Reversal Agents for Anticoagulants Understanding the Options. Katisha Vance, MD, FACP Alabama Oncology January 28, 2017

Reversal Agents for Anticoagulants Understanding the Options Katisha Vance, MD, FACP Alabama Oncology January 28, 2017

Objectives Appropriately recommend reversal agents for Vitamin K antagonists Appropriately recommend reversal strategies for the novel oral anticoagulants Be aware of agents on the horizon for the reversal of the novel oral anticoagulants

Case Vignette #1 A 68yom with a history of recurrent DVTs presents to the emergency department with bright red blood per rectum. He takes Warfarin 7.5 mg daily and had an INR of 2.8 in the coumadin clinic last week. He is pale and tachycardic. Repeat INR is 8 Hemoglobin and hematocrit are 5.4g/dL and 15%

Date of download: 1/3/2016 Copyright American College of Chest Physicians. All rights reserved. From: Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest. 2012;141(2_suppl):e44S-e88S. doi:10.1378/chest.11-2292 [Section 1.1] Vitamin K 1 is reduced to vitamin KH2. The major warfarin-sensitive enzyme in this reaction is the vitamin K oxide reductase mainly inhibited by the S-enantiomer of warfarin. S-warfarin is metabolized by the p450 cytochrome enzyme, CYP2C9. Reprinted with permission from Ansell et al. 8

Case Vignette #1 What is/are the best treatment(s) for reversal of this patient s anticoagulation? A. Fresh frozen plasma B. Oral Vitamin K C. IV Vitamin K D. Prothrombin Complex Concentrate E. IV Vitamin K and Prothrombin Complex Concentrate

Prothrombin Complex Concentrates

Prothrombin Complex Concentrates Profilnine, Bebulin & Kcentra Contain clotting factors: II, VII, IX, X Heparin and ATIII to keep inactivated Contain Proteins C, S Confers less risk of thrombosis Kcentra [package insert]. 2013

Prothrombin Complex Concentrates Advantages over FFP No cross matching No thawing time Less risk of viral transmission Less volume 200mL vs 800-1000mL Quicker reversal of INR No risk of TRALI Babilonia, et al. Thrombosis Journal 2014. PMID: 24742134

PMID: 23935011

PMID: 23935011

PMID: 23935011

Hanke, et al. Br J Anaest. 2013. PMID: 23335567 Safety

Kcentra Clinical Considerations Kcentra Restrictions Inclusion Criteria: Treatment of life-threatening bleeding or major bleeding associated with hemodynamic instability in patients taking warfarin (including those who present with intracranial hemorrhage and declining neurologic status) Rapid correction of INR in patients receiving warfarin and who require immediate reversal for life-sustaining procedures (anticipated need within 8 hours) Exclusion Criteria: Known history of heparin-induced thrombocytopenia Disseminated intravascular coagulation is suspected Bleeding in the absence of an anticoagulant

Kcentra Dosing Based on INR & weight (kg) INR 2-4: 25 units/kg INR 4.1-6: 35 units/kg INR >6: 50 units/kg >1 dose not studied, not recommended Kcentra [package insert]. 2013 Spahn et al. Critical Care 2013. PMID: 23601765

Kcentra Administration Administer within 4 hours of reconstitution Dedicated line required for administration 2 separate lines preferable (one for Vitamin K ) Administer as an infusion @ 500ml/hr (15-30 minute infusion) After infusion, replace Kcentra with 100cc bag NS and run at same rate Repeat INR 30 minutes after infusion

CO$T Kcentra $1.34 per unit Fresh Frozen Plasma <$100.00 unit/plasma ~$670 per vial (~500 units) $6700 for 5,000 unit dose (max dose)

Treatment of VKA Related Bleeding For patients with VKA-associated major bleeding, rapid reversal of anticoagulation with four-factor prothrombin complex concentrate rather than with plasma is recommended (Grade 2C). The additional use of Vitamin K 5 to 10 mg administered by slow IV infusion rather than reversal with coagulation factors alone is also recommended (Grade 2C).

Case Vignette #2 A 72yof with a history of rate-controlled atrial fibrillation and hypertension presents with new onset weakness. She has been on dabigatran (Pradaxa ) 220mg BID for the past year. Her last dose was administered 8 hours ago. She is hypotensive with SBPs in the 90s.

