CONTEMPORARY REVERSAL OF ANTICOAGULATION

Transcription

1 CONTEMPORARY REVERSAL OF ANTICOAGULATION Michael S. McHale, M.D., F.A.C.P. Avera Medical Group Hematology & Oncology Medications Coumadin / Warfarin Unfractionated Heparin Low Molecular Weight Heparin Argatroban Direct Thrombin Inhibitors Xa Inhibitor Kinetics of Drugs Warfarin Half Life hours Only free Warfarin is active 2 active isomers (R) and (S) S more potent than R Cleared / Metabolized by liver enzymes C4P2C9* % Reduction Unfractionated Heparin (UFH) C4P2C9* % Reduction T ½ 1 6 hours Binds to Endothelium Patient Size Important 1

2 Low Molecular Weight Heparin (LMWH) T ½ hours (Fondaparinux hours) Renal Disease Effects Renal Problems Weight Changes Dose Changes For Weight Changes Dose Changes Argatroban Direct Thrombin Inhibitor - DTI (Anti IIa) DTI s T ½ minutes Liver Disease Effects Dabigatran Reduced Effect Peak Plasma Concentration 1 ½ hours after initiation Rifampin T ½ hours Renal Excretion (80-85%) T ½ CCr hours T ½ CCr <30-28 hours 2

3 Verapamil Ketoconazole Quinidine Clarithromycin Amiodarone Increased Effect Rivaroxaban Peak Plasma 3 hours after initiation T ½ 6 13 hours (5-9) Renal Excreted 36% Carbamazepam Phenytoin Inhibit Effect Rifampin St.Johns Wort Increased Effect Ketoconazole / Itriconazole Ritonavir and Combination If Concurrent Renal Problem Avoid Erythromycin / Clarithromycin Diltiazem Verapamil Quinidine Dromeradone 3

4 Apixaban Peak Plasma Levels 1 3 hours Carbamazepam Decreased Effect T ½ 8 14 hours Phenytoin Renal Excretion 27% Rifampin St. Johns Wort Increased Effect Ketoconazole / Itraconozole Ritonavir and Combinations Clarithromycin Coumadin / Warfarin 5mg Daily Dosing of Drugs Concomitant Parenteral Anticoagulant Overlap 4 5 days until INR 2 on 2 consecutive days Warfarin Loading Will increase rate of fall of VII and Protein C CYP2C9*2 or 3 Give the dose you need Will not shorten time to therapeutic INR Reason for disparity in patients dosing and INR s 4

5 Unfractionated Heparin Endothelial Binding Large doses to overcome Nomogram Dry Weight LMWH Depends on Drug used Changes in dosing dependent on renal clearance and weight changes Dose may decrease with decrease inflammation (bound to proteins) Call your pharmacist Argatroban Dabigatran 150mg PO two times a day Protocol should exist Dosing Monitoring of PTT If CCr start at 75mg two times a day.05 micrograms per Kg loading dose Rivaroxaban Prevent / Prophylaxis after knee or hip surgery - 10mg / day Nonvascular atrial fib 15 20mg / day Therapy of PE or DVT 15mg two times per day for 3 weeks Then 20mg daily 5

6 2.5mg two times a day Apixaban How do you test for drugs? Presence or Efficacy INR Warfarin Drug Levels Heparin PTT Anti Xa Level TT / Reptilase Time Presence of Drug LMWH Argatroban Anti Xa Level PTT 6

7 Dabigatran Rivaroxaban Thrombin Time If normal, safe to assume that level of Dabigatran is low PT: Insensitive to Dabigatran PTT: Curvilinear response to the concentration of Dabigatran At high drug concentration, PTT is uncoaguable PT: Linear dose response Anti Xa assay specifically calibrated for rivaroxaban reliability predictor drug level? Availability Anti Xa assay Apixaban Fibrinogen Underestimated in patients on Dabigatran Heterozygous V Leiden Might Resemble Wild Type (Normal) When Treated With Direct Oral Anticoagulant Factor XIII Underestimated on Dabigatran XIII Activated by Thrombin 7

8 Reversal Warfarin Depends on INR / Bleeding Less than 5 Hold until INR therapeutic 5 10 Hold Warfarin Vitamin K 1 2.5mg PO >10 Hold Warfarin Vitamin K 2.5mg PO x1 Major Bleeding, Any INR Vitamin K 10mg IV 4 Factor Prothrombin Complex Concentrated (PCC) INR u/Kg u/Kg >6 50u/Kg FFP 10 15ml / Kg IF no PCC UFH Hold Drug Calculate Time / Half Life Protamine Weak anticoagulant effect at high dose (prolongs PT / PTT) Reverses LMWH 20 30% Fragmin > Lovenox > Arixtra Short Half Life Rebound Anticoagulant Effect Protamine Cleared faster than Heparin (High Dose) or LMWH LMWH Partially Reversed with Protamine Properties of Reversing Agents Protamine New Antidotes Vitamin K Anaphylaxis Subcutaneous / IM Erratic Absorption 8

