1. New Oral Anticoagulants (NOACs) Dabigatran and Rivaroxaban for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation
Dr Dipti Chitnavis/
Dr Claire Hughes
Consultants in Haematology
West Suffolk Hospital

2. Topics Trials Summary Trials Issues
Advantages and Disadvantages of NOACs compared to Warfarin
Effect on Coagulation Tests
Cardioversion/ Invasive Procedures
Management of Bleeding

3. Trial data: RE-LY and ROCKET AF
RE-LY: Randomized Evaluation of Long Term Anticoagulant Therapy Comparing the Efficacy and Safety of Two Blinded Doses of Dabigatran Etexilate With Open Label Warfarin for the Prevention of Stroke and Systemic Embolism in Patients With Non-valvular Atrial Fibrillation: Prospective, Multi-centre, Parallel-group, Non-inferiority Trial

4. RE-LY
Evaluated the non-inferiority of two doses of dabigatran compared with warfarin in people with AF who were at moderate to high risk of stroke
Primary efficacy endpoint was incidence of stroke (including haemorrhagic) and systemic embolism
Primary safety endpoint was major bleeding

5. RE-LY
Lower dose dabigatran (110mg twice daily) found to be non-inferior to warfarin at reducing the risk of stroke and systemic embolism in people with AF
Higher dose dabigatran (150mg twice daily) found to be statistically significantly more effective than warfarin

6. Mean rates for major bleeding: 2.71% per year for low dose dabigatran
RE-LY
Mean rates for major bleeding:
2.71% per year for low dose dabigatran
3.11% per year for high dose dabigatran
3.36% per year for warfarin
Whereas lower-dose dabigatran was associated with a reduced risk of major bleeding, there were no significant differences between higher-dose dabigatran and warfarin in this respect
NNT 154 OVER 1 YEAR

7. RE-LY
Dabigatran thus demonstrated superiority to warfarin in preventing strokes, particularly haemorrhagic strokes, in people with AF who are at moderate or high risk of strokes. This finding, taken together with no greater risk of major bleeding, suggests a possible role as an alternative to warfarin in such patients.
NNT 172 OVER 1 YR

8. ROCKET AF:
A Prospective, Randomized, Double-Blind, Parallel-Group, Multicenter, Non-inferiority Study Comparing the Efficacy and Safety of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Subjects With Non-Valvular Atrial Fibrillation

9. ROCKET AF
Designed to determine whether rivaroxaban was non-inferior to dose adjusted warfarin (target INR of ) in preventing stroke or systemic embolism among patients with non-valvular atrial fibrillation
Primary efficacy endpoint was composite event of stroke and systemic embolism
Primary safety endpoint was composite event of major/non-major clinically relevant bleeding

10. ROCKET AF
In the per-protocol treatment group, the event rates for stroke and systemic embolism were:
1.7% per year in the rivaroxaban group
2.2% per year in the warfarin group
In the intention to treat population as part of sensitivity analysis, the event rates for stroke and systemic embolism were:
2.1% per year for rivaroxaban
2.4% per year for warfarin

11. ROCKET AF
Clinically relevant bleeding event rates were:
14.9% per year in the rivaroxaban group
14.5% per year in the warfarin group
Intracranial haemorrhage occurred less frequently with rivaroxaban as did fatal bleeding.

12. ROCKET AF
Rivaroxaban was thus shown to be non-inferior to warfarin in preventing strokes or systemic embolism in people with atrial fibrillation who are at moderate to high risk for a stroke, while demonstrating a comparable risk of major and non-major clinically significant bleeding. Intracranial haemorrhage occurred less frequently than with warfarin, but the incidence of gastrointestinal bleeding increased.

13. Stroke prevention efficacy
Dabigatran low dose (110mg twice daily)
non-inferior to warfarin at reducing the risk of
stroke and systemic embolism in people with AF
Dabigatran standard dose (150mg twice daily) statistically significantly more effective in preventing stroke, particularly haemorrhagic stroke, in people with AF with a moderate/ high risk of stroke, compared to warfarin. The number needed to treat to prevent one systemic embolism or stroke per year is 172
Rivaroxaban non-inferior to warfarin at reducing the risk of stroke and systemic embolism in people with AF

14. Trials Issues RE-LY (Dabigatran) ROCKET (Rivaroxaban)
TTR Warfarin (INR 2-3) 64% (WSH TTR 71.95%)
Av. Age 71yrs
Rx discontinuation (Dabigatran>Warfarin)
Exclusions: Previous Hx of GI bleed
TTR Warfarin (INR 2-3) 55%
Av. Age 73yrs
Annual discontinuation rate (Rivaroxaban 23.7%; Warfarin 22.2%)
Dabig. May reflect many new to Warfarin
Dabitr discontinuation – serious SE BOTH DOSES GI dyspepsia
Rivaroxaban: nose bleeds & haematuria

15. Advantages & Disadvantages of NOACs & Comparison to Warfarin
Safety data
NOACs are new drugs with a lack of long-term safety and tolerability data; rivaroxaban is a ‘black triangle’ drug Warfarin used for many years; long-term safety data available
Antidote
NOACs have no specific antidote
Warfarin has specific antidote

