Choosing and Managing Direct Oral Anticoagulants (DOACs) Ana G. Antun, MD, MSc Assistant Professor, Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University 1
Outline Efficacy and safety of DOACs compared to VKA s. Candidates for DOACs High-risk population Drug-drug interaction Measure of DOACs activity Management of DOAC interruption Management of bleeding 2
Site of Action of DOACs Tsakiris DA, et al. Semin Hematol. 2014;51(2):98-101. 3
General Characteristics of DOACs Characteristics Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban Target IIa Xa Xa Xa Xa Pro-drug Yes No No No No Half Life (hrs.) 14-17 7-11 8-14 5-11 37 Route Elimination % Bioavailability Urine ~ 80 Feces ~ 20 ph dependent 6-7% Urine ~ 66 Feces ~ 26 Food dependent 66% Urine ~ 25 Feces ~ 50 Food dependent 50% Urine ~ 35 Feces ~ 60 Food dependent 62% Urine ~ 13 Feces ~ 80 Dosing Twice/day Once/day Twice /day Once/day Once/day Liver CP3A4 No < 2% Yes 57% Minor 25% Minor 35% No < 1% 34% Impact P-glycoprotein Yes Yes Yes Yes Yes Schaefer JK, et al. Ann Hematol. 2016;95(3):437-449. 4
DOACs vs. VKA Efficacy: noninferior Major Bleeding: 40% relative reduction Intracraneal and fatal bleeding: 60% relative reduction CRNM: clinical relevant nonmajor (minor) bleeding: 25% lower relative risk Gastrointestinal bleeding: no significant difference 5
Efficacy: DOACs vs. Warfarin van Es N, et al. Blood. 2014;124(12):1968-1975. 6
Safety: DOACs vs. Warfarin van Es N, et al. Blood. 2014;124(12):1968-1975. 7
Advantages and Disadvantages of DOACs Compared with VKA Advantages Disadvantages No routine monitoring No reliable, readily available measurement assay Improved safety profile Rapid onset (No bridging) Short half-life (advantage for invasive procedures or active bleeding) Fixed dosing Convenience Potential more cost-effective Fewer drug, disease and diet interactions Burnett AE, et al. J Thromb Thrombolysis. 2016;41(1):206-232. Dose reduction or avoidance in renal impairment and moderate or severe hepatic impairment No specific antidote Short half-life (mandates strict adherence) Less flexibility in dosing Fewer studies and approved indications (contraindicated in mechanical valve replacement) Potentially higher drug acquisition costs for patients DOACs drug interaction do exist that may preclude use 8
DOACs: Patient Selection Criteria Criteria for DOAC use Patient preference for and willingness to take DOAC No contraindication to DOAC therapy Adequate organ function No significant drug-drug interaction No significant disease state interaction Highly likely to be adherent to DOAC and follow up plan Confirmed ability to obtain DOAC from financial, insurance coverage stand point Comments Offer all therapeutic options with their respective advantages and disadvantages Pregnancy, breast feeding, mechanical valve Monitor renal function, age, concomitant use of p-gp/cyp3a4 inhibition Antiplatelet agents or NSAIDs History of GI bleed or at risk: warfarin, Apixaban or Edoxaban Drug cost vs generic warfarin + monitoring Assistance programs available Burnett AE, et al. J Thromb Thrombolysis. 2016;41(1):206-232. 9
Practical Management of DOACs in VTE Patient adherence assessment when choosing anticoagulant therapy Taking medication Laboratory monitoring Health care responsibility How often does the patient miss or forget to take doses of meds? If warfarin patient misses doses, switching to a shorter ½ life may predispose to the risk of thrombosis Sub-therapeutic INR is reliable indicator of doses have been missed Without lab monitoring, there is no opportunity to improve adherence Is once or twice daily dosing preferred? If patient is adherent to other twice daily med then DOAC is appropriate If patient prefers once daily meds then rivaroxaban or edoxaban Is Laboratory access difficult? Transportation challenges, difficult venous access, inflexible work or school schedule for difficulty complying with INR Annual renal function and complete blood count Is the patient reliable to notify provider about changes to health? Periprocedure anticoagulation plans Addressing medication interaction Unreliable patients to report issues may be better suited for warfarin 10
Special Populations To Avoid Pregnancy: category C Apixaban: category B (fetal exposure expected based on animal studies) Age: Avoid Dabigatran in patients > 75 years Extreme Weight < 50Kg > 120 Kg or BMI > 35 Kg/m2 Renal and hepatic insufficiency 11