9 Properties of Reversing Agents Fresh Frozen Plasma (FFP) Plasma Transfusion Less Coagulation Factors Than PCC s Limitations Must Be Thawed ABO Matching Large Volume Adverse Effect Fluid Overload Infectious Diseases Allergic Reactions TRALI 3 Factor PCC Similar Concentration of II, IX, X, Low VII United States Large amounts of X may overwhelm Inhibitor a Xa Bebulin VH 25 70u/Kg Profiline SD 1u/Kg - IX 1% Less likely to cause Thromboembolism than 4F PCC % 4F PCC II, VII, IX, X, Prot C, Prot S, AT III Higher VII than 3F PCC Risk of Thromboembolism KCENTRA 25 50u/Kg 9

10 FEIBA Activated 4F PCC u/Kg II, IX, X activated VII rfviia 15 90mcg/Kg Hemophilia A or B with Inhibitors VII Deficiency Acquired Hemophilia Glanzmanns Thrombasthenia Refractory to platelet transfusions Black Box Warning Arterial and Venous Thrombosis Antifibrinolytics Adjuncts Tranxenamic Acid Epsilon Aminocaproic Acid 4F PCC + 3F PCC have small amounts of Heparin Cryoprecipitate Fibrinogen Replacement Dabigatran Rivaroxaban Reversal of: Apixaban 10

11 Dabigatran apcc (FEIBA) 50u/Kg IV If no apcc, then 4F PCC If no 4F PCC, then 3F PCC + FFP Gastric Lavage / Charcoal if soon enough Hemodialysis Tranxenamic Acid / Epsilon Amino Caproic Acid Rivaroxaban / Apixaban 4F PCC 50u/Kg IV If no 4F PCC, then 3F PCC + FFP (for VII) Charcoal Tranxenamic Acid / Epsilon Amino Caproic Acid No Hemodialysis Antidotes (TO COME) Andexanet Alpha (PRT064445) Binds Xa Inhibitor Site Rivaroxaban and Apixaban and Heparin Idarucizumab (a Dabi-Fab) Monoclonal Antibody Dabigatran Aripazine (PER977) Binds Xa + IIa Dabigatran, Rivaroxaban, Apixaban and Heparin, Fondaparinux 11

12 Andexanet Alpha Directly reverse Xa inhibitor Binds to drugs in a dose dependent manner Makes patients own Xa molecule available? Works on complex of AT III and Factor Xa Inhibitors (LMWH, Fondaparinux) Idarucizumab Human mouse monoclonal antibody directed against Dabigatran Restores Dabigatran inhibition of fibrin formation Can assess fibrin levels by measuring fibrinopeptide A Substance released when fibrin is formed Aripazine D-Arginine Compound Dabigatran, Rivarxaban, Apixaban Fondaparinux LMWH in Vivo RNA Aptimer Reverse IXa Inhibitor Pegnivacogin Anivamersen Fast on and offset of anticoagulation Cardiac surgery with extracorporeal circulation Alternative to Heparin / Protamine Induction for Thrombolytic Therapy Acute MI Thrombotic stroke within 3 hours Acute peripheral arterial occlusive disease Massive PE with hemodynamic instability Contraindications for Thrombolytic Therapy 12

13 Absolute History of hemorrhagic stroke Major internal bleeding in prior 6 months Intracranial or intraspinal neoplasm Recent intracranial surgery Relative Surgery or Biopsy in prior 10 days HTN >200 systolic >110 diastolic Thrombocytopenia <100,000 Nonhemorrhagic CVA within 2 months Presence of a bleeding disorder PE - Indications for Thrombolytic Treatment Massive Acute PE Patient Hypotension Hypoxic despite high levels of oxygen Echocardiographic evidence of Right sided heart failure Treatment of Bleeding after Thrombolytics Local Control Reverse Heparin with Protamine if needed Obtain Coag Test PT / PTT - Need FFP FBGN - Need Cryo Plts <100,000 - Transfuse (Plts are activated by Plasma) IVC Filter Acute DVT in a patient who cannot be fully anticoagulated due to a high risk for bleeding Retrievable filter should be placed Removal once safely anticoagulated Filter risk of recurrent DVT Devise migration Filter Fracture Risks Embolyzation of the entire filter or fracture fragment to heart or lung Perforation of IVC Difficulty removing devise Thrombogenic risk factor 13

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