Dr. Kristin Thanavaro, MD presents on "The Indications and Uses of the Novel Anticoagulants" at the March 4 -6, 2016 Cardiac and Thoracic Surgery Associates, Cardiovascular Summit at The Westin Riverfront Resort and Spa.
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K. thanavaro the indications and uses of the novel anticoagulants
1. The Indications and Uses of the
Novel Anticoagulants (NOACs):
Kristin L. Thanavaro, MD
2. 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?
3. The Clotting Cascade:
• Warfarin inhibits the synthesis of vitamin K-dependent
clotting factors (II, VII, IX and X) and Proteins C and S
4. 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
5. 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
7. 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
8. 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
9. 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.
10. 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
11. 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.
12. 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.
14. 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
15. 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)
16. 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
17. 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.
18. 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.
19. 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
20. 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
21. Apixaban: Drug Interactions
• Dose reduce with:
– Ketoconazole/itraconazole
– Ritonavir
– Clarithromycin
• If already on 2.5mg dose, Apixaban should be
avoided
• *Rifampin—decreases Apixaban action
22. 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)
23. 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.
24. 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.
25. 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)
26. Edoxaban vs. Warfarin
• Similar to Warfarin in preventing stroke and
systemic embolism
• Less major bleeding, hemorrhagic stroke
• More gastrointestinal bleeding
27. Edoxaban: Interruption for Surgery
• Hold for 24 hours for low-risk bleeding
procedure
• Hold for 48 hours for high-risk bleeding
procedure
28. 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.
30. 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)
31. 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
32. 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
daily
10mg bid
then 5 mg bid
60 mg daily after
parenteral
treatment if CrCl
15-50 mL/min
Preventing
Recurrent
VTE
150mg 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.
33. 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
34. 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
36. 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.
Notes de l'éditeur
We’ll see later that the NOACs act further down in the common pathway
By inhibiting thrombin, dabigatran inhibits multiple procoagulant pathways
There was less bleeding than warfarin with 110mg dose (RE-LY)
Less ischemic stroke
All these medications potentiate the action of Dabigatran
Mostly bound to albumin, cannot be dialyzed out
CYP3A4 and P-glycoprotein inhibitors increase Rivaroxaban exposure
ROCKET-AF Trial
Less renal excretion than Rivaroxaban, more kidney friendly
Ok for use in mild hepatic impairment, but avoid if modest-advanced liver failure
2 large Apixaban trials were AVERROES (Apixaban vs. ASA) and ARISTOTLE (Apxiaban vs. Warfarin)
Of note, pts with Cr >2.5 or CrCL < 25 mL/min were excluded from the AF (and acute VTE) studies. But, approved later for use in ESRD.
ARISTOTLE
Half life 10 hours, 50% protein bound, No CYPP450 metabolism, but uses P-gp transporter
ENGAGE-TIMI AF Trial
REVERSE-AD study
Rivaroxaban/Apixaban have broad range of uses. Edoxaban and Dabigatran cannot be used for prevention of VTE and are only used for treatment after parenteral treatment.