Date of download: 1/3/2016 Copyright American College of Chest Physicians. All rights reserved. From: New Antithrombotic Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest. 2012;141(2_suppl):e120S-e151S. doi:10.1378/chest.11-2294 Dabigatran

Case Vignette #2 A 72yof with a history of rate-controlled atrial fibrillation and hypertension presents with new onset weakness. She has been on dabigatran (Pradaxa )220mg BID for the past year. Her last dose was administered 8 hours ago. She is hypotensive with SBPs in the 90s. Imaging studies show the following:

Hemorrhagic Stroke

Case Vignette #2 A 72yof with a history of rate-controlled atrial fibrillation and hypertension presents with new onset weakness. She has been on dabigatran (Pradaxa ) 220mg BID for the past year. Her last dose was administered 8 hours ago. She is hypotensive with SBPs in the 90s. What is the best treatment option for reversal of dabigatran in this case? A. Activated charcoal B. Fresh frozen plasma C. Idarucizumab (Praxbind ) D. Hemodialysis

Praxbind - Idarucizumab Humanized monoclonal antibody fragment (Fab) Binds/ neutralizes dabigatran and its metabolites Eliminated in the urine Praxbind [package insert].

Praxbind - Idarucizumab Clinical Application FDA Accelerated Approval October 2015 Emergency Surgery/Urgent Procedure Life Threatening/Uncontrolled Bleeding Praxbind [package insert].

Praxbind - Idarucizumab Clinical Application Contraindications: None Not studied in patients with CrCl <30* Warnings and Precautions: Thromboembolic risk Re-elevation of coagulation parameters Hypersensitivity Fructose intolerance Praxbind [package insert].

Praxbind - Idarucizumab Purpose: RE-VERSE AD Trial Efficacy & Safety of Idarucizumab for dabigatran reversal Study Design: Multicenter, prospective cohort study Interim data analysis on 90 of 300 pts Each patient received two 2.5 g infusions 15 minutes apart Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab RE-VERSE AD Trial Inclusion: 18 yo and on dabigatran Group A: Life-threatening bleed Group B: Urgent procedure required Study Treatment: 5gm IV idarucizumab (2-2.5gm 50mL boluses), no more than 15 min apart Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Primary: Endpoints Maximum percentage reversal within 4 hours administration Secondary: Restoration of hemostasis Proportion with normalization of dilute thrombin time Proportion with normalization of ecarin clotting time Reduction in concentration of unbound dabigatran Safety: All adverse events captured Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Baseline Characteristics Patient Characteristics Age (Median) 77 Race 87% white Cr Clearance (Mean) 62 ml/min Atrial Fibrillation 96% Last dose of dabigatran (Median) 15 hr Elevated dilute thrombin time at baseline 76% Elevated ecarin clotting time at baseline 90% Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Results 22 patients had dilute thrombin times that were within normal limits and 9 of those patients had normal ecarin-clotting times excluding these 22 pts from efficacy analysis 68 of 90 were assessed with dilute thrombin time (Group A - 40 patients and Group B - 28 patients) 81 of 90 were assessed with ecarin-clotting time (Group A - 47 patients and Group B - 34 patients). All patients received idarucizumab regardless of their inclusion in the efficacy analysis Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Primary : Results Maximum percentage reversal in Groups A and B was 100% Reversal was evident on first sample taken after infusion Secondary: Normalization of clotting time Dilute Thrombin Time Ecarin Clotting Time Group A 98% 89% Group B 93% 88% Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Safety Outcomes Safety Death 18/90 (20%) Serious Adverse Event 21/90 (23.3%) MI 1/90 (1%) Stroke 1/90 (1%) DVT/PE 3/90 (3.3%) Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Praxbind - Idarucizumab Monitoring Parameters Efficacy Monitoring: Baseline aptt, re-evaluation of aptt at 12 and 24 hours Monitor for signs and symptoms of bleeding Toxicity Monitoring: Monitor for hypersensitivity or immunogenic reactions Praxbind [package insert].

Praxbind - Idarucizumab Dosing: 5 g infusion Two- 2.5g/50mL (bolus,15-min apart) Limited data to support >5 g infusion Cost: NEJM Journal Watch, 11/2015 2.5g/50 ml vial ~$3500 Cost per treatment: $7000 Praxbind [package insert].

Praxbind - Idarucizumab Conclusions Praxbind is effective in reversing dabigatran (Pradaxa ) Minimal adverse event profile Resume anticoagulation as soon as medically feasible Pollack CV, et al. N Engl J Med. 2015 Aug 6;373(6):511-20.

Case Vignette #3 A 62yof with a history of atrial fibrillation presents with right lower quadrant abdominal pain. She takes Xarelto (rivaroxaban) 20mg daily and her last dose was 1 hour ago.

