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Management of Direct Oral Anticoagulants
Teresa Kwong, Pharm.D, BCPS, BCACP University of California Davis Health System
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Objectives Review considerations when initiating Direct Oral Anticoagulants (DOACs) Discuss chronic management issues related to DOACs Describe issues that arise during transitions of care Describe how DOACs are managed at UCD
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Timeline of Anticoagulation
Heparin 1930s Warfarin 1940s LMWH 1980s Direct Thrombin Inhibitors 1990s Indirect Xa Inhibitors Direct Oral Xa Inhibitors 2008
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DOACs on the Market Direct Thrombin Inhibitor
Dabigatran (Pradaxa®, 2010) Factor Xa Inhibitor Rivaroxaban (Xarelto®, 2011) Apixaban (Eliquis®, 2012) Edoxaban (Savaysa®, 2015) 1) Designed to be easier to use than warfarin 2) marketed as needing less monitoring, appealing, fixed dosing,
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Background July 2017 ISMP Medication Safety Alert (Institute for Safe Medication Practices)
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Background Anticoagulants accounted for 17% of all ED visits for outpatient ADEs Between 2005 and 2014 anticoagulant-related ED visits increased 2-fold July 2017 ISMP Medication Safety Alert (Institute for Safe Medication Practices) ISMP Institute for Safe Medication Practices Safety Alert Acute Care, July 27, 2017, Volume 22, Issue 15
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Initiating Treatment Is the patient an appropriate candidate?
What dose? Are there any interacting drugs? Is the patient transitioning from another anticoagulant? Renal, hepatic, HIV, elderly
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Initiating Treatment Is the patient an appropriate candidate?
Renal dysfunction Hepatic dysfunction Valvular disease Cancer patients Elderly Compliance HIV, elderly, complicance: bid, no monitoring
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Initiating Treatment Is the patient an appropriate candidate?
What dose? Various dosing schemes. Different doses for different indications, renal dysfunction U of Michigan 129 patients, 93% dosed correctly vs 79.1
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Dabigatran (Pradaxa®)
Indication/Dose Dose Adjustments NVAF: 150 mg BID VTE Treatment: 150 mg BID (preceded by 5-10 days of parenteral therapy) VTE Prophylaxis: 150mg BID Post-op VTE Prophylaxis: 220 mg daily (110 mg x1 if POD #0) CrCl P-gp inhibitor – 75 mg PO BID CrCl – 75mg BID; avoid use if on P-gp inhibitor CrCl <15 – no dosing recommendations VTE Treatment & Prophylaxis: CrCl < 50 + P-gp inhibitor – avoid use CrCl < 30 – no dosing recommendations Avoid use in severe hepatic impairment Avoid use with P-gp Inducers Various Dosing Schemes Insert chart about dosing Xarelto Starter pack NVAF: CrCl <30 excluded in RELY
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Apixaban (Eliquis®) Various Dosing Schemes Insert chart about dosing
Indication/Dose Dose Adjustments NVAF: 5 mg BID VTE Treatment: 10 mg BID for 7 days, then 5 mg BID VTE Prophylaxis: 2.5mg BID Post-op VTE Prophylaxis: 2.5 mg BID If 2 out of 3 criteria (age ≥ 80, wt ≤ 60 kg, SCr ≥ 1.5) – 2.5 mg PO BID ESRD on HD – 5 mg PO BID, or 2.5 mg BID if age ≥ 80 or wt ≤ 60 kg CrCl < 25 or SCr ≥ 2.5 – no dosing recommendations CrCl < 30 – no dosing recommendations Avoid in severe hepatic impairment Strong dual inducers of P-gp and CYP3A4 – avoid concomitant use Strong dual inhibitors of P-gp and CYP3A4 – 2.5mg BID Various Dosing Schemes Insert chart about dosing Xarelto Starter pack Crcl <25 or SCr >2.5 excluded from aristotle
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Rivaroxaban (Xarelto®)
Indication/Dose Dose Adjustments NVAF: 20 mg daily with a meal VTE Treatment: 15 mg BID with food for 21 days, then 20 mg daily with a meal VTE Prophylaxis: 20mg daily with a meal Post-op VTE Prophylaxis: 10 mg daily CrCl – 15 mg daily CrCl < 15 – avoid use VTE Treatment/Prophylaxis: CrCl < 30 – avoid use CrCl – use with caution Avoid use in moderate or severe hepatic impairment Avoid use with combined P-gp/CYP3A4 inhibitors/inducers Various Dosing Schemes Insert chart about dosing Xarelto Starter pack CrCl <30 excluded from ROCKET-AF & EINSTEIN
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Edoxaban (Savaysa®) Various Dosing Schemes Insert chart about dosing
Indication/Dose Dose Adjustments NVAF: 60 mg daily VTE Treatment: 60 mg daily (preceded by 5-10 days of parenteral therapy) Not yet labeled for post-op VTE prophylaxis CrCl > 95 – avoid use CrCl – 30 mg daily CrCl < 15 – avoid use CrCl – 30 mg daily Wt ≤ 60 kg – 30 mg daily Avoid in moderate or severe hepatic impairment Avoid use with P-gp Inducers Concomitant use with P-gp inhibitors: 30mg daily Various Dosing Schemes Insert chart about dosing Xarelto Starter pack Parenteral therapy used in vte treatment (hokusai trial) because it is gold standard to lead with parenteral therapy – vte treatment preceded with parenteral therapy b/c this is how it was studied.; NVAF >95 increased risk of ischemic stroke compared to warfarin
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Initiating Treatment Is the patient an appropriate candidate?
