Stolling en anesthesie. Erik Vandermeulen MD, PhD Dept. of Anesthesia

Transcription

1 Stolling en anesthesie Erik Vandermeulen MD, PhD Dept. of Anesthesia

2 Preoperative use of anticoagulation Vitamin K-antagonists (VKA) Fenprocoumon (Marcoumar ) Warfarin (Marevan ) Acenocoumarol (Sintrom ) Anti-Xa agents Rivaroxaban Apixaban Direct thrombin inhibitors Dabigatran

3 CHADS 2 -Score CHADS 2 risk factors C: Congestive heart failure 1 H: Arteral hypertension 1 A: Age >75y 1 D: Diabetes mellitus 1 S 2 : History of CVA/TIA 2 CHADS 2 -score Adjusted stroke rate (%/Year) 0 0, (You JY et al. 9 th ED ACCP Guidelines. Chest;141 (Suppl 2):e531S-e575S.)

4 CHA 2 DS 2 -VASc Score CHA 2 DS 2 risk factors C: Congestive heart failure 1 H: Arteral hypertension 1 A 2 : Age 75 y 2 D: Diabetes mellitus 1 S 2 : History of CVA/TIA 2 V: History of vascular disease 1 A: Age y 1 Sc: Female Sex category 1 CHA 2 DS 2 - Vasc score Adjusted stroke rate (%/Year) (Lip GY et al. Chest. 2010; 137(2):263-72)

5 Annual thromboembolic risk without VKA Thrombotic risk High (>10%) Valvular prosthesis (VP) Mitral VP Older aortic VP TIA or CVA (< 6m ago) Atrial fibrillation (AF) CHA 2 DS 2 -VASc score 5 TIA or CVA (<3 m ago) Degenerative valvular disease Thromboembolism (TE) Recent VTE (<3 m ago) Severe thrombophilia (e.g. homozygotic protein C- or S-deficiency...) Intermediate (5-10%) Low (2-5%) Bi-leaflet aortic VP with additional risk factors: congestive heart failure, arterial hypertension, age > 75 years, diabetes mellitus, history of TIA or CVA Bi-leaflet aortic VP without additional risk factors CHA 2 DS 2 -VASc score 3 or 4 CHA 2 DS 2 -VASc 2 (and no history of TIA of CVA ) VTE 3-12 m ago Mild trombophilia (e.g. heterozygotic protein C- or S-deficiency...) Multiple VTE VTE + active cancer Single VTE > 12 m ago and no thrombophilia (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

6 VKA: To bridge or not to bridge Interruption of anticoagulation for diagnostic or therapeutic procedures In patients with AF who do not have mechanical valves,, anticoagulation may be interrupted for a period of up to 1 week for surgical or diagnostic procedures without substituting heparin. In high-risk patients (particularly those with prior stroke, TIA, or systemic embolism), or when interruption of oral anticoagulant therapy for longer periods is required, UFH or low-molecular-weight heparin may be administered. (ACC/AHA/ESC 2006 Guidelines)

7 To bridge or not to bridge In patients with a mechanical heart valve or atrial fibrillation or VTE at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose SC LMWH or IV-UFH over no bridging during temporary interruption of VKA therapy (grade 1C). We suggest therapeuticdose LMWH over IV UFH (grade 2C). In patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV- UH, or low dose SC LMWH over no bridging during temporary interruption of VKA therapy (grade 2C). We suggest therapeutic-dose LMWH over other treatment options (grade 2C). In patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest bridging anticoagulation with low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (grade 2C). (Douketis JD et al. 8th ACCP Guidelines. Chest 2008;133: S)

8 To bridge or not to bridge - MkII In patients with a mechanical heart valve or atrial fibrillation or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during interruption of VKA therapy (grade 2C) In patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, the bridging or-no bridging aproach chosen is, as in the higher- and lower-risk patients, based on the assessment of individual patient- and surgery-related factors. In patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest NO bridging instead of bridging anticoagulation during interruption of VKA therapy (grade 2C). (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

9 VKA when to interrupt? Fenprocoumon (Marcoumar ) 10 d (t1/2: h) Warfarine (Marevan ) 5-7 d (t1/2: h) Acenocoumarol (Sintrom ) 4d (t1/2: 8-11 h) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

