Use of Anticoagulant Reversal Agents

Use of Anticoagulant Reversal Agents Lori Shutter, MD shutterla@upmc.edu Vice Chair of Education Director, Neurocritical Care Program Professor, Critical Care Medicine, Neurology & Neurosurgery University of Pittsburgh Medical Center

Disclosures Disclosures: No financial disclosures

Objectives Compare DOACs Review the role of PCCs, FFP, vitamin K, and DOAC inhibitors Discuss acceptable INR values Manage patients on antiplatelet agents Determine timing of restarting anticoagulation following ICH

Platelet and Coagulation Disorders in the ICU N Engl J Med 2014;370:847-59.

Reversal of Anticoagulation: Basics Discontinue warfarin; Target INR < 1.5 It may be difficult to achieve with FFP & vit K FFP 15 20 ml / kg Vitamin K, 10 mg IV. Usually only need 2-3 doses Prothrombin Complex Concentrate Recombinant Factor VIIa (selected patients?) If PTT > 50 Protamine 50 mg IV Platelet dysfunction Thrombelastography testing

TEG Thrombelastography technology analyzes functional activities of blood Coagulation & fibrinolytic factors, activators, inhibitors TEG ; Haemonetics Corp Components R value = time until first evidence of a clot K value = time from the end of R until the clot reaches 20mm (speed of clot formation) Angle = tangent of curve made as the K is reached and offers similar information to K MA (maximum amplitude) = reflection of clot strength

TEG Value Normal Range R 4 8 min k 0 4 min angle 47 74 deg MA 54 72 mm

Perioperative DOAC Discontinuation van Ryn et al. [2010], Spyropoulos & Douketis [2012], Baumann Kreuziger et al. [2012]. Ther Adv in Drug Safe. 2014;5(1):8-20.

DOACs and Lab Tests Palladino, et. Al., Am J Hematol 2012;87(suppl 1):s127-132

Pharmacokinetic Comparison of Reversal Agents Anticoagulation Reversal Pharmacokinetics Agent Onset Duration Rebound of Anticoagulant Vitamin K 2 8 hours Days for INR Dose-dependent FFP 1 4 hours 6 hours 4 6 hours PCC 10 15 minutes 12 24 hours ~ 12 hours rfactor VIIa 10 minutes 4 6 hours 6 12 hours Am J Health-Syst Pharm. 2013; 70 (Suppl1):21-31.

Fresh frozen plasma (FFP) MOA Dose Onset of Effect Duration of Effect Advantages Disadvantages Replenishes clotting factors 10 30 ml/kg, each bag administered over 30-60 min 20 30 minutes 20 to 24 hours Contains all clotting factors Low thrombotic risk Fast onset after administration Large volume typically needed Delay in administration due to matching, thawing, & administration Lowest INR achievable with FFP: 1.5-1.7 Int J Stroke 2011;6:228-40

Prothrombin complex concentrate MOA Dose Onset 3-Factor PCC: Replenishes clotting factor II, IX, and X 4-Factor PCC: Replenishes clotting factors II, VII, IX, and X 20 50 units/kg IV push over minutes Dosed on factor IX; variable dosing recs; round to vial size, administered no faster than 10 ml/min Onset: 10 minutes Duration of Effect Advantages Disadvantages Duration: 12 to 24 hours More evidence Less thrombosis risk Sustained effects Repletes all vitamin K dependent clotting factors Cost Controversial dosing 3-factor versus 4-factor?

Prothrombin Complex Concentrates Available in the United States 3- Factor PCCs Factors Covered (International Units relative to Factor IX)* II VII IX X Profilnine 148 11 100 64 Bebulin VH # 120 13 100 100 4- Factor PCCs Kcentra # & 118 70 100 152 *Approximate values; exact potency of factors varies per vial; # contains heparin, & protein C and S. **20 50 u/kg of 4-Factor PPC = 8 16 units FFP!!!! Sorenson B, et al. Crit Care 2011;15:201. Kcentra package insert. Kankakee, IL: CSL Behring; 2013

Kcentra Dosing: Warfarin Reversal (FDA approved) Dosed on actual body weight up to 100 kg Max rate of IV administration: 8.4 ml/min (210 U/min) Do not mix, separate line for admin

What if the INR is < 2? 21/134 patients presented with traumatic (43%) or spontaneous (57%) bleeding. Low-dose Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage with INR Less Than 2.0 Neuocrit Care. 2017 Dec;27(3):334-340

INCH Trial: VKA ICH Lancet Neurol 2016; 15: 566-73

INCH Trial: VKA ICH Lancet Neurol 2016; 15: 566-73

Hematoma Expansion Lancet Neurol 2016; 15: 566-73.

