4/25/2020 1 1 Objectives for the Indications of Direct Oral Factor Xa Anticoagulants • Identify patients suitable for Direct Acting Oral Anticoagulants (DOACs). • Know PK/PD issues impacting dosing and safety of DOACs • Recognize patient factors that may influence the choice of anticoagulant. • Obesity • Liver disease • Renal disease • Age • Comorbidities • Manage bleeding issues associated with DOACs 2 Patient Case • ET is a 77 yo woman admitted for Bilateral PE and A. fib. • Home Meds: Carvedilol 6.25mg PO BID • Weight 75kg Height 5’5” • GFR 30ml/min/m 2 • Enoxaparin 100mg (1.5mg/kg/d) SC Daily started • What oral anticoagulant would you start and for how long? 3
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Anticoagulation DOACS Presentation Final (003)€¦ · 4/25/2020 7 Site of Action of Direct Factor Xa Oral Inhibitors on the Coagulation Cascade European Heart JournalSupplements(2018)
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Objectives for the Indications of Direct Oral Factor Xa Anticoagulants
• Identify patients suitable for Direct Acting Oral Anticoagulants (DOACs).
• Know PK/PD issues impacting dosing and safety of DOACs
• Recognize patient factors that may influence the choice of anticoagulant.
Direct Thrombin InhibitorsArgatrobanBivalirudin (Angiomax®)Dabigatran (Pradaxa®)
Vitamin K AntagonistWarfarin (Coumadin®)
Oral Factor Xa InhibitorsRivaroxaban (Xarelto®)Apixaban ( Eliquis®)Edoxaban (Savaysa®)Betrixaban (Bevyxxa®)
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Coagulation Issues
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Risk Factors for VTE
• Age >60 years
• Expected hospitalization ≥3 days
• Active cancer
• History of stroke
• Active hormonal treatment
• ICU or CCU stay
• Acute infection requiring hospitalization
• Inherited or acquired thrombophilia
• Active pregnancy in second or third trimester
• Limited mobility
• BMI >35 kg/m2
• Previous VTE or superficial view thrombosis
• Current lower‐limb paralysis
• Prior central venous catheter or transvenous pacemaker
• Chronic respiratory failure
• Reduced mobility
• Chronic venous insufficiency
• Rheumatological disorder
• D‐dimer ≥2× ULN
• Trauma or surgery (≤1 month ago)
• Decompensated heart failure (New York Heart Association class III or IV)
Annals of Pharmacotherapy 2018, Vol. 52(6) 554–561 7
Prothrombotic State in Coexistent AF and CKD
Nature reviews Nephrology 2018;14:337‐351 8
Relative Changes in Thrombotic Factors in Liver Disease
↓Prothrombin ↑ Von Willebrands factor↓Thrombin ↑ Dura on of Thrombin Ac va on↓ An thrombin ↑ Thrombin Receptors on hepa c Stellate cells↓ Protein C & S↓ Plasminogen↓ Platelets
Pharmacological strategies to control hyperacoagulability and heart inflammation
Front. Pharmacol. 2019 10:142015
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Atrial fibrillation and Stroke
National Heart Lung and Blood Institute (NIH) 16
Direct Factor Xa Oral Inhibitors
Overview
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Khachatryan T, et.al Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization American Journal of Cardiovascular Drugs April 3 2019 DOI: 10.1007/s40256‐019‐00344‐6
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Site of Action of Direct Factor Xa Oral Inhibitors on the Coagulation Cascade
FDA Approved Indications1 Following initial therapy‐ 5‐10 days of parenteral anticoagulant2 Prophylaxis of DVT, which may lead to PE in patients undergoing knee and hip surgery3 Reduce the risk of major cardiovascular events in patients with chronic CAD or peripheral artery disease (PAD)
