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Practical Aspects Of Using Direct Oral Anticoagulants

Objectives y Identify appropriate use and dosing for different direct oral anticoagulants y Describe use of direct oral anticoagulants in specific patient populations y Describe peri-procedural management and reversal of direct

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Text of Practical Aspects Of Using Direct Oral Anticoagulants

Adele Robbins, PharmD, BCPS Clinical Pharmacy Specialist Cardiology & Anticoagulation Emory University Hospital Atlanta, GA Practical Aspects Of Using Direct Oral Anticoagulants Disclosures I have no conflicts of interest Objectives Identify appropriate use and dosing for different direct oral anticoagulants Describe use of direct oral anticoagulants in specific patient populations Describe peri-procedural management and reversal of direct oral anticoagulants History of Oral Anticoagulants 1948 Warfarin commercially available as rat poison 1954 Warfarin approved by FDA for medical use in humans 1978 Mechanism of warfarin discovered 2004 Ximelagatran reject by the FDA for hepatotoxicity 2009 Dabigatran FDA Approved Coagulation Cascade Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin Vitamin K Antagonist inhibiting Factors II, VII, IX and X Mainstay of therapy for over 60 years Dose varies but usually adjusted to target INR goal 2-3 Disadvantages: monitoring drug-drug interactions drug-food interactions long onset and offset of action inter-individual variation What s in a name? New (or Novel) Oral Anticoagulants Non Vitamin K Oral Anticoagulants (NOACs) Target Specific Oral Anticoagulants (TSOACs) Direct Oral Anticoagulants (DOACs) Pharmacokinetics/Pharmacodynamics Dabigatran Rivaroxaban Apixaban Edoxaban Bioavailability 3-7% 80-100% 50% 62% Metabolism Hepatic (gluceronidation) Hepatic (CYP3A4/5) Hepatic (CYP3A4/5) P-glycoprotein substrate Hepatic (CYP3A4) Renal Excretion 80% 36% 27% 50% Half Life 12-17 hours 5-9 hours 12 hours 10-14 hours Drug Interactions P-gp inhibitors Strong 3A4 inhibitors P-gp inhibitors & strong 3A4 inhibitors Strong3A4 inhibitors P-glycoprotein Inhibitors: ketoconazole, cyclosporine, quinidine, verapamil Strong 3A4 Inhibitors: amiodarone, ketoconazole, fluoxetine, erythromycin Clin Pharmacokinet 2009; 48 (1): 1-22 DOACs have been studied for: Prevention of thromboembolic complications in atrial fibrillation Acute treatment of venous thromboembolism Venous thromboembolism prophylaxis after orthopedic surgery Venous thromboembolism prophylaxis in medically ill patients Treatment of acute coronary syndromes Direct Oral Anticoagulants for Non-valvular Atrial Fibrillation Dabigatran (Pradaxa ) October 19, 2010 - FDA approved for the prevention of stroke in patients with non-valvular atrial fibrillation RE-LY Trial Interventions: Dabigatran 110 mg twice daily Dabigatran 150 mg twice daily Open label warfarin adjusted to INR goal 2-3 Concomitant use of aspirin (< 100 mg/day) and other antiplatelet agents were permitted NEJM 2009;361:1139-51. RE-LY Trial Primary Outcomes: Efficacy: Stroke or Systemic Embolism Safety: Major Hemorrhage Major Hemorrhage: reduction in Hgb < 20 g/L, transfusion 2 units of blood, or symptomatic bleeding in a critical area NEJM 2009;361:1139-51. RE-LY Trial NEJM 2009;361:1139-51. RE-LY Trial NEJM 2009;361:1139-51. RE-LY Trial Discussion Side Effects: Dyspepsia (150 mg , warfarin ) Higher rate of discontinuation with dabigatran Higher incidence of AMI with dabigatran Authors conclusion Dabigatran 150 mg BID was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage as compared to warfarin NEJM 2009;361:1139-51. Rivaroxaban (Xarelto ) November 4, 2011 FDA approved for prevention of stroke in patients with non-valvular atrial fibrillation ROCKET AF Trial Intervention Rivaroxaban 20 mg daily 15 mg daily if CrCl 30-49 ml/min Dose-adjusted warfarin to INR goal 2-3 Concomitant use of aspirin < 100 mg daily was permitted as well as monotherapy with thienopyridines NEJM 2011; 365:883-91. ROCKET AF Trial Primary Outcomes: Efficacy: Composite of stroke and systemic embolism Safety: Composite of major and non-major clinical bleeding Major bleeding: clinically overt bleeding associated with a fatal outcome, critical site/organ, fall in Hgb 2 g/dL, transfusion of 2 units of blood or permanent disability Non-major clinically relevant bleeding: clinically overt bleeding that dose not meet criteria for major bleeding but requires medical intervention or attention NEJM 2011; 365:883-91. ROCKET AF Trial NEJM 2011; 365:883-91. ROCKET AF Trial NEJM 2011; 365:883-91. ROCKET AF Trial Discussion Higher rate of discontinuation than other trials (~14%) Trend towards higher event rates after discontinuation of rivaroxaban ~35% of patients were also taking aspirin Authors Conclusions Rivaroxaban is non-inferior to warfarin in the prevention of stroke or systemic embolism in patients with atrial fibrillation NEJM 2011; 365:883-91. Apixaban (Eliquis ) December 28, 2013 FDA approved for the prevention of stroke in patients with non-valvular atrial fibrillation ARISTOTLE Trial Intervention Apixaban 5 mg BID mg BID if 2 of the following: age 80, weight < 60 kg, and SCr Dose adjusted warfarin to INR goal 2-3 Concomitant use of aspirin < 165 mg was permitted as well as monotherapy with thienopyrodines NEJM 2011; 365:981-92. ARISTOTLE Trial Primary Outcomes: Efficacy: stroke or systemic embolism Safety: Major bleeding NEJM 2011; 365:981-92. ARISTOTLE Trial NEJM 2011; 365:981-92. ARISTOTLE Trial NEJM 2011; 365:981-92. ARISTOTLE Trial Discussion Rate of discontinuation was lower for apixaban than warfarin of patient in apixaban group received reduce dose ~31% of patients also took aspirin Authors Conclusion Apixaban reduced the rate of stroke or systemic embolism, caused less bleeding and resulted in lower mortality as compared to warfarin in patients with non-valvular atrial fibrillaiton NEJM 2011; 365:981-92. Edoxaban (Savaysa ) January 8, 2015 FDA approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation ENGAGE AF TIMI 48 Trial Intervention Edoxaban 30 mg daily Edoxaban 60 mg daily Dose adjusted warfarin to INR goal 2-3 Edoxaban dose was cut in half in either group if a patient had CrCl 30-50 ml/min, weight 60 kg, or concomitant use of verapamil, dronedarone, or quinidine NEJM 2013; 369:2093-104. ENGAGE AF TIMI 48 Trial Primary Outcomes: Efficacy: time to first stroke or systemic embolic event Safety: major bleeding during treatment NEJM 2013; 369:2093-104. ENGAGE AF TIMI 48 Trial NEJM 2013; 369:2093-104. ENGAGE AF TIMI 48 Trial NEJM 2013; 369:2093-104. ENGAGE AF TIMI 48 Trial Discussion No difference in rate of MI ~25% of patients received reduced dose ~29% of patient also took aspirin; thienopyridine Authors Conclusion Both doses of edoxaban were non-inferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation and were associated with lower rates of bleeding and death from cardiovascular causes NEJM 2013; 369:2093-104. DOACs for AFib Dabigatran Rivaroxaban Apixaban Edoxaban Usual dose for AFib 150 mg BID 20 mg daily 5 mg BID 60 mg daily Alternative dosing Yes (not studied) 75 mg BID for CrCl 15 - 30 ml/min Yes -15 mg daily for CrCl < 50 ml/min Yes - mg BID if 2 or more of the following: age 80 yr, wt 60 kg or SCr Yes (not for CrCl > 95 ml/min) - 30 mg daily for CrCl 15-50 ml/min Avg