Reversal Agent Potential for Success AGENT 4-factor PCC DOSES TESTED IN STUDIES 12.5 100 IU/kg (50 IU/kg is only doses tested in humans DABIGATRAN Not beneficial RIVAROXABAN/ APIXABAN Probably beneficial apcc (FEIBA) 20 160 IU/kg Not beneficial Probably beneficial Factor VIIa 20 500 mcg/kg Not beneficial Possibly beneficial FFP N/A Probably ineffective Probably ineffective 3-factor PCC No data No data No data Activate Charcoal/ HD In Vitro/volunteers Possibly beneficial if given <2 hrs/yes Possibly beneficial if given <2 hrs/no Lazo-Langner A, Lang ES, Douketis J. Clinical Review: Clinical management of new oral Anticoagulants: a structured review with emphasis on the reversal of bleeding complications Critical Care. 2013; 17: 230 242.

DOAC Antidotes Am J Health-Syst Pharm. 2016; 73(suppl 2):S5-13

Idarucizumab (Praxbind ) Dabigatran Reversal Accelerated FDA APPROVAL 10/16/15 Dose: 5 g IV 2 separate consecutive infusions 2.5g/50 ml vials Limited data for repeat dosing ADRS: hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure Can reinitiate dabigatran 24 hours after infusion

FXa Inhibitor Antidote Andexanet alfa under FDA review PRT064445; Portola Pharmaceuticals, An imitation factor Xa without biological properties Reverses the anticoagulant action of the factor Xa inhibitors Crowther M, et al. AHA 2014 Scientific Sessions; November 15-19, 2014; Chicago, IL. J Thromb Haemost 2016;14: 623 7.

Considerations in patients with Major Bleeding or Emergent Surgery Pharmacologic Identification of specific DOAC and dose Time elapsed since last dose Renal function Determining half-life of DOAC Liver function and signs of coagulopathy Specific anticoagulation test or if not available screening test (aptt, pro-thrombin time, and anti-fxa activity) Clinical Signs of hemodynamic instability Identification of bleeding source Reason for emergency surgery Assessment of thromboembolic (CHA2DS2-VASc) and bleeding risk (HAS- BLED) Eur Heart J. 2017;38(22):1710-1716.

When are antidotes indicated? Life-threatening bleeding Bleeding into a critical organ or closed space Prolonged bleeding despite local hemostatic measures High risk of recurrent bleeding because of overdose or delayed clearance of DOACs Need for an urgent intervention associated with a high risk of bleeding Emergency surgery or intervention in patients at high risk for procedural bleeding: Neurosurgery (intracranial, extradural,or spinal), lumbar puncture, cardiac or vascular surgery (aortic dissection/aneurysm repair), hepatic or other major organ surgery Levy J, et al. Journal of Thrombosis and Haemostasis, 14: 623 627.

When should antidotes NOT Be Used? Elective surgery Bleeding managed with local hemostatic measures Bleeding has stopped Interventions can be delayed 8 h to permit clearance of effects Levy J, et al. Journal of Thrombosis and Haemostasis, 14: 623 627.

Anticoagulation Reversal Guidelines Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46. European Heart Journal 2013;34:489-500.

VKA reversal: NCS Guidelines 2016 Treatment: Vit K 10 mg IV X 1 3- or 4-factor PCC for VKA-assoc ICH & INR > 1.4. (Strong recommendation, moderate quality evidence) INR 15 60 min after dose, and serially every 6 8 h for the next 24 48 h Subsequent treatment guided by follow-up INR Caution: repeat PCC dosing may lead to increased thrombotic complications and risk of DIC. (Good Practice statement) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46.

Direct thrombin inhibitors Assess time & amount of last ingested dose, renal function, and possible medication interactions to assist in estimating the degree of anticoagulation exposure. (Good Practice statement) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46.

Direct thrombin inhibitors Treatment: Activated charcoal if within 2 hrs of oral dose Idarucizumab (5 g IV in two divided doses) to patients with ICH if within 3-5 t ½ s or renal dysfunction or failure If idarucizumag not available: 4-PCC (50 IU/kg) > 3-PCC; apcc (FEIBA) 50 IU/KG Hemodialysis (up to 60% dabigatran removed) Monitoring Assess for clinically significant bleeding Thrombin time (TT) Ecarin clotting time (ECT) Activated partial thromboplastin time (aptt) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46.

Factor Xa inhibitors Obtain information re: time elapsed since last dose of direct factor Xa inhibitor & possible medication interactions to assist in estimating the degree of anticoagulation exposure. (Good Practice statement) Treatment Activated charcoal if within 2 hrs of oral dose 4-PCC (50 IU/kg); 3-PCC; apcc IF ICH <3-5 t ½ s or liver failure Monitoring Assess for clinically significant bleeding Anti-Xa activity; Specific chromogenic anti-factor Xa assay Prothrombin time (PT) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46.