Renal Adjustment Dose Adjustment Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban CrCl < 30 ml/min AVOID AVOID No adjustment 50% dose reduction 50% dose reduction CrCl < 15 ml/min Single dose post HD AVOID AVOID 12
Drug to Drug Interaction P-Glycoprotein CYP3A4 Inhibitors Carvedilol Clarithromycin Cyclosporine Erythromycin Azoles Tacrolimus Tamoxifen Grapefruit juice Azoles Grapefruit juice Protease inhibitors Inducers Dexamethasone Rifampin Phenytoin Carbamazepine St. John s Wort Phenytoin 13
Hepatic Adjustment Dose Adjustment Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban P-gp inducer AVOID AVOID P-gp inhibitor AVOID if CrCl < 50 50% dose reduction 50% dose reduction CYP3A4 and P-gp inhibitor AVOID 50% dose reduction CYP3A4 and P-gp inducer AVOID AVOID Child-Pugh B AVOID Caution Caution AVOID Child-Pugh C AVOID AVOID AVOID AVOID 14
Special VTE Populations To Avoid Thrombophilia: Antiphospholipid syndrome (APS) Heparin induced thrombocytopenia (HIT) Cancer-associated thrombosis History of bleeding VTE despite therapeutic INR Need for thrombolysis Massive PE hemodynamically compromise Venous gangrene and threatened limb loss 15
Antiphospholipid Syndrome and VTE The Rivaroxaban in AntiPhospholipid Syndrome (RAPS) study: APLS with previous VTE on warfarin for 6 months Primary end point: endogenous thrombin potential: NOT reach noninferiority No recurrent thrombosis in 6 months. (Son M, et al. Thromb Res. 2015;135(5):1-35-1036.) The Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS) study (https://clinnct02157272) (to be completed 12/2018) The Rivaroxaban in Antiphospholipid Syndrome Pilot Study. (completed 12/2016) 16
Heparin Induced Thrombocytopenia DOACs for treatment of HIT as a primary or secondary therapy (non- DOAC transitioned to DOAC) Primary Endpoint: thrombosis during acute HIT: Rivaroxaban: None of 10 Hamilton patients and 2.2% (1/46) literature review Apixaban: 0/12 Dabigatran: 0/11 No bleeding Warkentin ET, et al. Blood. 2017 T. Warkentin Winship et al. Cancer Blood Institute June 2017 Emory University 17
Cancer-Associated VTE Known Concerns Need 20 % all VTE related to cancer Increase risk of recurrent VTE Higher risk of major bleeding Current guidelines: LMWH over VKA LMWH burdensome LMWH easier to manage on chemotx Indefinite anticoagulation DOACs: Simple oral regimen No monitoring attractive alternative DOACs no direct comparison with LMWH Drug to drug interaction with antineoplastic agents Gastrointestinal absorption of DOACs in vomiting or chemoinduced intestinal mucosal defect 1500 cancer patients provide guidance for those that LMWH is not an option. Favorable cancer prognosis Limited life expectancy excluded Absolute recurrent VTE rate 5.9% post 6 months treatment How to manage during active chemotherapy? HEAD TO HEAD COMPARISON WITH LMWH Outcome: recurrence and bleeding 18
Cancer-Associated VTE Name Description Completion CANVAS (NCT02744092) Rivaroxaban Prophylaxis in ambulatory cancer (NCT02555878) Rivaroxaban in the treatment of VTE in cancer PRIORITY (NCT03139487) DOACs vs LMWH+/- warfarin in VTE patients Phase III: Rivaroxaban vs. Placebo in ambulatory cancer patient on therapy Phase III: Rivaroxaban vs. LMWH (NCT02583191) Phase II: Safety and Efficacy of Dalteparin vs. Rivaroxaban in cancer associated VTE 9/2019 VTE recurrence 7/2018 (Emory) recurrence 3/2018 Enoxaparin Dalteparin Tinzaparin 5/2020 Bleeding upper GI, hepatobiliar pancreatic 19
Cancer-Associated VTE Name Description Completion AVERT (NCT02048865) CARAVAGGIO (NCT03045406) Apixaban or Dalteparin reducing VTE in cancer Apixaban vs. Placebo for the Prevention of VTE in cancer Phase III: Apixaban vs. Dalteparin for Treatment cancer associated VTE Phase III: Apixaban vs. Dalteparin (NCT02585713) 12/2019 Prevention 6/2019 recurrence 11/2018 Bleeding MYELAXAT Apixaban in prevention of VTE in MM treated with imids Completed For 6 months Cancer VTE (NCT02073682) Phase IV: Endoxaban vs. Dalteparin Completed (Emory) recurrence and bleeding 20
