 Surgeons are very concerned about bleeding at surgical site. Although in the case of orthopaedic surgery bleedings are mostly located at the surgical sites, it s important to note that in these definitions only important bleedings at extra-surgical sites are taking into account.

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32 RENOVATE II (dabigatran) 2050 pten met THR R/ 220 mgr DABI (1/2 dosis 1-4h. Postop) enoxa 40 mgr(start avond voor chirurgie) 28 à 35 dd behandeling 1 efficacy : total VTE en all cause 2 : major VTE +VTE related 1 safety : major bleeding

33 RESULTATEN : RENOVATE II DABI ENOXA p-value 1 Eff.outcome 7.7 % 8.8 % (non inf) 2 Eff. outcome 2.2 % 4.2 % p : 0.03 Major bleed 1.4 % 0.9% p : 0.40

34 In het kader van MOS kunnen de nieuwe orale antico s een aantrekkelijk alternatief zijn : Vb bij out of hospital profylaxie bij pten met THR Bij oudere pten met verminderde NF : vb pradaxa in een dosis van 150 mgr dd.(cfr RENOVATE 2)

35 Conclusies Patienten die een THR of TKR moeten ondergaan hebben een hoog risico op VTE Dit risico persisteert gedurende meerdere weken na ontslag uit het ZH Lange-term ijn complicaties van VTE verhogen de morbiditeit en verminderende quality of life Primaire VTE - preventie is dan ook essentieel!

36 THE END

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38 Primary efficacy endpoint Total VTE Enoxaparin regimen (%) Rivaroxaban regimen (%) p-value < *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. < Data from Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358:

39 Safety: components of bleeding Major bleeding Non-major bleeding Enoxaparin regimen (%) Rivaroxaban regimen (%) p-value Enoxaparin regimen (%) Rivaroxaban regimen (%) p-value *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. Data from Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358:

40 Secondary efficacy endpoints Major VTE Symptomatic VTE Enoxaparin regimen (%) Rivaroxaban regimen (%) p-value Enoxaparin regimen (%) Rivaroxaban regimen (%) p-value < * *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. Data from Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358:

41 Total VTE: summary Incidence (%) ARD 2.6% ( 3.7 to 1.5) p < RRR = 70% 3.7% Enoxaparin regimen Rivaroxaban regimen 1.1% 1 ARD 9.2% ( 12.4 to 5.9) p < RRR = 49% 18.9% 9.6% *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin. Data from 1 Eriksson BI et al. N Engl J Med 2008;358: ; 2 Kakkar AK et al. Lancet 2008;372:31 9; 3 Lassen MR et al. N Engl J Med 2008;358:

42 RECORD1, 2 and 3: conclusions In almost adult patients undergoing elective hip or knee replacement rivaroxaban compared with enoxaparin showed Superior efficacy for reducing total VTE: in head-to-head comparisons with enoxaparin (RECORD1 and 3) comparing extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin (RECORD2) Superior efficacy for reducing major VTE in RECORD1 and 3 Significant reduction of symptomatic VTE in RECORD3 Significant reduction of major and symptomatic VTE in RECORD2 Low and similar rates of bleeding events No evidence of drug-induced liver injury attributable to rivaroxaban Consistently low level of cardiovascular adverse events Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358:

43 Major VTE: summary 7 6 ARD, 4.5% ( 6.0 to 3.0) p < RRR = 88% Enoxaparin regimen Rivaroxaban regimen Incidence (%) % ARD, 1.7 ( 2.5 to 1.0) p < RRR = 88% 5.1% ARD, 1.6% ( 2.8 to 0.4) p = 0.01 RRR = 62% 2.6% *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin % 0.6% 1.0% 1 2* 3 Data from 1 Eriksson BI et al. N Engl J Med 2008;358: ; 2 Kakkar AK et al. Lancet 2008;372:31 9; 3 Lassen MR et al. N Engl J Med 2008;358: ARD, absolute weighted risk difference (95% CI); RRR, relative risk reduction.