10 Bridging with LMWH when to stop before surgery? Therapeutic or intermediate dose 24 h before surgery Last preoperative dose on the morning of the day before surgery should be halved (if once daily dosing) Low (prophylactic dose) 12 h before surgery (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

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12 Bridging with LMWH when to restart after surgery? Procedures with a low bleeding risk Therapeutic or intermediate dose of LMWH 24 h after surgery Low (prophylactic) dose of LMWH 6-8 h after surgery Procedures with a high bleeding risk Therapeutic or intermediate dose of LMWH h after surgery Low (profylactic) dose of LMWH 24 h after sugery? (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

13 VKA when to resume after surgery? Type of surgery, patients condition, bleeding risk, risk of reintervention, presence of drainage system h after surgery In patients who require temporary interruption of a VKA before surgery, we recommend resuming VKAs approximately h after surgery (evening or the next morning) and when there is adequate hemostasis instead of later resumption of VKAs (Grade 2C) LMWH bridging to be maintained until therapeutic INR by VKA ( 2,5) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

14 VKA: what are the options in case of minor/non-invasive procedures Minor dental procedures Root canal procedures, removal of caries We suggest no interruption of VKA and coadminister a prohemostatic agent (e.g. Tranexaminic acid orally or as mouthwash (Exacyl ) OR Extraction of teeth We suggest stopping VKAs 2-3 days before the procedure instead of alternative procedures (Grade 2C) Titrate VKA to INR Minor dermatological procedures Resection of nevi, basal or squamous cell carcinomas We suggest no interruption of VKA and optimizing local hemostasis instead of other strategies (Grade 2C) Cataract surgery We suggest no interruption of VKA (Grade 2C) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

15 VKA what are the options in case of emergency surgery INR 1.5 INR > h until surgery 2 mg Vitamin K 1 orally 8-12 h until surgery 10 mg Vitamine K 1 slow IV push Immediately before surgery Prothrombine concentrate (PPSB SD) IU/kg IV Factor II, VII or X < 30% Halflife < VKA FFP SD Volume overload Halflife < VKA (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

16 Antiplatelet agents (AP) Inhibitors of platelet activation Dipyridamole Acetyl-salicylic acid (ASA) Thienopyridines (TNP) Ticlopidin Clopidogrel (CLOP) Prasugrel (PRA) Ticagrelor SSRIs Inhibitors of platelet aggregation Glycoprotein IIb-IIIa receptor antagonists Abciximab Eptifibatide Tirofiban

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18 Antiplatelet agents Non-cardiac surgery In patients who are receiving ASA for the secondary prevention of cardiovascular disease and are having minor dental or dermatologic procedures or cataract surgery, we suggest continuing ASA around the time of the procedure instead of stopping ASA 7 to 10 days before the procedure (Grade 2C) In patients at moderate to high risk for cardiovascular events who are receiving ASA therapy and require non-cardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C) In patients at low risk for cardiovascular events who are receiving ASA therapy, we suggest stopping ASA 7 to 10 days before surgery instead of continuation of ASA (Grade 2C) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

19 Antiplatelet agents Cardiac surgery In patients who are receiving ASA and require CABG surgery, we suggest continuing ASA around the time of surgery instead of stopping 7 to 10 days before surgery (Grade 2C) In patients who are receiving dual antiplatelet therapy and require CABG surgery, we suggest continuing ASA around the time of surgery and stopping clopidogrel/prasugrel 5 days before surgery instead of continuing dual antiplatelet therapy around the time of surgery (Grade 2C) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

20 Antiplatelet agents Coronary stents In patients with a coronary stent who have interruption of antiplatelet therapy before surgery, we suggest AGAINST the use of bridging therapy with UFH, LMWH, direct thrombin inhibitors, or glycoprotein IIb/IIIa inhibitors (Grade 2C) In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C) In patients who require surgery within 6 weeks after placement of a baremetal stent or within 6 months after placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7 to 10 days before surgery (Grade 2C) (From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

21 Antiplatelet agents When to restart? As soon as possible ( 24 u) Type of surgery, condition of patient, bleeding risk, risk of re-intervention, presence of a drainage system Loading dose ASA: preoperative dose Clopidogrel: mg, thereafter 75 mg/d Prasugrel: mg, thereafter 10 mg/d (5 mg/d if 75 y)