Annals of Pharmacotherapy 2018, Vol. 52(6) 554–561
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Pharmacology of Direct Factor Xa Oral Inhibitors
• Direct, reversible inhibitor of factor Xa
• Inhibits free and clot‐bound factor Xa
• Inhibits prothrombinase ac vity → ↓Thrombin genera on and thrombus
• No direct platelet ac vity → ↓ thrombin induced platelet aggrega on
• Inhibition is dose dependent
Ther Drug Monit 2019;41(2):180–191J Thromb Thrombolysis 2016;41:15‐31
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PharmacokineticsApixabanEliquis®
RivaroxabanXarelto®
EdoxabanSavaysa®
BetrixabanBevyxxa®
Bioavailability >50%Small intestine
Incomplete absorption1st pass metabolism
80‐100% at 10mg dose66% at 20mg dose
Doses ≥ 15mg give with food
62% 34%Meal ≤ 6 h prior will decreaseplasma concentration
Onset: t max(hrs) 3‐4 2.5‐4 1‐2 2.5‐4
Terminal t1/2 (hrs) 12 (8‐15) (SS 3 days)
5‐9 (11‐13 Elderly) (SS 3 days)
10‐14(SS 3 days)
35‐45PD t1/2 19‐27 hrs
(SS 4 days)
Renal Elimination (%) 25 66 (36% as unchanged drug)
35‐50 66 (36% as unchanged drug)
Hemodialysis Not Dialyzable Not Dialyzable Not Dialyzable Not Dialyzable
CYP 450 Metabolism <32% 57% <25% <1%
Drugs (2019) 79:291–302Clin Pharmacokinet (2014) 53:1–16Seminars in Liver Dis 2019;39
PD t½: pharmacodynamic half‐life
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Indications and Dosing of Direct Factor Xa Oral Inhibitors
Apixaban(Eliquis®)
Betrixaban(Bevyxxa®)
Edoxaban(Savaysa®)
Rivaroxaban(Xarelto®)
Prevention/Treatment VTE 10mg po BID X 7 days then 5mg po BID X 6 months
VTE Prevention only160mg po day 1 followed by 80mg po daily for 35‐42 days
60 mg Daily >60kg30mg Daily ≤60kg
15mg po BID X 21 days followed by 20mg daily
(Doses ≤ Bioavailability same with fasting or food )
NonValvular A. fib (NVAF) 5mg po BID2.5mg po BID if patient >80yo, BW<60kg, ESRD
‐ 60 mg DailyDo not use edoxaban for NVAF if CrCl
is >95 mL/minute
20mg po QD with evening meals
Post –Op DVT ProphylaxisKnee/Hip
Hip: 2.5mg BID X 35 daysKnee: 2.5mg BID X 12 days
‐ ‐ 10mg po QD 10‐14 days(may extend to 35 days)
Acute Coronary Syndrome (ACS) (off‐label)
5mg po BID ‐ ‐ 2.5mg PO BID + ASA+Clopidogrel(X 1 year)
Heparin Induced Thrombocytopenia (off‐label)
10mg po BID X 7 days then 5mg po BID until platelet count
returns
‐‐
15mg BID with food X 21 days followed by 20mg QD until
platelet count returns
Conversion from Warfarin INR<2 Stop warfarin and start betrixaban when INR < lower limit of therapeutic range
INR<2.5 (some experts recommend starting when as close as possible to 2.0)1
INR<3.0
Khachatryan T, et.al Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization American Journal of Cardiovascular Drugs April 3 2019 DOI: 10.1007/s40256‐019‐00344‐6The Journal of Clinical Pharmacology 2016: 56(5) 628–636.NEJM 2019; 380;16:1509‐1524 AUGUSTUS TrialJ Am Heart Assoc. 2018;7:e010854. DOI: 10.1161/JAHA.118.010854
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Renal Dosing GuidelinesApixabanEliquis®
BetrixabanBevyxxa®
EdoxabanSavaysa®
RivaroxabanXarelto®
Oral: ↓ dose with any 2 below:• Age ≥80 years, • body weight ≤60 kg• serum creatinine ≥1.5 mg/dL
CLCr> 30ml/min ClCr≥51ml/minClCr> 95ml/min Avoid
ClCr>50ml/min
NVAF 5 mg twice daily Any 2 above 2.5mg BID*
160mg daily Day #1then 80mg daily
• Weight >60 kg: 60 mg daily.
