Anticoagulation ReversalSimon Mantha, MD, MPHMemorial Sloan-Kettering Cancer CenterMay 2013
Overview• Therapeutic interval on anticoagulation• PK/PD considerations• Approach to reversal and bridging– Rationale– Therapeutic options– Current guidelines– Future avenues
Therapeutic Interval onAnticoagulation• Best evidence exists for warfarin• Thrombotic complications more commonwith INR<2.0– Atrial fibrillation– VTE• Bleeding complications more commonwith INR>3.0
Risk of Complication Accordingto INR in Atrial Fibrillation*Singer DE et al, Circ Cardiovasc Qual Outcomes 2009.
Risk of Bleeding withOveranticoagulation• Relatively low for short periods in patientson warfarin– 1% risk of major bleeding at 30 days if INR5.0-9.0 in one study**Garcia et al, J Am Coll Cardiol 2006.
Risk of Thrombotic Complicationsoff Anticoagulation• Low for AF and low-risk CHADS2 score– Stroke risk off warfarin is about 2.5%/year(0.007%/day)• Higher for AF in the presence of artificialheart valve• Significant for recent VTE episode– Highest with first month after event– Decreases over the following 2 months
Therapeutic Interval onAnticoagulation• Less data is available for IV unfractionatedheparin– Subtherapeutic PTT in the first 24 hrs of VTEtreatment is associated with a higher risk ofrecurrent event*– Ideal “upper end” of the target range unclear*Raschke RA et al, Ann Intern Med 1993.
Therapeutic Interval onAnticoagulation• Other commonly used anticoagulants notdosed according to levels:– LMWH/fondaparinux– Dabigatran– Rivaroxaban– Apixaban
Therapeutic Interval onAnticoagulation• Distribution of blood levels available fromlandmark trials– Observed values– Not used for dosing in the original studies• Retrospective data– Not a “guarantee of outcome”– Should not be used routinely to guide therapy
PK/PD Considerations• For warfarin:– INR between 2.0 and 3.0 correlates withdecreased coagulation factors II, VII, IX and X– Factor II level thought to be the majordeterminant of anticoagulation• Half-life=60-72 hrs• INR initially prolongs secondary to rapid decreasein FVII (half-life=6 hrs)
Vitamin K Dependent CoagulationFactors on Warfarin*Lind, SE et al. Blood Coagul Fibrinolysis 1997.50 patientson chronic therapy(INR 2.68,range 1.7-5.1)
PK/PD ConsiderationsParameter Warfarin IV UFH Enoxaparin Fondaparinux Dabigatran RivaroxabanTmax of effect 5-7 days Immediate 3-5 hrs 2-3 hrs 2 hrs 2.5-4 hrsHalf-life ofdrug20-60 hrs 1-2 hrs 4.5-7 hrs 17-21 hrs 12-17 hrs 9-13 hrsElimination Hepatic RES Renal Renal MostlyrenalMostlyhepatic
Indications for Reversal• INR above the target range on warfarin• Upcoming invasive procedure– Bridging• Bleeding
Universal Considerations forReversal• How urgent is reversal?– Faster methods often have drawbacks• What is the expected “drug effect” half-lifeof the agent administered?• Is drug excretion impaired?• What is the risk of thrombotic event offanticoagulation?– Absolute Risk = Rate X Time
Reversal of Warfarin• Choices of antidote:– Vitamin K– FFP– Prothrombin complex concentrate (PCC)– Recombinant activated factor VII (rFVIIa)
Reversal of Warfarin• Vitamin K– Oral administration results in correction by 24hours– IV administration is marginally faster• Small risk of anaphylaxis– SC route is unreliable• Not faster than oral• Poor bioavailability
IV vs Oral Vitamin K*Lubetsky A et al, Arch Intern Med 2003.
Reversal of Warfarin• FFP– Each mL contains 1 U of factors II, VII, IX andX– Need large volume for meaningful correction:dose = (target factor activity – actual level) X body weighteg: 20% desired increase X 70 kg = 1400 U or 1.4 l or 5-6 bags ofFFP
Reversal of Warfarin• PCC– 3-factor concentrate contains only II, IX and X– 4-factor version was just approved in the US*• CSL Behring Kcentra/Beriplex• At least equivalent to FFP for stopping majorbleeding at 24 hrs (72.4% vs 65.4%)• Superior for INR reduction (≤1.3) at 30 min (62.2%vs 9.6%)• Less volume (105 mL +/-37 mL versus 865 mL +/-269 mL)*www.cslbehring.com
Reversal of Warfarin• Kcentra dosing*:*www.cslbehring.comPre-treatment INR 2-3.9 4-6 >6Dose of Kcentra(units of Factor IX /kg body weight)25 35 50Maximum dose(units of Factor IX)Not to exceed2500Not to exceed3500Not to exceed5000
Reversal of Warfarin• rFVIIa– Approved indications include hemophilia A orB with inhibitor, congenital factor VIIdeficiency and acquired hemophilia– “Bypassing” effect helps sustain coagulationin the absence of FVIII or FIX– Does not correct deficit in factors II, IX and X– (deceptively) corrects the INR– Doses used have varied (20-90 mcg/kg)
Guidelines for WarfarinReversal• ACCP 2012 Guidelines for warfarinoveranticoagulation (NO bleeding)– INR <4.5• Decrease the dose of warfarin– INR 4.5-10.0• Hold warfarin• Can administer small dose of vitamin K (notroutinely)– INR >10.0• Administer oral vitamin K
Guidelines for WarfarinReversal• ACCP 2012 Guidelines for warfarinreversal (major bleeding present)– IV vitamin K– First choice for immediate reversal (overFFP):• 4-factor PCC
Guidelines for Warfarin Bridging• ACCP 2012 Guidelines– High thrombotic risk: bridge– Moderate thrombotic risk: use clinicaljudgement (consider risk of bleeding)– Low thrombotic risk: do not bridge
Risk of Thrombotic Complicationsoff AnticoagulationRisk Stratum Indication for AnticoagulationAtrial Fibrillation Venous ThromboembolismHigh thromboticriskCHADS2 score of 5 or 6Recent (within three months)stroke or transient ischemicattackRheumatic valvular heartdiseaseRecent (within three months)VTESevere thrombophilia (eg,deficiency of protein C, proteinS, or antithrombin;antiphospholipid antibodies;multiple abnormalities)*ACCP Guidelines (9thEdition), Chest 2012.