Switching to/from DOACs Switching from Dabigatran Rivaroxaban Apixaban Edoxaban WARFARIN INR < 2.0 INR < 3.0 INR < 2.0 INR < 2.5 LMWH UFH Switching from DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Start within 0-2 hours of the time of next scheduled dose of LMWH Start immediately after stopping UFH To Warfarin Start warfarin and overlap with dabigatran CrCl 50 ml/min, overlap 3 days CrCl 30-50 ml/min, overlap 2 days CrCl 15-30 ml/min, overlap 1 day Start 4 hours after stop UFH Start warfarin and LMWH at the time of next scheduled DOAC dose and bridge until INR 2 For 60 mg dose, reduce to 30 mg and start warfarin For 30 mg dose, reduce dose to 15 mg and start warfarin Stop Edoxaban when INR 2 Nick van Es et al. Winship Blood 2014;124:1968 Cancer Institute Emory University 21
Potential Indication for DOACs Measurement Detection of clinically RELEVANT levels Urgent or emergent invasive procedure Detection of EXPECTED on-therapy levels Assessing adherence Detection of EXCESSIVE levels Hemorrhage Neuraxial anesthesia Breakthrough thrombosis Changes in renal function Major trauma Potential thrombolysis in acute VTE Hemorrhage Hepatic impairment Accidental or intended overdose Drug interactions Advanced age 22
Suggested laboratory measurements of DOACs Drug Clinically relevant drug levels Clinical objective Estimate drug levels on therapy Excessive drug level Dabigatran Anti-Xa inhibitors: Rivaroxaban Apixaban Edoxaban Betrixaban TT: normal levels likely excludes relevant drug levels Anti-Xa: normal likely excludes relevant drug levels Dilute TT, ECA, ECT Anti-Xa Assays should be calibrated for specific drugs based on anti-xa assay Dabigatran: based on dilute thrombin time Normal aptt, excludes excess drug Diluted TT, ECA, ECT can quantitate Anti-Xa and PT Normal PT likely excludes excess drug levels Anti-Xa suitable for quantitation 23
DOACs Eligibility Good Candidates VTE not requiring thrombolysis Adequate liver Function: Childs-Pugh A-B No significant drug interactions In cancer-associated VTE if refuse LMWH Caution GI bleed CKD Elderly Poor compliance CYP3A4 interaction Agents to use Apixaban-Edoxaban Apixaban-Betrixaban Anti-Xa Rivaroxaban-Edoxaban-Betrixaban Dabigatran 24
DOACs Eligibility Not Candidates VTE requiring thrombolysis or hemodynamic compromise End Stage Renal disease and dialysis Inadequate liver Function: C Antiphospholipid syndrome Cancer-associated VTE VTE despite therapeutic warfarin Bleeding 25
Invasive Procedures Cessation in hours (doses to held) ClCr ml/min Low Bleeding Risk Dabigatran High Bleeding Risk Apixaban/Rivaroxaban /Edoxaban Low Bleeding Risk High Bleeding Risk Resumption Low Bleeding Risk High Bleeding Risk > 80 ~ 24 (2) ~ 48 (4) ~ 12-24 (1-2) ~ 48 (2-4) 50-80 ~ 36 (3) ~ 72 (6) 30-50 ~ 72 (6) ~ 96 (8) ~ 12-24 (1-2) ~ 24-36 (1-4) ~ 48 (2-4) ~ 48 (2-4) ~ 24 hours post-op ~ 48-72 hours post-op 15-30 Not indicated ~ 38-48 (2-4) ~ 72 (3-6) Burnett AE, et al. J Thromb Thrombolysis. 2016;41(1):206-232. 26
DOACs-Related Bleeding Management Risk Stratification Mild Bleeding Moderate Bleeding Severe/life-threatening Local hemostatic measures: Consider anticoagulant withdrawal (balance thrombotic and bleeding risk) General measures: Hold anticoagulant Mechanic compression Monitor hemodynamic status Volume replacement Definite interventions Blood products: RBC transfusion Plasma Platelets: on antiplatelet agents General measures and Blood products Intensive care Hemodynamic support Consider o 4-factor PCC (50 IU/Kg) o Activated PCC (80 IU/Kg) Adjuvant Therapies Charcoal Hemodialysis for Dabigatran removal Desmopressin Antifibrinolytic 27
DOACs and Bleeding Management Time since last dose < 4 hours 4-36 hours > 36 hours, < 48 hours with renal failure Activated charcoal Reversed immediately No Assess activity Yes Targeted Reversal Agent Prolonged aptt: Dabigatran is present contributing to bleeding Prolonged PT: Anti-Xa present Available Not Available Active DOAC Uncontrolled bleeding No or low activity Continue resuscitation Idarucizumab for Dabigatran Adnexanet alfa for anti-xa (pending approval) Activated PCC (thrombosis) 28
Summary DOACs are a significant advance in VTE treatment Offer treatment options, convenience, similar efficacy with better safety than convention therapy DOACs are suitable treatment option for a broad spectrum of patient but caution should be taken in extreme ages and weights 29
Summary Whether can safely be used in high-risk populations (cancerrelated, APS, HIT) is not proven. Use should be limited in this population Several reversal strategies are under evaluation and specific antidotes are being developed, but most interventions need further evaluation. 30
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