1. Direct Oral Anticoagulants
Eliot Williams, MD PhD
Division of Hematology & Medical Oncology

2. History of anticoagulant therapy
Oral thrombin and Xa inhibitors
Warfarin mechanism elucidated (J. Suttie)
Warfarin clinical trials
Anticoagulant in spoiled sweet clover (K.P. Link)
First clinical use of 4-hydroxycoumarin (O. Meyer et al)
Warfarin dosing/INR
Parenteral anticoagulants – heparin early 20th C. Incredible shrinking drug; heparin derivatives still drugs of choice for treatment of acute VTE, in-hospital prophy
Oral anticoagulants – Wisconsin connection
Heparin discovered by medical student (McLean)
Clinical use of heparin
Cont infusion of heparin; aPTT monitoring
LMWH trials
Requirement for plasma cofactor discovered
(K. Brinkhous)
LMWH
(J. Hirsch)
Fondaparinux trials

3. Direct oral anticoagulants
Dabigatran (Pradaxa®) – thrombin inhibitor
FDA approval 2010: stroke prevention in non-valvular Afib; approved 2014 for VTE treatment
Rivaroxaban (Xarelto®) – Xa inhibitor
FDA approval 2010/11: postop VTE prophylaxis, stroke prevention in Afib, treatment of VTE
Apixaban (Eliquis®) – Xa inhibitor
FDA approval 2012: stroke prevention in Afib; approved 2014 for VTE prophylaxis after major orthopedic surgery
FDA approval for VTE treatment 2014
Edoxaban (Savayasa®) – Xa inhibitor
FDA approval 1/2015: stroke prevention in Afib; treatment of acute VTE

4. Anticoagulant drug mechanisms
Indirect inhibitors
Direct inhibitors
Indirect vs direct inhibitors. Parenteral vs oral. Thrombin vs Xa. Note that warfarin doesn’t block actions of clotting factors but just lowers blood levels.
Rivaroxaban
Apixaban
Edoxaban
Ansell, 2011 HTRS meeting

5. Dabigatran given as pro-drug.
Edoxaban

6. Pharmacology of oral anticoagulant drugs
Warfarin
DOACs
Bioavailability
99%
6-80% (some active drug in large bowel)
Tmax
72-96 hours
2-4 hours
Half-life
40 hours
5-17 hours
Metabolism
Cytochrome P450
Biliary/Renal
Drug Interactions
Many
Not so many
Food Interactions
Yes No
Genetic Variation
Major effects
Minor effects (?)
Monitoring
PT/INR
None
Reversal
Vit K/PCC/FFP
PCC?
Dialysis?

7. Cost per month of oral anticoagulants
Rivaroxaban (20 mg/day) : $290
Dabigatran (150 mg bid): $290
Apixaban (5 mg bid): $147
Warfarin (7.5 mg/day): $31
About 10x as expensive as warfarin, but much cheaper than LMWH.
Source: UWHC Pharmacy

8. Dabigatran Dose Stroke prevention in A fib: 110-150 mg bid
110 mg dose not available in US
For patients with CrCl 15-30: 75 mg bid
Not recommended for CrCl < 15 or dialysis dependent
Postop VTE prophylaxis*: mg once daily
VTE treatment/prevention of recurrent VTE: 150 mg bid (following LMWH or heparin Rx)
Less than 10% absorbed; relatively high rate of GI side effects
Crosses the placenta – do not use during pregnancy
Drug may degrade over time after exposure to air – must be kept in original packaging
Unused tablets should be discarded after 90 days
* Not FDA-approved indication

9. Rivaroxaban
Dose:
Stroke prevention in nonvalvular Afib: mg once daily
Post op VTE prophylaxis: 10 mg once daily
Acute VTE treatment: 15 mg twice daily
Secondary prevention of VTE: 20 mg once daily
Acute coronary syndrome*: mg twice daily
Use with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose recommended
Avoid use if CrCl < 30 (not dialyzable)
Avoid use in severe liver disease
*Not FDA-approved indication
Treatment trials have used higher/BID doses of R initially

10. Apixaban Dose: Stroke prevention in nonvalvular Afib: 5 mg bid
2.5 mg bid if age >80, weight < 60 kg, or serum creatinine > 1.5
Post op VTE prophylaxis: 2.5 mg bid
Treatment of acute VTE: 10 mg bid x 7 days, then 5 mg bid
Secondary prevention of VTE: 2.5 mg bid
Lowest dependence on renal excretion of new agents
Avoid use in severe liver disease (75% biliary excretion)
Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz?
*Not FDA-approved indication

11. Edoxaban Dose: Stroke prevention in Afib: 60 mg/d
30 mg/d if CrCl or body wt ≤ 60 kg
Post op VTE prophylaxis*: 30 mg/d
Treatment of acute VTE: 60 mg/d (following LMWH or heparin Rx)
Avoid use if CrCl > 95 ml/min (excessive excretion decreases efficacy)
Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz?
*Not FDA-approved indication

