The Indications and Uses of the Novel Anticoagulants (NOACs):

Kristin L. Thanavaro, MD

Overview:

• Warfarin • NOACs: Dabigatran, Rivaroxaban, Apixaban

and Edoxaban• Indications, dosing• Interruption for surgery• Management of bleeding, reversal agents• Switching between agents• How to choose the right one for your patient?

The Clotting Cascade:• Warfarin inhibits the synthesis of vitamin K-dependent clotting factors (II, VII, IX and X)

and Proteins C and S

Warfarin:

• Gold standard for prevention of systemic embolism• Indications: atrial fibrillation (valvular), deep venous

thrombosis, pulmonary embolism, ventricular thrombus

• Peak effect 72 hours, predominately hepatic metabolism

• Inexpensive, well-studied, reversible• But requires frequent blood monitoring, has

interactions with food and medication (CYP2C9), and can be influenced by genetic polymorphisms

NOACs:

• Dabigatran —Direct thrombin inhibitor

• Rivaroxaban• Apixaban —Factor Xa inhibitors• Edoxaban

*All studies compared to dose-adjusted Warfarin INR 2-3 (non-inferiority trials)*No head-to-head trials to date

The Clotting Cascade: Action of NOACs

Dabigatran:

• First approved NOAC in the US• Dabigatran elexilate (prodrug) hydrolyzed to

active metabolite• Direct thrombin inhibitor (free and clot-bound

thrombin)– Inhibits multiple procoagulant pathways

Dabigatran: Pharmacokinetics and Dosing

• 80% renal excretion• Plasma peak 2 hours, half-life 12-17 hours• Only 35% protein bound

For Non-valvular AF/Systemic Embolism:• 150 mg bid• 75 mg bid if CrCl 15-30 mL/min• Contraindicated if CrCl < 15 mL/min• *110 mg bid dose in RE-LY was not approved

Dabigatran vs. Warfarin

• Similar efficacy in preventing systemic embolism• No more major bleeding• More GI bleeding/dyspepsia• Less hemorrhagic stroke• Slightly higher risk of MI (0.8% vs 0.64%) in post-

hoc analysis. More likely protective effect of Warfarin than direct dabigatran effect.

Dabigatran: Adverse Effects

• Mostly GI• Pain/burning in throat, rash• Interactions with P-glycoprotein inhibitors• Dose reduce Dabigatran: ketoconazole,

dronedarone• Do not use Dabigatran: Rifampin• Consider alternative anticoagulant if renal

impairment: amiodarone, verapamil, diltiazem

Dabigatran: Interruption for Surgery

Creatinine Clearance (mL/min) Low-risk Surgery High-Risk Surgery

>50 24 hours 2 days

31-50 2 days 4 days

< 30 4 days 6 days

Adapted from Fawole, Daw and Crowther. Cleveland Clinic Journal of Medicine (2013) 80:7, 447.

Switching to/from Dabigatran:Conversion: Dosing:

Warfarin to Dabigatran

• Stop Warfarin, start Dabigatran when INR<2

Dabigatran to Warfarin

• CrCl > 50: Start Warfarin. Stop Dabigatran 3 days later• CrCl 30-50: Start Warfarin. Stop Dabigatran 2 days later• CrCl 15-30: Start Warfarin. Stop Dabigatran 1 day later

Parenteral Agent to Dabigatran

• LMWH: stop LMWH, start Dabigatran 0-2 hours before next dose LMWH due• Unfractionated heparin: start Dabigatran when stopping IV infusion

Dabigatran to Parenteral Agent

• CrCl > 30: start parenteral agent 12 hours after last Dabigatran dose• CrCl < 30: start parenteral agent 24 hours after last Dabigatran dose

Adapted from Kovacs et al. JACC (2015) 65:13, 1344.

