Management of Bleeding Associated with the Novel Oral Anticoagulants March 2014

Bleeding Category Mild (all of the criteria Moderate Major Life-Threatening below) (all of the criteria below) (one or more of the below) (one or more of the below) Hemoglobin  No significant  Bleeding associated with  Bleeding associated with  Bleeding associated with reduction reduction in - Reduction in hemoglobin of - Reduction in hemoglobin - Reduction in hemoglobin of and/or hemoglobin < 2 g/dL of at least 2 g/dL at least 5 g/dL - or transfusion of < 2 units of - or transfusion of at least 2 - Transfusion of at least 4 transfusion  No blood transfusion necessary blood units of blood units of blood needs  Asymptomatic  Symptomatic bleeding  Symptomatic bleeding in a  Potentially fatal hemorrhage contained, local excluding critical organs critical area or organ  Symptomatic intracranial bleed bleeding - (intraocular, intracranial, - (intraocular, intracranial,  Hypotension requiring the use intraspinal or intramuscular intraspinal or of intravenous inotropic agents with compartment intramuscular with  Surgical intervention necessary Symptoms syndrome, retroperitoneal, compartment syndrome, intra-articular, or pericardial) retroperitoneal, intra- articular, or pericardial).

General Measures Mild Bleeding Moderate or Major or Life-Threatening Bleeding  Hold one or more anticoagulant doses based on bleeding  Hold anticoagulant severity and renal function

 Consider other anticoagulant if ≥ 2 doses of drug need to  Consider activated charcoal (1-2 gm/kg) be interrupted and or it can no longer be used. Consider  If < 2 hours since last dose of dabigatran or rivaroxaban bridging agent if CHADS2 score > 4  If < 6 hours since last dose of apixaban Anticoagulant drug  Check and monitor for  Check and monitor for  possible medication interactions  possible medication interactions  renal function to verify correct dosing (see appendix)  renal function to verify correct dosing (see appendix)  hepatic function to verify correct dosing of rivaroxaban  hepatic function to verify correct dosing of rivaroxaban and and apixaban (see appendix) apixaban (see appendix)  Restart anticoagulation when bleeding is contained and no contraindications. Lab Not recommended Monitor CBC Interventions Local bleeding control Local bleeding control

1 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800 © Direct Thrombin Inhibitor (dabigatran/Pradaxa ) Mild Moderate Major Life-Threatening General See  See general measures above  See general measures above  See general measures above approach general  Maintain adequate diuresis  Maintain adequate diuresis measure  GI tract: GI consult  GI tract: GI consult  GI tract: GI consult s above  Vascular: vascular surgery  Vascular: vascular surgery and/or  Vascular: vascular surgery and/or and/or interventional radiology interventional radiology consult. interventional radiology consult. consult  Local hemorrhage including hematoma:  Local bleed including hematoma:  Local hemorrhage including compression and surveillance imaging Compression and surveillance imaging Bleeding hematoma: compression and  Intracranial or intraspinal bleed:  Intracranial or intraspinal bleed: Source surveillance imaging neurology and neurosurgery consults. neurology and neurosurgery consults. recommendat  Intraocular: ophthalmology consult  Intraocular: ophthalmology consult ions  Intramuscular or intra-articular:  Intramuscular or intra-articular: orthopedic consult. orthopedic consult.  Pericardial: cardiac surgery and  Pericardial: cardiac surgery and cardiology consults cardiology consults.  Retroperitoneal: general surgery consult  Retroperitoneal: general surgery consult Consider transfusion if Consider transfusion if symptomatic Recommend blood transfusion Transfusion symptomatic anemia or anemia or hemoglobin < 7 g/dL hemoglobin < 7 g/dL Not recommended Check dabigatran level Check dabigatran level Labs If dabigatran level not available, check If dabigatran level not available, thrombin time (TT) check thrombin time (TT) if TT not available, check aPTT (see if TT not available, check aPTT (see appendix) appendix) Not recommended  Consider hemodialysis  Recommend hemodialysis as soon as - especially if abnormal renal function, possible. continuous active bleeding and Hemodialysis abnormal dabigatran level, TT or aPTT tests. Not recommended If continuous active bleeding and abnormal Recommend PCC as soon as possible PCC, APCC or dabigatran level, TT or aPTT (see - if not available, recommend aPCC appendix). or rFVIIa (see appendix). rVIIa  Consider PCC, - if not available, aPCC or rFVIIa Coverage Consider other anticoagulant if ≥ 2 Cover with other anticoagulant (preferably Cover with other anticoagulant (preferably with other doses of dabigatran need to be low intensity unfractionated heparin) when low intensity unfractionated heparin) when interrupted &/or it can no longer be deemed safe, especially if CHADS2 deemed safe, especially if CHADS2 anticoagulant used. Consider bridging agent if score > 4 score > 4 and/or CHADS2 score is > 4 Resume Restart anticoagulation when Decision about restarting anticoagulation Decision about restarting anticoagulation bleeding is contained and no should be based on risks and benefits should be based on risks and benefits anticoagulant further risk of bleeding. 2 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800

