Speaker Disclosure Matthew K. Pitlick, Pharm.D., BCPS St. Louis College of Pharmacy/VA St. Louis HCS mpitlick@stlcop.edu Matthew K. Pitlick, Pharm.D., BCPS declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. Pharmacist Objectives At the conclusion of this program, the pharmacist will be able to: 1. Describe advantages and disadvantages of target specific oral anticoagulants 2. Interpret differences in reversal options for vitamin k antagonists and target specific anticoagulants 3. Design a reversal strategy for target specific oral anticoagulants Patient Case 1
Prevalence Atrial Fibrillation 1 5 million cases in 2010 12 million cases in 2030 Venous Thromboembolism 2 900,000 per year 1 Am J Cardiol. 2013;112(8):1142-7. 2 NEJM. 2009;365:981-92. Old School Warfarin Disadvantages: Unpredictable Bridging necessary Drug and food interactions Long half-life Close monitoring required New School Say no to NOAC Target Specific Oral Anticoagulant (TSOAC) Oral direct thrombin inhibitor Dabigatran (Pradaxa ) Oral Anti Xa inhibitor Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxoban not yet approved http://parade.condenast.com/ www.digitalspy.com FDA Approved Indications Anticoagulant Indication(s) Warfarin Stroke prevention in non-valvular and valvular atrial fibrillation VTE treatment and prophylaxis VTE prophylaxis after him/knee replacement Heart valves MI Dabigatran Stroke prevention in non-valvular atrial fibrillation Rivaroxaban Stroke prevention in non-valvular atrial fibrillation VTE treatment and prophylaxis VTE prophylaxis after him/knee replacement Apixaban Stroke prevention in non-valvular atrial fibrillation VTE prophylaxis after him/knee replacement Pharmacology Anticoagulant Standard Dose Dose Adjustment Warfarin Variable Variable Dabigatran A.fib = 150mg BID VTE tx = 150mg BID Rivaroxaban VTE tx = 15 mg BID X 21 days, 20mg daily VTE ppx = 10mg daily A.fib = 20gm daily Apixaban A.fib = 5mg BID Hip/Knee = 2.5mg BID 75mg BID if CrCl 15-30 ml/min Avoid CrCl <15 ml/min Avoid CrCl <15ml/min 15mg daily CrCl 15-50 ml/min (a.fib) Avoid use hepatic impairment 2.5 mg BID if >80 yrs, < 60 kg, or SCr > 1.5 mg/dl, or drug interaction 2
Pharmacology Mechanism of Action Anticoagulant Prodrug Mechanism Bioavailability Protein Bound Warfarin No VKA 98% Yes Dabigatran Yes DTI 6-8% No Rivaroxaban No Xa inhibitor 80% Yes Apixaban No Xa inhibitor 50% Yes Source: Joe Dunckley. Adapted with permission as outlined by http://creativecommons.org Pharmacokinetics Metabolism Anticoagulant Time to Peak Half-Life Renal Excretion Warfarin 1.5 36-42 92% Dabigatran 1-3 7-17 80-85% Rivaroxaban 2-4 12-13,6-9 36% Apixaban 1-3 8-14 25% Anticoagulant CYP450 P-glycoprotein Warfarin Yes No Dabigatran No Yes Rivaroxaban Yes (3A4) Yes Apixaban Yes (3A4) Yes Interactions Anticoagulant Drug Interactions Food Interactions Warfarin Assume so unless proven otherwise Vitamin K Alcohol Dabigatran P-Glycoprotein Substrate None Rivaroxaban P-Glycoprotein Substrate Increases bioavailability CYP3A4 Apixaban P-Glycoprotein Substrate CYP3A4 None Interactions Substrate of efflux transporter P-glycoprotein Inducers reduce effect Rifampin Inhibitors increase effect Dronederone Ketoconazole, Itraconazole Amiodarone Verapamil Quinidine Clarithromycin 3
Monitoring Anticoagulant Warfarin Dabigatran Rivaroxaban Apixaban Monitoring Assay PT/INR Drug level Thrombin time (TT) Ecarin Clotting Time (ECT) Hemoclot assay Drug level aptt Anti-factor Xa assay Drug level aptt Anti-factor Xa assay TSOAC Advantages Rapid onset No monitoring Fewer drug interactions No food interactions Shown noninferiority to warfarin Disadvantages No monitoring No reversal Short half-life Limited experience treating bleeding When is reversal needed? Bleeding Emergent Major vs. Minor Peri-Procedural Planned Urgent Reversal Options Anticoagulant Reversal Agent(s) Warfarin Antidote: phytonadione (vitamin K) Fresh Frozen Plasma (FFP) Recombinant Factor VIIa Prothrombin Complex Concentrates Dabigatran None? Rivaroxaban None? Apixaban None? 4