Date of download: 1/3/2016 Copyright American College of Chest Physicians. All rights reserved. From: New Antithrombotic Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest. 2012;141(2_suppl):e120S-e151S. doi:10.1378/chest.11-2294 Rivaroxaban Apixaban Edoxaban

Case Vignette #3 A 62yof with a history of atrial fibrillation presents with right lower quadrant abdominal pain. She takes Xarelto (rivaroxaban) 20mg daily and her last dose was 1 hour ago. She is evaluated and is found to have acute appendicitis. Emergency surgery is recommended. What are the options for anticoagulation reversal? a) Activated charcoal b) Prothrombin complex concentrate c) Andexanet alfa d) All of the above

Activated Charcoal Factor Xa inhibitors (FXaI) Can be effective if given within 2 hours of administration of a FXaI Repeat dose six hours after initial administration Apixaban and Rivaroxaban Package Insert

PCC (Kcentra) and FXaIs: Limitations in the literature More animal studies than human studies Human clotting factors behave differently in non-humans Small numbers Healthy volunteers Reversal agents merely added to blood samples Extrapolation to bleeding patients? Variable study design Different outcomes Coag assays, bleeding time, blood loss

PCCs FOR NOACS (HUMAN STUDIES) Author, Year N Study Design Findings Erenberg, 2011 12 Dabigatran or rivaroxaban po x 2.5 d Treated with 3F-PCC bolus iv Measured PT and ETP over 24 hours Marlu, 2012 10 Men Dabigatran or rivaroxaban po x1 Collected blood samples Treated blood (3-F PCC, rfviia, apcc) Khoo, 2013 8 Dabigatran+aPCC (FEIBA) Blood treated with apcc Dinklaar, 2013 9 Rivaroxaban+ 3F-PCC PCC added to rivaroxaban-treated samples Coagulation assays performed Korber, 2013 10 Rivaroxaban + PCC/rFVIIa Blood samples treated with rivaroxaban Added PCC and rviia Performed clotting assays Findings PCC reversed PT, ETP in rivaroxaban treated patients PCC did not reverse dabigatran Findings Dabigatran rfviia most effective Rivaroxaban - PCC most effective Findings apcc reversed dabigatran Findings PCC normalized thrombin generation Did not normalize PT w/ initial dose Dose of PCC required depended on type of assay Findings PCC had no effect on clotting tests rviia reversed PT and clotting factor time RIVAROXABAN: REVERSED WITH PCC IN 3/4 STUDIES Lazo-Langner, et al. Critical Care 2013. PMID: 23806169

Andexanet Alfa Modified recombinant Factor Xa (inactive) Derived from human Factor X High affinity for FXaI and ATIII Forms a catalytically inactive complex

Andexanet alfa Breakthrough therapy in 2013 Phase II, double blind, placebo controlled study completed Phase III trials with apixaban (Eliquis ), edoxaban (Savaysa ), rivaroxaban (Xarelto ) and enoxaparin (Lovenox) underway

ANNEXA-4 Ongoing, multicenter, prospective, open-label, singlegroup study Acute major bleeding with a factor Xa inhibitor within 18 hours Andexanet bolus(b) over 15-30 minutes, followed by a 2-hour infusion (I) >7hours since administration: B-400mg, I-480mg <7hours since administration: B-800mg, I-960mg NEJM 2016;375(12):1131-41

ANNEXA-4 After bolus: Median anti-factor Xa activity decreased by 89%-93% 12 hours after infusion, clinical hemostasis excellent or good in 37/47 patients Thrombotic events in 12/67 patients in 30-day followup Not FDA approved NEJM 2016;375(12):1131-41

Ciraparantag (PER 977) Synthetic, universal small molecule antidote for heparin, LMWH and NOACs Binds and neutralizes anticoagulants Addresses need for a broad-spectrum reversal agent http://www.perosphere.com

Ciraparantag (PER 977) Phase II trials Single IV dose provided complete and sustained reversal at 10 minutes No procoagulant signal Not FDA approved.

Discontinue drug Mechanical compression, surgical hemostasis, transfusion of RBC or platelets (if concomitant antiplatelet use) Activated charcoal (if last dose <2h) Consider dialysis Idarucizumab (Praxbind) Discontinue drug Mechanical compression, surgical hemostasis, transfusion of RBC or platelets (if concomitant antiplatelet use) Activated charcoal (if last dose <2h) Consider PCC (Kcentra) Future: Andexanet alfa, Ciraparantag

Big Picture Ideas: Discontinuation of NOACs sufficient in most cases Use of specific antidotes should be restricted to emergent cases ONLY! Availability, cost and unanticipated toxicities of reversal agents are potential issues