Risk of Thrombotic Complicationsoff AnticoagulationRisk Stratum Indication for AnticoagulationAtrial Fibrillation Venous ThromboembolismModeratethrombotic riskCHADS2 score of 3 or 4 VTE within the past 3 to 12monthsNonsevere thrombophilia (eg,heterozygous factor V Leidenor prothrombin gene mutation)Recurrent VTEActive cancer (treated withinsix months or palliative)*ACCP Guidelines (9thEdition), Chest 2012.
Risk of Thrombotic Complicationsoff AnticoagulationRisk Stratum Indication for AnticoagulationAtrial Fibrillation Venous ThromboembolismLow thromboticriskCHADS2 score of 0 to 2(assuming no prior stroke ortransient ischemic attack)VTE >12 months previous andno other risk factors*ACCP Guidelines (9thEdition), Chest 2012.
Guidelines for Warfarin Bridging• ACCP 2012 Guidelines– Last dose of warfarin 5 days before thesurgery– Parenteral anticoagulant:• Last dose of LMWH should be 24 hours before thesurgery• D/C IV UFH be 4-6 hours before the surgery• Restart 24-72 hours– Restart warfarin 12-24 hours after theprocedure
Reversal of IV UFH• Protamine– Binds heparin chains– Administer 1 mg of protamine per 100 U ofcirculating heparin:Time Elapsed Dose of Protamine (mg) to Neutralize 100 units ofHeparinImmediate 1-1.530-60 min 0.5-0.75>2 h 0.25-0.375
Reversal of IV UFH• Protamine– Excess amount acts as a mild anticoagulant– Risk of infusion reaction:• Hypotension/circulatory collapse• Pulmonary edema• Pulmonary hypertension
Reversal of LMWH• Protamine– Neutralizes about 60-75% of activity– Consider half-life of enoxaparin• Enoxaparin administered ≤8 hours prior: give 1 mgof protamine per mg of enoxaparin.• Enoxaparin administered > 8 hours prior: give 0.5mg of protamine per mg of enoxaparin.
Reversal of Dabigatran• Activated charcoal if ingestion <2 hoursprior– In vitro testing confirmed binding• Hemodialysis can help clear the drug– Useful for patients with renal failure– Case report data– Entails risks associated with central lineplacement
Reversal of Dabigatran• 4-factor PCC:– 12 healthy volunteers (in vivo); no correctionof hemostatic parameters*• aPCC:– 10 healthy volunteers (ex vivo); aPCCcorrected thrombin generation LT and ETP†• rFVIIa:– Partial correction of thrombin generation*Eerenberg ES et al, Circulation 2011.†Marlu R et al, Thromb Haemost 2012.
Reversal of Dabigatran• Thrombin generation in a patient with ICHon dabigatran:
Reversal of Rivaroxaban• Activated charcoal if ingestion <2 hrs prior• 4-factor PCC– 12 healthy volunteers (in vivo); PT and thrombingeneration ETP normalized*• aPCC– 10 healthy volunteers (ex vivo); correctedthrombin generation LT and ETP†• rFVIIa:– Partial correction of thrombin generation*Eerenberg ES et al, Circulation 2011.†Marlu R et al, Thromb Haemost 2012.
Future Avenues• Monoclonal antibody directed againstdabigatran showed efficacy in murinemodel*• “decoy” Xa drug neutralizes the effect ofenoxaparin and fondaparinux in rats†– Inactive mimetic binds the anticoagulant*Schiele F et al, Blood 2013.†Lu G et al, Nat Med 2013.
Ideal Anticoagulant• Orally administered• Not reliant on renal or hepatic clearance• Predictable PK/PD– One size fits all• No drug interactions• Minimal effect on normal hemostasis• Can turn on/off effect at will
Summary• For INR ≤10.0 holding warfarin is often allthat is required• Oral vitamin K can be used in non-bleeding patients– SC administration should not be used• 4-factor PCC is probably the best choicefor warfarin-associated ICH
Summary• Protamine has limited efficacy for reversalof enoxaparin• Dabigatran can be dialyzed– aPCC (FEIBA) is another option• PCC might reverse rivaroxaban effect– Minimal data