The Clotting Cascade: Action of NOACs

Rivaroxaban:

• First factor Xa inhibitor approved• Binds reversibly to free and platelet-bound

factor Xa• Peak plasma concentration in 2-4 hours• Half life 5-9 hours (9-13 elderly)• 66% renal excreted, hepatic metabolism• 95% protein bound

Rivaroxaban: Dosing

• Systemic Embolism in non-valvular AF:– 20mg with evening meal for CrCl>50 mL/min– 15mg with evening meal for CrCl 15-50 mL/min– Contraindicated if CrCl < 15 mL/min

• Drug interactions (potentiate effects):– Ketoconazole, itraconazole– Ritonavir, indinavir– Conivaptan– Amiodarone,verapamil, diltiazem– Rifampin (*decrease action)

Rivaroxaban vs. Warfarin

• Non-inferior to Warfarin in preventing stroke and systemic embolism

• Similar rates of major bleeding events• More clinically relevant bleeding events – (2.8% vs. 1.2%)

• Less intracranial hemorrhage and fatal bleeding

Rivaroxaban: Interruption for Surgery

Creatinine Clearance (mL/min) Low-risk Surgery High-Risk Surgery

>30 24 hours 2 days

< 30 2 days 4 days

Adapted from Fawole, Daw and Crowther. Cleveland Clinic Journal of Medicine (2013) 80:7, 447.

Switching to/from Rivaroxaban:Conversion: Dosing:

Warfarin to Rivaroxaban • Stop Warfarin, start Rivaroxaban when INR<3

Rivaroxaban to Warfarin

• Stop Rivaroxaban and start Warfarin/parenteral agent when next dose of Rivaroxaban would be due. Discontinue parenteral agent when INR is in range

Parenteral Agent to Rivaroxaban

• LMWH: stop LMWH, start Rivaroxaban 0-2 hours before next dose LMWH due• Unfractionated heparin: start Rivaroxaban when stopping IV infusion

Rivaroxaban to Parenteral Agent

• Discontinue Rivaroxaban, start parenteral agent at the time the next dose of Rivaroxaban would be due

Adapted from Kovacs et al. JACC (2015) 65:13, 1344.

Apixaban:

• Factor Xa inhibitor• Peak plasma concentration in 3-4 hours• Half life 10-14 hours• 27% renal excreted, 63% fecal excreted,

hepatic metabolism• 87% protein bound

Apixaban: Dosing

• Systemic Embolism/ NVAF:• 5 mg bid• 2.5 mg bid if two out of three factors met:• Age > 80 years• Body weight <60 kg• Creatinine >1.5 mg/dL

• ESRD on HD:– 5mg bid– Decrease to 2.5mg bid if > 80 yo or < 60 kg

Apixaban: Drug Interactions

• Dose reduce with:– Ketoconazole/itraconazole– Ritonavir– Clarithromycin

• If already on 2.5mg dose, Apixaban should be avoided

• *Rifampin—decreases Apixaban action

Apixaban vs. Warfarin

• Superior to Warfarin in preventing stroke and systemic embolism (1.27% vs. 1.6%)

• Less major bleeding events (2.1% vs. 3.1%)– ICH

• Slightly less all cause mortality (secondary outcome)

Apixaban: Interruption for Surgery

Creatinine Clearance (mL/min) Low-risk Surgery High-Risk Surgery

>30 24 hours 2 days

< 30 2 days 4 days

Adapted from Fawole, Daw and Crowther. Cleveland Clinic Journal of Medicine (2013) 80:7, 447.

Switching to/from Apixaban:Conversion: Dosing:

Warfarin to Apixaban • Stop Warfarin, start Apixaban when INR<2

Apixaban to Warfarin• Stop Apixaban and start Warfarin/parenteral agent when next

dose of Apixaban would be due. Discontinue parenteral agent when INR is in range

Parenteral Agent to Apixaban

• LMWH: stop LMWH, start Apixaban when next dose LMWH due• Unfractionated heparin: start Apixaban when stopping IV infusion

Apixaban to Parenteral Agent

• Discontinue Apixaban, start parenteral agent at the time the next dose of Apixaban would be due

Adapted from Kovacs et al. JACC (2015) 65:13, 1344.