44 Symptomatic VTE: summary 4 Enoxaparin regimen Rivaroxaban regimen Incidence (%) 3 2 ARD, 0.2 ( 0.6 to 0.1) p = 0.22 NS ARD, 1.0 ( 1.8 to 0.3) p = RRR = 80% 2.0% ARD, 1.3 ( 2.2 to 0.4) p = RRR = 66% *RECORD2 compared extended- duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin % 0 0.5% 0.7% 0.2% 0.3% 1 2* 3 Data from 1 Eriksson BI et al. N Engl J Med 2008;358: ; 2 Kakkar AK et al. Lancet 2008;372:31 9; 3 Lassen MR et al. N Engl J Med 2008;358:

45 The ACCP guidelines and the ICS recommend pharmaceutical prophylaxis after THR Option ACCP 1 ICS 2 LMWH Yes (1A) Yes (A)* Fondaparinux Yes (1A) Yes (A)* Oral vitamin K antagonist Yes (1A) Yes (A) IPC ± GCS Yes (1A)** Yes (A)** VFP ± GCS Yes (1A)** Yes (A)** GCS No (1A) Aspirin No (1A) Low-dose heparin No (1A) *Preferred options. **Options for patients at increased risk of bleeding. Data from 1 Geerts WH et al. Chest 2008;133: S; 2 Nicolaides AN et al. Int Angiol 2006;25: GCS, graduated compression stocking; IPC, intermittent pneumatic compression; VFP, venous foot pump.

46 The ACCP guidelines and the ICS recommend pharmaceutical prophylaxis after TKR Option ACCP 1 ICS 2 LMWH Yes (1A) Yes (A) Fondaparinux Yes (1A) Yes (B) Oral vitamin K antagonist Yes (1A) Yes (A) IPC ± GCS Yes (1A)** Yes (B) VFP ± GCS Yes (1B)** Yes (B) GCS Aspirin No (1A) Low-dose heparin No (1A) **Options for patients at increased risk of bleeding. Data from 1 Geerts WH et al. Chest 2008;133: S; 2 Nicolaides AN et al. Int Angiol 2006;25: GCS, graduated compression stocking; IPC, intermittent pneumatic compression; VFP, venous foot pump.

47 Guidelines for VTE prevention in patients undergoing THR recommend up to 35 days of thromboprophylaxis Guideline Classification Recommendation for duration of therapy Prevention of VTE: the 8 th ACCP Conference on Antithrombotic and Thrombolytic Therapy (2008) Geerts WH et al. Chest 2008;133: S. 1A 1A Thromboprophylaxis for at least 10 days Recommend thromboprophylaxis beyond 10 days and up to 35 days Prevention of VTE: International Consensus Statement (2006) Nicolaides AN et al. Int Angiol 2006;25: A C Not given Thromboprophylaxis with LMWH should continue for 4 6 weeks Thromboprophylaxis with fonadaparinux should continue for 4 6 weeks Use of IPC or VFP should continue as long as tolerated, and then be replaced by chemical prophylaxis for the rest of the period of risk IPC, intermittent pneumatic compression; VFP, venous foot pump.

48 Guidelines for VTE prevention in patients undergoing TKR suggest up to 35 days of thromboprophylaxis Guideline Classification Recommendation for duration of therapy Prevention of VTE: the 8 th ACCP Conference on Antithrombotic and Thrombolytic Therapy (2008) Geerts WH et al. Chest 2008;133: S. 1A 2B Thromboprophylaxis should continue for at least 10 days Suggest thromboprophylaxis extended beyond 10 days and up to 35 days Prevention of VTE: International Consensus Statement (2006) Nicolaides AN et al. Int Angiol 2006;25: Not given Effect of extending prophylaxis using LMWH to days beyond hospitalization less than in patients undergoing THR IPC, intermittent pneumatic compression; VFP, venous foot pump.

49 Incidence of symptomatic VTE after THR or TKR without extended thromboprophylaxis Patients with symptomatic VTE (%) In-hospital prophylaxis followed by placebo or no treatment 0 Planes et al Bergqvist et al Dahl et al NPHDO 1998 Manganelli et al Lassen el al Hull et al Hull et al Comp et al Total Data from Eikelboom JW et al. Lancet 2001;358:9 15.

