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 anticoagulants Prehistoric Oral Anticoagulation: Pre-2010 Warfarin – Vitamin K antagonist – Interferes with cyclic interconversion of Vitamin K. – Inhibits Vitamin K dependent coagulation 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 bleeding – 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 fibrinogen 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 thrombin 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 heparin 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 – 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 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 antidote Chest 2016: Choice of Long-Term (First 3 Months) & Extended (No Scheduled Stop) Anticoagulant 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. Antidotes 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 – Tranexamic Acid – Epsilon-aminocaproic Acid RBC transfusions prn anemia Platelet infusions prn thrombocytopenia or impaired platelet function Surgical/Endoscopic Intervention if appropriate Idarucizumab: 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,