New Anticoagulation Agents and Their Reversal Agents. Objectives. Background 12/21/2015

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1 New Anticoagulation Agents and Their Reversal Agents Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Broward Health Medical Center Objectives Review the pharmacology, indications, and place in therapy of the target-specific oral anticoagulants (TSOACs) Discuss how to switch between TSOACs and parenteral anticoagulants, and how to manage them perioperatively Examine reversal strategies, management approaches, and pipeline reversal agents Background Venous thromboembolism and pulmonary embolism Third most common cause of cardiovascular disease and death 4 to 6 times higher in patients above 70 years of age Risk doubles with each decade of aging Nonvalvular atrial fibrillation Absence of mitral valve disease, prosthetic heart valve, or mitral valve repair 5-fold increased risk of stroke Increases with age and risk factors Added January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation Journal of the American College of Cardiology Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis" CHEST Journal 1

2 Warfarin for Acute VTE/PE Treatment of an acute VTE/PE Parenteral anticoagulation and warfarin started on the same day Enoxaparin 1 mg/kg SQ every 12 hrs with warfarin Continue parenteral for a minimum of 5 days AND until INR is > 2 for at least 24 hrs Warfarin Delayed onset (5-7 days) Inhibits synthesis of new factors Hyper-coagulable state (24-48 hrs) Depletion of protein C Bridge in high risk patients Coagulation factors affected: Factor VII t 1/2 = 4-6 hrs Factor IX t 1/2 = hrs Factor X t 1/2 = hrs Factor II t 1/2 = > 60 hrs Protein C t 1/2 = 4-6 hrs Protein S t 1/2 = hrs Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis" CHEST Journal Advances in Treatment Warfarin 1953 Dabigatran 2010 Apixaban Rivaroxaban 2015 Edoxaban Nomenclature New (or novel) oral anticoagulants or Target- Specific Oral Anticoagulants NOAC vs TSOAC ISMP has reported medication errors Cardiologist wrote in a note consider NoAC due to drug interactions with warfarin Was interpreted as no anticoagulation Instead of NOAC use an alternative or nothing Direct oral anticoagulant (DOAC) or TSOAC Or just do not use abbreviations Barnes, Geoffrey D., et al. Journal of Thrombosis and Haemostasis (2015) ISMP Medication Safety Alert! Nurse Advise-ERR (ISSN ) 2014 Institute for Safe Medication Practices (ISMP) 2

3 Factor Xa inhibitors Target-Specific Oral Anticoagulants Rivaroxaban, apixaban, and edoxaban Direct thrombin (IIa) inhibitors Dabigatran Clotting Cascade Targets Factor Xa inhibitors Apixaban, rivaroxaban, and edoxaban Rivaroxaban (Xarelto ) Indication and dosing: Renal Dosing CrCl > 50 ml/min CrCl ml/min CrCl <15 ml/min or HD CrCl > 30 ml/min CrCl < 30 ml/min CrCl > 30 ml/min CrCl < 30 ml/min CrCl > 30 ml/min CrCl < 30 ml/min Nonvalvular Atrial Fibrillation 20 mg daily with largest meal 15 mg daily with largest meal Avoid Acute treatment of DVT/PE 15 mg BID with food x 21 days, then 20 mg daily with largest meal Avoid Secondary prevention of DVT/PE 20 mg daily with largest meal Avoid Prophylaxis for DVT (after knee/hip replacement) 10 mg daily WITHOUT regards to meals, start 6-10 hrs after surgery Hip: 35 days (minimum 10 days) Knee: days Avoid Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc

4 Food increases bioavailability Dose > 15 mg requires food to help with absorption Crushable Yes; can administer with applesauce or mix with 50 ml of water Do not administer distal to the stomach Missed Doses Rivaroxaban (Xarelto ) Pearls Administer dose as soon as possible on the same day Two 15 mg tablets can be taken simultaneously To ensure 30 mg per day, then continue BID dosing Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc Rivaroxaban (Xarelto ) Pearls Elimination 66% renal; 33% biliary Not dialyzable High protein binding Boxed warnings Premature discontinuation increases risk of thrombotic events Neuraxial anesthesia or spinal puncture Increased risk for hematomas and subsequent paralysis Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc Indication and dosing: Renal Dosing No risk factors present Patients with > 2 of the following: Age > 80, weight < 60 kg, SCr > 1.5 CrCl < 15 ml/min or HD Adult dosing Renal impairment Adult dosing Renal impairment CrCl > 30 ml/min CrCl < 30 ml/min Apixaban (Eliquis ) Nonvalvular Atrial Fibrillation 5 mg BID 2.5 mg twice a daily Avoid Acute treatment of DVT/PE 10 mg twice a day x 7 days, then 5 mg BID No dose adjustments NOT studied with SCr > 2.5 mg/dl or CrCl < 25 ml/min Secondary prevention of DVT/PE after at least 6 months of treatment 2.5 mg BID No dose adjustments NOT studied with SCr > 2.5 mg/dl or CrCl < 25 ml/min DVT Prophylaxis (after knee/hip replacement) 2.5 mg twice a day, start hrs after surgery Hip 35 days; Knee 12 days No dose adjustments NOT studied in these patients Apixaban (Eliquis) package insert. Bristol-Myers Squibb Company; Princeton, NJ

5 Apixaban (Eliquis ) Pearls Grapefruit juice May increase levels; otherwise not affected by food Monitor for signs and symptoms of bleeding Crushable Yes; mix with 60 ml of D 5 W and administer immediately through NG tube Missed Doses Administer dose as soon as possible on the same day Do NOT double a dose to make up for a missed dose Apixaban (Eliquis) package insert. Bristol-Myers Squibb Company; Princeton, NJ Apixaban (Eliquis ) Pearls Elimination 27% renal; biliary, and direct intestinal Not significantly dialyzable High protein binding (92-94%) 14 % decrease in exposure Boxed warnings: Premature discontinuation increases risk of thrombotic events Neuraxial anesthesia or spinal puncture Increased risk for hematomas and subsequent paralysis Apixaban (Eliquis) package insert. Bristol-Myers Squibb Company; Princeton, NJ Indication and dosing: Edoxaban (Savaysa ) Renal Dosing CrCl > 95 ml/min CrCl ml/min CrCl ml/min CrCl < 15 ml/min CrCl > 51 ml/min CrCl ml/min Or Weight < 60 kg CrCl < 15 ml/min Nonvalvular Atrial Fibrillation Not recommended (increase risk of ischemic stroke) 60 mg daily 30 mg daily Not recommended Acute treatment of DVT/PE; AFTER 5-10 days of parenteral anticoagulation 60 mg daily 30 mg daily Not recommended Secondary prevention of DVT/PE Not FDA approved Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc

6 Edoxaban (Savaysa ) Pearls Grapefruit juice May increase levels; otherwise not affected by food Monitor for signs and symptoms of bleeding Crushable No data available regarding crushing and/or mixing into food Missed Doses: Administer dose as soon as possible on the same day Do NOT double a dose to make up for a missed dose Elimination 50% renal; metabolism and intestinal/biliary Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc Edoxaban (Savaysa ) Pearls Not significantly dialyzable Protein binding 55% 4 hour session reduced total exposure by < 7% Boxed warnings Reduced efficacy in patients with CrCl > 95 ml/min Nonvalvular atrial fibrillation Premature discontinuation increases risk of thrombotic events Neuraxial anesthesia or spinal puncture Increased risk for hematomas and subsequent paralysis Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc Edoxaban contraindicated with good renal function? Nonvalvular atrial fibrillation only Reduced efficacy in patients with CrCl > 95 ml/min 50% of the dose is eliminated by the kidneys rate of ischemic stroke compared to warfarin Blood levels are lower in patients with better renal function 30% less in patients with CrCl of > 80 ml/min 40% less in patients with CrCl > 95 ml/min Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc

7 Direct Thrombin Inhibitor: Dabigatran (Pradaxa ) Indication and dosing: Renal Dosing CrCl > 50 ml/min CrCl ml/min, AND concurrent P-gp inhibitors dronedarone / ketoconazole CrCl ml/min CrCl < 15 ml/min or HD CrCl > 30 ml/min CrCl < 30 ml/min CrCl > 30 ml/min CrCl < 30 ml/min Nonvalvular Atrial Fibrillation 150 mg BID 75 mg BID 75 mg BID (Contraindicated per CHEST) Contraindicated per CHEST Acute treatment and secondary prevention of DVT/PE; AFTER 5-10 days of parenteral anticoagulation 150 mg BID No dose adjustments NOT studied in these patients NEW DVT Prophylaxis after hip replacement 110 mg once, followed by 220 mg daily for days No dosing recommendations provided NOT studied Pradaxa (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Dabigatran (Pradaxa ) Pearls Acidic environment required Acid suppressive therapy may decrease absorption Not Crushable Do not break, chew, or open capsules, and do not put in NG tube 75% in absorption and potentially serious adverse reactions Store in original container Prodrug, if exposed to moisture will hydrolyze to inactive form Missed Doses Take as soon as possible unless it is within 6 hours of next dose Pradaxa (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Dabigatran (Pradaxa ) Pearls Elimination 80% renal Dialyzable ~ 49% can be removed over 4 hours Boxed warnings Contraindicated in patients with mechanical heart valves Premature discontinuation increases risk of thrombotic events Neuraxial anesthesia or spinal puncture Increased risk for hematomas and subsequent paralysis Pradaxa (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc

8 Evidence for use in Nonvalvular Atrial Fibrillation Efficacy and Safety in Atrial Fibrillation versus Warfarin Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Trial RE-LY ROCKET-AF ARISTOTLE Study Design Non-inferiority Non-Inferiority Non-Inferiority / Superiority ENGAGE AF-TIMI 48 Non-Inferiority Primary Dose 150 mg BID 20 mg daily 5 mg BID 60 mg daily Warfarin TTR 64% 55% 62.2% 64.9% Stroke / SE Superior Non-inferior Superior Non-inferior Major Bleeding Non-inferior Non-inferior Superior Superior ICH Superior Superior Superior Superior GI Bleeding Greater incidence Greater incidence No significant difference Greater incidence risk of MI vs Other Placebo ICH= intracranial hemorrhage, SE= Systemic embolism, TTR= time in therapeutic range Evidence for use in DVT/PE Treatment Efficacy and Safety in DVT/PE treatment versus Warfarin Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Trial RE-COVER I-II EINSTEIN DVT-PE AMPLIFY HOKUSAI Recurrent VTE Non-inferior Non-inferior Non-Inferiority Non-inferior Major bleeding Non-inferior Non-inferior / Superior in PE trial Superior for apixaban Non-inferior Relevant bleeding Superior for dabigatran Non-inferior Superior for apixaban Superior for edoxaban Lekura, Jona. Annals of Pharmacotherapy 49.4 (2015): Hazards of Warfarin 8

9 TSOAC Advantages TSOACs offer several advantages over warfarin Feature Warfarin TSOAC Onset Slow Rapid Dosing Variable Fixed Food Interactions Yes No Interactions Many Few Blood Monitoring Yes No Offset Long Short Ruff CT, et. al. Lancet 2013, 383(9921): Drug Interactions? TSOACs are mainly metabolized by CYP3A4 or are substrates of P-gp Big Inducers (PS PORCS) Phenytoin Smoking Phenobarbital Oxcarbazepine Rifampin Carbamazepine St. John s Wort Big Inhibitors (G <3 PACMAN) Grapefruit Protease Inhibitors Azoles Cyclosporine & Cimetidine Macrolides Amiodarone/Dronedarone Non-DHP CCB Converting FROM Warfarin Rivaroxaban (Xarelto ) Dabigatran (Pradaxa ) Apixaban (Eliquis ) Edoxaban (Savaysa ) D/C warfarin, start rivaroxaban when INR < 3.0 D/C warfarin, start apixaban or dabigatran when INR < 2.0 D/C warfarin, start edoxaban when INR 2.5 Pradaxa (dabigatran) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc Apixaban (Eliquis) package insert. Princeton, NJ: Bristol-Myers Squibb Company, Inc Savaysa (edoxaban) package insert. Parsippany, NJ: Daiichi Sankyo, Inc

