In Hospital Bleeding Management

Transcription

1 In Hospital Bleeding Management Geno J Merli, MD, MACP, FSVM, FHM Professor Medicine & Surgery Co-Director Jefferson Vascular Center Sidney Kimmel Medical College Thomas Jefferson University Hospitals

2 Disclosure Financial Relationships Geno J. Merli, MD, MACP, FHM, FSVM Jannsen: Research (Medically ill) Bristol-Meyer Squibb: Research (Jeff-Fast) Portola: Research (Medically ill) LoweRisk LLC, Co-Chief Development Officer

3 Assess Patient Anticoagulant LABs Imaging Consultation Intervention Warfarin IIa Inhibitor TSOAC Xa Inhibitor TSOAC

4 Assess Patient History & Physical Anticoagulant LABs Imaging Consultation Drug Class Indication Last Dose ½ Life Clearance CBC As Indicated PTT/PT By H&P SCr LFTs Thrombin Time As Indicated By H&P

5 Laboratory Testing Target Specific Oral Agents Lab Test Useful Lab test Strong ECT Dabigatran Rivaroxaban Apixaban Edoxaban TT Chromo* anti-xa PT# Chromo* anti-xa Chromo* anti-xa aptt Weak PT/INR * Chromogenic assay # PT reagent neoplastin has most linear correlation Palladino M et al: Am J Hem 87 Suppl:S127, 2012

6 Target Specific Anticoagulants Key Points Rivaroxaban Apixaban Edoxaban Dabigatran Target Factor Xa Factor Xa Factor Xa Factor IIa T ½ 7-11 hrs 12 hrs 6-11 hrs single doses 9-10 hrs multiple doses hrs Clearance 30% Renal 60% Liver 25% Renal 75% Liver 33% Renal 60% Liver 80% Renal Metabolism CYP 450 CYP3A4 CYP2J2 CYP3A4 No No P-GP Yes Yes Yes Yes Dialysis removes 60% Dabigatran

7 Intervention Warfarin Vit K + 4 PCC Vit K + 3 PCC FFP rf VIIa IIa Inhibitor TSOAC Dialysis Idarucizumab Xa Inhibitor TSOAC Vit K + 4 PCC Vit K + 3 PCC Andexanet Goals of Intervention 1. Fluid Resuscitation 2. Provide Rescue Clotting Factors 3. Increase Production of Normal Clotting Factors 4. Provide Anticoagulant Reversing Factor

8 Liver Function Coagulation Factors Vitamin K Warfarin Vitamin K Utilization Reduced Vitamin K Dependent Factors Half-Life II (60 hrs) VII (4-6 hrs) IX (24 hrs) X (48-72 hrs) C (8 hrs) S (30 hrs Warfarin ½ Life: 35 hrs

9 Blood Products Warfarin Anticoagulated Patient Product Factors Dosing Vitamin K # II, VII, IX, X, Protein C&S FFP * II, VII, IX, X, Protein C&S 10 mg, IV 10 mg, PO 15 cc/kg over 3 to 6 hrs, 250 cc/unit 3 Factor PCC* II, IX, X 50 U/kg 4 Factor PCC* II, VII, IX, X 50 U/kg Protein C&S rf VIIa* VII (activated) 15 mcg/kg # IV= Effect 12 hrs, PO= Effect 24 hrs * Immediate affect Prothrombin Time (INR)

10 Dabigatran Reversal 4 Factor Prothrombin Complex Concentrate Ecrin Clotting Time PCC Placebo Dabigatran 150mg BID PCC or Placebo Eerenberg E, et al Circulation 2011;124:

11 Four Factor vs Three Factor PCC Rivaroxaban Reversal Agent Reduction PT (sec) Beriplex (50 IU/kg) Four Factor Profilnine (50 IU/kg) Three Factor 2.5 sec 3.5 sec sec Rivaroxaban 20mg, BID x 4 days 30 minute following infusion effect noted Levi M, et al Abstract ISTH July 2013

