The DOACs. Update on Anticoagulation 10/20/2017. Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Objectives

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1 Objectives Update on Anticoagulation JEFF REIST PHARMD, BCPS CLINICAL ASSOCIATE PROFESSOR UNIVERSITY OF IOWA COLLEGE OF PHARMACY At the conclusion of this program, the participant should be able to: List the direct oral anticoagulants (DOACs) currently approved for use in the United States For each DOAC, list the appropriate dose for their approved indications Describe how the DOACs fit into current clinical guidelines for the treatment of VTE and stroke prophylaxis in patients with atrial fibrillation Describe anticoagulant reversal strategies for the DOACs Compare the advantages and disadvantages of DOACs compared to warfarin The DOACs DOACs: MOA Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) WARFARIN RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN Figure adapted from: Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach, 3 rd Ed DOAC Approval Timeline Guidelines Dabigatran Apixaban AFib DVT/PE Oct 2010 Aug 2014 Dabigatran Rivaroxaban Apixaban Apixaban VTE px THR VTE px TKR/THR AFib VTE px TKR/THR Nov July Dec March Rivaroxaban AFib Rivaroxaban DVT/PE Dabigatran DVT/PE Edoxaban AFib Nov 2011 Nov 2012 April 2014 DVT/PE Jan AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation Recommend anticoagulation with either warfarin, dabigatran, rivaroxaban, or apixaban 2016 Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report For VTE without cancer, use dabigatran, rivaroxaban, apixaban, or edoxaban over warfarin therapy For VTE with cancer use low molecular weight heparin over warfarin, dabigatran, rivaroxaban, apixaban or edoxaban 5 1

2 2016 VTE Guidelines Update 2014 AHA/ACC/HRS A-Fib Guidelines VTE treatment: use dabigatran, rivaroxaban, apixaban, or edoxaban over warfarin therapy for VTE treatment If cancer and VTE: Use LMWH over oral anticoagulation Unprovoked VTE treatment decision if decide to STOP Check D-Dimer D-dimer drawn one month after may influence treatment decision Patients with a positive level have 2x risk for recurrence Gender: men have 75% higher risk of recurrence Suggest using aspirin to prevent recurrent VTE In patients with nonvalvular AF, the CHA 2 DS 2 -VASc score is recommended for assessment of stroke risk For patients with nonvalvular AF with prior stroke, transient ischemic attack, or a CHA 2 DS 2 -VASc score of 2 or greater, oral anticoagulants are recommended Options include warfarin (INR 2.0 to 3.0), dabigatran, rivaroxaban, or apixaban For patients with AF who have mechanical heart valves, warfarin is recommended, and the target international normalized ratio (INR) intensity (2.0 to 3.0 or 2.5 to 3.5) should be based on the type and location of the prosthesis CHEST 2016; 149(2): January CT, et al AHA/ACC/HRS. Circulation 2014;129 CHA 2 DS 2 -VASc Score Recommended over CHADS 2 Dabigatran (Pradaxa ) Congestive Heart Failure Hypertension Age 75 (Doubled) Diabetes Mellitus Prior Stroke, TIA or Embolism (Doubled) Vascular Disease Age Sex category (Female +1) Chronic Kidney Disease Direct Thrombin (Factor IIa Inhibitor) Strengths available 75 mg, 110 mg and 150 mg capsule Prodrug Conversion to active form by plasma esterase Indications Prevention of stroke and systemic embolism in patients with atrial fibrillation Treatment of DVT/PE After initial treatment with heparin or LMWH Prevention of VTE post-op in total hip replacement surgery NOT indicated for people with mechanical heart valves Dabigatran Dosing: Non-valvular Atrial Fibrillation Dabigatran Dosing: Treatment of DVT/PE CrCl > 30 ml/min 150 mg orally twice a day CrCl ml/min 75 mg orally twice a day CrCl < 15 ml/min DO NOT USE Renal dosing was approved by FDA based on modeling NOT on clinical use Must assess renal function prior to initiation and with continued use CrCl > 30 ml/min 150 mg orally twice a day CrCl < 30 ml/min Do not use, not studied in this population Must initially treat for 5-10 days parenteral anticoagulant Heparin or low molecular weight heparin (LMWH) such as enoxaparin Conversion from a parenteral anticoagulant to dabigatran Initiate dabigatran 2 hours prior to the time of the next scheduled dose of parenteral anticoagulant (LMWH such as enoxaparin) Initiate at the time of discontinuation for a continuously administered parenteral anticoagulant (IV heparin infusion) 2