10 Converting TO Warfarin Dabigatran (Pradaxa ) Dabigatran affects INR. Warfarin s effect on the INR can be measured only after dabigatran has been stopped for 2 days. Starting time of warfarin is based on CrCl: CrCl 50: start 3 days before D/C dabigatran CrCl 30-50: start 2 days before D/C dabigatran CrCl 15-30: start 1 day before D/C dabigatran Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Rivaroxaban and apixaban affects the INR. Discontinue the TSOAC and initiate both warfarin and a parenteral anticoagulant at the time the next dose of the TSOAC would have been due. Edoxaban (Savaysa ) Edoxaban can affect the INR. When monitoring patient s INR, check just prior to edoxaban dose. 60 mg: Reduce to 30 mg and start warfarin. Stop edoxaban when INR mg: Reduce to 15 mg and start warfarin. Stop edoxaban when INR 2.0 CrCl < 15: no recommendation Perioperative Management Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Switch FROM parenteral anticoagulants Switch TO parenteral anticoagulants AC= anticoagulant Start dabigatran 0 to 2 hrs prior to the next scheduled dose of the parenteral AC; discontinue parenteral AC UFH infusion: stop infusion and initiate simultaneously CrCl 30 Wait 12 hrs CrCl < 30 Wait 24 hrs AFTER the last dose of dabigatran before initiating parenteral AC Start rivaroxaban 0 to 2 hrs prior to the next scheduled dose of the parenteral AC; discontinue parenteral AC UFH infusion: stop infusion and initiate simultaneously Start apixaban at the next scheduled dose of the parenteral AC; discontinue parenteral AC Start edoxaban at the next scheduled dose of the parenteral AC; discontinue parenteral AC UFH infusion: start edoxaban 4 hrs after stopping infusion Start the parenteral AC at the time the next scheduled dose of the factor Xa inhibitor was to be administered Perioperative Management Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Procedural Pre-op CrCl 50: 1-2 days prior to standard risk procedures; Stop 3-5 days prior to high risk procedures CrCl < 50: Stop 3 to 5 days prior to standard risk procedures; Stop > 5 days prior to high risk procedures CrCl 30: Stop at least 24 hours prior to standard risk procedures; Stop at least 48 hrs prior to high risk procedures CrCl < 30: Stop at least 48 hours prior to standard risk procedures; Stop at least 72 hours prior to high risk procedures. Stop at least 24 hours prior to procedures Procedural Post-op Low risk surgery restart hours post-op; High risk surgery restart hours post-op 10

11 No More Monitoring? No routine blood monitoring Monitoring still necessary Patient education Correct dosing Transitioning of care Drug interactions Renal function TSOAC Concerns Increased risk of exposure with reduced renal clearance Dabigatran in particular Short t ½ of TSOACs poses risk with non-compliance BID dosing Price and formulary issues The ability to reverse TSOACs For emergency surgery / urgent procedures In life-threatening / uncontrolled bleeding Sarich, Troy C., et al. American Heart Journal (2015): Reversal Based on Urgency Categorized into 3 groups No rush (> 24 hr) Expedited (1-24 hr) Emergent (1 hr) Intervention may need to be modified based on clinical status Nutescu, Edith A., et al, American Journal of Health-System Pharmacy (2013):

12 Assessing Bleeding in Patients Receiving TOSACs Physical examination / medication history Perform vitals and check for external evidence of hemorrhage Diagnosis of internal hemorrhage Endoscopy, CT scan, ultrasound Bleeding severity Epistaxis vs > 2 g/dl drop in hemoglobin Laboratory tests Need for emergent procedures Allergies Concern for heparin-induced thrombocytopenia Nutescu, Edith A., et al, American Journal of Health-System Pharmacy (2013): Coagulation Assays Activated partial thromboplastin time (aptt) Intrinsic pathway Prothrombin time (PT) & International normalized ratio (INR) Extrinsic and common pathway Thrombin time (TT) Directly assesses activity of thrombin Ecarin clotting time (ECT) Specific assay for thrombin generation A measure of direct thrombin inhibitor activity Anti-factor Xa Can calculate plasma concentrations of factor Xa Patel, Deepa V., US Pharm 2 (2015): 18. Utility of Coagulation Assays Direct Thrombin Inhibitor Factor Xa Inhibitors aptt (+/-) (-) PT/INR (-) (+/-) TT (+/-) (-) ECT (+/+) (-) Anti-factor Xa (-) (+/+) (+/+) = Clinically reliable assay (+/-) = May impact/variable response at supratherapeutic levels (-) = No evidence to support use Patel, Deepa V., US Pharm 2 (2015):

