1. Anticoagulants How much, which one & how long?
Stephanie M. Dentoni, MD,FSVM
California Vein & Vascular Institute

2. I Have No Financial Interests To Disclose

3. Practical Use of Novel Anticoagulants

4. Objectives and Goals Introduce Novel Anticoagulant
Review Practice Pharmacokinetics
Outline Indications with Respect to VTE
Warnings and Side Effects
Discuss Practical Usage
Clinical Pearls

5. Overview of Anticoagulants
Heparin was first discovered in 1916 by Jay Mc Lean and William Harry Howell
Use of heparin in clinical practice was 20 years later
Low molecular weight heparin was discovered in 1976 with clinical trials starting in the early 1980’s
Sweet clover disease lead to the discovery of the first oral anticoagulant: dicourmarol
Now, the turn of the century there are several oral anticoagulants available for use

6. Limitations of Traditional Anticoagulants
Subcutaneous administration
Difficult to administer - subcutaneous
Limits long term use
Long half-life
Bleeding complications
Monitoring
Slow Onset
warfarin
Variable dosing
Warfarin/food and drug interactions
Accumulation with renal insufficiency
LMWH
Heparin Induced Thrombocytopenia

7. Benefits of New Oral Anticoagulants
Specific target in the coagulation cascade
Factor II
Factor X
Predictable dose response
Ease of administration
No monitoring required
Short half life
No significant food interactions
Less drug interactions

8. Novel Oral Anticoagulants
Dabigatran Rivaroxaban Apixaban Edoxaban

9. Dabigatran

10. Dabigatran Prodrug – dabigatran etexilate
Reversibly inhibits the active site of thrombin
Bioavailability of 6%
Peak plasma levels = 2 hours
Half-life hours
Renal excretion
Concomitant use of quinidine is contraindicated due to increasing plasma levels of dabigatran by reducing clearance
Reduced dose recommended with co-administration of amiodarone and verapamil

11. Dabigatran Indications
Nonvalvular Atrial Fibrillation
Prevention of venous thromboembolism
Treatment of venous thromboembolism

12. Dabigatran Dosing 150mg po twice daily
110mg po twice daily for special populations
Greater than 80 years old
Concomitant use of verapamil

13. Dabigatran Administration
Oral
With or without food
Swallowed with water
Capsule should not be broken or opened
Increased bioavailability
Increased risk of bleeding

14. Missed Dose of Dabigatran
Can take dose up to 6 hours prior to next scheduled dose
Do not double dose
Do not take missed dose within 6 hours of the next dose

15. Laboratory Values and Dabigatran
aPTT is elevated
aTT is elevated
ECT is elevated
INR is abnormal
Cannot determine the amount of anticoagulant or the level
TT and ECT may be useful for monitoring but studies are needed

16. Start dabigatran 0-2 hours prior to next dose of LMWH
Treatment for VTE
5 days of LMWH
Start dabigatran 0-2 hours prior to next dose of LMWH

17. Contraindications for Dabigatran
CrCl less than 30
Clinically significant bleeding
Lesion or medical condition considered high risk for bleeding
Concomitant administration with other anticoagulants
Hepatic or liver impairment that will have an impact on survival
Concomitant treatment with ketaconazole, itraconizole, cyclosporin, dronedrone
Prosthetic heart valves
Pregnancy or breast feeding

18. Transferring from Warfarin to Dabigatran
Stop Warfarin
When INR falls below 2, start dabigatran

19. Rivaroxaban

20. Rivaroxaban Direct Xa inhibitor Oral bioavailability of 80%
Rapid onset with half-life of 7-11 hours
Elimination:
1/3 unchanged through renal excretion
1/3 via the liver CYP3A4 dependent and independent pathways with fecal excretion
1/3 metabolized in the liver with inactive metabolites and excreted through the kidneys

21. Contraindications with Rivaroxaban
Active, severe bleeding
Severe hypersensitivity reaction to rivaroxaban

22. Warnings Rivaroxaban Not approved for prosthetic heart valves
Combined P-gp and strong CYP3A4 inhibitors and inducers significantly alter the anticoagulant effect
ketaconazole and ritonavir
Use with caution in pregnancy due to bleeding risk
Avoid concomitant use of other anticoagulants

23. Indications Nonvalvular atrial fibrillation Treatment of DVT or PE
Prevention of DVT or PE in hip and knee replacement surgery patients

24. Rivaroxaban Dosaging 10mg tablets – prophylactic dose
With or without food
15mg tablets – treatment dose
With food
20mg tablets – treatment dose

25. Rivaroxaban Dosage in DVT/PE
LMWH is not needed initially
15mg po BID for 3 weeks
then 20 mg po QD
for the proper length
of treatment

26. Rivaroxaban Dosing for VTE Prevention in Hip and Knee Replacement
Hip replacement
10 mg po qd for 35 days
Knee replacement
10mg po qd for 12 days

27. Transition to Other anticoagulants
Discontinue warfarin and start rivaroxaban when the INR is below 3.
No data on switching from rivaroxaban to warfarin
Recommended: discontinue warfarin and start parenteral anitcoagulation and warfarin at the next scheduled dose to avoid periods of inadequate anticoagulation
Transitioning to another rapid onset anticoagulant, start at the next scheduled dose

28. Missed Dose Those taking 15mg twice daily Those taking 20mg once daily
Take the missed dose as soon as possible for a total of 30mg a day
May double the dose and take 30mg at once to achieve 30mg daily dose
Those taking 20mg once daily
Take the next dose immediately and continue on a daily dose (every 24 hours)
Do not double dose

