Emerging Therapies for Reversal of Anticoagulation

Angela Slampak-Cindric, Pharm.D., BCPS Clinical Pharmacist 2016: “Surviving the Stampede” Objectives

 Outline pharmacologic options for the reversal of oral anticoagulation  Describe the benefits and limitations of emergent anticoagulation reversal strategies  Develop a patient specific treatment plan for reversing the effects of oral Prehistoric Oral Anticoagulation: Pre-2010

– antagonist – Interferes with cyclic interconversion of Vitamin K. – Inhibits Vitamin K dependent factors II, VII, IV and X. – Inhibits carboxylation of regulatory anticoagulation Proteins C, S and Z.

Chest.2012;141(2_suppl):e44S-e88S. www.clipartkid.com Warfarin: Clinical Considerations

 Multiple indications – Atrial fibrillation, DVT, PE, Prosthetic Cardiac Valve, VTE Prophylaxis, Antiphospholipid Syndrome  Many drug interactions – Binders, Inhibitors, Potentiators  Dietary considerations – Vitamin K containing foods and supplements  Laboratory Monitoring required – INR What if I need to reverse the anticoagulation?

1 2 to 3 4 5 6 7 8 9 10 Warfarin Reversal

 Therapeutic Options – Interruption of VKA treatment – Vitamin K

 Phytonadione: Plant derived Vitamin K1 – Blood derivatives  Fresh Frozen Plasma (FFP)  Prothrombin complex concentrates (PCCs)  Recombinant activated factor VII

Chest.2012;141(2_suppl):e44S-e88S. Timeline: Effect on INR

rFVIIa

PCC

FFP Vitamin K (IV)

0 hrs 12 hrs 24 hrs Vitamin K (phytonadione)

 Promotes liver synthesis of clotting factors: II, VII, IX, X  Dose: 10 mg IV – IV is route of choice for life threatening – Mix in 50 ml of NSS or D5W and administer over 20 to 60 minutes – IV push: Not recommended. Give each 1 mg over at least 1 min.  Associated with anaphylactic reactions  Time to reversal: 6-24 hours

Crowther MA, et al. Ann Intern Med. 2002;137: 251-254. Whitling AM, et al. Arch Intern Med. 198; 158: 2136-2140. Vitamin K (phytonadione)

 Oral Vitamin K – Treatment of choice when rapid reversal is not needed. (supratherapeutic INR but no bleeding)  SubQ or IM: Not recommended – SubQ absorption is erratic. – Depot formation interferes with restarting anticoagulation. – Hematoma possible with IM injection – May be less effective or delayed compared to PO  Warfarin resistance occurs with higher doses

Crowther MA, et al. Ann Intern Med. 2002;137: 251-254. Whitling AM, et al. Arch Intern Med. 198; 158: 2136-2140. Fresh Frozen Plasma

 Coagulation factors and  Dose: 15 to 30 ml/kg  Requires thawing  Potential carrier of infective agents  Long infusion time: 3 to 6 hours  Time to reversal: typically 12-32 hours (unpredictable and extended)  Volume can be prohibitive, TRALI possible – Usually requires 2 to 4 liters to normalize INR  Transfusion reactions may occur

Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92. Makris M et al. Thromb Haemost. 1997; 77:477-80 Matthews M et al. Neurocrit Care. 2006; 5:141-52. Factor VIIa Concentrate (rFVIIa)

 Activates platelets to augment burst  Combination with vitamin K and clotting factor replacement  Dose: 10-90 mcg/kg IV – Administer over 2-5 min. Administer alone. Do not mix with other agents. Take blood product precautions.  Time to reversal: 15 min after bolus infusion  Short acting  Adverse effects: Thrombosis  Expensive  Limited evidence: Restrict to life threatening bleeding when alternate agents unavailable Prothrombin Complex Concentrate (PCC)

 Factors II, VII, IX, X, prothrombin, proteins C,S, and Z in variable amounts  Labeled in terms of Factor IX content  Prepared from pooled human plasma  Viral inactivation steps during manufacturing  Rapid administration and Small volume  Doesn’t require blood type matching  Rapid INR reversal (often w/in 10 minutes)  Risk of thrombosis The Name Game

“I need factor IX stat!..... I mean factor IX complex…. Wait.. I meant FCC… Maybe the PCC???..... Just send it STAT!” PCC Products in the US

Unactivated Prothrombin Complex Concentrates (PCC) 3 Factor: Contain factors II, IX, and X Profilnine SD® (little to no factor VII). Bebulin VH® *Bebulin contains 4 Factor: Contain factors II, VII, IX and X KCentra® Contains heparin

Activated Prothrombin Complex Concentrates (aPCC) 4 Factor: Contains Factors II, VII, IX, X; factor VII is FEIBA NF® mostly activated *Potentially more thrombotic PCC Dosing

 Dose: 25-50 IU/kg – Based on Factor IX content – Round dose to nearest vial size – Cost: ~$1.54 dollars per unit  Kcentra® Pretreatment Dose MAX INR (IU/kg) (IU)

2 to less than 4 25 2500 4 to 6 35 3500

Greater than 6 50 5000 Evidence Based Recommendations?