CHADS2 TTR 64% 55% Major Bleeding Similar Similar Reduced Reduced GI Bleed Increased Increased Similar Similar Direct Oral Anticoagulants for Venous Thromboembolism Dabigatran (Pradaxa ) April 7, 2014 - FDA approved for treatment of venous thromboembolism RE-COVER Trial Treatment Dabigatran 150 mg BID (n = 1273) Wafarin (n = 1266) Primary Endpoint: Recurrent VTE or VTE related death Dabigatran ( ) vs Warfarin ( ), HR (p < ) Safety Endpoint: Major bleeding Dabigatran ( ) vs Warfarin ( ), HR NEJM 2009;361:2342-52. RE-COVER Trial Discussion Dabigatran had higher rates of GI bleeding 3% dyspepsia with dabigatran Initial parenteral anticoagulant therapy ~9 days Authors Conclusion Dabigatran was just as effective and safe as warfarin in the treatment of acute venous thromboembolism NEJM 2009;361:2342-52. Rivaroxaban (Xarelto ) November 2, 2012 FDA approved for the treatment of venous thromboembolism EINSTEIN Trial Treatment: Rivaroxaban 15 mg BID x21 days, followed by 20 mg qDay (n = 1718) Enoxaparin-VKA (n = 1705) Primary Endpoint: Recurrent VTE: Rivaroxaban ( ) vs Warfarin ( ), p < Safety Endpoint: Major bleeding or clinically relevant non-major bleeding Rivaroxaban ( ) vs Warfarin ( ), p = NEJM 2010;363:2499510. EINSTEIN Trial Discussion Open label Parenteral anticoagulant < 48 hours Author s Conclusion Rivaroxaban was noninferior to enoxaparin-warfarin for the treatment of venous thromboembolism NEJM 2010;363:2499510. Apixaban (Eliquis ) August 21, 2014 - FDA approved for the treatment of acute venous thromboembolism AMPLIFY Trial Treatment Apixaban 10 mg BID x 7 days, followed by 5 mg BID (n = 2691) Enoxaparin-warfarin (n = 2704) Primary Endpoint: Recurrent VTE Apixaban ( ) vs warfarin ( ), p < Safety Endpoint: Major bleeding Apixaban ( ) vs warfarin ( ), p < NEJM 2013;369:799-808. AMPLIFY Trial Discussion Parenteral anticoagulation for < 48 hours Authors Conclusions Apixaban in noninferior to conventional therapy for treatment of acute venous thromboembolism NEJM 2013;369:799-808. Edoxaban (Savaysa ) January 8, 2015 FDA approved for treatment of acute venous thromboembolism Hokusai VTE Trial Treatment Edoxaban 60 mg qDay (n = 4118) 30 mg qDay for CrCl 30-50 ml/min or weight < 60 kg Enoxaparin-warfarin (n = 4122) Primary Endpoint: Recurrent VTE Edoxaban ( ) vs Warfarin ( ), HR (p < ) Safety Endpoint: Major or clinically relevant non-major bleeding Edoxaban ( ) vs Warfarin ( ), HR (p = ) NEJM 2013;369:1406-15. Hokusai VTE Trial Discussion Enrolled higher risk patients including PE with right ventricular dysfunction Initial parenteral anticoagulant therapy Authors Conclusions Edoxaban was noninferior to warfarin therapy for the treatment of VTE and caused less bleeding NEJM 2013;369:1406-15. DOACs for VTE Dabigatran Rivaroxaban Apixaban Edoxaban Usual dose for VTE 150 mg BID 15 mg BID x21 days, then 20 mg daily 10 mg BID x 7 days, then 5 mg BID 60 mg daily Initial Parenteral Anticoagulant Necessary Yes No No Yes Cancer Patients ~5% % TTR 60% 58% Not reported Recurrent VTE Similar Reduced Similar Similar Bleeding Similar Similar Reduced Reduced Other Indications VTE Prophylaxis After Orthopedic Surgery NOT FDA approved for ACS or VTE prophylaxis in medically ill patients Bleeding outweighed benefit Dabigatran Rivaroxaban Apixaban Hip replacement: 220 mg daily for up to 35 days Hip replacement: 10 mg daily for up to 35 days Knee replacement: 10 mg daily for 12 days Hip replacement: mg BID for 35 days Knee replacement: mg BID for 12 days Practical Considerations Specific Populations Peri-procedural management Monitoring and Reversibility Special Populations to Consider Renal Impairment Obesity Elderly Gastrointestinal Disease Dual