• Weight ≤60 kg: 30 mg daily.
ClCr >50ml/min20mg daily
ClCr 15 to 50 mL/min15mg daily*
ClCr<15ml/minContraindicated
Prevention/Treatment VTE
10 mg twice daily for 7 days followed by 5 mg twice
daily.
≥15 to <30ml/min ClCr 15 to 50 mL/minute30mg daily
DVT 15mg BID X 21 days then 20mg daily
DVT prophylaxis following Knee and Hip replacement surgery
2.5 mg twice daily beginning 12 to 24 hours
postoperative
80mg daily Day #1 then40mg dailyESRD/HD
No Guidelines
ESRDAvoid
ClCr<30ml/minAvoid
Ther Drug Monit. 2019;41(2):180‐191.The American Journal of Medicine 2019; 132:1078‐1083Circulation. 2015;131:972‐979Semin Thromb Hemost 2018;44:353–363
* Increased Risk of bleeding when compared to patients on full dose and non‐severe CKD or ESRD
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Dose Interruption in Patients Having Invasive Procedures
Apixaban(Eliquis®)
Betrixaban(Bevyxxa®)
Edoxaban(Savaysa®)
Rivaroxaban(Xarelto®)
24‐48hrs min, depending on bleeding risk
Anticoagulant effect expected to persist for ≥72 hours.
Low risk:24 hoursHigh risk:72 hours
24hrs minimum, with 3‐5 days depending on Renal Function
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Adverse Reaction Risk Factors of Direct Factor Xa Oral Inhibitors
J Am Coll Cardiol 2013;61:2495–502Journal of Cardiology 2019; 73: 515–521Hematology Am Soc Hematol Educ Program. 2018 Nov 30; 2018(1): 339–347.
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Reversal Options for Direct OralFactor Xa InhibitorsApixaban(Eliquis®)
Betrixaban(Bevyxxa®)
Edoxaban(Savaysa®)
Rivaroxaban(Xarelto®)
Andexanet alfa(Andexxa®)
≤5 mg ≤ 8 hours or unknown period of time: Initial, 400 mg IV bolus at target rate of 30 mg/min; follow with 4 mg/min (480mg) continuous IV infusion for up to 120 minutes
80mg800mg bolus 4h after last betrixabandose followed by 2h infusion8mg/minPhase II study
≤40 mg400 mg IV bolus at target rate of 30 mg/min; follow with 4 mg/min (480mg) continuous IV infusion for up to 120 minutes. Phase II study
≤10 mg ≤ 8 hours or unknown time: Initial, 400 mg IV bolus at target rate of 30 mg/min; follow with 4 mg/min (480mg) continuous IV infusion for up to 120 minutes. 1
>5 mg (or unknown dose) ≤8 hours or unknown period of time: Initial, 800 mg IV bolus at target rate of 30 mg/min; follow with 8 mg/min (960mg)continuous IV infusion for up to 120 minutes
>40 mg800 mg IV bolus at target rate of 30 mg/min; follow with 8 mg/min (960mg) continuous IV infusion for up to 120 minutes.
10 mg (or unknown dose) ≤8 hours or unknown period of time: Initial, 800 mg IV bolus at target rate of 30 mg/min; follow with 8 mg/min (960mg) continuous IV infusion for up to 120 minutes. 1
Onset: 2 minutesPharmacodynamic half‐life ≈1hr
Onset: 2 minutesPharmacodynamic half‐life ≈1hr
4‐factor PCC (Kcentra®)
25‐50 IU/kg 25‐50 IU/kg 25‐50 IU/kg 25‐50 IU/kg
Ciraparantag‐Investigational
Khachatryan T, et.al Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization American Journal of Cardiovascular Drugs April 3 2019 DOI: 10.1007/s40256‐019‐00344‐6
4‐factor PCC (Kcentra®)Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, and Protein S]
1. Product Information: ANDEXXA(R) lyophilized powder for intravenous injection, coagulation factor Xa recombinant, inactivated‐zhzo lyophilized powder for intravenous injection. Portola Pharmaceuticals, Inc (per manufacturer), South San Francisco, CA, 2018.