Heparin MOA: Enhances antithrombin III activity while inactivating thrombin and prevents the conversion of fibrinogen to fibrin Low Molecular Weight Heparinoids MOA: Enhances antithrombin III activity while inactivating thrombin which prevents the conversion of fibrinogen to fibrin and inhibits factor Xa

PROTAMINE MOA Dose Administration Heparin Reversal Combines with heparin to form a stable complex that neutralizes anticoagulant activity Protamine 1 mg / 1 mg of enoxaparin given in previous 8 hrs Max dose of 50 mg over 10 min Faster infusions cardiovascular collapse; Excessive doses (>100 mg) may worsen bleeding by acting as an anticoagulant LMWH Reversal Onset of Effect ~ 5 minutes ~ 5 minutes Advantages Disadvantages Rapid reversal of heparin portion in enoxaparin Does not affect factor Xa inhibition of LMWH mechanism Potential for rebound bleeding Hypersensitivity risk Combines with heparin to form a stable complex that neutralizes anticoagulant activity Protamine 1 mg / 100 units of heparin given in previous 2-3 hrs Max dose of 50 mg over 10 min Faster infusions cardiovascular collapse); Excessive doses (>100 mg) may worsen bleeding by acting as an anticoagulant Rapid and predictable reversal of heparin Potential for rebound bleeding (8-18 hrs after dose) Hypersensitivity risk (hypotension), PROTAMINE PI especially in pts with a fish allergy

ANTIPLATELET REVERSAL AFTER ICH PATCH Trial

Antiplatelet Reversal in ICH Receipt of antiplatelet agents prior to ICH or traumatic bleeding is associated with worse outcomes Medications for reversing platelet function (eg. DDAVP) incompletely effective No rigorous clinical study to actually support giving platelet transfusion for patients with antiplatelet exposure prior to ICH Other examples of continued coagulopathy suggest potential for hematoma expansion after ICH

PATCH Trial Platelet transfusion initiated within 6 hours of symptom onset Patients with non-traumatic supratentorial ICH Glasgow Coma Score 8-15 Receipt of ASA, clopidogrel or dipyridamole within 7 days of presentation Patients with planned ICH evacuation were excluded Platelet transfusion (1-ASA, 2-clopidogrel) No platelet transfusion Baharoglu MI, et al. Lancet 2016; 387: 2605-2613.

Key PATCH Trial Results ~78% of patients received ASA prior to admission Median admission GCS was 14-15 ~70% of ICH were deep supratentorial Basal ganglia or thalamic ICH Median ICH volume was ~10ml Adverse events 42% transfusion vs 29% standard care (OR 1.74, 95%CI 0.96-3.17) Baharoglu MI, et al. Lancet 2016; 387: 2605-2613.

Key PATCH Trial Results Primary outcome was worse in transfusion group Death or dependence at 3 months Adjusted OR 2.05, 95%CI 1.18-3.56, p = 0.0114 Baharoglu MI, et al. Lancet 2016; 387: 2605-2613.

In which antiplatelet-associated ICH patients should platelet transfusion still be considered? Patients receiving clopidogrel (?) Under-represented in PATCH Patients requiring CNS procedures EVD Operation for hematoma evacuation Patients with traumatic ICH

Antiplatelet Agent (APA) Reversal NCS Recommendations Discontinue antiplatelet agent (Good Practice statement) Suggest against platelet transfusion for patients with APA associated ICH who will NOT undergo a neurosurgical procedure, regardless of the type of platelet inhibitor, platelet function testing, hemorrhage volume, or neurological exam. (Conditional recommendation, low-quality evidence) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46. European Heart Journal 2013;34:489-500.

APA Reversal NCS Recommendations Suggests platelet transfusion for patients with aspirinor ADP inhibitor- associated ICH who will undergo a neurosurgical procedure. (Conditional recommendation, moderate quality of evidence) Platelet function testing prior to platelet transfusion if possible. (Strong rec, moderate quality evidence) When platelet function testing is not readily available, empiric platelet transfusion may be reasonable. (Conditional rec, low quality evidence) Recommend against platelet transfusion for patients with laboratory documented platelet function within normal limits or documented antiplatelet resistance. (Strong recommendation, moderate quality evidence) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46. European Heart Journal 2013;34:489-500.

APA Reversal NCS Recommendations Suggests against platelet transfusion in NSAID or GP IIb/IIIa inhibitor-related ICH, even in the context of neurosurgical intervention. (Conditional recommendation, very low-quality evidence) Suggests consideration of a single dose of desmopressin (DDAVP) in ICH (0.4 mcg/kg IV) associated with aspirin/cox-1 inhibitors or ADP receptor inhibitors. In patients deemed appropriate (e.g., those undergoing a neurosurgical procedure), DDAVP can be used in addition to platelet transfusion (Conditional recommendation, low-quality evidence) Frontera J et al, Neurocrit Care 2016; Feb;24(1):6-46. European Heart Journal 2013;34:489-500.

When can you resume coagulation? Wish I knew Varies patient to patient Factors: Risk of stroke Risk of bleeding

Antithrombotic Reversal Strategies: Summary DOACs have variable kinetic characteristics that cause variable anticoagulant effects. Indications for reversal should be identified before any reversal strategy is initiated. Determination the last dose of the DOAC is crucial 4PCC are recommended for OACs that do not have antidotes available. Idarucizumab is currently FDA approved and available for dabigatran reversal. Platelets may worsen outcomes and should only be administered in life threatening bleeding situations where benefit > risk.

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