Disclosures. I have served as an advisory board member, consultant, speaker, and / or received research funding from: Sanofi-Aventis

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1 TSOACs: Glee Lenoir, Pharm D. Pharmacy Clinical Coordinator The Medical Center Nursing Conference March 2015 Disclosures I have served as an advisory board member, consultant, speaker, and / or received research funding from: Sanofi-Aventis Janssen Pharmaceuticals Off-label use may be mentioned: dabigatran, rivaroxaban, apixaban, edoxaban, FEIBA, Kcentra Anticoagulant Therapy What are the options? 1930s heparin 1950s warfarin 1990s Low molecular weight heparin 1990s direct thrombin inhibitors 2000s factor Xa inhibitor 2010s TSOACs More new drugs are coming... 1

2 Warfarin (Coumadin ) Dosing Roulette Oral Gold Standard Rat Poison? Warfarin (Coumadin ) Action: inhibits vitamin K dependent clotting factors factors VII, IX, X, II Half Life: hours (avg:40hrs) it takes days to reach steady-state Monitoring: PT/INR Home monitoring finger stick devices Dosing: dependent on INR INR Goal: 2-3 usual ( other) Cost- generic $4/month Warfarin (Coumadin ) Indications: Prophylaxis and treatment for VTE and thromboembolic disorders, adjunct to reduce risk of systemic embolism such as recurrent MI or stroke Antidote: Vitamin K (phytonadione) Available as oral tablets Subcutaneous route is preferred injection route IM route should be avoided due to risk of hematoma formation May be given IV for life-threatening bleeding Administer IV slowly not to exceed 1mg/min Dilute 10mg dose in 50ml saline over 20 min Does not work immediately! VTE= venous thromboembolism (DVT-deep vein thrombosis &/or PE-pulmonary embolism) 2

3 Warfarin (Coumadin ) Food/nutrient interactions Examples: Foods high in vitamin K Dark green leafy vegetables Nutritional supplements Ensure, Boost, Slim Fast, Carnation instant breakfast Vitamins, minerals, herbals Alcohol (Et 2 OH) Acute ingestion- increase INR Chronic ingestion- decrease INR EtOH-related liver diseaseincrease INR Independently increases hemorrhagic risk Partial List of Anticoagulant Drugs Under Development Dabigatran Pradaxa (Boehringer Ingelheim) Edoxaban Savaysa (Daiichi Sankyo) Rivaroxaban Xarelto (Janssen) Apixaban Eliquis (Bristol-Myers Squibb / Pfizer) Weitz JI et al. Chest

4 VTE prophylaxis (THR, TKR) Non- Valvular Afib (NVAF) Approval History Dabigatran Rivaroxaban Apixaban Europe Mar 2008 Canada Jun 2008 Canada Oct 2010 USA Oct 2010 Europe Aug 2011 VTE treatment Canada Sep 2014 USA Apr 2014 Europe Jun 2014 Europe Sep 2008 Canada Sep 2008 USA July 2011 USA Nov 2011 Europe Dec 2011 Canada Jan 2012 Europe Dec 2011 Canada Feb 2012 USA Nov 2012 Europe May 2011 Canada Mar 2012 USA Mar 2014 Europe Nov 2012 Canada Dec 2012 USA Dec 2012 Europe Jul 2014 Canada Sep 2014 USA Aug 2014 Edoxaban was approved Jan 2015 in US for NVAF and VTE treatment; Canada - Nov 2013 for NVAF Summary of Major Clinical Trials VTE prophylaxis VTE treatment NVAF REMODEL REMOBILIZE RENOVATE RENOVATE 2 RECORD 1 RECORD 2 RECORD 3 RECORD 4 ADVANCE 1 ADVANCE 2 ADVANCE 3 STARS J4 & J5 STARS J5 RECOVER REMEDY RESONATE RECOVER 2 EINSTEIN-DVT EINSTEIN-EXT EINSTEIN-PE AMPLIFY AMPLIFY-EXT Hokusai VTE Dabigatran Rivaroxaban Apixaban RELY RELYABLE ROCKET-AF ARISTOTLE AVERROES ENGAGE AF Edoxaban FDA Approved Indications As of February, 2015 Dabigatran Rivaroxaban Apixaban Edoxaban VTE prophylaxis (THR, TKR) x x Nonvalvular Afib VTE treatment 4