© © Direct Factor Xa Inhibitors (rivaroxaban/Xaralto , apixaban/Eliquis ) Mild Moderate Major Life-Threatening General See See general measures above  See general measures above  See general measures above approach general  Maintain adequate diuresis  Maintain adequate diuresis measure  GI tract: GI consult  GI tract: GI consult  GI tract: GI consult above  Vascular: vascular surgery  Vascular: vascular surgery and/or  Vascular: vascular surgery and/or and/or interventional radiology interventional radiology consult. interventional radiology consult. consult  Local hemorrhage including hematoma:  Local bleed including hematoma: Bleeding  Local hemorrhage including compression and surveillance imaging Compression and surveillance imaging hematoma: compression and Source  Intracranial or intraspinal bleed:  Intracranial or intraspinal bleed: surveillance imaging neurology and neurosurgery consults. neurology and neurosurgery consults. recommendat  Intraocular: ophthalmology consult  Intraocular: ophthalmology consult ions  Intramuscular or intra-articular:  Intramuscular or intra-articular: orthopedic consult. orthopedic consult.  Pericardial: cardiac surgery and  Pericardial: cardiac surgery and cardiology consults cardiology consults.  Retroperitoneal: general surgery consult  Retroperitoneal: general surgery consult Consider transfusion if Consider transfusion if symptomatic anemia  Recommend blood transfusion Transfusion symptomatic anemia or or hemoglobin < 7 hemoglobin < 7 g/dL Labs Not recommended Check heparin levels (aka Anti-Xa) Check heparin levels (aka Anti-Xa) if not available, check PT (in seconds) if not available, check PT (in seconds)

to estimate medication clearance (see to estimate medication clearance (see appendix) appendix) Not beneficial Not beneficial Not beneficial Hemodialysis Not recommended If continuous active bleeding and abnormal Recommend PCC, PCC or, APCC heparin levels (aka Anti-Xa) or PT (see - if not available, consider aPCC or appendix for level monitoring and dosing) rFVIIa as soon as possible (see rVIIa  Consider PCC, appendix for dosing) - if not available, aPCC or rFVIIa Coverage Consider other anticoagulant if ≥ 2 Cover with other anticoagulant (preferable Cover with other anticoagulant (preferably with other doses of the drug need to be low intensity unfractionated heparin) when low intensity unfractionated heparin) when interrupted and or it can no longer deemed safe especially if CHADS2 deemed safe, especially if CHADS2 anticoagulant be used. Consider bridging agent if score > 4 score > 4 and/or CHADS2 score is > 4 Resume Restart anticoagulation when Decision about restarting anticoagulation Decision about restarting anticoagulation bleeding is contained and no should be based on risks and benefits should be based on risks and benefits anticoagulant further risk of bleeding.

3 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800 APPENDIX

Dabigatran (Pradaxa): Rivaroxaban (Xarelto): Apixaban (Eliquis): Non-valvular - 150 mg po BID (CrCl; >30 mL/min) - 20 mg po daily (CrCl >50 mL/min) - 5 mg po BID atrial - 75 mg po BID (CrCl: 15-30 mL/min) - 15 mg po daily (CrCl 15-50 mL/min) - Consider 2.5 mg po BID fibrillation - Avoid using if CrCl <15 mL/min if at least 2 of: 1- Age ≥ 80 - Consider using 75 mg po BID if used 2- Cr ≥ 1.5 mL/min with permeable glycoprotein transport 3- Weight ≤ 60 kg system (P-gp) inhibitors such

systemic ketoconazole and dronedarone in patients with impaired renal function (CrCl 30-50 mL/min). Avoid concomitant use if CrCl <30 mL/min. VTE Not currently indicated - 10 mg po daily for 35 days (after - 2.5 mg po BID starting prophylaxis THR) 12-24 hours after surgery with total hip - 10 mg po daily for 12 days (after 1- Knee: for 12 days and knee TKR) 2- Hip: for 35 days replacement - Avoid using if CrCl <30 mL/min (THR/TKR) Treatment of Not currently indicated - 15 mg po BID for 3 weeks then 20 Not currently indicated acute VTE: mg po daily - Avoid using if CrCl <30mL/min VTE risk Not currently indicated - 20 mg daily Not currently indicated reduction - Avoid using if CrCl <30mL/min Drug - Avoid using with P-gp inducers such - Avoid using with strong P-gp and - Reduce apixaban dose interactions as rifampin. CYP3A4 inhibitors such as to 2.5 mg or avoid - Consider reducing dabigatran dose to systemic ketoconazole, concomitant use with 75mg twice daily if used with strong P- itraconazole and ritonavir or with strong dual inhibitors of gp inhibitors like systemic inducers such as phenytoin or CYP3A4 and P-gp. ketoconazole and dronedarone. rifampin. - Avoid concomitant use with strong inducers of CYP3A4 and P-gp. Dosing: For detailed prescription information, please refer to the manufacturer’s prescribing information for each medication!