Antiplatelet Therapy Pregancy Non-Compliance DOACs & Renal Impairment All DOACs are renally excreted to some degree Patients with est. CrCl 30 ml/min (or CrCl 25 ml/min or SCr > mg/dl in ARISTOTLE) were excluded from clinical trials DOAC PK/PD & Renal Dysfunction Dabigatran Cmax by AUC by with CrCl 15-49 ml/min Rivaroxaban Cmax by 12% AUC by 52% with CrCl 30-49 ml/min Apixaban No in Cmax AUC 44% with CrCl 15-29 ml/min Edoxaban Total exposure CrCl <30 m/min: 72% Peritoneal dialysis: 93% Circulation 2016:134:37-47. J Thromb Thrombolysis 2016;41:15-31. Savaysa (Edoxaban) Product Information 2016. DOACs & Renal Impairment VTE Trials Excluded patients with CrCl 30 ml/min No dose reduction in renal impairment 6-9% of patients had moderate renal impairment (CrCl 30-50 ml/min) Afib Trials RE-LY, ROCKET-AF, and ENGAGE-AF excluded patients with a CrCl 30 ml/min ARISTOTLE excluded patients with CrCl 25 ml/min or SCr > mg/dl 17-19% of patients had moderate renal impairment (CrCl 30-50 ml/min) Renal Dysfunction & Afib ARISTOTLE Apixaban superior regardless of renal function ENGAGE-AF Similar efficacy & 24% bleeding Circulation 2016:134:48-51. Worse outcomes with CrCl > 95 ml/min RE-LY Similar efficacy regardless of renal function Bohula EA et al. Circulation 2016; 134:24-36. ROCKET-AF Patients with 20% reduction in CrCl had CVA & GI bleeding Circulation 2016:134:37-47. DOACs & Renal Impairment Rivaroxaban and apixaban have dosing recommendations per the manufacturer and FDA for use in ESRD Based on PK/PD trials in HD patients Used surrogate markets as endpoints (anti-Xa levels, PTT, INR) No safety or efficacy outcomes DOACs & Obesity Weight is a factor in many PK/PD properties Dabigatran & Rivaroxaban Extremes of weight (<50 kg or >120kg) do not affect pharmacology Apixaban Weight < 50 kg have 20-30% increased exposure Weight > 120 kg have 23-30% less exposure Edoxaban No PK/PD data available for extremes of weight J Thromb Thrombolysis 2016;41:15-31. DOACs & Elderly Elderly patients have decreased drug clearance Elderly people are at greater bleeding risk Afib trials Average age 70-78 years VTE trials Average age 55-58 years DOACs & Gastrointestinal Disease DOACs vary largely in terms of their absorption/bioavailability (3-100%) Increased rates of GI bleeds with dabigatran and rivaroxaban Dabigatran has a side effect of dypepsia Capsule is formulated with tartaric acid to increase absorption Use of PPIs or H2 Blockers do not alter absorption Patients with severe hepatic impairment were excluded from clinical trials J Thromb Thrombolysis 2013; 36:212-222. DOACs & Dual Antiplatelet Therapy Rivaroxaban and apixaban were both studied in combination with dual antiplatelet therapy for Acute Coronary Syndromes ATLAS trial Rivaroxaban mg BID and 5 mg BID showed a decrease in mortality from MI and stroke, however this was outweighed by increase in major bleeding ( vs %, p < ) and intracranial hemorrhage ( vs %, p = ) APPRAISE-2 trial Apixaban 5 mg BID vs. placebo Terminated early due to increase in major bleeding ( vs %, p = ) and intracranial hemorrhage ( vs %, p = ) J Thromb Thrombolysis 2013; 36:212-222. DOACs & Pregnancy No Data = DO NOT USE DOACs & Noncompliant Patients On/Off direct anticoagulant effect Somewhat short half life (t1/2 = 5-17 hrs) Rebound thrombotic events with abrupt discontinuation Summary of Special Populations Population Preferred Anticoagulant Renal Impairment Rivaroxaban, Apixaban, Heparin Obesity Dabigatran, Rivaroxaban, Enoxaparin Elderly Warfarin, Apixaban History of GI Bleed Apixaban, Edoxaban Hepatic Impairment Warfarin Pregnancy Enoxaparin, Heparin Non-compliant Patients Warfarin, Rivaroxaban, Edoxaban Real World