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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
- 6. The Clotting Cascade: Action of NOACs
- 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.
- 13. The Clotting Cascade: Action of NOACs
- 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
- 35. Thank you!
- 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.
Notas del editor
- 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.