1. Update on the New Oral Anticoagulants
Eliot Williams, MD PhD
Division of Hematology & Medical Oncology

2. Nothing to disclose

3. 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

4. New oral anticoagulants
Dabigatran (Pradaxa®) – thrombin inhibitor
FDA approval 2010: stroke prevention in non-valvular Afib
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
Edoxaban – Xa inhibitor
Not yet FDA approved

5. 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.
Ansell, 2011 HTRS meeting

6. Dabigatran given as pro-drug.
Edoxaban

7. Pharmacology of oral anticoagulant drugs
Warfarin
New agents
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?

8. 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

9. 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
Prevention of recurrent VTE*: 150 mg bid
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

10. Rivaroxaban Dose: Stroke prevention in Afib: 15-20 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

11. Apixaban Dose: Stroke prevention in 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
Secondary prevention of VTE*: mg bid
Treatment of acute VTE*: 10 mg bid
Secondary prevention of VTE*: 5 mg bid
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

12. NOACS for ATRIAL FIBRILLATION

13. NEW 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

14. NEW ORAL ANTICOAGULANTS 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. NEW ORAL ANTICOAGULANTS VS WARFARIN: SECONDARY EFFICACY AND SAFETY OUTCOMES
Ruff et al, Lancet 2013

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

19. LESSONS FROM AF TRIALS WITH NEW ORAL AGENTS
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

20. Relative efficacy and safety of apixaban vs warfarin, according to adequacy of individual INR control
Favors apixaban Favors warfarin
The benefit of switching from warfarin to a NOAC 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

21. Can the new oral agents 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 NOACs IN PATIENTS WITH MECHANICAL VALVES

22. NOACS for TREATMENT OF VTE

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

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

25. NOACs for treatment of VTE
Efficacy comparable to warfarin
Modest safety advantage
Practical advantages
No monitoring
No injections
No transitioning – single agent treatment
Shorter hospital stay

26. NOACS for VTE PROPHYLAXIS

27. Less thrombosis, more bleeding with NOACs
NOACs 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

28. NOACS for ACUTE CORONARY SYNDROME

29. New oral anticoagulants 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

30. Monitoring
Lotsa luck

31. Effects of NOACs on routine coag tests
PT/INR and PTT are relatively insensitive to the effects of these drugs
Reagent-dependent – results will vary among labs
Normal PT and PTT do not rule out significant blood level of NOAC
If PT or PTT elevated → assume significant blood levels of NOAC
Thrombin time very sensitive to dabigatran effect – normal TT implies no drug on board
Rivaroxaban & apixaban do not affect TT

32. Measuring blood levels of NOACs
Dabigatran:
Modified thrombin time assay (Hemoclot®)
Rivaroxaban and apixaban:
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.

33. REVERSAL? No specific antidote for any of the new OACs
New agents in development may solve this problem
Activated charcoal will reduce drug absorption if administered within a few hours of ingestion
Rivaroxaban & apixaban effect may be reversed by giving prothrombin complex concentrate (PCC) (limited data)
Dabigatran is dialyzable
60% removed/3 hours, with rebound effect
Case reports suggest that recombinant factor VIIa (NovoSeven™) is ineffective vs dabigatran (Thromb Haemost 2012;108:585)

34. Risk-benefit profile of NOACs vs warfarin remains favorable in patients with moderate renal insufficiency (GFR < 50) Meta-analysis of 9 phase III trials
Thrombotic events
Major bleeding
% of drug excreted by kidneys →
VKA better
NOAC better
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 2014;12:337

35. Transitioning
Lotsa luck

36. 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.

37. 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.

38. 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

39. Who are the best candidates for new oral anticoagulants?
Patients who have unstable INR on warfarin not due to poor compliance
Reasonably good renal & hepatic function
No mechanical valve
Not pregnant (drugs cross placenta)
< 75 years old
No history of lower GI bleeding
Not at high risk for ACS (dabigatran)