3 Dabigatran Dosing: Post-op VTE Prophylaxis Dabigatran: Drug Interactions Following total hip replacement CrCl >30 ml/min Initial dose of 110 mg orally given 1-4 hours after completion of surgery Maintenance dose of 220 mg daily for days For DVT and PE or Post-op VTE prophylaxis With rifampin Avoid use With amiodarone, dronedarone, clarithromycin, quinidine, verapamil and CrCl <50 ml/min Avoid use Dabigatran: Drug Interactions For non-valvular a-fib With rifampin Avoid use With amiodarone, dronedarone, clarithromycin, quinidine, verapamil and CrCl <30 ml/min Avoid use With dronedarone or ketoconazole (oral) and CrCl ml/min Reduce dose to 75 mg twice a day Dabigatran: Safety in Older Adults (> 75) Use with extreme caution Beers criteria recommend DO Not Use in older patients with CrCl<30 ml/min No manufacturer dosing recommendations, however Numerous case reports of excess anticoagulation in this population Risk of bleeding increases with age 5-fold variation in plasma concentrations in patients receiving the same dose Factors affecting increased plasma concentrations Increasing age, decreased CrCl, lower body weight and female gender Reilly PA et al. J Am Coll Cardiol 2014 Feb 4;63(4):321-8 Dabigatran: Administration Dyspepsia common side effect (~35%) Administer with food Do not break chew or open capsules 75% increase in absorbance leading to potential toxicity Must be dispensed and stored in original bottle Should not put in med boxes Must be protected from moisture Expires 4 months after bottle opened Adherence is key! Effects start to wear off 15 hrs. after last dose! Rivaroxaban (Xarelto ) Factor Xa inhibitor Strengths available 10 mg, 15 mg and 20 mg tablets Indications Prevention of DVT and PE in total hip and knee replacement surgery Prevention of stroke and systemic embolism in patients with atrial fibrillation Treatment of DVT/PE NOT indicated for people with mechanical heart valves 3

4 Rivaroxaban Dosing: Non-valvular Atrial Fibrillation Rivaroxaban Dosing: Treatment of DVT/PE CrCl > 50 ml/min 20 mg once daily with evening meal CrCl 15 to 50 ml/min 15 mg once daily with evening meal CrCl < 15 ml/min Do not use Beers criteria recommend to avoid use in older adults with CrCl <30 ml/min Do not have to initially treat with parenteral anticoagulant CrCl 30 ml/min 15 mg twice daily with food for 21 days followed by 20 mg once daily CrCl < 30 ml/min Do not use Rivaroxaban Dosing: Treatment of DVT/PE Rivaroxaban Dosing: Post-op VTE Prophylaxis Duration of use Provoked 3 months Unprovoked > 3 months Often up to 6 months DVT/PE Secondary Prevention (after 6 months of treatment) CrCl 30 ml/min 20 mg once daily Knee replacement 10 mg once daily for 12 days Hip replacement 10 mg once daily for 35 days Avoid with CrCl < 30 ml/min Use with caution with CrCl ml/min Rivaroxaban: Administration Apixaban (Eliquis ) Administer doses 15 mg/day with food Higher doses have better bioavailability with food Doses of 10 mg/day may be administered without regard to meals Lower doses have good bioavailability with or without food For non-valvular a-fib give with evening meal May crush and mix with applesauce if needed May crush and mix with 50 ml water via NG/gastric tube Avoid administration distal to the stomach Factor Xa inhibitor Strengths available 2.5 mg and 5 mg tablets Indications Prevention of stroke and systemic embolism in patients with atrial fibrillation Prevention of DVT and PE in total hip and knee replacement surgery Treatment of DVT and PE NOT indicated for people with mechanical heart valves 4

5 Apixaban Dosing: Non-valvular Atrial Fibrillation Apixaban Dosing: Treatment of DVT/PE 5 mg BID is the normal dose 2.5mg BID if at least 2 of the following: A: Age >80 years B: Body weight <60 kg C: Serum Creatinine >1.5 mg/dl 2.5mg BID or avoid if on strong dual CYP3A4 + P-gp inhibitors clarithromycin, ketoconazole, itraconazole, ritonavir End-stage renal disease on dialysis dose is 5mg BID Reduced to 2.5mg BID if >80 yo or body weight <60kg Do not have to initially treat with parenteral anticoagulant CrCl 30 10mg BID for 7 days then 5mg BID for 6 months CrCl < 30 No dosage information from manufacturer Not recommended due to lack of clinical evidence in this population DVT/PE Secondary Prevention (after at least 6 mo. of Tx) 2.5 mg twice daily Apixaban Dosing: Post-op VTE Prophylaxis Apixaban: Administration Total Hip Replacement: 2.5mg BID for 35 days Total Knee Replacement: 2.5mg BID for 12 days Give Initial dose hours post surgery if hemostasis established No dosage recommendation for CrCl< 30 ml/min but such patients excluded from trials Not recommended due to lack of clinical evidence in this population Administer without regard to meals May crush tablets and suspend in 60 ml of water or apple juice or mix with applesauce if unable to swallow tablets Crushed tablets may be suspended in 60 ml of water or D5W for administration via NG tube Crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours Large amounts of grapefruit juice may increase levels of apixaban Edoxaban (Savaysa ) Edoxaban Dosing: Non-valvular Atrial Fibrillation Factor Xa inhibitor Strengths available 15 mg, 30 mg and 60 mg tablets Indications Prevention of stroke and systemic embolism in patients with atrial fibrillation Treatment of DVT and PE CrCl ml/min 60mg once daily CrCl ml/min 30 mg once daily Avoid if CrCl <15 ml/min Avoid if CrCl >95 ml/min Increased risk ischemic stroke compared to warfarin at the 60mg dose in this population 5