13 Management of Emergent Bleeding Stop anticoagulant Hemodynamic and hemostatic resuscitation Volume replacement Massive transfusion protocol Hemostasis of bleeding site Consider activated charcoal If last dose < 2 hrs ago and patient can protect their airway Clotting factor supplementation Reversal agent Nutescu, Edith A., et al, American Journal of Health-System Pharmacy (2013): Clotting Factors for Reversing Anticoagulants Prothrombin Complex Concentrates (PCC) Three-factor PCC (PCC3) Four-factor PCC (PCC4) Activated PCC (apcc) Recombinant Factor VIIa (rfviia) Fresh frozen plasma (FFP) PL Detail-Document, Clotting Factors for Reversing Anticoagulants Pharmacist's Letter/Prescriber s Letter. October 2013 Factor Pearls Product Description Pros Cons Fresh Frozen Plasma (FFP) Kcentra Bebulin Profilnine Human plasma containing all the clotting factors PCC4 (II,VII,IX,X) Factors are nonactivated Contains proteins C & S PCC3 (II,IX,X) Non-therapeutic amounts of factor VII Cheap Widely available Fast infusion Lower risk of infection than FFP Non-inferior to FFP for hemostasis and lowers INR faster Small volume Faster than FFP Low infection risk Requires cross matching Takes hours to thaw Risk of infection Expensive Higher thrombosis risk then FFP Contains small amounts of heparin (allergy risk) Factor VII also required Expensive Bebulin contains small amounts of heparin (allergy risk) PL Detail-Document, Clotting Factors for Reversing Anticoagulants Pharmacist's Letter/Prescriber s Letter. October

14 Factor Pearls Product Description Pros Cons FEIBA apcc (II, VII, IX, X) Factor VII mainly activated (VIIa) Other factors in non-activated form Small volume Fast infusion Lower risk of infection than FFP Expensive Carries 6% risk of thrombosis due to activated factor VII NovoSeven RT Recombinant activated factor VII Not a blood product Small volume Expensive Short duration of action Not recommended as monotherapy Thrombosis risk similar to FEIBA FEIBA= PL Detail-Document, Clotting Factors for Reversing Anticoagulants Pharmacist's Letter/Prescriber s Letter. October 2013 Antidotes for TOSACs Dabigatran Idarucizumab (Praxbind ) Oral factor Xa inhibitors Andexanet alfa (Phase 3 trials) Antidotes for TOSACs Idarucizumab (Praxbind ) Recently approved for the reversal of dabigatran Humanized monoclonal antibody fragment (Fab) ~350 x higher affinity to dabigatran than thrombin Neutralizes anticoagulant effect within minutes Advantages Target specific, will not affect other anticoagulants Should not be pro-thrombotic Rebound effect hrs later, may need to re-dose Praxbind (idarucizumab) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc

15 Antidotes for TSOACs Andexanet alfa (Phase 3 trials) Inactive human recombinant factor Xa inhibitor Factor Xa decoy that targets factor Xa inhibitors Potential to reverse Xa inhibitors and low molecular weight heparin Crowther, Mark, et al., Circulation (2014): Management of Emergent Bleeding Dabigatran Withhold drug Hemodynamic and hemostatic resuscitation Activated charcoal (if last dose < 2 hrs ago) Hemodialysis Reversal strategies in order of preference Idarucizumab apcc PCC4 PCC3 plus rfviia (PCC4) Nutescu, Edith A., et al, American Journal of Health-System Pharmacy (2013): Management of Emergent Bleeding Oral factor Xa inhibitors Withhold drug Hemodynamic and hemostatic resuscitation Activated charcoal (if last dose < 2 hrs ago) Not significantly dialyzable Reversal strategies in order of preference PCC4 apcc PCC3 plus rfviia (PCC4) PCC3 Nutescu, Edith A., et al, American Journal of Health-System Pharmacy (2013):

16 Conclusion TSOACs offer unique advantages over warfarin Anticoagulation services can play a pivotal role managing the different TSOAC nuances Current limited data highlights the importance of post marketing reporting Conventional laboratory assays do not correlate well with bleeding or reversal of anticoagulation A protocolized approach to reversing anticoagulation should be established based on urgency True or False Assessment Questions Dabigatran s bioavailability will be decreased in patients who take proton pump inhibitors True Food increases absorption of the 20 mg rivaroxaban dose but does not affect the 10 mg rivaroxaban dose True All TSOACs require 5-10 days of parenteral anticoagulation prior to treatment for a DVT or PE False Questions? 16