PROPHYLAXIS IN THE ORTHOPEDIC PATIENT: Martin H. Ellis MD Hematology Institute and Blood Bank Meir Medical Center Kfar Saba

Transcription

1 VENOUS THROMBOEMBOLISM PROPHYLAXIS IN THE ORTHOPEDIC PATIENT: Martin H. Ellis MD Hematology Institute and Blood Bank Meir Medical Center Kfar Saba

2 OVERVIEW Biochemistry of coagulation Pathogenesis of VTE Prevalence of VTE in the orthopedic patient Strategies t for VTE prophylaxis Novel oral anticoagulants

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5 INTRINSIC PATHWAY EXTRINSIC PATHWAY XII XIIa XI XIa Tissue Factor VIIIa IX IXa VIIa VII Ca 2+ Pr-S PL X Xa ANTITHROMBIN Protein C APC TM Va II IIa Ca 2+ PL Fibrinogen Fibrin XIII Cross-linked Fibrin COMMON PATHWAY Fibrinolysis

6 HOW BLOOD REALLY CLOTS VESSEL INJURY IX X TF VIIa IXa VIIIa X XIa TFPI XI Xa Va TM APC Prothrombin Platelets l THROMBIN TAFi Fibrinogen Fibrin Fibrinolysis

7 Contributing Factors Virchow triad - Venous stasis : More time for clotting Small clots not washed away Increased blood viscosity - Vessel wall damage Accidental trauma Surgical trauma - Blood coagulability increase : Increase in tissue factor Presence of activated factors Decrease in coagulation inhibitors

8 VTE Risk in Orthopedic Surgery Stasis Vessel wall damage Endothelial Damage Virchow s Triad Altered blood components Elevated fibrinogen, F VIII, F VII, platelet microparticle generation

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10 DVT - Symptoms leg pain leg cramps leg swelling redness of the leg

11 VTE risk in orthopedic surgery (%) THR TKR Hip # Untreated (Proximal) (7-30) (2-15) (10-15) 15) UFH (Proximal) 30 (15) (8) 25 LMWH (Proximal) (2) (6) (4)

12 Thromboembolism Incidence 45% of patients undergoing TKA had venographically proven DVT in the ipsilateral limb, within 24 hours after surgery 2% of the patients develop clinical pulmonary embolism Fatal pulmonary embolism occurring in % of patients Khaw FM, Moran CG, Pinder IM, Smith SR. The incidence of fatal Khaw FM, Moran CG, Pinder IM, Smith SR. The incidence of fatal pulmonary embolism after knee replacement with no prophylactic anticoagulation. J Bone Joint Surg Br 1993; 75:

13 VTE PROPHYLAXIS:OPTIONS Unfractionated heparin LMWH Intermittent pneumatic compression device Graduated compression stockings Coumadin Pentasaccharide (Fondaparinux) Direct Factor Xa inhibitors (Apixaban, Rivaroxaban) Direct thrombin inhibitors (Dabigatran) a Aspirin

14 Antithrombotic drugs: LMWH Small particles chemically derived d from UFH Predictable dose-response relation routine monitoring unnecessary Equivalence to UFH/Coumadin in all clinical settings studied (?? Prosthetic cardiac valves) Easily administered- home therapy possible Very rarely causes H.I.T.

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16 LMWH

17 Antithrombotic drugs: Fondaparinux (Arixtra) Synthetic pentasaccharide Specific inhibitor of F Xa More effective than Enoxaparin in VTE prophylaxis (orthopedic studies) As effective as Enoxaparin in DVT and PE treatment

18 New antithrombotic drugs: Dabigatran (Pradaxa) Oraldirect thrombin inhibitor Inhibits clot-bound thrombin reversibly Predictable dose-response routine monitoring unnecessary Given 1-4 hours post half daily dose Equivalent/superior i to LMWH and Coumadin in prevention and treatment studies (VTE and chronic AF)

19 New antithrombotic drugs: Apixaban (Eliquis) Oral direct anti-xa inhibitor Inhibits Xa reversibly Predictable dose-response routine monitoring unnecessary Given hours post op mg bid Equivalent/superior to LMWH and Coumadin in prevention and treatment studies (VTE and chronic AF)

20 New antithrombotic drugs: Rivaroxaban (Xarelto) Oraldirect anti-xa inhibitor Inhibits Xa reversibly Predictable dose-response routine monitoring unnecessary Equivalent/superior to LMWH and Coumadin in prevention and treatment studies (VTE and chronic AF)

21 CLINCAL STUDIES: NOVEL ORAL ANTICOAGULANTS

22 Dabigatran for prevention of VTE after major orthopaedic surgery: phase III studies Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies Study Type of Comparator Number of Time to 1st Treatment surgery patients administration duration of dabigatran RE-MODEL TKR Enoxaparin hours 6 10 days 40 mg od, starting evening before surgery RE-MOBILIZE TKR Enoxaparin 30 mg bid, starting hours postsurgery RE-NOVATE THR Enoxaparin 40 mg od, starting evening before surgery post-surgery hours post-surgery hours post-surgery days days TKR: total knee replacement; THR: total hip replacement Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