12. DOACS for ATRIAL FIBRILLATION

13. DIRECT ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL FIBRILLATION
Drug being compared
# subjects
CHADS2
(mean)
TTR
(median)
RE-LY
Dabigatran
(two doses)
18,113
2.1
67%
ROCKET-AF
Rivaroxaban
14,264
3.5
58%
ARISTOTLE
Apixaban
18,201
66%
ENGAGE
AF-TIMI 48
Edoxaban
21,105
2.8
68%
All randomized; RE-LY unblinded
All designed as non-inferiority trials
Primary outcome was stroke or embolism
All funded by drug manufacturer
NEJM 2009; 361: 1139
NEJM 2011; 365:883
NEJM 2011; 365:981
NEJM 2013;369:2093

14. DOACS VS WARFARIN: RISK OF STROKE OR EMBOLISM
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg bid
Edoxaban 60 mg qd
Combined
Ruff et al, Lancet 2013

15. DOACS VS WARFARIN: SECONDARY EFFICACY AND SAFETY OUTCOMES
Ruff et al, Lancet 2013

16. DOACS VS WARFARIN: RISK OF MAJOR BLEEDING
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg bid
Edoxaban 60 mg qd
Combined
Ruff et al, Lancet 2013

17. Bleeding rates with dabigatran vs warfarin as a function of age
Intracranial bleeding lower with dabigatran at all ages
Extracranial bleeding rates higher with dabigatran above age 75
Circulation 2011;123:2363

18. Bleeding rates with dabigatran vs warfarin in atrial fibrillation: a “real-world” study
JAMA Intern Med 2015;175:18

19. Bleeding rates with dabigatran vs warfarin in atrial fibrillation: a “real-world” study
Favors warfarin→
JAMA Intern Med 2015;175:18

20. Dabigatran use associated with higher risk of coronary events
←Risk lower with dabigatran Risk higher with dabigatran→
Arch Intern Med 2012;172:397

21. LESSONS FROM AF TRIALS WITH DOACS
Main result: New agents at least as effective as warfarin, can be given without routine monitoring
Other/unexpected findings:
Reduction in intracranial bleeding
Higher MI rates (dabigatran)
Higher rates of GI bleeding (active drug in lower intestine)
Extracranial bleeding risk higher in older patients

22. Relative efficacy and safety of apixaban vs warfarin, according to predicted adequacy of individual INR control
Favors apixaban Favors warfarin
The benefit of switching from warfarin to a DOAC appears to be greatest in patients with relatively poor INR control
This is patient-level data comparing outcomes with apixaban and warfarin (in Afib) vs adequacy of anticoagulant control in warfarin pts vs matched controls. Bottom group is all adverse outcomes (bleeding or clotting), note that the benefit of apixaban greatest when warfarin control is worst
Wallentin et al, Circulation 2013

23. Can DOACs be used in patients with mechanical valves?
Randomized trial of dabigatran vs warfarin in patients with mechanical valves showed more thrombotic complications (5% vs 0) and more bleeding (4% vs 2%) with dabigatran (Eikelboom et al, NEJM 2013; 369:1206)
DO NOT USE DOACs IN PATIENTS WITH MECHANICAL VALVES

24. DOACS for TREATMENT OF VTE

25. Efficacy of DOACs for treatment of acute VTE is comparable to warfarin meta-analysis of phase 3 trials
J Thromb Haemost 2014;12:320

26. Safety of DOACs for treatment of acute VTE is superior to warfarin meta-analysis of phase 3 trials
J Thromb Haemost 2014;12:320

27. Efficacy and safety of alternative treatments for acute VTE vs LMWH/VKA
Unfractionated heparin + VKA inferior to LMWH + VKA
Single-agent rivaroxaban and apixaban appear safer than LMWH + VKA
JAMA 2014;312:

28. Safety and efficacy of DOACs for initial and extended treatment of VTE A systematic review
Gómez-Outes et al, J Cardiovasc Pharmacol Ther, 2015

29. DOACs for treatment of VTE
Efficacy comparable to warfarin
Fewer bleeding complications
Practical advantages
No monitoring
No injections
No transitioning – single agent treatment
Shorter hospital stay

30. DOAC treatment of AF or VTE associated with lower overall mortality vs warfarin Meta-analysis of 13 phase III trials
Four trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board.
J Thromb Haemost 2015;13:2012

31. DOACS for VTE PROPHYLAXIS

32. Less thrombosis, more bleeding with NOACs
DOACs vs LMWH after total hip or knee arthroplasty A systematic review of the literature
Dabigatran vs LMWH
Xa inhibitors vs LMWH
Mortality
Less thrombosis, more bleeding with NOACs
Symptomatic DVT
Nonfatal PE
Major bleeding
Ann Intern Med 2013;159:275