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13 Idarucizumab DEVELOPMENT Monoclonal antibody then humanized and directly expressed as a Fab fragment in hamster cells PROPERTIES Potent binding affinity ~350 times higher than binding of dabigatran to thrombin No procoagulant or anticoagulant effects expected Short half life Intravenous administration, immediate onset of action EXPECTED LOW RISK OF ADVERSE REACTIONS No Fc receptor binding No endogenous targets Fully humanized antibody fragment (Fab) Glund S et al. AHA Abstr 17765; Schiele F et al. Blood 2013;121:

14 Idarucizumab Healthy Volunteers dtt (s) End of idarucizumab injection (5-min infusion) Dabigatran + placebo Dabigatran plus: Placebo (n=9) 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) Dabigatran Antidote Time after end of infusion (hours) Glund S et al. AHA Abstr 17765

15 Dilute Thrombin Time Ecrin Clotting Time 51 Serious Bleeding 51 Serious Bleeding Two 2.5 Gram IV, 15 mins apart Pollack C, et al NEJM 2015

16 Andexanet Alfa Recombinant Modified Version Human FXa Acts as a FXa decoy and retains high affinity for all FXa inhibitors GLA domain removed to prevent anticoagulant effect S419 A419 FXa Inhibitor High affinity retained GLA S S Catalytic Domain Activity eliminated to prevent thrombin generation N-terminal residues retained to reduce immunogenicity Ansell J. Nat Med. 2013;19(4)402.

17 Andexanet Alfa: Apixaban Phase II Apixaban 5mg bid x 6 d prior to andexanet/placebo bolus 420mg bolus + 4mg/min infusion over 2 hours: > 90 % reversal at 2 minutes > 90 % reversal at 2 hours Highly statistically significant Reversal sustained throughout antidote infusion Anti-FXa activity returns to normal decay curve after termination of infusion Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected Similar activity against rivaroxaban and enoxaparin Anti-FXa (ng/ml) End of Bolus Anti-FXa Activity End of Infusion Placebo (Cohorts 1-3, n=9) 420mg bolus only (n=6) 420mg bolus + 480mg infusion (n=6) Time after bolus in hours Crowther MA, et al. J Thromb Haemost. 2013;11:AS20.

18 Andexanet Alfa: Rivaroxaban Phase II Rivaroxaban 20mg qd x 6 d prior to andexanet/placebo 800mg bolus + 8mg/min infusion over 2 hours: - > 90% reversal at 2 minutes - > 90 % reversal at 2 hours - Highly statistically significant Reversal sustained throughout antidote infusion - Anti-FXa activity returns to normal decay curve after termination of infusion Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected Anti-FXa (ng/ml) End of Bolus Anti-FXa Activity End of Infusion Placebo (Cohorts 1-3, n=9) 800mg bolus + 960mg infusion (n=6) Time after bolus in hours Crowther MA, et al. Blood. 2013;122:A3636.

19 Andexanet Alfa: Enoxaparin Phase II Anti-FXa Activity Hit clinical threshold for enoxaparin reversal ( 0.2 IU/ml) Restoration of thrombin generation within normal range Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected Anti-FXa (IU/mL) 0.5 End of Bolus AnXa vs. Placebo *p<0.0001; **p<0.005 Lower limit of detection Placebo (Cohorts 1-3, n=9) 210mg bolus only (Cohort 1, n=6) 420mg bolus only (Cohort 2, n=6) 210mg (Lyo) bolus only (Cohort 3, n=6) Time after bolus in hours 22 Crowther MA, et al. J Thromb Haemost. 2014;12(suppl 1):7.

20 Bleeding Anticoagulation ICH GI/GU Emergent Surgery Emergent Procedure Trauma Assess Patient Anticoagulant LABs Imaging Consultation Intervention Warfarin IIa Inhibitor TSOAC Xa Inhibitor TSOAC

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