Reversal Options Prothombin Complex Concentrates (3 and 4 factor) Activated Prothombin Complex Concentrates Recombinant factor VIIa Antidotes Hemodialysis (dabigitran only) Animal Study Limitations Wide range in effects, many positive Wide variability in study design Different doses Different species Different outcomes (coagulation assays, bleeding time, blood loss) Human clotting factors behave differently in non-humans Prothrombin Complex Concentrate 3 factor (II, IX, X) Bebulin, Profilnin 4 factor (II, VII, IX, X) (Kcentra ) Varying amounts of protein C & S and heparin Risk of thrombosis Many studies but no highest quality evidence for TSOAC reversal Prothrombin Complex Concentrate Erenberg 2011 4 factor PCC 1 Healthy volunteer study (n=12) Rivaroxaban = reversed PT prolongation Dabigatran = did not reverse (aptt, ECT, TT) Marlu 2012 2 Volunteer study n = 12 PCC effective for rivaroxaban reversal 1 Circulation. 2011;124:1573-9. 2 Thromb Haemost. 2012;108:584-5. Prothrombin Complex Concentrate Dinkelaar 2013 1 Rivaroxaban = mixed results, normalize thrombin generation, not PT Dose of PCC depended on assay type Korber 2013 2 N = 10 rivaroxaban = no effect on clotting assays Prothrombin Complex Concentrate Human Study Summary 4 Factor PCC no impact on dabigatran 4-Factor PCC mixed results on rivaroxaban Doses used similar to warfarin reversal (20-50 units/kg) 1 J Thromb Haemost. 2013;11(6):1111-8 2 Clin Appli Thromb Hemost. 2013;7:735-40. 5
Activated PCC (appc) Factor 8 inhibitor bypassing activity (FEIBA) Activated factors II, VII,, IX, X Risk of thrombosis Activated PCC (appc) Khoo 2013 1 N = 8 Reversed dabigatran 1 Int J Lab Hematol. 2013;35(2):222-4 Recombinant Factor VIIa Initiates thrombin generation by activating Factor X Recombinant Factor VIIa Marlu 2012 1 Effective for dabigatran reversal Case reports poor outcomes Korber 2013 2 Rivaroxaban = reversed PT and clotting factor time prolongation 1 Thromb Haemost. 2012;108:584-5. 2 Clin Appli Thromb Hemost. 2013;7:735-40. TSOAC Antidotes Dabigatran Idarucizumab Rivaroxaban/Apixaban Andexanet (recombinant factor Xa) Idarucizumab Investigational humanized antibody fragment Phase 3 trial ongoing: RE-VERSE AD Has shown reversal and no prothrombotic effects in healthy patients 1 1 Circulation. 2013; 128(22):530 6
Andexanet Antidote for rivaroxaban/apixaban Recombinant Factor Xa Binds Xa inhibitor site Has shown reversal and no prothrombotic effects PER977 Small synthetic molecule Directly binds Xa and IIa Reverses dabigatran, rivaroxaban, apixaban Human Study Limitations Variable designs Healthy Volunteers Reversal agents added to blood samples Clotting tests proxy for bleeding Reversal Summary Warfarin Dabigatran Rivaroxaban Apixaban Charcoal No Yes Likely Likely Hemodialysis No Yes No No Vitamin K Yes No No No rfviia Yes Possible Possible Unknown 3-Factor PCC Likely Possible Possible Unknown 4-factor PCC Yes Possible Possible Unknown apcc Yes Possible Possible Unknown Idarucizumab No Yes No No Andexanet No No Yes Yes PER977 Yes? Yes Yes Yes Discontinue anticoagulant Compress Fluid replacement, transfusion Follow institutional protocol No proven/fda approved reversal agent or antidote 7
Risk factor management Indications, drug dosage, treatment duration Advanced age History of major bleeding Combordities uncontrolled hypertension, CVD, anemia, falls Concurrent antithrombotic therapy Strategies to minimize bleeding risk Review all clinical problems and conditions Assess bleed severity (minor vs. major) Stratify bleeding risk preoperatively Use anticoagulation tests if necessary General Measures Assess vital signs and resuscitate Discontinue anticoagulant Assess blood count and coagulation cascade Gastric lavage and charcoal Severe or life threatening Multidisciplinary team care in ICU Mechanical compression Surgical intervention if appropriate Hemodialysis (dabigatran only) Nonspecific prohemostatic agents apcc 50-100 units/kg (preferred) dabigatran PCC 50 units/kg rivaroxaban/apixaban rfviia 120 units/kg Antidotes when available Patient Case Matthew K. Pitlick, Pharm.D., BCPS St. Louis College of Pharmacy/VA St. Louis HCS mpitlick@stlcop.edu 8