6 Edoxaban Dosing: Treatment of DVT/PE DOACs Place in Therapy 60mg once daily 30mg once daily if any of the following: CrCl ml/min Body weight < 60 kg On certain P-gp inhibitors verapamil, quinidine; the short-term use of azithromycin, clarithromycin, erythromycin, oral itraconazole, oral ketoconazole Avoid if CrCl <15 ml/min Must initially treat for 5-10 days parenteral anticoagulant Heparin or low molecular weight heparin (LMWH) such as enoxaparin Conversion from a parenteral anticoagulant to edoxaban Initiate edoxaban at the time of the next scheduled dose of the LMWH (enoxaparin) Initiate edoxaban 4 hours after discontinuation IV heparin infusion Advantages No monitoring Fewer drug/diet interactions Faster onset Stroke prevention in a-fib o Superior: apixaban, dabigatran o Non-inferior: rivaroxaban, edoxaban Treatment of DVT/PE o All approved o All non-inferior VTE prevention in TKA/THA o Rivaroxaban or apixaban o THR only: dabigatran Decreased intracranial bleeding Disadvantages No monitoring Cost $$$ (assistance good) Adherence is critical Fast offset Renal dosing GI bleeding Reversibility issues factor Xa Hemorrhagic events Lack of clinical experience Reversal of Dabigatran Reversal of Factor Xa Inhibitors Dabigatran only DOAC with a reversal agent Idarucizumab (Praxbind ) Indication is reversal of dabigatran if needed for Emergency surgery/urgent procedures Life-threatening or uncontrolled bleeding Dosing 5 g IV (2 vials of 2.5 g/50 ml) idarucizumab No reversal agent currently on the market Potential new agents in development Andexanet alfa Novel recombinant protein as decoy for factor Xa inhibitors Aripazine Synthetic small molecule that binds directly to a variety of anticoagulants to inhibit effect Being studied for reversal of oral factor Xa and IIa inhibitors, fondaparinux, LMWH (enoxaparin) and unfractionated heparin Management of Bleeding with DOACs Maintain adequate diuresis to enhance renal elimination Activated charcoal if <2 hours since last dose Prothrombin complex concentrate - PCC Contains factors II, VII, IX and X Activated (i.e. Feiba ) or inactivated (i.e. Profilnine, Kcentra ) Effectiveness unknown, limited data, theoretical speculation, cost $$$ Tranexamic acid given with PCC (does not work alone) Hemodynamic stability: packed red blood cells (RBCs) and/or platelet concentrates in thrombocytopenia Other: fresh frozen plasma (FFP), cryoprecipitate, and recombinant factor VIIa should not be utilized as will not reverse anticoagulation Conversion Between DOACs and Crowther MA, Warkentin TE. J Thromb Haemost. Jul 2009;7 Suppl 1:

7 Dabigatran Apixaban to Dabigatran Stop warfarin and start dabigatran when INR <2 to Apixaban Stop warfarin and start apixaban when INR <2 Dabigatran to CrCl >50 ml/min: Start warfarin and stop dabigatran 3 days later Apixaban to Start warfarin and stop apixaban 3 days later OR CrCl ml/min: Start warfarin and stop dabigatran 2 days later CrCl ml/min: Start warfarin and stop dabigatran 1 day later Stop apixaban and start parenteral anticoagulant and warfarin at the time the next dose of apixaban would be due. Stop parenteral anticoagulant when INR is therapeutic Pradaxa Package Insert: Eliquis Package Insert: Rivaroxaban Edoxaban to Rivaroxaban Rivaroxaban to Stop warfarin and start rivaroxaban when INR<3 Start warfarin and stop rivaroxaban 3 days later OR Stop rivaroxaban and start a parenteral anticoagulant and warfarin at the time the next rivaroxaban dose would be due. Stop parenteral anticoagulant when INR is therapeutic to Edoxaban Stop warfarin and start edoxaban when INR <2.5 Edoxaban to Reduce edoxaban dose by 50% and begin warfarin concomitantly. Stop edoxaban when INR is stabilized above 2.0 OR Stop edoxaban and start a parenteral anticoagulant and warfarin at the time the next dose of edoxaban would be due. Stop parenteral anticoagulant when INR is therapeutic Xarelto Package Insert: Savaysa Package Insert: DOACs vs. for A-Fib: Efficacy and Safety Drug: Study Primary Efficacy (stroke or systemic embolism) Major Bleeding Comparisons Dabigatran: RE-LY Dabigatran Superior Non-Significant Apixaban: ARISTOTLE Apixaban Superior Apixaban Significantly Less Edoxaban: ENGAGE AF-TIMI Edoxaban Non-Inferior Edoxaban Significantly Less Rivaroxaban: ROCKET-AF Rivaroxaban Non-Inferior Non-Significant 7

