New Anticoagulants Linda Liu, M.D.

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1 Difficult Task New Anticoagulants Professor UCSF Dept of Anesthesia 15 minutes! Emphasis on 2 new oral anticoagulants Dabigatran Rivaroxaban Relation to anesthesia Rapid reversal Regional anesthesia UC SF 1 UC SF 2 Coagulation Cascade Injury Clot UC SF 4 1

2 Waterfall/Cascade Model Intrinsic Pathway (aptt) Kallikrein fxii fxi fix fviii Extrinsic Pathway (PT) Tissue Factor fvii fx fii Fibrin Anticoagulants Historically Narrow therapeutic window Variable dose response among pts Interactions with drugs and diet Maintenance is difficult Laboratory control needs to be standardize UC SF 5 UC SF 6 Waterfall/Cascade Model Intrinsic Pathway (aptt) Kallikrein Direct Thrombin Inhibitors Intrinsic Pathway (aptt) Kallikrein fxii Extrinsic Pathway (PT) fxii Extrinsic Pathway (PT) fxi Tissue Factor fxi Tissue Factor fix fviii fx fvii fix fviii fx fvii Antithrombin Heparin (-) fii Fibrin Warfarin Antithrombin Heparin (-) fii Fibrin DTI Warfarin UC SF 7 UC SF 8 2

3 New DTI-Dabigatran etexilate Dabigatran Indications Pradaxa Approved by FDA 10/2010 In Europe and Canada since 2008 New oral anticoagulant in > 50 yrs! Half life: hours VTE prevention after hip and knee surgery Treat acute DVT/PE Cardiac events in ACS Prevent stroke and emboli in nonvalvular AF UC SF 9 UC SF 10 Dabigatran Monitoring Recs Dabigatran and PT Predictable pharmacokinetics Low drug-drug or drug-food interactions Fixed qd or BID dose 80% eliminated by the kidneys No monitoring is recommended except elderly or renal failure patients Douxfils et al, J Thromb Haemost 107:5, 2012 UC SF 11 UC SF 12 3

4 Dabigatran and PTT Dabigatran and ECT UC SF 13 UC SF 14 Dabigatran and Thrombin Time Problems Thrombin time is too sensitive Linear with lower concentrations Greatly prolonged at higher levels Nl TT excludes the presence of significant drug levels Drug conc >120 sec UC SF 15 UC SF 16 4

5 FXa Inhibitors Intrinsic Pathway (aptt) Kallikrein fxii Extrinsic Pathway (PT) fxi Tissue Factor fxa inhibitors fix fvii fviii fx Antithrombin fii Warfarin (-) Heparin Fibrin Oral Xa inhibitors-rivaroxaban Xarelto Affects PT and PTT somewhat Predictable pharmacokinetics Half-life 8-12 hours No monitoring recommended UC SF 17 UC SF 18 Rivaroxaban Testing Rivaroxaban Chromogenic anti-factor Xa assay Not yet available as rivaroxaban assay Not yet STAT lab FDA approval July 2011 for DVT prophylaxis after hip/knee replacement surgery FDA approval Sept 2011 for stroke prophylaxis in Afib FDA denied approval for ACS UC SF 19 UC SF 20 5

6 Emergency Cases Withholding dabigatran Renal Function Standard Bleeding Risk High Bleeding Risk CrCl > 50 ml/min Hold 24 hours Hold 2-4 days CrCl ml/min Hold 2 days Hold 4 days CrCl < 30 ml/min Hold 2-5 days Hold > 5 days UC SF 21 UC SF 22 Dabigatran Reversals Dialysis: ~60% removed over 2-3 hours Oral activated charcoal may effectively absorb drug after recent ingestion Eriksson et al: J Thromb Haemost 1, 2490, 2003 Circulation 2011;124: UC SF 23 UC SF 24 6

7 Side Note on PCC Contain: prothrombin (II), VII, IX, X, protein C and S 4 factor PCC contain VII Cofact 3 factor PCC do not contain VII Bebulin Dabigatran Reversal aptt UC SF 25 UC SF 26 Dabigatran Reversal What does this mean? Unclear what relationship laboratory tests have to clinical bleeding Are they surrogate markers for bleeding tendency? Manufacturer recommends: PCC - may be helpful in rats with tail incision, rabbits with kidney incisions rfviia - corrected rat tail bleeding time FFP - may be helpful in mice UC SF 27 UC SF 28 7

8 Withholding rivaroxaban Rivaroxaban Reversals Renal Function Standard Bleeding Risk CrCl > 50 ml/min Hold 1-2 days CrCl ml/min No data CrCl < 30 ml/min Do not use High Bleeding Risk Hold 3-4 days No data Do not use No data on activated charcoal Is highly protein bound so unlikely that it can be removed by hemodialysis No data on FFP in animal or human studies UC SF 29 UC SF 30 Rivaroxaban Reversal Circulation 2011;124: UC SF 31 UC SF 32 8

9 Rivaroxaban reversals Pt bleeding on dabigatran or rivaroxaban therapy PCC Reduced PT in human volunteers Reversed prolonged BT in rats on high dose rivaroxaban rfviia Reduced rat mesenteric bleeding time Modest decrease in bleeding time in baboon Mild Bleeding Delay dose or temporarily discontinue Local control measures Moderate Bleeding Supportive Rx Fluids FFP Monitoring Severe Bleeding HD dabigatran PCC-rivaroxaban rfviia Fishman et al: Emerg Med J 25: , 2008 UC SF 33 UC SF 34 Regional Anesthesia ASRA Recommendations Guidelines not based on randomized controlled trials Instead: case reports, retrospective reviews, limited small studies, or theoretical knowledge of pharmacokinetics and pharmacodynamics Although there have been no reported spinal hematomas, the lack of information regarding the specifics of block performance and the prolonged half-life warrants a cautious approach. UC SF 35 UC SF 36 9

10 ASRA Recommendations For patients undergoing deep plexus or peripheral nerve block, we recommend that recommendations regarding neuraxial techniques be similarly applied Recommendations-General Monitoring should be at least q2-4 hours x 12 hours Infusion should be limited to drugs minimizing sensory and motor block Horlocker et al, ASRA Guidelines 3 rd Ed, 2010 UC SF 37 UC SF 38 Closing Summary Questions? Exciting: clinical anticoagulant therapy Dissatisfying: Only INR standardized for warfarin Any other coagulation test used to monitor any other anticoagulant lacks standardization We have no reversal agents UC SF 39 UC SF 40 10