5 Pharmacokinetics Dabigatran Rivaroxaban Apixaban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Peak Effect (h) Half-life (h) ~ (14-17 elderly) (11-13 (28 severe elderly) renal) Dosing Frequency Twice daily Daily* Twice daily Daily Clearance 80% Renal 20% Biliary 66% Renal 34% Biliary 25% Renal 75% Biliary 50%Renal 50%Biliary * Despite short half-life, once daily dosing possible due to persistence of anti-xa activity Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9): Renal Dosing Dabigatran Non-valvular Afib : >50 ml/min 150mg po BID ml/min (+dronedarone or ketoconazole) 75mg po BID ml/min 75mg po BID <15 ml/min no recommendations VTE treatment: >30 ml/min 150mg po BID (after 5-10 days of parenteral anticoagulation) (if crcl<50 ml/min and is receiving P-gp inhibitor, then avoid coadministration) <30 ml/min no recommendations Hemodialysis: no recommendations Note hemodialysis removes ~57% over 4 hours Renal Dosing Rivaroxaban Postoperative thromboprophylaxis (TKR,THR): >30 ml/min 10mg po daily <30 ml/min not recommended Non-valvular Afib: >50 ml/min 20mg po daily ml/min 15mg po daily <15 ml/min not recommended VTE treatment: >30 ml/min 15mg po BID x 21 days, then 20mg po daily <30 ml/min not recommended Hemodialysis: Avoid use in this population 5

6 Renal Dosing Apixaban Postoperative thromboprophylaxis (TKR,THR) 2.5mg po BID beginning 12-24hrs post-op (note: patients with significant, impaired, CrCl<30 ml/min were excluded from clinical trials) Non-valvular Afib: 5mg po BID unless two of the following exist: creatinine >1.5mg/dl; age >80 years; weight <60 kg then 2.5mg po BID VTE treatment: 10mg po BID x 7 days, then 5mg po BID (note: patients with Cr>2.5 or CrCl<25 ml/min were excluded from clinical trials) NVAF indication: ESRD requiring hemodialysis 5mg po BID; reduce to 2.5mg BID if age>80 yrs or weight <60 kg Renal Dosing Edoxaban Non-valvular Afib: >95 ml/min DO NOT USE ml/min 60mg po daily ml/min 30mg po daily <15 ml/min no information VTE treatment: >50 ml/min 60mg po daily (following 5-10days of parenteral anticoagulant) 15-50ml/min or <60kg or concomitant P-gp inhibitor 30mg po daily Hemodialysis: does not significantly contribute to clearance Drug Interactions Dabigatran and edoxaban interact with drugs that affect the transporter P-glycoprotein (P-gp) Rivaroxaban and apixaban also interact with P- gp drugs, as well as those that affect the microsomal enzyme CYP3A4 Examples Ketoconazole Rifampicin Cyclosporine Itraconazole Clarithromycin Tacrolimus Amiodarone Protease inhibitors Carbamazepine Verapamil St. John s wort Phenytoin Increased risk of major bleeding seen in studies of all 3 drugs when used with anti-platelet agents Schulman S, Crowther MA. Blood 2012; 119(13): Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):

7 PT / INR aptt Thrombin Time Other Laboratory Monitoring Dabigatran Rivaroxaban Apixaban Increases with dose Very insensitive Increases with dose Not linear, plateaus Most sensitive Normal TT = no drug Too sensitive Ecarin clotting time is the best assay, but is not widely available PT / INR and aptt are both prolonged, but to a varying degree, and depend upon the reagents used No effect Anti-Xa assay can be used, but must be standardized to the drug No effect Anti-Xa assay very similar to LMWH, and may not need to re-calibrate? Non-valvular Atrial fibrillation VTE Prophylaxis VTE Treatment Non-valvular Atrial fibrillation RE-LY (Connolly SJ et al. NEJM 2009; 361: ) N = 18,113 (mean CHADS 2 =2.1) Dabigatran 150 mg bid vs. warfarin Superior in efficacy when warfarin avg TTR 64% Similar rates of major bleeding Dabigatran associated with less ICH Significantly more GI bleeding MUST TAKE WITH FOOD! Baumann-Kreuziger LM, et al. J Trauma Acute Care Surg

8 Non-valvular Atrial fibrillation ROCKET AF (Patel MR et al. NEJM 2011; 365:883-91) N = 14,264 (mean CHADS 2 =3.5) Rivaroxaban 20 mg daily vs. warfarin Rivaroxaban was non-inferior to warfarin No overall difference in major bleeding Rivaroxaban associated with less ICH and fatal bleeding, but more GI bleeding Take with evening meal Non-valvular Atrial fibrillation ARISTOTLE (Granger CB et al. NEJM 2011; 365:981-92) N = 18,201 (mean CHADS 2 =2.1) Apixaban 5 mg bid vs. warfarin Apixaban was superior in preventing stroke with less overall bleeding and lower all cause mortality Apixaban associated with less ICH No increase in GI bleeding ENGAGE AF-TIMI 48 Non-valvular Atrial fibrillation (Giugliano RP NEJM 2013; 369: ) N = 21,105 (mean CHADS 2 =2.8+1) Edoxaban 60 mg daily vs. warfarin Edoxaban was non-inferior in preventing stroke Edoxaban was associated with less ICH More GI bleeds Increase rate of ischemic stroke with CrCl>95ml/min 8