23 Dabigatran for prevention of VTE after major orthopaedic surgery: results DVT, PE and all-cause mortality (%) Enoxaparin Dabigatran Dabigatran (150 mg) (220 mg) RE-NOVATE p<0.0001* 6.0 p<0.0001* RE-MOBILIZE RE-MODEL Major bleeding (%) 31.1 p= p=0.02 p=0.0005* * 36.4 p=0.0345* * RE-NOVATE RE-MOBILIZE RE-MODEL *Non-inferior to enoxaparin; inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

24 Dabigatran trials PRIMARY EFFICACY OUTCOME: TOTAL VTE or ALL-CAUSE MORTALITY Enox 40 Dabi 150 Dabi 220 EV VENTS (%) RENOVATE -HIP RENOVATE II HIP

25 PRIMARY EFFICACY OUTCOME: TOTAL VTE OR ALL-CAUSE MORTALITY Enox 40 Dabi 150 Dabi 220 EVE ENTS (% %) REMODEL-KNEE x 2 REMOBILIZE-KNEE

26 Apixaban for Prevention of VTE After Major Orthopaedic Surgery Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients t Total VTE and All-Cause Mortality (%) Major Bleeding (%) Percent Percent mg 10mg Apixaban (Total Daily Dose) 20mg Warfarin (INR ) Enoxaparin (30mg bid) mg 10mg Apixaban (Total Daily Dose) mg 0 0 Warfarin (INR ) Enoxaparin (30mg bid) Lassen et al. Blood 2006

27 Apixaban ADVANCE trials 30 P< P=0,06 24 APIXABAN ENOXAPARIN EVENT TS (%) P<0, ADV-1 TKR ADV-2 TKR ADV-3 TKR

28 Rivaroxaban -RECORD trials

29 Rivaroxaban trials TOTAL VTE Comparator Rivaroxaban INCIDE ENCE (% ) P<0, P<0, P<0,01 P=0, RECORD 1 RECORD 2 RECORD 3 RECORD 4

30 P<0,01 P<0,01 P=0,02 P=0,16

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32 Total VTE from Record trials Rivaroxaban RECORD 1 (hip) RECORD 2 (hip) RECORD 3 (knee) RECORD 4 (knee) n Endpoint 18 (1.1%) 17 (2.0%) 79 (9.6%) 67 (6.9%) Enoxaparin n Endpoint 58 (3.7%) 81 (9.3%) 166 (18.9%) 97 (10.1%) Total VTE = occurrence of: any DVT (symptomatic, or asymptomatic), nonfatal PE, or death of any cause in RECORD studies of rivaroxaban after major orthopedic surgery. All differences favor rivaroxaban, aba and all reach statistical significance ce (P<05) Pooled rates of bleeding from Record trials Rivaroxaban, no.per 1000 patients Enoxaparin, no.per 1000 patients Major bleeding Major bleeding +surgical site bleeding P

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34 Pharmacology and clinical status of apixaban, rivaroxaban, and dabigatran Apixaban Rivaroxaban Dabigatran Brand name Eliquis Xarelto Pradaxa Target Factor Xa Factor Xa Factor IIa Tmax, h Half-life, h Renal 25% 66% 60% Food effect Not Reported Delays absorption Delays absorption Effect of age Not Reported Variable None Effect of body weight Not Reported None None Clinical status Approved in Europe for VTE prevention after orthopedic surgery Approved in Israel, Canada and deurope for VTE prevention after orthopedic surgery Approved in Israel, Canada and deurope for VTE prevention after orthopedic surgery

35 Novel OACs: Things to consider No antidote No laboratory monitoring No prolongation of PT,aPTT Possible use of thrombin time (TT) Short half-life lif Convenient in event of bleeding Need for strict compliance

36 VTE prophylaxis: p areas of controversy Timing of first LMWH dose USA: Enoxaparin 30 mg bid 12 hrs postop Europe & Israel: Enoxaparin 40 mg qd 12 hrs preop Use of epidural catheters FDA advisory warning Insert catheter > 12 hours after Enoxaparin dose Remove catheter > 8 hours after Enoxaparin dose Administer i Enoxaparin > 2 hours after catheter t removal ACCP, 2004

37 Intermittent pneumatic compression Various technologies available Intermittent compression Continuous circulation therapy Needs to be applied 18 hours/day Therefore convenience of appliance is important

38 SAFE Study: IPC ± Aspirin VS Enoxaparin 5.10%5.20% 5.60% I P C E I P E C 0.00% VTE MAJOR BLEEDING 21% 0.32% I P C 10% E I P C 0.13% E COMPOSITE OUTCOME ALLOGENIC BLOOD UNITS TRANSFUSED JBJS Am 2012