 American College of Chest Physicians Evidence Based Clinical Practice Guidelines – Serious or Life threatening bleeding  Hold warfarin therapy  Give four factor PCC rather than plasma supplemented with IV Vitamin K.  Repeat if necessary, depending on the INR.

Holbrook et al. Chest 2012; 141(2_suppl):e:152S-184S. New Era: 2010 & Beyond Direct Oral Anticoagulants

 Direct Thrombin Inhibitors – (Pradaxa®)  Factor Xa Inhibitors – (Xarelto®) – (Eliquis®) – (Savaysa®)

Redondo S, et al. J Hematol Oncol. 2011;4:53. Arepally GM, et al. Anu Rev Med. 2015;66:241-53. Mega Jl, et al. Lancet. 2015;386(9990):281-91. www.clipartbest.com Allure of Direct Oral Anticoagulants

 Prescribed at relatively fixed doses  Closer to one size fits all  Lower bleeding risk?  Fewer incidents of intracranial hemorrhage compared with warfarin in a randomized phase III study  No therapeutic drug monitoring  No dietary restrictions Greinacher A et al. Thromb Haemost. 2015; 113(5):931-42. Frequently Cited Limitation

 No

Chest 2016: Choice of Long-Term (First 3 Months) & Extended (No Scheduled Stop)

In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy.

Kearon C et al. Chest. 2016;149(2):315-352. for Target Specific Oral Anticoagulants Dabigatran: Potential Interventions

 Oral Activated charcoal (if last dose within prior 2 hours)  Hemodialysis (HD) – Shown to clear 50-60% of dabigatran – Standard HD may not be practical if hemodynamically unstable – CVVHD not ubiquitous  Activated PCC (FEIBA) – Factor VIII Inhibitor Bypassing Activity Dabigatran: Potential Interventions

 Anti-fibrinolytic Agents – – Epsilon-  RBC transfusions prn anemia  Platelet infusions prn thrombocytopenia or impaired platelet function  Surgical/Endoscopic Intervention if appropriate : Praxbind®

 FDA approved October 2015  Humanized monoclonal antibody fragment; binds dabigatran specifically  Affinity for dabigatran~350 times greater than thrombin  Indicated when reversal is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding Idarucizumab for Dabigatran Reversal

 Interim analysis of RE-VERSE AD trial  Multicenter prospective cohort study  Enrolling 2 type of patients taking dabigatran – Patients who develop life threatening bleeding requiring urgent reversal – Patients who require urgent reversal for an invasive procedure

Pollack CV et al. N Engl J Med. 2015; 373;6. Methods: Idarucizumab for Dabigatran Reversal

 Plan to recruit up to 300 patients; reported results of 90 thus far  Patients received: – 5 grams of IV idaruzicumab – Two 50 ml bolus infusions (2.5 grams/infusion) no more than 15 min apart

Pollack CV et al. N Engl J Med. 2015; 373;6. Methods: Idarucizumab for Dabigatran Reversal

 Blood samples drawn at intervals to assess for % dabigatran reversal  Calculated via:  Dilute thrombin time – Involves human thrombin which is inhibited by direct thrombin inhibitors in a concentration dependent manner  Ecarin clotting time – Uses metalloprotease from saw-scaled viper venom which generates meizothrombin – Direct thrombin inhibitors inhibit meizothrombin Pollack CV et al. N Engl J Med. 2015; 373;6. Results: Idarucizumab for Dabigatran Reversal

 Median maximum % reversal = 100%  Normalized test results in 88-98% of patients  Effect evident within minutes  Concentration of unbound dabigatran remained < 20 ng/mL at 24 hrs in 79%  Hemostasis restored at median of 11.4 hours in assessable patients  One thrombotic event occurred w/in 72 hrs