8 A-Fib Dosing for DOACs DOACs vs. for VTE: Efficacy and Safety Dosing Dabigatran Apixaban Edoxaban Rivaroxaban Renal Elimination 80% 27% 50% 66% Drug: Study Primary Efficacy Major Bleeding (VTE Recurrence) Dabigatran: RE-COVER Non-Inferior Non-Significant Normal A-Fib Dosing 150 mg BID 5 mg BID 60 mg daily 20 mg daily with evening meal Apixaban: AMPLIFY Non-Inferior Apixaban Significantly Less Renal A-Fib Dosing CrCl mg BID 2.5 mg BID if 2 of the following: Age 80 Weight 60 kg SCr 1.5 CrCl mg daily Avoid CrCl < 15 or > 95 CrCl mg daily with evening meal Edoxaban: Hokusai-VTE Non-Inferior Edoxaban Significantly Less Rivaroxaban: Non-Inferior Non-Significant EINSTEIN-DVT and EINSTEIN-PE VTE Dosing for DOACs VTE Post-op Prevention Dosing for DOACs VTE Treatment Dabigatran Apixaban Edoxaban Rivaroxaban Normal Dose 150 mg BID after 5-10 days of parenteral anticoagulation 10 mg BID x 7 days then 5 mg BID 60 mg daily after 5-10 days of parenteral anticoagulation 15 mg BID x 21 days then 20 mg daily VTE Prevention TKR or THR Normal Dose Knee Replacement Dabigatran Apixaban Rivaroxaban Not Approved 2.5 mg BID x 12 days 10 mg daily x 12 days Other Dosing 75 mg BID if on P-gp inhibitor and CrCl Renal Dosing CrCl < 30 Do Not Use 2.5 mg BID after 6 months CrCl < 25 Not studied- Do Not Use 30 mg daily if: 60 kg OR On certain P-gp inhibitors CrCl mg daily 20 mg daily for long-term prevention CrCl< 30 Do Not Use Normal Dose Hip Replacement 110 mg day 1 then 220 mg daily x days Renal Dosing CrCl < 30 DO Not Use 2.5 mg BID x 35 days 10 mg daily x 35 days CrCl < 30 CrCl 30-50: Not Studied Do Not Use with caution CrCl < 30 DO Not Use Pricing Comparison Take Home Points Brand Name Generic Name Strength Quantity Retail Cash Price Eliquis Apixaban 10 mg #60 $ Xarelto Rivaroxaban 20 mg #60 $ Savaysa Edoxaban 60 mg #30 $ Pradaxa Dabigatran 150 mg #60 $ mg #30 $31.77 Assess kidney function prior to initiation of and periodically thereafter Caution with CrCl < 30 ml/min Dabigatran has significant GI upset Rivaroxaban and Apixaban can be used as initial therapy for DVT or PE without having to give either enoxaparin or heparin first Useful for outpatient therapy Patient adherence with therapy is key! Anticoagulation wears off within hours after a missed dose Not indicated for patients with heart valves at this time 8

9 References References January CT, Wann LS, Alpert JS et al AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation. Circulation. 2014;130: Kearon C, Akle EA, Ornelas J et al. Antithrombic therapy for VTE disease chest guideline and expert panel report. CHEST 2016;149(2): Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12): Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22): Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7): Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9): Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15): Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26): Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14): Alberts MJ, Eikelboom JW, Hankey GJ. Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation. Lancet Neurology. 2012;11: Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012;119: Dabigatran In: DRUGDEX SYSTEM (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 10/19/2017) Apixaban In: DRUGDEX SYSTEM (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 10/19/2017) Rivaroxaban In: DRUGDEX SYSTEM (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 10/19/2017) Edoxaban In: DRUGDEX SYSTEM (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: (cited: 10/19/2017) Reilly PA, Lehr T, Haertter S et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial. J Am Coll Cardiol 2014 Feb 4;63(4):