What dose? Are there any interacting drugs? Renal, hepatic, HIV, elderly
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Initiating Treatment University of Washington Anticoagulation website. (1) based on human data, from Hansten PD and Hom JR. The Top Drug Interactions: A Guide to Patient Management, 2014 ed, H&H Publications, Freeland WA 2014.
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Initiating Treatment Is the patient an appropriate candidate?
What dose? Are there any interacting drugs? Is the patient transitioning from another anticoagulant? Renal, hepatic, HIV, elderly
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Transitioning from Warfarin to DOAC
Stop warfarin and start rivaroxaban when INR < 3.0 Rivaroxaban Stop warfarin and start edoxaban when INR < 2.5 Edoxaban Stop warfarin and start dabigatran/apixaban when INR < 2.0 Dabigatran Apixaban
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Transitioning from DOAC to Warfarin
Start warfarin and overlap with dabigatran; CrCl > 50 mL/min, overlap 3 days CrCl mL/min, overlap 2 days CrCl mL/min, overlap 1 day Dabigatran Stop DOAC; start warfarin and LMWH at time of next scheduled dose and bridge until INR >2.0 Rivaroxaban Apixaban For 60mg dose, reduce dose to 30mg and start warfarin concomitantly For 30mg dose reduce dose to 15mg and start warfarin concomitantly Stop edoxaban when INR >2.0 Edoxaban
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Chronic Management Issues
Cost Lab Follow Up Continuous patient education
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Chronic Management Issues
Cost Manufacturer coupons available Patient Assistance Programs Medicare Part D coverage gap Xarelto – free 30 day, $0 copay ($3400), Eliquis – free 30 day, $10 copay ($3800), Savaysa $4/month (as little as), Pradaxa $0/($2400)
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Chronic Management Issues
Cost Lab Follow Up Marketed as “no labs needed” Serum creatinine and CBC
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Chronic Management Issues
Cost Lab Follow Up Continuous patient education Adverse reactions Medication changes Compliance Periprocedural management Interacting drugs and other blood thinners
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Periprocedural Management
Shorter half life vs warfarin Idarucizumab (Praxbind), andexanet alfa (factor xa decoy, RAELWMH), ciraparantag (universal antidote) Kcentra (PCC), Feiba (Factors II, IX, X
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Chronic Management Issues
Cost Lab Follow Up Continuous patient education
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Transitioning Care Cost after discharge Provider follow up
Patient Education
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UC Davis Anticoagulation Services
Outpatient Anticoagulation Clinic Thrombosis Clinic Inpatient CLOT service Transitions of Care service Emergency Department Pharmacists
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DOAC Management at UCD Is the patient an appropriate candidate?
What dose? Are there any interacting drugs? Is the patient transitioning from another anticoagulant? Cost Lab Follow Up Continuous patient education Renal, hepatic, HIV, elderly
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Resources Utilized at UCD
Anticoagulation Website Patient educational handouts Best Practice Alerts Anticoagulation Specialists
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Ongoing Issues at UCD How often should the clinic be in contact?
Should the Anticoagulation Clinic monitor all patients on DOACs? Time spent with DOAC patients Initial education: min Initial Dosing adjustments: 15 min Insurance issues: min Follow ups: 5-45 min Follow ups : fill histories, adjustment for labs, procedures, insurance issues.
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Recap Consider patient characteristics when initiating a DOAC
DOAC patients need monitoring throughout therapy Consider costs and long term management when transitioning from hospital/ED to outpatient Offer providers resources to assist with prescribing and monitoring DOACs
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Discussion Questions Do your providers currently have resources to assist with DOAC management? Is there process during transitions of care to ensure patients receive the appropriate follow up?
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References ISMP Institute for Safe Medication Practices Safety Alert Acute Care, July 27, 2017, Volume 22, Issue 15 Xarelto [package insert]. Jansen Pharmaceuticals; Revised May Savaysa [package insert]. Daiichi Sankyo; Revised September Pradaxa [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc.; Revised November Eliquis [package insert]. Bristol-Myers Squibb; Revised July UC Davis Health Policies & Procedures. Managing Warfarin in the UCDMC Adult Anticoagulation (AC) Clinic. Policy ID: IV-79 Ashjian E, Kurtz B, et al. Evaluation of a pharmacist-led outpatient direct oral anticoagulant service. American Journal of Health-System Pharmacy April 2017, 74 (7)
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Appendix
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Appendix Dabigatran Rivaroxaban Apixaban Edoxaban Target IIa Xa Tmax
1-3 hours 2-4 hours 3-4 hours 1-2 hours T1/2 12-17 hours 5-9 hours 12 hours 10-14 hours Drug interactions P-gp CYP3A4, P-gp Renal Clearance 80% 66% 27% 50% Dialyzable Yes No
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Appendix – VTE trials Dabigatran (RECOVER)
Noninferior for recurrent VTE Reduced major or clinically-relevant non-major bleeding Rivaroxaban (EINSTEIN DVT, PE) Noninferior for recurrent VTE Reduced major bleeding Apixaban (AMPLIFY) Noninferior for recurrent VTE Reduced major or clinically-relevant non-major bleeding Edoxaban (HOKUSAI) Noninferior for recurrent VTE Reduced major or clinically-relevant non-major bleeding Higher GI bleeds with dabigatran Lower ICH and higher GIB with rivaroxaban
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Appendix – Afib Trials Dabigatran (RELY)
Superior for stroke prevention No difference in major bleeding Rivaroxaban (ROCKET-AF) Noninferior for stroke prevention No difference in major bleeding Apixaban (ARISTOTLE) Superior for stroke prevention Reduced major bleeding Edoxaban (ENGAGE) Noninferior for stroke prevention Reduced major bleeding
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