Pollack CV et al. N Engl J Med. 2015; 373;6. Clinical Considerations

 Difficult to assess mortality benefit without a control group  Clotting assays – Availability – Dilute thrombin time in study was normal on study entry in nearly 25% of patients  Cost – 50 mg/mL; 50 mL vial: ~$1750 – 2 vials per dose IV Idarucizumab Administration

 One dose (5 g) is provided as two 2.5 g vials  Begin administration within 1 hour once solution has been removed from vial  May be administered as 2 consecutive IV bolus injections or IV infusions  May be administered using a preexisting IV line after flushing with NS prior to infusion  Do not administer another infusion in parallel via the same IV access  Do not mix with other medicinal products Product Information: PRAXBIND(R) intravenous injection, idarucizumab intravenous injection. Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015. Adverse Effects

 Common  Serious – Endo: Hypokalemia (7%) – Hematologic: – GI: Constipation (7%)  Coag/bleeding tests abnormal – Psych: Delirium (7%)  Thromboembolic – Resp: Pneumonia (6%) disorder (4% ) – Other: Fever (6%) – Immunologic:  Hypersensitivity reaction

Product Information: PRAXBIND(R) intravenous injection, idarucizumab intravenous injection. Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015. New Era: 2010 & Beyond Direct Oral Anticoagulants

 Direct Thrombin Inhibitors – Dabigatran (Pradaxa®)  Factor Xa Inhibitors – Rivaroxaban (Xarelto®) – Apixaban (Eliquis®) – Edoxaban (Savaysa®)

Redondo S, et al. J Hematol Oncol. 2011;4:53. Arepally GM, et al. Anu Rev Med. 2015;66:241-53. Mega Jl, et al. Lancet. 2015;386(9990):281-91. www.clipartbest.com Factor Xa Inhibitors: Reversal Strategies

 Imminent Risk of Death – Un-activated 4-factor PCC (50 units/kg)  No clinical evidence to support use  Based on ability to attenuate bleeding or correct coag studies in experimental models – 3-factor PCC if 4-factor unavailable  +/-FFP Oral direct factor Xa inhibitors are highly protein bound: NOT dialyzable Factor Xa Inhibitors: Reversal Strategies

 Major bleeding – Oral activated charcoal if last dose recent  Rivaroxaban: Within 8 hours  Apixaban: Within 6 hours  Edoxaban: Within 2 hours  RBC transfusions prn  Platelet infusions prn  Surgical/Endoscopic Intervention if appropriate Factor Xa Inhibitors: Reversal Strategies

 Major Bleeding – Anti-fibrinolytic agents  Tranexamic Acid – PO: 1 to 1.5 g Q8 to 12H – IV: 10-20 mg/kg IV bolus then 10 mg/kg IV Q6-8H  Epsilon-aminocaproic Acid – 2 g IV Q6H (typical); can give up to 1 g Q1H – Desmopressin – 0.3 mcg/kg sub Q or IV : PRT064445

 Recombinant modified decoy of Factor Xa  Produced in Chinese hamster ovary cells  Able to bind directly to: – Direct Factor Xa inhibitors – Antithrombin activated by low molecular weight heparin or  Potential universal antidote for direct and indirect inhibitors both PO and IV

Das A et al. Exp Hematol Oncol (2015) 4:25. Gomez-Outes et al. Cardiovasc Drug Discov. 2014; 9(1):2-10. Phase II Proof of Concept

 IV andexanet rapidly reversed: – apixaban, rivaroxaban, edoxaban, enoxaparin  Reversal assessed as: – Reduction in anti-factor Xa activity & unbound factor Xa inhibitor concentration – Restoration of thrombin generation  Half life – 1 hr; Given as bolus + 1-2 hr infusion

Siegal DM et al. N Engl J Med. 2015; 373;25. Phase III Parallel Trials

 A Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixiban and Rivaroxaban – ANNEXA-A – ANNEXA-R

Siegal DM et al. N Engl J Med. 2015; 373;25. Andexanet Alfa for Reversal of Factor Xa Inhibitor Activity

 Two part randomized double blind placebo controlled studies – Safety – Efficacy  Healthy older volunteers

Siegal DM et al. N Engl J Med. 2015; 373:2413 ANNEXA-A

 Participants received: – 5 mg of apixaban PO BID x 3.5 days – 400 mg IV bolus of andexanet (30 mg/min) – OR – 400 mg IV bolus of andexanet PLUS  4 mg/min continuous infusion x 120 minutes

Siegal DM et al. N Engl J Med. 2015; 373:2413 ANNEXA-R

 Participants received: – 20 mg of PO rivaroxaban daily x 4 days – 800 mg IV bolus of andexanet (30 mg/min) – OR – 800 mg IV bolus of andexanet PLUS 8 mg/min continuous infusion x 120 minutes