39 VTE prevention using a portable compression device as monotherapy in hip and knee arthroplast a multicenter registry study (funded by MCS) TJA THA TKA N=3060 N=1509 N=1551 Age Male(%) Height (in) Weight (lbs) IPCD (Wi Ai ) li d i t ti l d f i i f 10 d IPCD (Wiz-Air) applied intraoperatively and worn for minimum of 10 days CLINCAL evaluation for VTE performed at 3 months

40 TJA THA TKA N=3060 N=1509 N=1551 VTE 28(0.92%) 8(0.53%) 20(1.29%) DVT - total 23(0.75%) 5(0.33%) 18(1.16%) Proximal 3(0.1%) 1(0.07%) 2(0.13%) PE 5(0.16%) 3(0.20%) 2(0.13%) INCIDENCE OF VENOUS THROMBOEMBOLIC EVENTS. NO FATAL PE OCCURRED Conclusion: Efficacy of IPCD equivalent to pharmacologic thromboprophylaxis Improved safety

41 VTE prophylaxis: ACCP guidelines 2012 PROCEDURE RECOMMENDED PROPHYLAXIS Elective total hip or LMWH 40 mg/d started 12 h before surgery, or knee replacement 12 to 24 h after surgery; or 20 mg 4 to 6 h after surgery, followed by 40 mg/d the following day; or coumadin (INR 2-3), started preoperatively or immediately postoperatively, fondaparinux, apixaban, rivaroxaban, dabigatran (all grade 1B), or IPCD (grade 1C) Hip-fracture surgery LMWH, fondaparinux, coumadin (INR 2-3), LDUH, Aspirin (grade 1B) or IPCD (grade 1C) Chest 2012;141;7S-47S

42 VTE treatment: anticoagulant options Heparin (unfractionated) Warfarin Sintrom (Dicoumarol) Low Molecular Weight Heparins (LMWHs) Heparanoids (Orgaran, Danaparoid) Pentasaccharide (Fondaparinux) Direct Factor Xa inhibitors (apixaban, rivaroxaban) Direct thrombin inhibitors (dabigatran, hirudin)

43 DISEASE ALGORITHM FOR ANTICOAGULATION:UFH Suspected VTE Confirmed VTE ALGORITHM Obtain baseline aptt, PT, CBC Check for contraindication to heparin therapy Order imaging study Consider giving heparin, 5,000 IU IV Bolus with Heparin, 80 IU/kg IV; start maintenance infusion at 18 IU/kg Check aptt at 6 h, to maintain a range corresponding to a therapeutic heparin level Check platelet count between days 3 and 5 Start Coumadin therapy on day 1 at 5 mg;adjust subsequent daily dose according to the INR Stop heparin therapy after >4 to 5 d of combined therapy, when INR is> 2.0 Anticoagulate with Coumadin for > 3 mo (INR 2-3)

44 BODY WEIGHT-BASED DOSING OF IV HEPARIN aptt (sec) DOSE CHANGE IU/KG/H ADDITIONAL ACTION NEXT aptt (hr) <35 (1.2 x mean normal) +4 Rebolus with 80IU/kg 6 35 to 45 (1.2 to 1.5 x mean normal ) +2 Rebolus with 40 IU/kg 6 46 to 70 (1.5 to 2.3 x mean normal) to 90 (2.3 to 3.0 x mean normal) >90 (>3x mean normal) -3 Stop infusion 1 h 6

45 ALGORITHM FOR ANTICOAGULATION: LMWH DISEASE ALGORITHM Suspected VTE Obtain baseline aptt,pt, CBC Check for contraindication to heparin therapy Order imaging study Consider giving UFH IU IV; or LMWH Confirmed VTE - Give LMWH (Enoxaparin) - Start Coumadin therapy on day 1 at 5 mg;adjust daily dose according to the INR - Check platelet count between days 3 and 5 - Stop LMWH 1 day after INR reaches 2 -Anticoagulate with Coumadin for >3 mo ( INR 2-3)

46 PATIENT FEATURES DURATION OF TREATMENT: VTE LENGTH OF TREATMENT Most patients Oral anticoagulant therapy for 6 months (grade 1A) First event, with a Treat>3 mo (grade 1A) reversible or time-limited risk factor First episode of idiopathic VTE Recurrent idiopathic VTE, or a continuing risk factor Symptomatic isolated calf thrombosis Treat >6 mo (grade 1A) dependent upon presence of thrombophilic factor(s) Treat continuously (grade 1C) Oral anticoagulants for 6 to 12 wk (grade 1A); OR Serial lu/s doppler of fthe lower extremity over the next 10 to 14 d to assess for proximal extension of thrombus (grade 1C)