9 VTE Prophylaxis (THR, TKR) Rivaroxaban Apixaban vs. Enoxaparin Equal or better efficacy Similar bleeding risk Advantage of oral administration Both agents have been trialed for VTE prophylaxis in medically ill patients and were associated with unacceptable rates of bleeding VTE Treatment Dabigatran Rivaroxaban Apixaban vs. Conventional therapy Edoxaban Non-inferior to warfarin, with same or less overall bleeding risk Less major bleeding (eg. ICH) Edoxaban & dabigatran require 5-10 days of overlap with parenteral anticoagulant Time in Therapeutic Range (INR ) RE-MEDY = 65% EINSTEIN = 58% EINSTEIN-PE = 63% AMPLIFY = 61% Hokusai VTE=65.6% Management of Bleeding Dabigatran Rivaroxaban Apixaban Antidote None None None Activated charcoal* Dialysis Yes Yes Yes ~35% protein bound ~60% removed in 2-3 h ** Highly protein bound Dialysis ineffective * Activated charcoal indicated within 2 3 hours of drug ingestion ** Dabigatran has a very large volume of distribution (60 70 L); expect multiple dialysis sessions to be required Highly protein bound Dialysis ineffective 9

10 Hemostatic Agent Options for Management of Bleeding Name Category Available in US? Aminocaproic acid antifibrinolytic Yes Tranexamic acid antifibrinolytic Yes Profilnine, Bebulin 3 factor PCC Yes Cofact, Kanokad 4 factor PCC No Octaplex, Kaskadil 4 factor PCC, + PC, PS No Beriplex / Kcentra 4 factor PCC, + PC, PS Yes FEIBA Activated PCC Yes NovoSeven rfviia Yes (None are approved in the US for this indication) Use of Factor Concentrates for Management of Bleeding Factor Concentrates are NOT antidotes They create hypercoagulability Specific reversal agents are in trials Thrombotic risk is significant! Hospitals have in house protocols but there are no specific guidelines available Should be restricted for LIFE THREATENING bleeding only! Antidotes in development: Aripazine (PER977), Andexanet (PRT064445), Idarucizumab (BI ) 10

11 Drug Dabigatran Rivaroxaban Edoxaban Apixaban Perioperative Management Package Insert Recommendations For CrCl >50, stop 1 to 2 days prior For CrCl <50, stop 3 to 5 days prior Consider longer* if major surgery, spinal puncture, spinal or epidural catheter Stop at least* 24 hours prior Stop at least* 48 hours prior (moderate or high risk procedures) Stop at least* 24 hours prior (low risk procedures) Lab testing If TT (dabigatran) or anti-xa (rivaroxaban, apixaban) are normal, drug has cleared. If tests are abnormal there is still drug on board but cannot quantitate risk *Clinical decisions should be individualized based on patient parameters that could influence clearance and risk of bleeding versus risk of clotting Advantages Direct anticoagulants Predictable pharmacokinetics No bridging needed* No monitoring needed Few diet / drug interactions *most indications Disadvantages Renal / hepatic excretion No antidotes Unable to monitor directly Limited experience Lack of long-term safety data To use or not to use? Non-valvular Atrial Fibrillation Those already on warfarin, with good INR control, have little to gain by switching New agents may have better safety profile (less intracranial hemorrhage) Consider patient compliance and cost of drug and testing Drug interactions with the new agents and drugs for afib, etc. must be considered 11

12 To use or not to use? Prevention of VTE Dabigatran and edoxaban are not approved in the US for this indication Rivaroxaban and apixaban are good alternatives to LMWH / warfarin in this setting Look closely at the trial comparator dose of enoxaparin before chosing agent Approval currently only for THR and TKR To use or not to use? Treatment of VTE Special attention should be given to dosing regimens when prescribing/counseling Patients may no longer require hospitalization but should have careful follow-up Rivaroxaban and apixaban are also indicated for extended treatment of VTE after at least 6 months of treatment but more bleeding than placebo To use or not to use? We need more experience in patients with: Malignancy Pregnancy Mechanical heart valves Thrombophilia (APC, PC, PS, AT double heterozygotes or homozygotes for FVL/PGM) Extremes of body weight Those with more than low bleeding risk Real world compliance (not on studies) RE-ALIGN Study (NEJM 2013; 369: ) Dabigatran vs. warfarin Aortic and mitral valves Terminated early due to EXCESS thromboembolic and bleeding events in dabigatran group 12

13 Take Home Points The new oral anticoagulants are not necessarily better than warfarin; they are different, and each has advantages and disadvantages Careful patient selection is crucial for the safe use of TSOACs Management of bleeding complications from the TSOACs is a major clinical challenge; we have no guidelines and real world clinical experience is limited QUESTION? COMMENTS? DISCUSSION? 13