1. Novel Oral Anticoagulants: Practical considerations in VTE
Ido Weinberg, MD MSc
Assistant Professor of Medicine
Harvard Medical School
Massachusetts General Hospital

2. Disclosures
I do not have disclosures relevant to this talk

3. Background
Nat Rev Cardiol Jul;10(7):

4. Background – Cont’d Eur J Intern Med. 2014 Sep;25(7):600-6
Points to make:
Rapid onset
Moderate half-life
Varying elimination pathways. Dabigatran mostly renal
Drug interactions exist
Eur J Intern Med Sep;25(7):600-6

5. Background – Cont’d
Can Fam Physician Nov;60(11):989-95

6. Rivaroxaban VTE dosing

7. Apixaban VTE dosing * No dose adjustment for renal impairment
Apixaban package insert. Accessed 1/4/2015 at

8. Dabigatran dosing Dabigatran package insert. Accessed 1/4/2015 at

9. Drug interactions: CYP3A
Inhibitors
Inducers
Amiodarone
Carbamazepine
Clarythomycin
Phenytoin
Diltiazem
St John’s Wort
Ketoconazole
Phenobarbital
Fluoxetine
Verapamil
Rifampin
Merli G. Throm Thrombolysis 2011

10. Drug interactions: P-Glycoproteins
Substrates
Inhibitors
Inducers
Colchicine
Amiodarone
Carbamazepine
Cyclosporine
Clarithromycin
Rifampin
Digoxin
Erythromycin
St John’s Wort
Fexofenadine
Ketoconazole
Tipranavir
Indinavir
Quinidine
Morphine/Sirolimus
Saqunavir/Verapamil
Merli G. Throm Thrombolysis 2011

11. Between Warfarin and rivaroxaban?

12. Between Warfarin and apixaban

13. Between Warfarin and dabigatran
Dabigatran package insert. Accessed 1/4/2015 at

14. Less severe ICH with Rivaroxaban vs. Warfarin
All rivaroxaban patients had afib, while 79% of warfarin patients had afib
Stroke Sep;45(9):2805-7

15. Less bleeding with NOAC’s vs. Warfarin
12 RCT involving patients were combined in a meta-analysis
The second reference is just a smaller meta-analysis that showed similar results
Blood Oct 9;124(15):2450-8
J Thromb Haemost. 2014;12(3):320-8

16. Net clinical benefit for NOACs for VTE (and Afib)
Nat Rev Cardiol Dec 2. doi: /nrcardio [Epub ahead of print]

17. Management of NOAC-related bleeding
Prothrombin complex concentrates (PCC) contain high doses of vitamin K-dependent coagulation factors and variable amounts of proteins C and S. Four-factor PCC (factors II, VII, IX, X) is commercially available in Europe and Canada
3-factor PCC (factors II, IX, X) is licensed for use in the USA.
There is little clinical data regarding PCC use to reverse bleeding. There is data from healthy volunteers and animal studies
PCC increases the chance for thrombosis
Charcoal – in vitro evidence for dabigatran removal
rFVIIa – Not associated with improved bleeding in NOACs
Eur Heart J Feb;34(7): b

18. NOACS safe in CKD (CrCl<50 ml/min)
Most of the studies did not have any patients with CrCl<30. Nonetheless NOACs have been approved for use in CrCl 15-30
Apixaban dose was reduced to 2.5 mg BID in renal failure
J Am Soc Nephrol. 2014 Mar;25(3):431-42

19. Renal failure – Suggested dosing
Can Fam Physician Nov;60(11):989-95

20. NOAC effect can be assumed from common coagulation studies
Dabigatran - TCT – Most sensitive to detect the presence of dabigatran. Prolonged PT is sensitive to dabigatran, but normal PT is not sensitive to its absence
Rivaroxaban - Chromogenic Xa – sensitive to rivaroxaban. Prolonged PT is sensitive to rivaroxaban, but normal PT is not sensitive to its absence.
Apixaban – Chromogenic Xa – most useful to detect apixaban
Normal TCT / normal PT / Normal chromogenic Xa  Not much coagulation effect by dabigatran, rivaroxaban, apixaban, respectively
Eur Heart J Feb;34(7): b

21. NOACs affect hypercoagulable studies
Courtesy of Dr. Jessica Mintz

22. Peri-procedural anticoagulation cessation: Consider VTE and procedural risk
Blood Oct 11;120(15):

23. Peri-procedural NOAC comparable to Coumadin
Circulation Sep 25;126(13):1630-9

24. Suggested pre-procedural NOAC dosing
Blood Oct 11;120(15):
Heidbuchel H et al. EHRA Practical guidelines. European heart journal. 2013

25. Suggested post-procedural NOAC dosing
Blood Oct 11;120(15):

26. Peri-procedural management: Expert consensus:
Short half-life  Pre-procedural interruption: 1 or 2 day
Fast onset of action  Rapid restitution of anticoagulant activity after the procedure
No heparin bridging therapy
Eur Heart J Jul 21;35(28):

27. NOACs can be used in frail patients (but know the risks)
NOAC effect in elderly and low body mass patients
Anticoagulation efficacy*
Bleeding risk*
Apixaban =
Dabigatran
↑ (in patients > 85 years)
Rivaroxaban
= / ↑
* Compared to Warfarin, per sub-group analysis of phase III trials for DVT/PE/Afib
Frailty = Old / low body mass
Eur J Intern Med Sep;25(7):600-6

28. Anticoagulation choices: Special scenarios
Yeh et al. Evolving use of new oral anticoagulants. Blood 2014

29. NOAC FAQ

30. Does it matter if NOACs are taken with meals?
Dabigatran capsules should be taken with meals to reduce the risk of dyspepsia
Rivaroxaban should be taken with a meal to enhance absorption
Apixaban can be taken with or without meals
Clin Gastroenterol Hepatol Mar;11(3):246-52
Int J Clin Pharmacol Ther Jul;51(7):549-61
Br J Clin Pharmacol Feb;75(2):476-87

31. Which NOACs can be crushed?
Apixaban and rivaroxaban
Can Fam Physician Nov;60(11):
Clin Gastroenterol Hepatol Mar;11(3):246-52
Int J Clin Pharmacol Ther Jul;51(7):549-61
Br J Clin Pharmacol Feb;75(2):476-87

32. Can NOAC users take nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen?
Short term – Probably yes
Long term – Probably no (increased bleeding)
Prefer acetaminophen when possible
Consider other anti-platelet agents (ASA, clopidogrel etc.) only when a dual indication exists (increased bleeding)
Thromb Haemost Jul;108(1):183-90
Thromb Res Aug;130(2):147-51
Eur Heart J Feb;34(7): b

33. Where is information lacking?
Cancer
Antiphospholipid antibody-related thrombosis
Liver dysfunction
CrCl < 15 ml/min
High-risk PE
HIT
Superficial vein thrombophlebitis

34. Thank you