Pharmacology of Anticoagulants Nathan Culver, PharmD, BCPS

anticoagulant Medication Classes Direct Thrombin Inhibitors (DTI) Argatroban Bivalrudin Dabigatran (Pradaxa®) Betrixaban (Bevyxxa®) Factor Xa Inhibitors Enoxaparin Fondaparinux Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Vitamin K antagonists Warfarin (Coumadin®, Jantoven®)

Citation: Antithrombotics, Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank's Toxicologic Emergencies, 10e; 2015. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=1163&sectionid=65096168 Accessed: October 05, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved

  Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism of action Inhibition of II, VII, IX, X Selective, competitive, direct inhibition of activated Factor II (thrombin) Selective, competitive, direct inhibition of activated Factor X Pro-drug No Yes Half-life 32 12 -14 9-12 12 8-10 Bio-availability 98% 6.5% >80% >50% >45% Excretion Liver Renal (80%) Renal (66%) Renal (25%) Renal (35%)

Laboratory monitoring

Dabigatran Laboratory Monitoring In patients receiving dabigatran 150mg bid Observed Serum concentrations1 Peak values 64 – 443 ng/ml Trough values 31 – 225 ng/m Dabigatran Laboratory Monitoring Thrombin Time (TT) and diluted Thrombin Time (dTT) – Quantitative and specific The TT test measure will depend on the coagulometer and on the thrombin lot used for the measurement. It is therefore advisable to use the calibrated Hemoclot®Thrombin Inhibitor assay (a diluted TT [dTT] assay) with dabigatran standards to calculate the concentration of Pradaxa rather than to determine TT. A TT measure with the calibrated Hemoclot® Thrombin Inhibitor assay (HYPHEN BioMed, Neuville-sur-Oise, France) of >200 ng/mL dabigatran plasma concentration (approximately >65 seconds) prior to the next drug intake after 150 mg twice-daily dosing (trough measure, i.e. 10−16 hours after the previous dose) is associated with a higher risk of bleeding A normal TT measure indicates no clinically relevant anticoagulant effect of Pradaxa Activated Partial Thromboplastin Time (aPTT) - semi-quantitative, not specific An aPTT test may be useful in determining an excess of anticoagulant activity, despite aPTT being less sensitive to the activity of Pradaxa above therapeutic levels. Please note: in the first 2–3 days after surgery, false prolonged measures may be detected. An aPTT 2–3 fold of control at trough (when the next dose is due) is associated with a higher risk of bleeding Ecarin clotting time (ECT) - Quantitative and specific ECT provides a direct measure of the activity of direct thrombin inhibitors Approximately 3−4 times elevated ECT over control prior to the next drug intake of Pradaxa (at trough) is associated with a higher risk of bleeding

Rivaroxaban Laboratory Monitoring Anti-Xa activity High degree of correlation when calibrated for rivaroxaban In the absence of a drug-specific calibration curve, use of a curve calibrated for unfractionated or low molecular weight heparin is a reasonable surrogate for excluding drug levels ≥ 25–30 ng/mL. Prothrombin Time (PT) Rivaroxaban prolongs the PT in a concentration-dependent manner. PT reagents vary markedly in their sensitivity to rivaroxaban. The PT has insufficient sensitivity to exclude on-therapy levels of rivaroxaban. In a study of ex vivo samples from patients taking rivaroxaban 20 mg daily at steady state, 19% to 93% of samples at trough had a normal PT, depending on the reagent. Activated Partial Thromboplastin Time (aPTT) Less sensitive than PT, not useful clinically Other Urinary assays 5-15 times higher than blood levels Stroke Prevention in AF (20mg daily) VTE Treatment VTE Prevention (10mg daily) Peak values 160 – 360 ng/ml 175 – 360 ng/ml 91 – 196 ng/ml Trough values 4 – 96 ng/ml 19 – 60 ng/ml 1.3 – 38 ng/ml

Apixaban Laboratory Monitoring Apixaban dose Observed Peak Concentration Observed Trough Concentration VTE Prophylaxis 2.5mg bid 41-146 ng/ml 23-109 ng/ml VTE Treatment 5mg bid 10mg bid   30-153 ng/ml 59-302 ng/ml 111-572 ng/ml 11-90 ng/ml 22-177 ng/ml 41-335 ng/ml Stroke Prevention in AF 69-221 ng/ml 91-321 ng/ml 34-162 ng/ml 41-230 ng/ml Apixaban Laboratory Monitoring Anti-Xa activity High degree of correlation when calibrated for rivaroxaban In the absence of a drug-specific calibration curve, use of a curve calibrated for unfractionated or low molecular weight heparin is a reasonable surrogate for excluding drug levels ≥ 25–30 ng/mL Prothrombin Time (PT) Less sensitive for apixaban than rivaroxaban or edoxaban Most PT reagents are inadequately sensitive to detect not only on-therapy, but even above on-therapy levels of apixaban with minimal change in values up to concentrations of 200 ng/mL in both patient and spiked sampl Activated Partial Thromboplastin Time (aPTT) Levels > 500 ng/ml only marginally increase aPTT Other Urinary assays 5-15 times higher than blood levels http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf

Edoxaban Laboratory Monitoring Anti-Xa activity Commercial product newly available Data with Anti-Xa correlated to heparin shows sensitivity Prothrombin Time (PT) Some effect but limited correlation available Activated Partial Thromboplastin Time (aPTT) Limited sensitivity and conflicting data Other No urine screen

References 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol2017;Dec 1 Zehnder JL. Drugs Used in Disorders of Coagulation. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.proxy.library.vcu.edu/content.aspx?bookid=2249&sectionid=175220898. Accessed October 09, 2018. Buxton IO. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds.Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.proxy.library.vcu.edu/content.aspx?bookid=2189&sectionid=166182905. Accessed October 10, 2018. https://www.acc.org/~/media/Non- Clinical/Images/Tools%20and%20Practice%20Support/Mobile%20Resources/ManageAnticoag/B18120_ManageAnticoag_App_Fact_Sheet.p df

Reversal

DOAC: Reversal Travis Gatesman, pharmd Clinical pharmacy specialist, neurology October 10, 2018

objectives Introduce factor Xa inhibitors (FXa) & direct thrombin inhibitors (DTI) Guideline recommendations Reversal agents Anticoagulant reversal PowerPlan Future agents

Factor Xa Inhibitor Reversal

Factor Xa inhibitors Apixaban (Eliquis®) Rivaroxaban (Xarelto®) T½ = 12 hours Removal by HD ≈ 14% over 4 hours Rivaroxaban (Xarelto®) T½ = 5 hours Not dialyzable Edoxaban (Savaysa®) T½ = 10-14 hours Apixaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018 Rivaroxaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018 Edoxaban. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Guidelines: Neurocritical Care & ICH ≤ 2 hours of ingestion (No intracranial hemorrhage) Activated charcoal 50g (intubated or low aspiration risk) Intracranial hemorrhage Within 3-5 terminal T1/2 (normal hepatic fx) PCC (50 Units/kg) Frontera JA, et al. Neurocrit Care 2016;24(1):6-46 Hemphill JC, et al. Stroke 2015;46:2032-60

Prothrombin Complex Concentrate (Kcentra®) Mechanism Factors II, VII, IX, & X. It also contains protein C and S Dosing 50 Units/kg if ICH occurred within 3-5 terminal T1/2 [timing may be altered in setting of renal (DTI) or hepatic impairment (FXa)] PK Parameters Onset = rapid (within 10 min) t1/2 = 1.5-60 hours depending on which factor Duration = 6-8 hours Side Effects Clotting events (1%) Monitoring Signs of thrombosis PCC 4 factor. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Direct Thrombin Inhibitors Reversal

Direct Thrombin Inhibitors Argatroban Bivalirudin (Angiomax®) Dabigatran (Pradaxa®) T½ = 12-17 hours (≤34 in severe renal impairment) Removal by HD ≈ 65% over 4 hours Idarucizumab (Praxbind®) Dabigatran. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Guidelines: Neurocritical Care Activated charcoal 50g (intubated or low aspiration risk) ≤ 2 hours of ingestion (no intracranial hemorrhage) Idarucizumab If none available then PCC (50 Units/kg) Ongoing bleeding then idarucizumab and/or HD Intracranial hemorrhage Within 3-5 terminal T1/2 (normal GFR) If none available then HD Renal insufficiency or overdose Frontera JA, et al. Neurocrit Care 2016;24(1):6-46

Idarucizumab (Praxbind®) Mechanism Humanized monoclonal antibody that binds specifically to dabigatran and its acylglucuronide metabolites Dosing 2.5 grams IV every 15 mins x 2 doses (5 grams total) May repeat if clinically indicated (more bleeding, re-elevation, urgent surgery) PK Parameters Onset = effects observed within “minutes” (median hemostasis 11.4 hours) t1/2 = 47 min (terminal 10.3 hours) Duration ≤ 24 hours Side Effects Common = headache, constipation, nausea (5%) Uncommon = clotting events (<1%) Monitoring aPTT & signs of bleeding, Dabigatran Overdose = 2 hours after exposure, then q12h till aPTT normalize Idarucizumab. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Idarucizumab: Efficacy Study Design Results Conclusion Limitations Idarucizumab for Dabigatran Reversal 2015 (RE-VERSE AD) -Multicenter, prospective cohort -Primary outcome: Maximum reversal of dTT or ECT -Randomized 90 pts Primary: dTT – 22 pts normal prior to treatment, 68 treated = normal in 98% (group A) & 93% (group B). ECT – 9 pts normal prior to treatment, 81 treated = 89% (group A) & 88% (group B) Among patients receiving dabigatran who develop serious bleeding or need an urgent invasive procedure, idarucizumab reverses the anticoagulant effects of dabigatran within minutes of administration -For most clinically relevant bleeds it’s hard to say when exactly the bleeding stopped - Giving idarucizumab did not prevent majority of pts from going to sgy ->80 y/o excluded -Selection bias w/ who needed reversal and timing of Sgy ->80% white ->60% pts on 110mg --No control group Idarucizumab for Dabigatran Reversal – Full Cohort Analysis 2017 (RE-VERSE AD) -Same as initial -Randomized 503 pts -median reversal was 100% with respect to dTT or ECT -median bleeding cessation time was 2.5 hrs (group A) & 1.6 hrs (group B) In emergency situations, idarucizumab rapidly, durable, and safely reversed the anti-coagulant effect of dabigatran Pollack CV, et al. NEJM. 2015; 373(6):511-20 Pollock CV, et al. NEJM. 2017; 377:431-41

