Targeting a Network Anticoagulation Issue. Anthony J. Macchiavelli, M.D., FHM

Transcription

1 Targeting a Network Anticoagulation Issue Anthony J. Macchiavelli, M.D., FHM

2 Disclosure Statement Janssen - Speaker Bureau Nonbranded Janssen research MARINER Janssen research MERCURY PE Portola research APEX Daiichi Sankyo Consultant Boehringer Ingelheim - Consultant

3 Estimated Rates of Emergency Hospitalizations for Adverse Drug Events in Older U.S. Adults, Budnitz DS et al. N Engl J Med 2011;365:

4 Case fall while on warfarin with INR presents to Sending Medical Center with altered mental status CT of Head follows... Given Vitamin K 5mg IV x 1 Transferred to trauma center 1200 arrives at trauma center 1215 INR given 4 Factor Prothrombin Complex Concentrate 1255 INR 1.4 Initial CT at trauma center

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8 To ARMC City Division Ground Transport From Cape 40 Minutes From Shore 23 Minutes

9 Anticoagulation and Reversal: Current State

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12 Extrinsic pathway Intrinsic pathway VII VIIa TF VIIa/TF IX Ca2+ XI HK XII XIIa PK HK Ca2+ PL IXa VIIIa VIII XIa X Xa Ca2+ PL Prothrombin PL Va Fibrinogen Thrombin V Fibrin Monomer Fibrin Polymer XIIIa XIII Cross linked Fibrin Polymer

13 Case 2 A 64 year old male with past medical history significant for atrial fibrillation and unsteady gait, presented to the Emergency Room after a witnessed fall four hours earlier. The family notes that the patient has progressive confusion, difficulty with speech, and weakness in the right upper and lower extremity. Recently the patient was treated by his Primary Care Physician for tracheobronchitis with a course of trimethoprim-sulfamethoxazole. He takes Cardizem 120mg/day and Coumadin 5mg/day. INR is 5.6. Head CT follows

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15 How would you reverse the anticoagulation in this patient?

16 Vitamin K Antagonists 1.Warfarin 2.Acenoumarol 3.Phenprocoumon 4.Fluindione

17 Extrinsic pathway Intrinsic pathway VII VIIa TF VIIa/TF IX Ca2+ XI HK XII XIIa PK HK Ca2+ PL IXa VIIIa VIII XIa X Xa Ca2+ PL Prothrombin PL Va Fibrinogen Thrombin V Fibrin Monomer Vitamin K Antagonists Fibrin Polymer XIIIa XIII Cross linked Fibrin Polymer

18 Warfarin Associated ICH Managment Time to anticoagulation reversal Stop warfarin therapy Vitamin K Fresh frozen plasma Prothrombin complex concentrate (F IX) Factor VIIa concentrate 5-14 days 6-24 hours 3-6 hours for infusion 15 minutes after a 10 minute to 1 hour infusion 15 minutes after a bolus infusion

19 A, Time to international normalized ratio (INR) correction (intention-to-treat efficacy population). Ravi Sarode et al. Circulation. 2013;128: Copyright American Heart Association, Inc. All rights reserved.

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21 Prothrombin Complex Concentrate (PCC) Before April 29, 2013 only 3 factor PCC in US Unactivated 4 factor PCC Approved by FDA April 29, 2013 Therapeutic levels of f II, VII, IX, X Indicated for urgent reversal of acquired coagulation factor deficiency induced by vitamin k antagonist therapy in adults with acute major bleeding