22 Anti Xa agents Rivaroxaban (Xarelto ) in high dose 20 mg once daily t 1/2 =11-13 h 66% liver metabolism, 33% renal metabolism Strong correlation between plasma concentrations and axa-activity and PT prolongation PT, anti- Xa assay for specific agent (under development) Apixaban (Eliquis ) in high dose 5 mg twice daily t 1/2 =10-15 h 75% liver metabolism, 25% renal metabolism Strong correlation between plasma concentrations and axa-activity and PT prolongation PT, anti- Xa assay for specific agent (under development)

23 Anti Xa agents (From Kubitza D et al. Eur J Clin Pharmacol 2005; 61, )

24 Anti Xa agents - PT (From Douxfils J et al. Thrombosis Research 2012; 130 (Suppl 2), )

25 Anti Xa agents - PT No data available that associate PT changes with bleeding risk No data suggesting that PT is a valid marker for the anticoagulant efficacy In emergency situations in patients on rivaroxaban, a prolonged PT therefore may at most suggest the recent intake of the drug; prolonged PT would suggest the likely intake of rivaroxaban in the last 7 hours. Conversely, a non-delayed PT will only suggest that rivaroxaban was likely taken more than approximately 7 hours ago. The planning of an urgent surgical/invasive procedure based on the results of the PT/aPTT (as for VKAs and unfractionated heparin) is not a validated strategy and cannot be recommended at the current time

26 Anti Xa agents - Measuring axa (From Douxfils J et al. Thrombosis Research 2012; 130 (Suppl 2), )

27 Rivaroxaban: A Practical Guide V1.0 6 July 2012 Anti Xa agents *Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR surgery 9.

28 Anti Xa agents Stopping before surgery No bridging therapy with LMWH is required

29 Anti Xa agents - Reversal (From Eerenberg ES et al. Thrombosis Research 2011; 124, )

30 Anti Xa agents - Reversal (From Marlu R et al. Thromb Haemost 2012; 108, )

31 factors that increase the bleeding risk including a potential overdose, concomitant use of antiplatelet or other antithrombotic agents, the use of non-steroidal anti-inflammatory drugs (NSAIDs), co-existing bleeding disorders, renal or hepatic impairment. There is insufficient (pre)clinical experience on the management of severe bleedings and the guidance provided in table 8 and figure 13 is based on expert consensus and are not Anti Xa agents - Reversal clinically validated. Hemostatic agent Recommendations PCC: 4 factor concentrate PPSB S.D. (flacon 200ml - FIX 40I E ) Confidex (flacon 20 ml - FIX 500IE) Octaplex (flacon 20 ml - FIX 400 à 620IE) Desmopressin Minirin Amp (4 µg/ml) for iv. use Tranexamic Acid Exacyl apcc: activated prothrombin concentrate (Feiba S-Tim 4 ) recombinant human FVIIa (Novoseven ) Table 8: Recommended a-specific pro-hemostatic agents The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs*. Desmopressin can be considered in case of associated coagulopathy or thrombopathy**. A standard dose scheme for bleeding disorders is 0,03 µg/kg with a maximum of 20 µg. Tranexamic acid associated to direct anti-xa (antithrombin-independent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates. 21 This writing group does not recommend the use of Feiba S-Tim 4 for life-threatening bleedings in patients treated with rivaroxaban. There is no clinical experience with rhfviia in rivaroxaban treated subjects. Due to the short half-life of rhfviia, a repeat dose may be needed. This writing group does not recommend the use of Novoseven for life-threatening bleedings in patients treated with rivaroxaban.

32 Anti Xa agents

33 Direct thrombin inhibitors Dabigatran (Pradaxa ) in high dose mg once daily t 1/2 =12-17 h Mainly renal metabolism aptt, TT, dtt (calibrated diluted Thrombin Time), Ecarin Clotting Time (ECT)

34 Direct thrombin inhibitors - APTT Only approximate indication of the anticoagulation intensity Useful to determine an excess of anticoagulant activity in patients who are bleeding or at risk of bleeding Limited sensitivity and not suitable for precise quantification of the anticoagulant effect, especially at high plasma concentrations of dabigatran. (From Douxfils J et al. Thromb Haemost 2012; 107, )