Siegal DM et al. N Engl J Med. 2015; 373:2413 Siegal DM et al. N Engl J Med. 2015; 373:2413 Results

 ANNEXA-A Andexanet Placebo

Anti-factor Xa Reduction (p<0.001) 94% 21%

Unbound Apixaban Reduction (p<0.001) 9.3 ng/mL 1.9 ng/mL

Thrombin Generation Restoration (p<0.001) 100% 11%

 ANNEXA-R Andexanet Placebo

Anti-factor Xa Reduction (p<0.001) 92% 18%

Unbound rivaroxaban Reduction (p<0.001) 23.4 ng/mL 4.2 ng/mL

Thrombin Generation Restoration (p<0.001) 96% 7%

Siegal DM et al. N Engl J Med. 2015; 373:2413 Clinical Considerations

 Correction of anti-factor Xa established  Half life  Healthy older adults  Efficacy and safety data in patients who require urgent reversal not presented  Transient increases in D-dimer and prothrombin fragments 1 and 2 Andexanet alfa: PRT064445

 Slated to be marketed as AndexXa®  Phase 3b-4 study in Pts w/factor Xa inhibitor acute major bleeding ongoing  August 17, 2016 manufacturer released statement that FDA has issued a Complete Response Letter – Requesting additional information primarily related to manufacturing Antidote for all DOACs: PER977: Ciraparantag

 Synthetic molecule  Broad spectrum reversal agent for: – Low molecular weight heparin – Unfractionated heparin – Dabigatran – Rivaroxaban – Apixaban – Edoxaban PER977: Ciraparantag

 Currently in Phase 2 Clinical Trials – Single IV bolus produced complete & sustained reversal of edoxaban – Restored hemostasis in 10 to 30 minutes and sustained for 24 hours  Preliminary studies – Direct & specific binding & reversal for all DOACs &  No pro-coagulant signals observed Laulicht B et at. ISTH abstract 2013; :AS 47.1. Ansell JE et al. N Engl J Med 2014; 371:2141. Patient Scenario 1

 Pt is a 60 year old female with a past medical history of HF, HTN, DM, GERD and atrial fibrillation for which she is anticoagulated with warfarin. She tripped while at the zoo with her grandson and struck her head on a concrete retaining wall. Patient Scenario 1

 CT scan in ED reveals acute ICH requiring urgent INR Reversal. INR=3.1  In addition to holding warfarin, what do you recommend? A. FFP 30 ml/kg + 10 mg IV Vitamin K B. 4 Factor PCC 25 IU/kg + 10 mg IV Vit K C. 4 Factor PCC 50 IU/kg + 10 mg IV Vit K D. rFVIIa 1 mg + 10 mg IV Vitamin K Patient Scenario 2

 Pt is a 45 year old male who is anticoagulated with dabigatran for a DVT he experienced after orthopedic surgery. He presents to the ED as a trauma alert following a helmeted motorcycle collision. He sustained multiple fractures, is hemodynamically unstable and is being rushed to the OR for exploratory laparotomy. Patient Scenario 2

 Last dose of dabigatran was taken 6 hours ago.  What reversal strategy to you recommend? A. Oral activated charcoal + emergent HD B. Activated PCC (FEIBA) C. Idarucizumab 2.5 g IV Q15 min x 2 doses D. 4 Factor PCC + 10 mg IV Vitamin K Patient Scenario 3

 A 28 year old morbidly obese female with a history of GERD is receiving rivaroxaban for treatment of bilateral pulmonary emboli in the setting of oral contraceptive use and smoking. She presents to the ED with complaints of fatigue, dizziness, severe abdominal pain and hematemesis. She also reports that’s she’s had dark stools. Patient Scenario 3

 Baseline Hgb: 12.5 g/dL  Hgb today: 7.8 g/dL  Reversal is requested. What do you recommend? A. Emergent HDAndexanet + Oral activatedalfa charcoal B. Idarucizumab 2.5Ciraparantag g IV Q15 min x 2 doses C. 4 Factor PCC D. Blood transfusion + Endoscopic intervention Summary

 Emerging pharmacologic options for the reversal of oral anticoagulation are increasingly available  Clinicians are charged with balancing therapeutic benefits with adverse effects and pharmacoeconomic impact  Each patient’s unique characteristics and product availability will drive decision making Emerging Therapies for Reversal of Anticoagulation

Angela Slampak-Cindric, Pharm.D., BCPS Clinical Pharmacist [email protected]