Direct Oral Anticoagulants Allison Paroskie, MD

Outline Anticoagulation Review of New Direct Oral Anticoagulants Laboratory Testing Reversal / Techniques with Bleeding

Anticoagulants Heparin Warfarin: vitamin K antagonist Unfractionated & low molecular weight Factors II and X Warfarin: vitamin K antagonist Factors II, VII, IX, X New oral anticoagulants Direct thrombin inhibitors Dabigatran Xa inhibitors Rivaroxaban, apixaban, betrixaban, edoxaban

“Ideal” Oral Anticoagulant Antithrombotic effect without bleeding Predictable dose response No need for routine monitoring Reduced need for dose adjustment No food interaction Limited drug interactions

Direct Oral Anticoagulants

Direct Oral Anticoagulants Thrombus

Direct Oral Anticoagulants Bleeding Increased GI bleeding in DTI’s Reduction in ICH Trend towards reduced major bleeding Otherwise no clear increased bleeding for any of the new ODI (“clear” because it is difficult to compare bleeding between studies thus a direct comparison has not been made)

Direct Oral Anticoagulants Dabigatran Rivaroxaban Direct specific competitive inhibitor of free and fibrin-bound thrombin Renal clearance ½ life: 11 hours Extended if poor renal function No adjustment if 50-100 kg Food has no significant effect Direct specific competitive inhibitor of Xa Limits thrombin generation in a dose dependent manner Metabolized in liver ½ life: 7 – 11 hours No adjustment if 50-120 kg Food increases absorption

Direct Oral Anticoagulants Drug Interactions

Warfarin Drug Interactions

Laboratory Testing

Useful Timing for Testing Baseline Assessment for bleeding diathesis: CBC, PT, aPTT Preoperatively Concern of delayed clearance Adverse events (thrombosis or hemorrhage) Assessment for under- or over-anticoagulation May require reversal Assessment of adherence Dose adjustments if extreme body weight and/or known drug-to-drug interactions

Laboratory Assessment

Direct Thrombin Inhibitors Ecarin Clotting Time (ECT) Thrombin Time (TT) Snake venom that converts FII to meizothrombin; DTI inhibition of meizothrombin can be measured Linear and dose dependent 3 x baseline Measurement of plasma clotting time after adding thrombin Linear and dose dependent Excessive response 10 x baseline Normal result rules out anticoagulant effect No reflection of drug concentration Dilute TT Activated Partial Thromboplastin Time (aPTT) 1.7 x baseline Not linearly related Between–reagent variability

Direct Xa Inhibitors Anti-Xa Prothrombin Time (PT) Measurement of residual Xa with synthetic substrates upon mixing plasma with Xa Responsive to Xa Linear dose response 1.5 x baseline Varies based on reagents

Other Helpful Lab Tidbits Antithrombin activity can be overestimated Fibrinogen activity can be underestimated Factor XIII activity can be underestimated Activated protein C resistance may be affected Protein C & S levels, and lupus anticoagulant testing can be affected

Summary of Laboratory Testing

Reversal / Treatment with Bleeding

Supportive Measures Discontinuation of medication Oral activated charcoal Recent intake / overdose Local / mechanical control Dialysis – dabigatran

Supportive Medications Antifibrinolytic agents No studies Safety demonstrated in surgical and traumatic bleeding Desmopressin Stimulates release of VWF & FVIII from vascular endothelium (primary hemostasis) Reduced skin bleeding in animals anticoagulated with thrombin inhibitors Topical thrombin

Supportive Blood Products pRBCs Volume expansion Improvement of symptomatic anemia Platelets Correction of thrombocytopenia Perhaps beneficial if anti-platelet agents are also used Fresh Frozen Plasma Dilutional coagulopathy No role in reversal of oral agents Cryoprecipitate

Reversal of DTI Activated prothrombin complex concentrate Factors II, IX, X, VII Reduction in bleeding time in mice Reversal of impaired thrombin generation (ex-vivo) Associated increased risk of thromboembolic complications

Reversal of DTI Inactive factor prothrombin complex concentrate Factors II, IX, X, (VII) Animal models resulted in limited hemorrhage Inability to reverse thrombin generation in ex-vivo studies Case series: 4 patients with excessive levels (renal impairment) pRBC, FFP, PCC, rFVIIa

Reversal of DTI Recombinant FVIIa Does not reverse thrombin generation in ex-vivo studies Not effective in minimizing clinical bleeding

Reversal of DTI Monoclonal antibodies Humanized, highly selective antibody is in development Rapid dose dependent decrease in experimentally induced blood loss Clinical studies in 2013-2014

Reversal of DXI Prothrombin complex concentrates Shortened the aPTT and clotting time (TEG), but no change in clinical bleeding Normalizes PT in healthy controls

Reversal of DXI Recombinant VIIa Normalizes PT and bleeding time in animal models, but no effect on blood loss (supratherapeutic doses)

Reversal of DXI PRT4445 Universal reversal agent for Xa inhibitors Recombinant protein that binds Xa inhibitors Pre-clinical data shows reversal in fondaparinux and enoxaparin Health controls: tolerated with no safety concerns

Conclusions Non-inferior / equivalent anti-coagulation to warfarin Bleeding risks are equivocal Improved pharmacodynamics and pharmacokinetics Moderately helpful monitoring Minimal reversal techniques

References Dager WE. Developing a management plan for oral anticoagulant refersal. Am J Healthy-Syst Pharm, 2013:70;S21-31. Schulman S and Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood, 2012:119;3016-3023. Weitz JI and Gross PL. New oral anticoagulants: which one should my patient use? Hematology, 2012; 536-540. Nitzki-George D, Wozniak I, Caprini JA. Current state of knowledge on oral anticoagulant reversale using procoagulant factors. The Annals of Pharmacotherapy, 2013: 47;841-855. Haas, S. Facts and artefacts of coagulation assays for factor Xa inhibitors. Thrombosis and Haemostasis, 2010:103.4:686. Tripodi A. The laboratory and the direct oral anticoagulants. Blood, 2013: 121;4032-4035. Schulman S et al. Adherence to anticoagulant treatment with diabigatran in a real-world setting. Journal of Thrombosis and Hemostasis, 2013:11;1295-1299. Baglin T. Clinical Use of new oral anticoagulant drugs: dabiggatran and rivaroxaban. British Journal of Hematology, 2013; 1-8. Samama MM, et al. Evlauation of the anti-factor Xa chromogenic assay for the measuremnt of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost, 2012: 107; 379-3897. Funk, DM. Coagulation assays and anticoagulant monitoring. . Hematology, 2012; 460-465. Schiele F, et al. A specific antidote for dabigatran: functional and structural characterization. Blood, 2013: 121; 3554-3562. Majeed A and Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Practice & Research Clinical Haematology, 2013: 26; 191-202. Hawes. EM, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a corss-sectional pharmacodynamic study based on peak and trough plasma levels. Journal of Thrombosis and Haemostasis, 2013; 11: 1493-1502.