22 WARFARIN Toxicity Severity Bleeding Recommendation (Yes/No) INR No Omit 1 or 2 doses of warfarin Repeat INR in 24 hours INR > 10 No Hold warfarin AND give Vitamin K orally (2.5-5mg) Repeat INR in 24 hours (CHEST 2012) If more rapid reversal is necessary: give Vitamin K IV (less than or equal to 5mg) ANY INR and severe or life threatening bleeding (or emergent reversal) Yes Hold warfarin Give Vitamin K 10mg via slow IV* infusion Plus 4 Factor Prothrombin Complex Concentrate (4FPCC) 25-50units/kg based on baseline INR via slow IV infusion x 1 ** 4FPCC contraindicated in patients with HIT Or Vitamin K 10mg via slow IV infusion Plus Fresh Frozen Plasma (FFP***): 15-20ml/kg or 4-5 units in adults. Vitamin K via IV infusion may need to be repeated every 12 hours Supportive care Fluid replacement and hemodynamic support Blood product transfusion (CHEST 2012) *Vitamin K given SQ not recommended due to erratic absorption ** For Dosing guidelines see appendix C ***1unit of FFP increase factor levels by 3-5% at an INR of 2-3 (baseline levels are 20-30%)

23 Warfarin Interactions May increase INR Acetaminophen Allopurinol Amiodarone Antibiotics (PCN, doxy, fluroquinolones, macrolides, metronidazole, TMP-Sulfa) Azole antifungals Cancer therapies Cholesterol lowering agents Cimetidine Glucocorticoids Omeprazole SSRIs Tramadol May decrease INR Antibiotics (dicloxacillin, griseofulvin, nafcillin, rifampin) Antiepileptic Azathioprine Cholestyramine Herbals Ritonavir Sucralfate Vitamin K

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26 Case 3 An 85 year old male with a past medical history of hypertension, Atrial fibrillation and transient ischemic attacks presented to the Emergency Department after being found on the floor of his bathroom by his wife shortly after hearing a loud noise consistent with fall. The patient was unconscious and un arrousable. Medications as outpatient were: Dabigatran 150 mg. BID, ASA 81 mg. daily, HCTZ 12.5 mg daily, Amlodipine 10 mg daily. CT of head follows

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28 Dabigatran Non Valvular Atrial Fibrillation VTE Treatment Reduction in risk of recurrent VTE DVT Prophylaxis in THR

29 Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Connolly SJ et al. N Engl J Med 2009;361:

30 Direct Thrombin Inhibitors 1.Lepirudin 2.Bivalrudin 3.Argatroban 4.Dabigatran

31 Extrinsic pathway Intrinsic pathway VII VIIa TF VIIa/TF IX Ca2+ XI HK XII XIIa PK HK Ca2+ PL IXa VIIIa VIII XIa X Xa Ca2+ PL Prothrombin PL Va Fibrinogen Thrombin V Fibrin Monomer DIRECT THROMBIN INHIBITORS Fibrin Polymer XIIIa XIII Cross linked Fibrin Polymer

32 Evaluation of Usage Patterns of Dabigatran in Patients with Non Valvular Atrial Fibrillation** *severe mitral/aortic disease, moderate mitral stenosis/regurgitation and valve replacement/repair ** 2014 Ray, Gali, Sok, Vuong, Gerace, Macchiavelli

33 Reversal Options?

34 Hemodialysis

35 Idarucizumab Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. FDA approved

36 Time Course of the Dilute Thrombin Time and Ecarin Clotting Time before and after the Administration of Idarucizumab. Pollack CV Jr et al. N Engl J Med 2015;373:

37 Time Courses of Plasma Concentrations of Unbound Dabigatran and Idarucizumab before and after the Administration of Idarucizumab. Pollack CV Jr et al. N Engl J Med 2015;373:

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39 Case 4 A 66 year old male with past medical history of morbid obesity, obstructive sleep apnea, hypertension, hyperlipidemia, atrial fibrillation, and a remote history of craniotomy after a motorcycle accident presented to the Emergency Department after a sudden change in speech leaving him incomprehensible. Among his14 routine medications the was taking Rivaroxaban 20 mg daily. CT of head follows

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41 Rivaroxaban Non Valvular Atrial Fibrillation VTE Treatment DVT Prophylaxis in THR and TKR

42 Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Per- Protocol Population and in the Intention-to-Treat Population. Patel MR et al. N Engl J Med 2011;365:

43 Apixaban Non Valvular Atrial Fibrillation VTE Treatment DVT Prophylaxis in THR and TKR Reduction in risk of recurrent VTE

44 Kaplan Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:

45 Edoxaban Non Valvular Atrial Fibrillation VTE Treatment

46 Factor Xa Inhibitors 1.Idraparinux 2.Fondaparinaux 3.Rivaroxaban 4.Apixaban 5.Edoxaban 6.Betrixaban 7.Darexaban

47 Extrinsic pathway Intrinsic pathway VII VIIa TF VIIa/TF IX Ca2+ XI HK XII XIIa PK HK Ca2+ PL IXa VIIIa VIII XIa X Xa Ca2+ PL Prothrombin PL Va Fibrinogen Thrombin V Fibrin Monomer Factor Xa Inhibitors Fibrin Polymer XIIIa XIII Cross linked Fibrin Polymer

48 Reversal Options?

49 12 healthy male volunteers 6 received 20mg Rivaroxaban twice daily for 2 ½ days 6 received 150 mg Dabigatran twice daily for 2 ½ days Both followed by 50IU/kg bolus of 4 Factor PCC Completely reversed the anticoagulant effect of Rivaroxaban No influence on the anticoagulant effect of Dabigatran

50 APIXABAN AND RIVAROXABAN Bleeding Severity Recommendation Mild Bleeding Delay next dose or discontinuation Moderate Bleeding Symptomatic treatment Mechanical compression Surgical Intervention Fluid replacement and hemodynamic support Blood product transfusion Oral activated charcoal suspension (if previous dose ingested within 2 hours) Dose: 50 grams x1 dose If hemostasis not achieved proceed to steps below Severe or Life-Threatening bleeding 4 Factor Prothrombin Complex Concentrate (4FPCC) 50units/kg via slow IV infusion x 1* 4FPCC contraindicated in patients with HIT If hemostasis not achieved: Fresh Frozen Plasma -10ml/kg (round to the nearest 200ml [1 unit of FFP = 200ml]) 4 units of FFP** increase most factors ~10% *See Appendix A for factor content and Appendix B for dosing and administration (Expert consensus recommendations based on current literature, not FDA approved for this indication) **When using FFP consider volume in patients with heart failure or fluid

51 Case 5 The patient is a 77-year-old male with multiple medical comorbidities, who presented to the Emergency Department this morning with reports of altered level of consciousness and weakness. The patient reports that he apparently fell out of bed sometime early this morning. He actually denies ever striking anything or sustaining any injuries. He denies any loss of consciousness. In any case, while in bed this morning, the patient was noted to have upper extremity weakness by his daughter. PAST MEDICAL HISTORY: Coronary artery disease, COPD requiring O2 at 3 L/min at home, lung carcinoma, atrial fibrillation. Current medications include Rivaroxaban CT of head

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54 Andexanet alpha (PRT4445) Universal Factor Xa Inhibitor Antidote Potentially indicated to address life-threatening bleeding Phase 1 trial completed September healthy volunteers received PRT received placebo - well tolerated - no safety signals noted Phase 2 trial completed - Factor Xa and PRT purpose to determine dose of PRT4445 for reversal of various Xa Inhibitors Phase 3 trials completed Awaiting FDA approval

55 Andexanet Alpha Andexanet reversed the anticoagulant activity of Apixaban and Rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.

56 Time Courses of Anti Factor Xa Activity before and after Administration of Andexanet. Siegal DM et al. N Engl J Med 2015;373:

57 Time Courses of Thrombin Generation before and after the Administration of Andexanet. Siegal DM et al. N Engl J Med 2015;373:

58 Time Courses of Plasma Concentrations of Unbound Apixaban or Rivaroxaban before and after Administration of Andexanet. Siegal DM et al. N Engl J Med 2015;373:

59 Time Courses of Prothrombin Fragments 1 and 2 and d-dimer Levels before and after the Administration of Andexanet. Siegal DM et al. N Engl J Med 2015;373:

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61 Antiplatelet Agents 1. Aspirin 2. Dipyridamole 3. Thienopyridenes (Clopidogrel and Prasugrel) 4. Cyclopentlytriazolopyrimidines (Ticagrelor) 5. Glycoprotein IIa/IIIb Inhibitors

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63 Reversal Options?