4 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800

Factor Products Four Factor Prothrombin Active Prothrombin Complex Recombinant active factor VII Complex Concentrate (PCC), Concentrate (APCC), Feiba: (rVIIa): Kcentra: - 50 units/kg IV. - 50-80 units/kg IV - 20 mcg/kg

- May repeat another dose in 12 hours - May repeat another dose in 12 - May repeat dose every 2 hours if bleeding continues hours if bleeding continues until hemostasis is achieved or Dose - Maximum dose 5000 units/day - Maximum dose: 200 units/kg/day until the treatment is judged - Dosing might change based on the - Dosing might change based on ineffective. Max dose of 90mcg/kg bleeding severity and thrombotic risk the bleeding severity and - Dosing might change based on of the patient thrombotic risk of the patient the bleeding severity and thrombotic risk of the patient - Side effects: DIC and systemic - Side effects: DIC and systemic - Side effects: DIC and systemic Side Effects thromboembolism thromboembolism thromboembolism - Contraindicated in patients with Considerations known heparin-induced thrombocytopenia. Contains heparin

Lab Assessments Direct Thrombin Inhibitor Direct Factor Xa Inhibitors © © © (dabigatran/Pradaxa ) (rivaroxaban/Xaralto , apixaban/Eliquis ) o Dabigatran level o Heparin level (aka Anti-Xa) - The preferred test if available (performed at Allina Health - The assay used to calculate heparin levels shows reasonable Central Lab at Abbott Northwestern) linear correlation with increasing levels of direct factor X o Thrombin time: inhibitors - Useful to rule out presence of dabigatran - A heparin (Anti-Xa) level of <0.1 U/mL suggests lack of - A normal thrombin time essentially rules out clinically significant factor X inhibitor activity significant levels of dabigatran o PT/INR: o aPTT - The PT (reported in seconds) shows some correlation with - Can be used if dabigatran level and TT tests are not the direct factor aX inhibitor level; however, correlation with available. the calculated INR is weaker. - A normal aPTT rules out clinically significant levels of - PLEASE CONTACT THE LAB to request reporting of the PT dabigatran in seconds. - An elevated aPTT cannot quantify the amount of dabigatran - A normal PT rules out clinically significant levels of the direct present factor Xa inhibitor. - Due to variability of PT/INR reagents, this test is not recommended to try to rule out the presence of the direct factor X inhibitor. - Heparin levels (aka Anti-Xa) should be ordered instead. Note: A specific assay for rivaroxaban and apixaban levels should be available in 6-12 months, pending reagent availability in the USA. 5 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800

Disclaimer: “Guidelines are not meant to replace clinical judgment or professional standards of care. Clinical judgment must take into consideration all the facts in each individual and particular case, including individual patient circumstances and patient preferences. They serve to inform clinical judgment, not act as a substitute for it. These guidelines were developed by a Review Organization under Minn. Statutes §145.64 et. seq., and are subject to the limitations described as Minn. Statues §145.65.”

References 1- J Thromb Thrombolysis. 2013 Aug 9. [Epub ahead of print] 2- Eur Heart J 2013;34:489 3- J Thromb Thrombolysis 2013;35:387 4- J Thromb Thrombolysis 2013;35:391 5- Blood. 2013 May 2;121(18):3554-62.doi: 10.1182/blood-2012-11- 468207Epub 2013 Mar 8 6- Am J Health Syst Pharm. 2013;70 (10 Suppl 1):S12-21. 7- Int J Lab Hematol. 2013 Jun;35(3):262-8. doi: 10.1111/ijlh.12065. 8- Am J Hematol. 2012;87 Suppl 1:S141-5. 9- Clinical Chemistry 2012;59:807 10- Circulation 2012;126:343 11- Thromb Haemost 2012;10:1841 12- Blood. 2012;119:3016-3023 13- Circulation 2011;124:1573 14- ASH 2011. Abstract 2316 15- Thromb Haemost. 2010;103:1116–1127. 16- J. Thromb. Haemost. 2009 Jul;7 Suppl 1:107–10. 17- Transfusion. 2004 Apr;44(4):605-17

6 Thrombophilia and Anticoagulation Clinic, Minneapolis Heart Institute, Abbott Northwestern Hospital. November 2013. Tel: 612-863-6800