48 th Annual Meeting Terminology Non-VKA Oral Anticoagulants: Prevention & Treatment of Bleeding Stacy A. Voils, PharmD, MS, BCPS Navigating the Oceans of Opportunity Target-specific oral anticoagulants (TSOCs) Direct oral anticoagulants (DOACs) Non-monitored oral anticoagulants (NOACs) Non-warfarin oral anticoagulants (NOACs) Non-VKA oral anticoagulants (NOACs) Chest 2014;145;1177. Disclosure I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Public Health Impact Most common use of oral anticoagulants atrial fibrillation More common in elderly / aging US population Expected to affect 16 million by year 2050 Increase in pharmacologic options for anticoagulation Three OACs (in addition to warfarin) since late 2010 Major hemorrhage Annual incidence 1 3 % > 60,000 emergency department visits annually for anticoagulant-related bleeding Objectives Anticoagulation-related ICH Compare and contrast clotting factor concentrates commonly used for anticoagulation reversal Discuss evidence for reversal of non-vka oral anticoagulant (NOAC) medications Use laboratory data to confirm successful reversal of NOAC medications Prevent bleeding in patients receiving NOAC medications Represent 18 25% of intracranial hemorrhage (ICH) Risk increases with: Age History of bleeding Concomitant anti-platelet therapy Intensity / duration of anticoagulation (e.g. INR >4.5 for warfarin) History of CVA, DM, renal/liver disease, alcohol abuse Hematoma expansion More likely Longer duration Associated with inadequate reversal Mortality higher Chest 2012;141;e44S-e88S 1
Available Direct Thrombin Inhibitors Pharmacokinetics NOACs Bivalirudin IV only; typically reversal not necessary due to short T1/2 Argatroban Dabigatran (Pradaxa ) FDA approved for: 10/2010: Stroke prevention in non-valvular atrial fibrillation 04/2014: Treatment and prevention of recurrent DVT/PE 1 st oral direct thrombin inhibitor Am J Health-Syst Pharm 2013; 70:1914-29 Factor Xa Inhibitors Fondaparinux (Arixtra ) Rivaroxaban (Xarelto ) 1 st oral factor Xa inhibitor FDA approved DVT/PE prevention in patients with knee/hip replacement (July 2011) Stroke prevention in non-valvular atrial fibrillation (November 2011) Treatment and prevention of recurrent DVT/PE (November 2012) Apixaban (Eliquis ) Oralfactor Xa inhibitor FDA approved Stroke prevention in non-valvular atrial fibrillation (December 2012) DVT/PE prevention in patients with knee/hip replacement (March 2014) Edoxaban (Savaysa ) NDA 1/9/14 Betrixaban (PRT054021) Phase III studies ongoing New Oral Anticoagulants (NOAC) / Renal Dysfunction Underrepresentation in major afib clinical trials Dabigatran CrCl < 30 ml/min excluded in Re-Ly trial (PI: decrease dose to 75mg BID for CrCl 15 30 ml/min, avoid <15 ml/min) Apixaban CrCl < 25 ml/min excluded in AVERROES and ARISTOTLE trials (any 2 of the following: Age 80 years, body weight 60 kg, or serum creatinine 1.5 mg/dl, then reduce dose to 2.5 mg twice daily) Rivaroxaban CrCl < 30 ml/min excluded in ROCKET-AF trial (PI: decrease dose from 20mg/d to 15mg/d for CrCl 15 50 ml/min, avoid <15 ml/min) Stroke 2013;44:2935-41. Non-VKA Oral Anticoagulants (NOACs) Less stroke risk in atrial fibrillation (afib) versus warfarin Marketed as safer than warfarin Monitoring not required * * Apixaban vs. aspirin 2
Major Bleeding: Dabigatran Reversal of NOACs (Yes, I know there s no antidote but we have to do something!) Circulation 2011;123:2363-2372. Major Bleeding: Dabigatran Prothrombin Complex Concentrate (PCC) Pooled human plasma containing vitamin K-dependent clotting factors Factors II, VII, IX and X Some products contain Protein C/S and heparin (Bebulin, KCentra ) Variable amounts of factor 7 3-factor PCC low or no factor 7 4-factor PCC adequate factor 7 US available products Profilnine, Bebulin (both 3-factor PCCs) Kcentra (4-factor PCC); FEIBA (activated 4-factor PCC or apcc) Circulation 2011;123:2363-2372. D D RCT, crossover trial in 12 healthy male volunteers, mean 24 y.o. Rivaroxaban 20mg twice daily (n=6) for 2.5 days Dabigatran 150mg twice daily (n=6) for 2.5 days D Intervention 50 IU/kg PCC or placebo *PCC=Cofact (3-factor) Blood sampled at 15 min, 30 min, 1, 2, 4, 6, and 24 hours after infusion 11-day washout period Intervention repeated Stroke 2013;44:2935-41. Circulation 2011;124:1573-9. 3
Reversal of Direct Thrombin Inhibitors Results (rivaroxaban) Prothrombin time (PT) and endogenous thrombin potential (ETP) completely reversed in 15 minutes Both measures sustained at 24 hours Hemodialysis Six healthy patients with ESRD Results (dabigatran) APTT, endogenous thrombin potential (ETP), or ecarin clotting time (ECT) not reversed with PCC APTT normalized at 24 hours Dabigatran 50mg single dose 4-hour hemodialysis session Dabigatran concentrations measured at 2 and 4 hours 62% removed at 2 hours 68% removed at 4 hours Circulation 2011;124:1573-9. Clin Pharmacokinet 2010;49:259-68. Reversal of Direct Thrombin Inhibitors Randomized, crossover trial in 10 healthy male volunteers Rivaroxaban 20mg once Dabigatran 150mg once Intervention Blood sampled at