Edoxaban:• Newest factor Xa inhibitor• Rapid onset of action (peak effect 1-2 hours)• 35% renal excretion, hepatic metabolism• Cannot be used with CrCl > 95 mL/min because the drug

may clear too quickly (increased risk of ischemic CVA)– CrCl 50-94 mL/min: 60mg daily– CrCl 15-50 mL/min: 30mg daily

• May need dose reduction: verapamil, quinidine, dronedarone

• Avoid with rifampin (decrease action)

Edoxaban vs. Warfarin

• Similar to Warfarin in preventing stroke and systemic embolism

• Less major bleeding, hemorrhagic stroke• More gastrointestinal bleeding

Edoxaban: Interruption for Surgery

• Hold for 24 hours for low-risk bleeding procedure

• Hold for 48 hours for high-risk bleeding procedure

Switching to/from Edoxaban:Conversion: Dosing:

Warfarin to Edoxaban • Stop Warfarin, start Edoxaban when INR < 2.5

Edoxaban to Warfarin

• Stop Edoxaban and start Warfarin/parenteral agent when next dose of Edoxaban would be due. Discontinue parenteral agent when INR is in range -OR-

• Dose reduced Exoxaban by 50% and start Warfarin. Check INR weekly and stop Edoxaban when INR > 2

Parenteral Agent to Edoxaban

• LMWH: stop LMWH, start Edoxaban when next dose LMWH due• Unfractionated heparin: start Edoxaban 4 hours after stopping

IV infusion

Edoxaban to Parenteral Agent

• Discontinue Edoxaban, start parenteral agent at the time the next dose of Edoxaban would be due

Adapted from Kovacs et al. JACC (2015) 65:13, 1344.

Management of Bleeding:

Factor Xa Inhibitors:• No antidote, but short half lives• Vitamin K and FFP do not reverse the anticoagulant

effects. Not dialyzable• Life Threatening Bleeding:• Gastric lavage/activated charcoal (2-3 hrs)• Give blood/platelets• 4 Factor Plasma Prothrombin Concentrate (PCC)—II, VII,

IX, X. – May have some clinical benefit, but data are lacking– Risk of MI and systemic thrombosis– Expensive

• Reversal agent pending (Andexanet alfa, Aripazine)

Bleeding with Dabigatran:

• Dialysis• Idarucizumab: antibody to Dabigatran• 5 grams IV X 1 (may consider repeat dose)• Completely reverses the anticoagulant effects

of Dabigatran within minutes, restores hemostasis

• No evidence of prothrombotic effects

DVT/PE Treatment:

Indication Dabigatran Rivaroxaban Apixaban Edoxaban

Prevention of VTE Not indicated 10 mg daily 2.5 mg bid Not indicated

Treatment of VTE

150 mg bid after parenteral tx (if

CrCl> 30 mL/min)

15 mg bid for 21 days then 20mg

daily10mg bid

then 5 mg bid

60 mg daily after parenteral

treatment if CrCl 15-50 mL/min

Preventing Recurrent

VTE150mg bid if CrCl

> 30 mL/min 20mg daily 2.5 mg bid Not indicated

Adapted from Roca and Roca. Cleveland Clinic Journal of Medicine (2015) 82:12,849.

Choosing the Right Anticoagulant:• Warfarin: – Moderate+ valve disease/prosthetic valves– LV thrombus

• Other considerations:– Reversibility– Once daily vs. bid dosing (compliance)– Renal function– Co-administration of other medications– Cost– Patient preference

Summary:

• NOACs: indications, dosing, dose adjustment• Interruption for surgery• Switching between anticoagulants• Management of bleeding and reversal agents• Choosing the right one for your patient

Thank you!

Works Cited:• Fawole A, Daw HA and Crowther MA. Cleveland Clinic Journal of Medicine

(2013) 80:7.

• Gonsalves WI, Pruthi RK and Patnaik MM. Mayo Clinic Proceedings (2013) 88:5.

• Kovacs RJ and Flaker GC et al. JACC (2015) 65:13.

• Pollack CV and Reilly PA et al. NEJM (2015) 373:6.

• Roca B and Roca M. Cleveland Clinic Journal of Medicine (2015) 82:12.

• Tanaka-Esposito C and Chung MK. Cleveland Clinic Journal of Medicine (2015) 82:1.