50 Extended-duration thromboprophylaxis reduces the incidence of VTE after THR and TKR Meta-analysis: nine studies (THR/TKR) N = 3999 Extended-duration (30 42 days) prophylaxis reduces venographic DVT and symptomatic VTE Prevalence (%) % In-hospital prophylaxis followed by: Placebo/no treatment Extended prophylaxis 9.6% 0 3.3% 1.3% Data from Eikelboom JW et al. Lancet 2001;358:9 15. Venographic DVT Symptomatic VTE

51 Use of prophylaxis in patients undergoing THR: data from the Global Orthopaedic Registry % 81% 95% 92% USA (n = 1227) Other (n = 2723) Patients (%) % 57% 47% 62% 20 0 *In accordance with recommended timing, duration, and intensity. 1% 12% LMWH Warfarin IPC ACCP (2001)- recommended prophylaxis ACCP (2001)- recommended prophylaxis, in accordance with recommended regimen* Adapted from Friedman RJ et al. Curr Med Res Opin 2008;24; IPC, intermittent pneumatic compression.

52 Use of prophylaxis in patients undergoing TKR: data from the Global Orthopaedic Registry Patients (%) % 93% 39% 77% 99% 96% USA (n = 2065) Other (n = 2145) 61% 69% 20 0 LMWH *In accordance with recommended timing, duration, and intensity 1% Warfarin 16% IPC and LMWH/warfarin Adapted from Friedman RJ et al. Curr Med Res Opin. 2008;24; % 3% IPC alone ACCP (2001)- recommended prophylaxis ACCP (2001)- recommended prophylaxis in accordance with recommended regimen* IPC, intermittent pneumatic compression.

53 Anticoagulantia Alle anticoagulantia houden een bloedingsrisico in Belang van het evenwicht doeltreffendheid - veiligheid NICE 2007

54 3 grote Fase III orthopedie-studies Total VTE and all cause mortality ENOXA DABI 150o.d. DABI 220 o.d. REMOBILIZE (THR ; usa) REMODEL ( TKR ; eu) RENOVATE ( THR ; eu) * zo clinically relevant major VTE events : geen verschil

55 MAJEURE BLOEDINGEN ENOXA DABI 150 DABI 220 REMOBILIZE REMODEL RENOVATE

56 Efficacy endpoints Primary Total VTE: any DVT, non-fatal PE and all-cause mortality Secondary Major VTE: proximal DVT, non-fatal PE and VTE-related death DVT (any, proximal, distal) Symptomatic VTE Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358: All outcomes underwent blind adjudication by an independent committee.

57 Safety endpoints Main Major bleeding starting after the first blinded dose and up to 2 days after last dose Other Any bleeding on treatment* Non-major bleeding* Haemorrhagic wound complications* Cardiovascular adverse events Liver enzyme levels Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358: *Up to 2 days after last dose of study medication. All outcomes underwent blind adjudication by an independent committee.

58 RECORD phase III programme: study design Rivaroxaban 10 mg o.d. was compared with enoxaparin in > patients undergoing total hip or knee replacement surgery Rivaroxaban regimen (10 mg o.d.) Enoxaparin regimen THR 10 mg o.d.; 5 weeks 40 mg o.d.; 5 weeks * THR 10 mg o.d.; 5 weeks 40 mg o.d.; 2 weeks TKR 10 mg o.d.; 2 weeks 40 mg o.d.; 2 weeks TKR 10 mg o.d.; 2 weeks 30 mg b.i.d.; 2 weeks *RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. In contrast to the other trials, RECORD2 was a comparison of regimens, rather than a drug versus drug comparison. Followed by oral placebo for 3 weeks. Data from Eriksson BI et al. N Engl J Med 2008;358: ; Kakkar AK et al. Lancet 2008;372:31 9; Lassen MR et al. N Engl J Med 2008;358: ; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.