baseline and 2 hours after anticoagulant Ex vivo administration of: rfviia 30, 60, and 120 mcg/kg apcc 20, 40, 80 and 160 IU/kg 4-PCC 12.5, 25 and 50 IU/kg 15-day washout period Intervention repeated Dabigatran PI recommendation for bleeding complications Maintain adequate hydration/diuresis (80% renal clearance) Hemodialysis removes ~60% of drug over 2-3 hours (limited data) Consider plasma, factor 7 or PCC (clinical usefulness not established) Measurement of aptt or ecarin clotting time (ECT) may help guide therapy Thromb Haemost 2012;108:217 224. http://bidocs.boehringer-ingelheim.com/biwebaccess/viewservlet.ser?docbase=renetnt&folderpath=/prescribing%20information/pis/pradaxa/pradaxa.pdf Reversal of Direct Thrombin Inhibitors Results (dabigatran) Only apcc corrected all thrombin generation tests PCC partially effective (inc. ETP); rfviia ineffective apcc 20 40 IU/kg (higher doses resulted in excess thrombin generation) Results (rivaroxaban) Only apcc corrected all thrombin generation tests PCC corrected all thrombin generation tests except lag time; rfviia corrected all thrombin generation tests except ETP PCC 12.5 IU/kg / apcc 20 IU/kg effective (smallest dose) In development from Boehringer/Ingelheim under the name idarucizumab Antibody fragment (adabi-fab) affinity for dabigatran ~350X greater than affinity for thrombin Effective for dabigatran reversal in rat and pig models No effect on coagulation tests or platelet aggregation Thromb Haemost 2012;108:217 224. Blood 2013;121(18):3554-3562. Critical Care 2014, 18(Suppl 1):P99 4
Reversal of Factor Xa inhibitors Laboratory Tests to Confirm Reversal of Factor Xa Inhibitors In development from Portola under the name andexanet alfa (PRT064445) Portola also manufacturer of betrixaban Restored hemostasis in liver laceration rabbit model with rivaroxaban Corrected blood loss in rat tail transection model with enoxaparin and fondaparinux Nature Med 2013;19(4):446-53. Thromb Haemost 2014;111:[epub ahead of print] Laboratory Tests to Confirm Reversal of Direct Thrombin Inhibitors Direct Thrombin Inhibitor Reversal (e.g. dabigatran / Pradaxa ) Ecarin clotting time (ECT) strong correlation with dabigatran conc. Dabigatran little effect on PT/INR at clinically relevant conc. Thromb Haemost 2010; 103: 1116 1127. Average dabigatran peak 184 ng/ml (150 mg twice daily) DTI Activated charcoal if < 2 hours since last dose apcc 25 50 IU/kg or PCC 25 50 IU/kg Consider hemodialysis, especially if renal failure (nephrology and toxicology consults recommended) Consider platelet transfusion if history of concomitant antiplatelet use 30 minutes after apcc or PCC administration: Thrombin time APTT Thrombin time and APTT normal: supportive care Thrombin time normal, APTT slightly elevated: supportive care Thrombin time or APTT elevated: consider additional dose of apcc or PCC 25 IU/kg or rfviia Laboratory Tests to Confirm Reversal of Direct Thrombin Inhibitors FXa Inhibitor Reversal (e.g. rivaroxaban/xarelto, apixaban/eliquis ) ECT and thrombin generation tests NOT CLINICALLY AVAILABLE! Thrombin time (TT) and aptt useful for qualitative assessment FXa inhibitor Activated charcoal if within 1 hour since last dose PCC 25 50 IU/kg Consider platelet transfusion if history of concomitant antiplatelet use 30 minutes after PCC or rfviia administration: Prothrombin time Chromogenic FXa assay (if available) Prothrombin time or anti Xa level normal: supportive care Prothrombin time or anti Xa level elevated: consider additional dose of PCC 25 IU/kg, rfviia, or apcc Thromb Haemost 2010; 103: 1116 1127. 5
Summary Coagulation Tests Prevention of Bleeding NOACs Apixaban Decrease dose to 2.5mg twice daily if serum creatinine 1.5 mg/dl and either age 80 years or body weight 60 kg Avoid in severe liver failure (Child-Pugh C) Dose decrease to 2.5mg twice daily for strong dual CYP3A4/P-gp drug interactions Contraindicated in above scenario if at least two of the following: serum creatinine 1.5 mg/dl, age 80 years or body weight 60 kg Eur Heart J 2013;34:489-498. Prevention of Bleeding NOACs and Surgery Unanswered Questions Is factor replacement useful for reversing newer anticoagulants? What is the optimal dose of pharmacologic factor replacement? Are clinical outcomes affected by mode of anticoagulation reversal? Are there safety differences with hemostatic therapy? (e.g. FFP vs. 4-PCC, 3-PCC vs. 4-PCC, apcc) Cleve Clin J Med 2013;80:443-51. Prevention of Bleeding NOACs Dabigatran Decrease dose to 75mg BID for CrCl 15 30 ml/min Contraindicated if CrCl 15 30 ml/min AND concomitant P-gp inhibitor use (ketoconazole, dronedarone, amiodarone, quinidine, verapamil, clarithromycin, etc.) Rivaroxaban Decrease dose to 15mg/day CrCl 50 ml/min Contraindicated CrCl <30 ml/min (DVT/PE) or CrCl <15 ml/min (afib) Discontinue in ARF Avoid in moderate-to-severe liver failure (Child-Pugh B/C) Avoid if strong dual CYP3A4/P-gp inhibitors 48 th Annual Meeting Non-VKA Oral Anticoagulants: Prevention & Treatment of Bleeding Stacy A. Voils, PharmD, MS, BCPS Navigating the Oceans of Opportunity 6