Reverse the New Anticoagulants? Mitchell J Daley, PharmD, BCPS

Transcription

1 Reverse the New Anticoagulants? Mitchell J Daley, PharmD, BCPS Clinical Pharmacy Specialist, Critical Care University Medical Center Brackenridge / Dell Seton Medical Center at the University of Texas Seton Healthcare Family Clinical Adjunct Faculty University of Texas College of Pharmacy

2 Disclosure No financial conflicts of interest to disclose related to this subject manner Discuss off-label uses of laboratory and medication therapy

3 Learning Objectives Describe how to assess for the presence of TSOA Discuss available options for TSOA reversal

4 Target Specific Oral Anticoagulants (TSOA) Direct Thrombin Inhibitor Dabigatran (Pradaxa ) Intrinsic Pathway Factor Xa Inhibitor XI Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Betrixaban (Portola - in development) Damaged Surface XII IX XIIa X XIa Extrinsic Pathway IXa VIIa VII VIIIa Tissue Factor Va Xa Prothrombin Thrombin (II) (IIa) Fibrinogen (I) Fibrin (Ia)

5 Approach to Reversal 1. Recognize TSOA coagulopathy 2. Determine if drug present / assess urgency 3. Pharmacologic reversal

6 Recognizing Dabigatran Coagulopathy Assay Relationship Pearl Diluted thrombin time (Hemoclot ) Diluted plasma, constant thrombin concentration Ecarin clotting time (ECT) Ecarin converts prothrombin to meizothrombin Thrombin clotting time (TT) Directly assess the activity of thrombin Activated partial thromboplastin time (aptt) Measures intrinsic pathway Quantitative, direct, linear Quantitative, direct, linear Qualitative, direct, linear Qualitative, indirect, curvilinear Not routinely available Use in clinical trials Lacks standardization in reagents; very sensitive Normal suggests little to no dabigatran acitivity Van Ryn, et al. J Thromb Haemost 2010;103:1116.

7 Recognizing Factor Xa Inhibitor Coagulopathy Assay Relationship Pearl Chromogenic anti-fxa assay Factor Xa cleaves chromogenic substrate directly proportional to activity Prothrombin time Clotting time triggered with tissue factor Quantitative, direct, linear Rivaroxaban: qualitative Apixaban: insensitive Edoxaban: qualitative, can t rule out No data on threshold values Requires local calibration and validation Dependent on reagent May see modest elevations Garcia D, et al. J Thromb Haemost 2013;11:245. Cuker A, et al. J Thromb Thrombolysis 2015;39:288.

8 Recognizing TSOA Coagulopathy Is Difficult Lack of optimal and readily available assay Limited medical history Example: RCT of idarucizumab for dabigatran reversal Efficacy outcome: ECT & dtt reversal at central laboratory Patients given study drug & excluded from efficacy analysis ~25% normal dtt ~11% normal ECT Pharmacologic reversal should be guided by bleeding Pollack CV, et al. N Eng J Med 2015;373:511.

9 Approach to Reversal 1. Recognize TSOA coagulopathy 2. Determine if drug present / assess urgency 3. Pharmacologic reversal

10 Applying Pharmacokinetics Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban Half-life by renal function, hrs Clcr: > 80 ml/min Clcr: ml/min Clcr: ml/min Clcr: < 30 ml/min Renal elimination, % Protein binding, % Typical duration of anticoagulation, days Drug drug interactions examples 1-3 AKI >3-5 d P-glycoprotein inhibitors 1-2 > in AKI? 1-2 > AKI? P-glycoprotein inhibitors Cytochrome 3A4 inhibitors > AKI? P-glycoprotein inhibitors Nutescu EA, et al. Am J Health Syst Pharm 2013;70:1914.

11 Approach to Reversal 1. Recognize TSOA coagulopathy 2. Determine if drug present / assess urgency 3. Pharmacologic reversal Coagulation factor replacement / hemostatic agents Antidotes

12 PCC Considerations Do what you can, with what you have, where you are -Theodore Roosevelt PCC recommended for TSOA reversal from multiple guidelines if antidotes not available Dabigatran: activated or 4 factor PCC 50 unit/kg Anti-factor Xa: activated or 4 factor PCC 50 unit/kg Not considered standard of care in RCT Nutescu EA, et al. Am J Health Syst Pharm 2013;70:82. Enriquez A, et al. Eurospace 2015; doi: /eurospace/euv030. Frontera JA, et al. Neurocrit Care 2016:24:6-46.