33. Extended-duration (30 day) prophylaxis with DOACs vs LMWH after total hip arthroplasty A meta-analysis of RCT data
Symptomatic VTE
Total VTE +
All-cause mortality
Major bleeding
J Thromb Haemost 2014;12:107

34. DOACS for ACUTE CORONARY SYNDROME

35. DOACs plus antiplatelet therapy in ACS: meta-analysis
Favors NOA Favors placebo
Non-significant decrease in overall mortality, large increase in risk for major bleeding
Four trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board.
Arch Intern Med 2012; 172:1537

36. Monitoring
Lotsa luck

37. Effects of DOACs on routine coag tests
PT/INR and PTT are relatively insensitive to the effects of DOACs
Reagent-dependent – results will vary among labs
Normal PT and PTT do not rule out significant blood level of DOAC
If PT or PTT elevated → assume significant blood levels of DOAC
Thrombin time very sensitive to dabigatran effect – normal TT implies no drug on board
Direct Xa inhibitors do not affect TT

38. Measuring blood levels of DOACs
Dabigatran:
Modified thrombin time assay (Hemoclot®)
Rivaroxaban, apixaban, edoxaban:
Anti-Xa activity (similar to LMWH assay)
Neither assay FDA-approved or widely available now
When to consider measuring drug level:
Detect/quantify overdose
Screen for drug accumulation (eg, impaired renal or liver function)
Assure low drug level prior to surgery
Limited usefulness for assessing compliance due to short drug half-lives
Dabigatran assays likely to be available only via send-out for most hospitals. More hospitals doing anti-Xa assays but still not routinely available most places. Compliance testing dicey due to rapid onset and short duration of drug effect. Probably better off counting pills.

39. “Analyses conducted by Boehringer Ingelheim showed that in August 2011 the company had calculated that there was an optimal plasma concentration of the drug. In June 2012 another analysis showed that measuring blood dabigatran concentrations and changing the dose as needed could reduce major bleeds by 30-40% in comparison to well-controlled warfarin”
BMJ 2014;349:4756

40. Is a “one size fits all” approach to dosing best
Is a “one size fits all” approach to dosing best? An alternative approach to dabigatran dosing
Boehringer Ingleheim web site, 2015

41. REVERSAL OF DOAC ANTICOAGULANT EFFECT

42. IDARUCIZUMAB FOR DABIGATRAN REVERSAL
Idarucizumab (Praxbind®) is a monoclonal antibody fragment that binds to dabigatran with high affinity (350x that of thrombin)
5 mg of idarucizumab (2 x 2.5 mg vials) completely reverses the anticoagulant effect of dabigatran when the drug is taken at usual recommended doses
This effect occurs within minutes of drug administration and restores normal hemostasis (NEJM 2015; 373:511)
Idarucizumab approved by FDA in October 2015

43. ANDEXANET ALFA FOR FACTOR Xa INHIBITOR REVERSAL
Modified recombinant factor Xa lacking procoagulant activity
Binds factor Xa inhibitors with high affinity and thus acts as a “decoy protein”
Short half-life: given as bolus plus a 1-2 hour infusion
In healthy volunteers taking either apixaban or rivaroxaban, the drug reduced anti-factor Xa activity by > 90% and restored normal hemostatic function in >95% of subjects (NEJM 2015;373:2413)
Not yet FDA-approved

44. OTHER OPTIONS FOR FACTOR Xa INHIBITOR REVERSAL
Activated charcoal reduces drug absorption if administered within a few hours of drug ingestion
4-factor prothrombin complex concentrate (PCC) reverses laboratory indices of drug effect (limited clinical data)

45. Transitioning
Lotsa luck

46. Transitioning to NOACs
Unfractionated heparin to NOAC:
Start NOAC when UFH infusion stopped
LMWH to NOAC:
Start NOAC 2 h before next scheduled sq dose of LMWH
Warfarin to NOAC:
When INR < 2.0
Note that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.

47. Transitioning from NOACs
NOAC to parenteral anticoagulant:
CrCl >30: start 12 hours after last NOAC dose
CrCl <30: start 24 hours after last NOAC dose
NOAC to warfarin:
CrCl >50: start warfarin 3 days before NOAC stopped
CrCl 31-50: start warfarin 2 days before NOAC stopped
CrCl 15-30: start warfarin 1 day before NOAC stopped
Remember that NOACs can prolong PT/INR
Note that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.

48. When to stop drug before surgery
Stop NOAC at least 3 drug half-lives prior to surgery
Dabigatran: h
Rivaroxaban: h
Apixaban: h
Allow more time if:
Age > 75
Impaired renal or liver function
High bleeding risk

49. Who are the best candidates for new oral anticoagulants?
Patients who have unstable INR on warfarin not due to poor compliance
Adequate renal & hepatic function
No mechanical valve
Not pregnant (drugs cross placenta)
Not at extremes of weight (can’t adjust dose)
Not at high risk of lower GI bleeding
Not at high risk for ACS (dabigatran)