Reversal PowerPlan

Anticoagulant reversal powerplan

Factor Xa Reversal PowerPlan

Factor Xa Reversal PowerPlan

Direct Thrombin Inhibitors PowerPlan

Future reversal agents

Future Agents Andexanet alfa (Andexxa®) – Factor Xa reversal agent Ciraparantag (PER977) – “Universal” reversal agent

Anticoagulants Reversal Site of Action Tiffany YH, et al. Vasc Health Risk Manag. 2016; 12:35-44

Andexanet Alfa (Andexxa) Mechanism Binds and sequesters the factor Xa inhibitors; inhibits the activity of Tissue Factor Pathway Inhibitor, increasing tissue factor-initiated thrombin generation Dosing High Dose: 800 mg @ 30 mg/min x 2 min, then 8 mg/min for up to 120 min Low Dose: 400 mg @ 30 mg/min x 2 min, then 4 mg/min for up to 120 min PK Parameters Onset = Rapid T1/2 = 5-7 hours Side Effects Most common = Infusion site (18%), DVT (6%), Stroke (5%), MI (3%) Monitoring Signs of bleeding, signs of thrombotic event Andexant. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Andexanet Alfa: Dosing Andexant. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed August 2018

Andexanet Alfa: Efficacy Study Design Results Conclusion Limitations Andexanet for reversing Xa inhibitors 2015 (ANNEXA) -RPCT, DB, intention-to-treat -Primary outcome: Change in anti-Xa activity -Randomized 145 Primary: ANNEXA-A1: 94 vs 21% (P<0.001) ANNEXA-A2: 92 vs 33% (P<0.001) ANNEXA-R1: 92 vs 18% (P<0.001) ANNEXA-R2: 97 vs 45% (P<0.001) Secondary: ≥80% reversal 100 vs 0% (P<0.001) Andexanet effectively reverses the anticoagulant effects of factor Xa inhibitors apixaban and rivaroxaban within minutes of administration -Different doses are required depending on the factor Xa inhibitor used. ? Challenging hx -Patients who require urgent reversal were excluded Andexanet for reversing Xa inhibitors – Interim Analysis 2016 (ANNEXA-4) -MC, Pro, Open label, single group -evaluated 67 pts -rivaroxaban activity decreased by 89% (95% CI, 58 to 94) -apixaban activity decreased by 93% (95% CI, 87 to 94) -12 hours after andexanet infusion, hemostasis was excellent or good in 37 of 47 pts in efficacy group (79%; 95% CI, 64 to 89) In this interim analysis, andexanet demonstrated that it has reduced anti factor Xa activity and achieve hemostasis in 79% of patients -Thrombosis rate 18% during 30 day F/U -Interim analysis -No edoxaban data -Single group so no comparison -Severe bleeding was excluded Siegal DM, et al. NEJM. 2015; 373(25):2413-24 Connolly SJ, et al. NEJM. 2016; 375(12):1131-41

Ciraparantag Mechanism Dosing It inactivates anticoagulants via noncovalent hydrogen binding, which blocks the binding to the target sites of factor IIa and Xa (It does not bind to coagulation factors or other plasma proteins) Dosing Single 100-300 mg IV Once (Still under investigation) Miling, TJ, Kaatz S. Am J Med. 2016; 129(11 suppl):S80-88 Tiffany YH, et al. Vasc Health Risk Manag. 2016; 12:35-44

Ciraparantag: Efficacy Study Design Outcomes Conclusion Safety/efficacy of escalating doses of PER977 alone and following one dose of edoxaban (Phase I) -RCT -8:2 to PER977 or placebo -Randomized 80 pts Primary: To evaluate the safety, tolerability, and plasma and urinary pharmacokinetics of a range of single IV dose of PER977 Secondary: Pharmacodynamics Achieved baseline hemostasis within 10–30 minutes following administration (whole-blood clotting time); effects sustained for 24 hours PER977 Administered to Subjects With Steady State Edoxaban Dosing and Re-anticoagulation With Edoxaban (Phase II) -Randomized 4:1 to PER977 or placebo -Randomized 69 pts Not yet published ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 - . Identifier NCT01826266. Phase I trial; April 2013 ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 - . Identifier NCT02207257. Phase II trial; September 2015

Conclusion DOAC Reversal New Agents to come! Questions? Inside of 2 hours (non-life threatening) = Activated Charcoal? Inside 3-5 terminal T1/2 = PCC (50 Units/kg) or idarucizumab New Agents to come! Questions?