35 Direct thrombin inhibitors (d)tt Result of TT test depends on the coagulometer and the thrombin lot A calibrated diluted thrombin time (dtt) with dabigatran standards to calculate the dabigatran plasma concentration is necessary Linear relationship between dabigatran concentration and the dtt, which is therefore suitable for the precise quantitative assessment of dabigatran concentrations Normal TT measurement indicates no clinically relevant anticoagulant effect of dabigatran (From Douxfils J et al. Thromb Haemost 2012; 107, )

36 Direct thrombin inhibitors ECT & PT ECT provides a direct measure of the activity of direct thrombin inhibitors PT/INR is unreliable in patients on dabigatran ECT Supplementary Figures: Figure 6: I nfluence of dabigatran on prothrombin time (PT ). PT showed a concentrationdependent prolongation of clotting time. Innovin was characterised by the best sensitivity with a 2 x CT of 175 ng/ml. The box in blue and red represents the therapeutic range in the orthopaedic indication and in AF patients, respectively. Cut-off at C trough of 67 ng/ml and 200 ng/ml are defined for the orthopaedic indication (220 mg qd) and for the twice daily dosing in AF patients (150mg bid), respectively (4). PT (From Douxfils J et al. Thromb Haemost 2012; 107, )

37 Direct thrombin inhibitors - Reversal (From Eerenberg ES et al. Thrombosis Research 2011; 124, )

38 Direct thrombin inhibitors - Reversal (From Marlu R et al. Thromb Haemost 2012; 108, )

39 prolonged bleeding time in rats treated with a high dose of dabigatran 13. Activated prothrombin complex concentrate reversed the prolonged bleeding time but not the prolonged aptt in rats treated with a high dose of dabigatran At this time, there is insufficient (pre)clinical experience on the administration of hemostatic agents in patients bleeding on dabigatran; the guidance provided in table 5 is based on expert consensus and is not clinically validated. Direct thrombin inhibitors Reversal Table 5: Recommended a-specific pro-hemostatic agents Hemostatic agent PCC: 4 factor concentrate PPSB S.D. (vial 20 ml FIX 400IE) Confidex (vial 20 ml FIX 500IE) Octaplex (vial 20 ml FIX 400 to 620IE) Desmopressin Minirin Amp (4μg/ml) for si u e Recommendations The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs. Desmopressin can be considered in case of associated coagulopathy or thrombopathy. A standard dose scheme for bleeding disorders is 0,03μg/kg with a maximum of 20μg apcc: activated prothrombin concentrate Feiba S-Tim4 Recombinant human FVIIa Novoseven There is some experimental evidence to support the role of apcc in reversing the anticoagulant effect of dabigatran, but data on its usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited 4. In view of the limited availability in Belgium, this writing group does currently not recommend the use of Feiba S- Tim4 for life-threatening bleeding in patients treated with dabigatran. There is some experimental evidence to support the role of rhfviia in reversing the anticoagulant effect of dabigatran, but data on its usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited 4. This writing group does therefore not recommend the use of Novoseven for life-threatening bleeding in patients treated with dabigatran.

40 Direct thrombin inhibitors Reversal Hemodialyis can be considered (From Stangier J et al. Thromb Haemost 2010; 49, )

41 Direct thrombin inhibitors Renal function (CrCl ml/min) Estimated half-life (h) Stop dabigatran before elective surgery High risk of bleeding or major surgery Standard risk days 24 hours 50 - < days 1-2 days 30-< days 2-3 days (>48 hours) Resume after elective surgery High risk of bleeding or major surgery Standard risk 48 hours 24 hours No bridging therapy with LMWH is required

42 Platelet aggregation inhibitors - Prasugrel (From Wiviott SD et al. NEJM 2007; 357, )

43 Platelet aggregation inhibitors - Prasugrel (From Wiviott SD et al. NEJM 2007; 357, )

44 Platelet aggregation inhibitors - Prasugrel Stop 7 days before surgery Resume >6 24h after surgery (From Farid NA et al. Drug Metab Disp 2007; 35, )

45 Platelet aggregation inhibitors - Ticagrelor (From Wallentin L et al. NEJM 2009; 361, )

46 Platelet aggregation inhibitors Ticagrelor (From Wallentin L et al. NEJM 2009; 361, )

47 Platelet aggregation inhibitors Ticagrelor Stop 5 days before surgery Resume >6 24h after surgery (From Gurbel PA et al. Circulation 2009; 120, )