64 Antiplatelet Agents Agent Recommendation for Severe/Life threatening bleed Aspirin, Sustained Release Aspirin/Dipyridamole Desmopressin 0.3mcg/kg x 1 IV Consider platelet transfusion if intervention required Clopidogrel, Prasugrel, Ticagrelor Desmopressin 0.3mcg/kg x 1 IV Consider platelet transfusion if intervention required Abciximab Platelet transfusion Eptifibatide, Tirofiban Desmopressin 0.3mcg/kg x 1 IV REVERSAL-platelet transfusions + infusion of 10 units of cryoprecipitate.

65 Heparins 1. Unfractionated Heparin 2. Enoxaparin 3. Dalteparin 4. Tinzaparin 5. Nadroparin (Canada)

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67 Reversal Options?

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69 Toxicity Severity ENOXAPARIN Recommendation Mild to Moderate Symptomatic and supportive Monitor for clinical evidence of bleeding Severe- Enoxaparin Symptomatic and supportive Blood product transfusion Fluid replacement and hemodynamic support Protamine will neutralize about 60% of Anti-factor Xa Protamine 1mg to neutralize 1mg of enoxaparin ( <8hrs) Protamine 0.5mg to neutralize 1mg of enoxaparin (>8hrs) Protamine may not be necessary if >12hrs since last enoxaparin dose Protamine to be given slow IV injection see Appendix C. A second dose of Protamine may be necessary if aptt remains prolonged 2 to 4 hours after first infusion. The aptt may remain prolonged as Anti-Xa activity is never completely neutralized (maximum 60-75%) Enhanced elimination procedure: Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the large volume of distribution of LMWHs. *dosing for other LMWH may vary

70 Tissue Plasminogen Activators 1. Alteplase 2. Tenecteplase 3. Reteplase

71 Bleeding Severity Alteplase, Tenecteplase, and Reteplase Recommendation Severe or Life-Threatening bleeding STOP infusion of t-pa NOTIFY STROKE PHYSICIAN STAT Order emergency head CT STAT and blood type Order STAT labs including, but not limited to CBC, PT, PTT, platelets, fibrinogen, and D-dimer o If fibrinogen < 100 mg/dl, administer 0.15 units/kg of Cryoprecipitate If still bleeding at 1 hour and fibrinogen is still < 100 mg/dl, repeat Cryoprecipitate dose o Aminocaproic acid (Amicar) 5gm IV bolus over minutes o If platelet dysfunction, administer 4 units of single donor platelets o For uncontrolled, life threatning bleeding, consider aminocaproic acid (Amicar) 10gm in 500 ml NSS as an IV infusion over 1 hour as last resort Supportive care If heparin has been administered in the past 3 hours, follow heparin reversal guidelines above

72 PER977 (Perosphere) Cationic molecule binds to unfractionated heparin and low molecular weight heparin Binds reversibly to Factor Xa inhibitors Binds to Direct Thrombin Inhibitors Baseline hemostasis restored in minutes after fully anticoagulated state No evidence of procoagulant state Phase 2 clinical trials are ongoing

73 Ansell JE et al. N Engl J Med 2014;371: Effect of PER977 on Whole-Blood Clotting Time.

74 An Anticoagulation Network Joint Commission: CSTK-4 (Procoagulant Reversal Agent Initiation for ICH) INR > 1.4 Metric: Time of Symptom Onset Metric: Time of Presentation Metric: Time to anticoagulant reversal agent Metric: Time to reversal Drip and Ship

75 Thank you