Data Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban versus Warfarin in Nonvalvular Atrial Fibrillation Methods: using large US insurance database, they identified patients with nonvalvular afib who were prescribed a DOAC; each cohort was propensity score matched Conclusions Apixaban was associated with lower risk of both stroke and major bleeding Dabigatran was associated with similar risk of stroke but lower risk of major bleeding Rivaroxabn was associated with similar risk of both stroke and major bleeding JAHA 2016;5:e003725 Switching to DOACs From Warfarin: Dabigatran: start when INR < Apixaban: start when INR < Rivaroxaban: start when INR < Edoxaban: start when INR Switching to DOACs From UFH: Start apixaban/rivaroxaban/dabigatran when UFH infusion stopped Start edoxaban 4 hours after UFH infusion stopped From LMWH: Start DOAC at the time of next schedule dose of LWWH Switching from DOACs To Warfarin: Stop apixaban/rivaroxaban, switch to UFH/LMWH and bridge to warfarin Overlap dabigatran: If CrCl > 50 ml/min: overlap for 3 days If CrCl30-50 ml/min: overlap for 2 days If CrCl < 30 ml/min: overlap for 1 day Reduce edoxaban dose by 50% and discontinue when INR 2 Switching from DOACs To UFH: Start heparin bolus/infusion at the end of the dosing interval of the previous DOAC ( 12 hrs for twice daily, 24 hrs for once daily) May need to wait longer depending on DOAC and renal impairment To LMWH: Start LMWH at the end of the dosing interval of DOAC Peri-Procedural Management Drug Low Bleeding Risk Procedure High Bleeding Risk Procedure Dabigatran CrCl 50: hold for 1-2 days CrCl 30-50: hold for 2-3 days CrCl <30: hold for 3-4 days CrCl 50: hold for 3-4 days CrCl 30-50: hold for 4-5 days CrCl <30: hold for 5-6 days Apixaban CrCl 50: hold for 1 day CrCl 15-49: hold for 2 days CrCl 50: hold for 2 days CrCl 15-49: hold for 3-4 days Rivaroxaban CrCl 30: hold for 1 day CrCl < 30: hold for 2 days CrCl 30: hold for 2 days CrCl < 30: hold for 3 days Edoxaban CrCl 30: hold for 1 day CrCl < 30: hold for 2 days CrCl 30: hold for 2 days CrCl < 30: hold for 3-4 days J Thromb Thrombolysis 2013; 36:212-222. Monitoring of DOACs Dabigatran Rivaroxaban Apixaban Edoxaban aPTT PT/INR ECT N/A N/A N/A Anti-Xa N/A TT N/A N/A N/A ECT = Ecarin Clotting Time TT = Thrombin Time **PT/INR effect will depend on reagent used in lab; a normal value does not equate to normal coagulation Int. Jnl. Lab. Hem. 2014, 36, 261 268 Reversal of DOACs Minor Bleeding Hold DOAC and supportive care Major Bleeding Idarucizumab (Praxbind) 5 gm IV bolus (adminitered as two gm doses 15 minutes apart) Contains 4 gm of sorbitol not for patients with hereditary fructose intolerance Monitoring PTT at baseline, 2 and 12 hours after dose Recombinant Factor VIIa (Novoseven) Prothrombin Complex Concentrate (PCC) Other Special Considerations Dabigatran Capsules must be swallowed whole. Do not open contents and dilute. Should be stored in original container Apixaban, Rivaroxaban, and Edoxaban Tablets are not scored, therefore do not cut in half May be crushed and mixed with water to administer Rivaroxaban should be taken with food Future of DOACs Use and popularity continue to increase Betrixaban currently being reviewed by the FDA for prevention of venous thromboembolism in medically ill patients Andexanet-Alfa currently being studied for reversal of Factor Xa Inhibitors (including enoxaparin and fondaparinux) Recombinant modified human factor X decoy protein Adele Robbins, PharmD, BCPS Clinical Pharmacy Specialist Cardiology & Anticoagulation Emory University Hospital Atlanta, GA Practical Aspects Of Using Direct Oral Anticoagulants

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