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Andexanet alfa Reversal PrecautionsImmunologic Cardiovascular Hematologic Neurologic Respiratory Death
Re‐elevation or incomplete reversal of anti‐FXa activity has been reported
Khachatryan T, et.al Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization American Journal of Cardiovascular Drugs April 3 2019 DOI: 10.1007/s40256‐019‐00344‐6
4‐factor PCC (Kcentra®)Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, and Protein S]
Product Information: ANDEXXA(R) lyophilized powder for intravenous injection, coagulation factor Xa recombinant, inactivated‐zhzo lyophilized powder for intravenous injection. Portola Pharmaceuticals, Inc (per manufacturer), South San Francisco, CA, 2018.
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ApixabanApixabanEliquis®
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Direct Acting Factor Xa InhibitorsApixaban (Eliquis®)
FDA Approved Indications1
• Reduce the risk of stroke in patients with NVAF
• DVT prophylaxis following Knee and Hip replacement surgery
• DVT and Pulmonary Embolism treatment
New Uses
• Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation2
• Heparin‐induced thrombocytopenia 3,4
1. FDA www.accessdata.fda.gov2. N Engl J Med 2019; 380:1509‐15243. https://clinicaltrials.gov/ct2/html/images/ct.gov‐nlm‐nih‐logo.png4. Pharmacotherapy 2019;39(8):837–853
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Direct Acting Factor Xa InhibitorsApixaban (Eliquis®)
• Pharmacokinetics• Effects of other agents‐
• ↑anti‐Xa activity
• LMWH
• UFH
• Fondaparinux
• P2Y12 agents (Clopidogrel)
• VKA
• Dipyridamole
• Dextran
• Glycoprotein IIb/IIIa inhibitors
Clinical Pharmacokinetics (2019) 58:1265–1279 35
Direct Acting Factor Xa InhibitorsApixaban (Eliquis®)
• Pharmacokinetics• Serum levels achieved up to 10mg dose are proportional
• Studies have demonstrated a direct relationship between drug clearance and ClCr.• Age – AUC higher as age increases, but impact is small and age alone is not a dose determining factor.
• Body Weight – extremes in weight effect AUC and Cmax but benefit‐risk not effected and body weight alone is not a dose determining factor.
• Sex – AUC higher in men vs women but sex alone is not a dose determining factor.
• Race – AUC higher in Asian vs non‐Asian patients but race alone is not a dose determining factor.
• Renal – AUC increases proportionally as renal function decreases
• Hepatic – AUC changes for Child‐Pugh A and B are minimal, but as hepatic function worsens the loss if inherent clotting factors may increase bleeding.
Clinical Pharmacokinetics (2019) 58:1265–1279 36
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Direct Acting Factor Xa InhibitorsApixaban (Eliquis®)
Dosing
• Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): • Oral: 5 mg twice daily unless patient has any 2 of the following:
• Age ≥80 years
• Body weight ≤60 kg
• Serum creatinine ≥1.5 mg/dL (133 mcmol/L)
• Reduce dose to 2.5 mg twice daily.
• Venous thromboembolism:• Deep vein thrombosis and/or pulmonary embolism treatment:
• Oral: 10 mg twice daily for 7 days followed by 5 mg twice daily.
• Total hip arthroplasty or total knee arthroplasty (alternative to low‐molecular‐weight heparin):
Direct Acting Factor Xa InhibitorsRivaroxaban (Xarelto®)
FDA Approved Indications • Coronary artery disease (stable) or peripheral artery disease
• Reduction in the risk of recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients at continued risk of DVT and PE.
• Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
• Treatment of DVT or PE.
• Prophylaxis of venous thromboembolism (VTE) and VTE‐related death during hospitalization and posthospitaldischarge in adults admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding.
• Venous thromboembolism prophylaxis in total hip or knee arthroplasty: Postoperative thromboprophylaxis of DVT, which may lead to PE in patients undergoing total hip arthroplasty or total knee arthroplasty.
Direct Acting Factor Xa InhibitorsRivaroxaban (Xarelto®)
Dosing• Coronary artery disease (stable) or peripheral artery disease (prevention of major cardiovascular events):
• Oral: 2.5 mg twice daily; administer in combination with daily low dose aspirin.
• HIT with or without thrombosis: • Oral: 15 mg twice daily with food for 21 days or until platelet count recovery, whichever is longer, followed by 20 mg once daily with food.
• Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): • Oral: 20 mg once daily with the evening meal.
• Total hip arthroplasty or total knee arthroplasty (alternative to LMWH): • Oral: 10 mg once daily initiated at least 6 to 10 hours after surgery or when hemostasis established.
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BetrixabanBevyxxa®
Betrixaban
FDA Approved Indications Additional Options
VTE prevention in acute medically ill hospitalizedpatients
Pending: Prevention of thromboembolism in atrialfibrillation
Seminars in Thrombosis & Hemostasis 2019;45 (5): 490-501
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Edoxaban
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Edoxaban(Savaysa®)
Direct Acting Factor Xa InhibitorsEdoxaban (Savaysa®)
FDA Approved Indications
• Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
• Treatment of Deep Vein Thrombosis and Pulmonary Embolism
Additional Options
• Prevention of stroke after Transcatheter aortic valve implantation (TAVR)
• American Heart Journal 2018;205:63‐69
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Direct Thrombin InhibitorDabigatran (Pradaxa®)
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DabigatranDabigatranPradaxa®
Direct Acting Thrombin InhibitorDabigatran (Pradaxa®)
FDA Indications• Reduce the risk of stroke and systemic embolism in
patients with non-valvular atrial fibrillation
• Treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days
• Reduce the risk of recurrence of DVT and PE in patients who have been previously treated
• Prophylaxis of DVT and PE in patients who have undergone hip replacement surgery
• CrCl 30 to 50 mL/min with concomitant use of P-gpinhibitors:
• CrCl <30 mL/min with concomitant use of P-gpinhibitors:
• Reduce dose to 75 mg twice daily if given with P-gp inhibitors
• Avoid co-administration
• Treatment of DVT and PE• Reduction in the Risk of
Recurrence of DVT and PE
• CrCl >30 mL/min:• CrCl <30 mL/min or on dialysis:
• 150mg twice daily• Dosing recommendations NOT provided
CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration
Prophylaxis of DVT and PE FollowingHip Replacement Surgery
• CrCl >30 mL/min:
• CrCl <30 mL/min or on dialysis:
• 110 mg for first day, then 220 mg once daily
• Dosing recommendations cannot be provided
CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration
Dabigatran Reversal AgentIdarucizumab (Praxbind®)
• Dose: IV 5gm administered as 2 separate 2.5gm doses no more than 15 minutes apart 1,2,3
• Additional full dose may be considered if clinically relevant bleeding together with elevated coagulation parameters is observed.
• Administration: Two consecutive infusions or Bolus injection by injecting both vials consecutively one after another via syringe.
• MOA: Binds specifically to dabigatran and its acylglucuronide metabolites with an affinity for dabigatran that is ~350 times greater than that of thrombin, and neutralizes the anticoagulant effect within minutes
• Source: Humanized monoclonal antibody fragment (Fab)
• Risks: Thromboembolic events in patients with underlying disease states placing them at risk for embolic events.
• Restarting Antithrombotic Therapy: Resumption of anticoagulant therapy should be considered as soon as medically appropriate.
Pradaxa® treatment can be initiated 24 hours after administration of PRAXBIND® 1