29. Laboratory/Monitoring
PT is elevated and may be useful in monitoring
aPTT is prolonged
There is no reliable correlation between elevation of these values and therapeutic effect

30. Reversal of Rivaroxiban
No Antidote or reversal agent
Activated Charcoal to reduce absorption
Not expected to be dialyzable due to high protein binding
Prothrombin Complex Concentrate (PCC) may be considered in severe hemorrhage

31. Apixaban

32. Apixaban Factor Xa inhibitor Peak plasma concentration 2-4 hours
Half life 5 – 6 hours and 12 hours with repeated dosing
No active circulating metabolites
Excretion
Renal – 27%
25% in urine, biliary and intestinal

33. Apixaban Containdications
Severe hypersensitivity to Apixaban
Active, pathalogical bleeding

34. Apixaban Warnings
Not recommended in hemodynamic instability with PE or thrombolysis or embolectomy
Not recommended with prosthetic heart valves
Not to be used with neuroaxial anesthesia
Not to be used with strong inhibitors or inducers of CYP3A4 and P-gp
Not to be used with other anticoagulants
Category B in pregnancy
In animal models, 12% of maternal dose is excreted during lactation

35. Apixaban Indications Nonvalvular Atrial Fibrillation
DVT and PE treatment
VTE prophylaxis in hip and knee replacement

36. Dosage Postoperative prophylaxis DVT/PE Hip – 2.5mg po BID x 35 days
Knee – 2.5 mg po BID x 12 days
DVT/PE
10mg po BID x 7 days then
5mg po BID

37. Apixaban Warfarin Conversion
Apixaban affects INR
If converting from apixaban to warfarin, start Heparin or LMWH at next scheduled dose of apixaban and discontinue LMWH when INR reaches the target range
Converting from warfarin to apixaban
Start apixaban when the INR is less than 2.

38. Apixaban Administration
Take with or without food
May crush tablet
If missed dose, take immediately and then every 12 hours there after
Do no double dose for missed doses

39. Medications Contraindicated with Apixaban (9)
Carbamazapine
Dexamethasone
Fosphenytoin
Phenytoin
Prothrombin Complex Concentrate
Rifabutin
Rifampin
St. John’s Wort
Warfarin

40. Laboratory Abnormalities with Apixaban
Increases INR
Increases PT
Increase aPTT
Not reliable for monitoring

41. Reversal of Apixaban No specific antidote or reversal agent
Bleeding effects last 24 hours
Due to high plasma protein binding, it is not expected to be dialyzable
PCC or recombinant factor VIIa may be considered but no evidence for efficacy
Activated charcoal reduces absorption

42. Edoxaban

43. Edoxaban Factor Xa inhibitor Plasma availability 62%
Half life hours
Peak plasma concentration hours
Excretion primarily unchanged in the urine with a minority from the biliary and intestinal system
Take with or without food
No data on the effect of crushing
Do not double dose if missed

44. Contrindications Edoxaban
Active, prolonged bleeding

45. Warnings Edoxaban Prosthetic heart valves Neuroaxial anesthesia
Pregnancy Category C, discontinue with breast feeding
No medications are contraindicated
Avoid the use of rifampin (strong inducer of P-gp)
Avoid the use of concomitant anticoagulants, thrombolytics and antiplatelet agents
Coadministration of P-gp inhibitors during treatment for VTE should reduce dose to 30mg
Reduce dose in renal insufficiency
Not recommended in moderate to severe liver dysfunction/disease

46. Indications and Dosages Edoxaban
Nonvalvular atrial fibrillation
Treatment of DVT and PE
Parenteral anticoagulation for 5-10 days then
Greater than 60kg: 60mg po QD
Less than or equal to 60kg: 30 mg po QD
Renal impairment with GFR 15-15ml/min: 30mg po QD
Not recommended in moderate to severe liver disease

47. Anticoagulation Transition with Edoxaban
Stop warfarin and start edoxaban when the INR is less than or equal to 2.5
Other oral anticoagulants except warfarin, start at the next scheduled dose
To parenteral anticoagulants, stop anticoagulant and start edoxaban at the next scheduled dose
To warfarin: decrease dose of edoxaban by 50% and start warfarin. Discontinue edoxaban when the INR is >2

48. Transition of Edoxaban
To warfarin: decrease to 30mg a day and start warfarin. Discontinue edoxaban when INR is greater than 2 (if takeing 30mg then decrease to 15mg)
Discontinue edoxaban and start parenteral AC and warfarin at the next scheduled dose
To another short acting agent: discontinue edoxaban and start new agent at the next scheduled dose

49. Clinical Pearls and Summary
Dabigatran tablet/capsule cannot be altered – significantly increases bioavailability
Dabigatran increases the TT and ECT
Rivaroxaban in doses of 15mg and 20mg must be taken with food
Rivaroxaban can be used as monotherapy without initial use of parenteral anticoagulation
PCC may be useful for bleeding complications with rivaroxaban
Apixaban is pregnancy category B

50. Clinical Pearls and Summary
Tablet may be crushed for administration with Apixaban
9 medications contraindicated with Apixaban
When transitioning edoxaban to warfarin, parenteral anticoagulation may not be needed, may overlap a lower dose of edoxaban with warfarin until the INR is in target range
Edoxaban is not approved for VTE prophylaxis in hip and knee replacement surgical patients

51. Thank You