13 Approach to Reversal 1. Recognize TSOA coagulopathy 2. Determine if drug present / assess urgency 3. Pharmacologic reversal Coagulation factor replacement / hemostatic agents Antidotes

14 Hopeful Future: TSOA Antidotes Drug Mechanism Which TSOA Early Results Current Status Idarucizumab (Praxbind ) From Boehringer Monoclonal antibody; binds dabigatran (>350 affinity) Dabigatran Reversed coagulation markers within 5 minutes Sustained for >12 hours in Phase III study ongoing FDA approved Andexanet From Portola Modified factor Xa; binds anti-xa (similar affinity) Xa inhibitors (direct and indirect) Plasma anti-xa reduced >90% within 2 minutes Dose dependent response Phase III study ongoing Ciraparantag / Aripazine From Perosphere Synthetic molecule; direct binding Universal Baseline hemostasis achieved in minutes Phase II study ongoing Mo Y, et al. Pharmacotherapy 2015;35:198. Ansell JE, et al. N Eng J Med 2014;371:2141.

15 Idarucizumab: RE-VERSE AD Study Population Intervention Endpoints Pollack Phase 3 Multicenter Single arm Patients on dabigatran A: life threatening hemorrhage B: urgent (<8 hr) surgical or invasive procedure Goal = 300 pt; interim = 90 pt 5 g intravenous idarucizumab (2.5 g / 50 ml x 2) 1 0 endpoint: - Maximum percent dabigatran reversal (dtt or ECT) 2 o endpoint: - Proportion of patients with normalization by 4 hours - Reduction in concentration of unbound dabigatran - Clinical outcomes Demographics Group A = 51 patients; Group B = 39 Age 76.5 y, ecrcl 58 ml/min; time from dabigatran 15.4 hr Type of bleeding: ICH (20%), trauma (10%), GI (22%) Pollack CV, et al. N Eng J Med 2015;373:511.

16 Unbound Dabigatran Levels Pollack CV, et al. N Eng J Med 2015;373:511.

17 ECT Reversal Pollack CV, et al. N Eng J Med 2015;373:511.

18 Idarucizumab Reverses Dabigatran 100% maximum percentage reversal & normalized labs in 88-98% Unbound dabigatran levels <20 ng/ml: 93% of pts at 12 hours 79% at 24 hours Clinical outcomes Investigator-reported time to hemostasis: 11.4 hours Urgent procedures: 92% normal intraoperative hemostasis Mortality: 20% (5 fatal bleeding events) Thrombotic events: 5 patients; only 1 within 72 hours Remains to be defined Repeat dosing? Overdose? Pollack CV, et al. N Eng J Med 2015;373:511.

19 Does Idarucizumab Improve Outcomes? Considerations Lack of control group Broad inclusion (mortality: 20% vs % previously) How important is neutralizing the anticoagulant effect? Warfarin vs. dabigatran in intracranial hemorrhage In-hospital mortality dabigatran 20% (n=101) vs. warfarin 22% (n=2,290) Propensity score adjustment 0.93 ( ) Bauer K. N Eng J Med 2015;373:569. et al. Circulation 2013;128:2325. Alonso A, et al. Stroke 2014;45:2286. Granger, et al. Circulation 2012;125:159. Majeed,

20 Hopeful Future: TSOA Antidotes Drug Mechanism Which TSOA Early Results Current Status Idarucizumab (Praxbind ) From Boehringer Monoclonal antibody; binds dabigatran (>350 affinity) Dabigatran Reversed coagulation markers within 5 minutes Sustained for >12 hours in Phase III study ongoing FDA approved Andexanet From Portola Modified factor Xa; binds anti-xa (similar affinity) Xa inhibitors (direct and indirect) Plasma anti-xa reduced >90% within 2 minutes Dose dependent response Phase III study ongoing Ciraparantag / Aripazine From Perosphere Synthetic molecule; direct binding Universal Baseline hemostasis achieved in minutes Phase II study ongoing Mo Y, et al. Pharmacotherapy 2015;35:198. Ansell JE, et al. N Eng J Med 2014;371:2141.

21 Andexanet Study Population Intervention Endpoints Siegal Phase 2 Placebo controlled Elderly (50-75), healthy volunteers Received rivaroxaban and apixaban for ~4 days Andexanet: mg bolus -or- Andexanet: mg bolus & 4-8 mg/min for 2 hr -or- Placebo 1 0 endpoint: - % change in anti-factor Xa activity Phase 3 trial primary outcome good or excellent clinical hemostasis Siegal DM, N Eng J Med epub ahead of print

22 Conclusions Identify TSOA coagulopathy: Dabigatran: TT, aptt, and maybe rapid TEG Factor Xa inhibitors: protime and chromogenic anti-xa Establish time from last dose (3-5 half-lives) Prolonged with end-organ dysfunction? Drug-drug interactions? Reversal options in a transition period Dabigatran:? dialysis and / or apcc? idarucizumab Xa inhibitors: 4 factor or activated PCC andexanet This transition will: Challenge our approach to reversal Improve outcomes?

23 Reverse the New Anticoagulants? Mitchell J Daley, PharmD, BCPS Clinical Pharmacy Specialist, Critical Care University Medical Center Brackenridge / Dell Seton Medical Center at the University of Texas Seton Healthcare Family Clinical Adjunct Faculty University of Texas College of Pharmacy