16. Half-life
Dabigatran: hours (normal renal function)
Rivaroxaban: 5-9 hours (young); hours (elderly)
Warfarin: 40 hours
Risk of NOAC treatment failure unless compliance is consistently good; compliance is critical as protection from stroke will be lost with omission of only one dose, compared to warfarin
NOACs may be suitable for patients who are compliant with warfarin treatment, and yet are not well controlled (TTR<60%)

17. Swallowing difficulty
Dabigatran: cannot be crushed or administered by nasogastric tube
Rivaroxaban: can be crushed
Warfarin: can be crushed; oral solution available
Suitability for monitored dosage systems (MDS)
Dabigatran and warfarin: not suitable
Rivaroxaban: suitable

18. Risk of bleeding Dabigatran: less major bleeding on lower dose compared to warfarin Rivaroxaban: more nose bleeds and haematuria, less intracranial haemorrhage, less fatal bleeding compared to warfarin

19. Risk of GI bleeding
Dabigatran standard dose (150mg twice daily) causes a higher risk of GI bleeding, and at both doses is associated with increased GI side effects, compared to warfarin
Rivaroxaban causes a higher risk of GI bleeding, and is associated with increased major GI bleeding and increased GI side effects, compared to warfarin
RE-LY exclude pmh GI bleed
Se dyspepsia

20. Renal impairment
Dabigatran: avoid if creatinine clearance <30ml/min; caution advised if eGFR 40-50
Rivaroxaban: avoid if creatinine clearance <15ml/min; caution if creatinine clearance 15-29ml/min; caution advised if eGFR 40-50
Warfarin is not contra-indicated in renal impairment
Renal function monitoring see p.15
Calculate Cr Cl prior to rX

21. Hepatic impairment
Dabigatran: avoid in liver disease, hepatic impairment expected to impact on survival, elevated liver enzymes >2 upper limit of normal
Rivaroxaban: contraindicated in hepatic disease associated with coagulopathy and clinically significant bleeding risk, including Child Pugh B and C
Warfarin: caution with unstable liver function

22. Avoid dabigatran if high risk of coronary heart disease
Risk of MI
The standard dose of dabigatran (150mg twice a day) was associated with a small but significant increase in MI; for every 476 people on dabigatran standard dose (150mg twice daily), one additional MI was observed
No. needed to harm (NNH) 476
vs (NNT 172)
Avoid dabigatran if high risk of coronary heart disease r
?clinical benefit of warfarin?

23. Cardioversion
Patients can stay on dabigatran and warfarin while being cardioverted
No data on rivaroxaban in cardioversion

24. Invasive procedures-elective
Discontinuation may be required depending on bleeding risk/ type of procedure.
Timing of discontinuation depends on CrCl
SPCs provide specific information

25. Unplanned surgery
Problems if patients on NOACs require unplanned surgery or procedures; omit dabigatran dose prior to the procedure; stop rivaroxaban 24 hours prior to intervention
Patients requiring emergency surgery can have the anticoagulant effects of warfarin reversed with dried prothrombin complex and intravenous vitamin K1

26. Assessing anticoagulant effect
No clearly defined mechanism by which to determine if NOACs are working effectively in individual patients making compliance difficult to assess
For patients on warfarin, INR can be monitored to ensure patient is within therapeutic range and compliant with treatment

27. Effects on coagulation tests
Dabigatran
Rivaroxaban
APTT and TT prolonged
NOT ACCURATE MEASURE OF ANTICOAGULATION
D-dimers lowered!
Haemoclot Thrombin Inhibition
TIMING of test!
PT prolonged
(Do not use INR)
NOT ACCURATE MEASURE OF ANTICOAGULATION
D-dimers lowered!
Anti-Xa specific for Rivaroxaban
TIMING of test!
Dabig: APTT MAY BE LINEAR- beware high APTT in case may not be linear- assay dep. Steep increase at low levels If>2x high risk bleeding
TT may be too sensitive- if normal not therapeutic at least- linear response
Clauss fib false low results- varies with agent
Riv: PT linear- inf normal at least not therapeutic
Clauss fib false low result pos I Dabig. No effect I Riv.
Standard comments from lab

28. Management of bleeding on NOACs General non-pharmacological measures
STOP antithrombotics
Document timing and amount of last dose
Consider renal/hepatic impairment
Estimate half- life of drug
Mechanical measures
FBC, APTT/ PT/TT/Fibrinogen/Creat/LFT
Quantitative lab test to assess anticoagulation
Resusc measures
Surgical measures

29. Management of bleeding on NOACs -specific measures
Dabigatran
Rivaroxaban
Oral activated charcoal (if last dose in last 2 hours)
Haemodialysis/haemofiltration and charcoal haemoperfusion
APCC (FEIBA), PCC (Octaplex/Beriplex), or rVIIa if ongoing life-threatening
PCC (Octaplex/Beriplex), APCC (FEIBA) or rVIIa if ongoing life-threatening

30. Advantages of NOACs Standard dosing No routine monitoring
No food interaction
Fewer drug interactions (Appendix 6 of the WSCCG Guidelines)
Monitored dosage system possible (Rivaroxaban)

32. NPSA requirements for Warfarin (VKAs) & NOACs
Counselling
Alert Card
Patient support
Regular review of anticoagulation

33. Key Points
Efficacy from trial data may not be applicable to each patient
Assess patient carefully for suitability for anticoagulation (falls risk?)
Compliance important with shorter half-lives
Assess cautions/contraindications of NOACs compared to warfarin (renal/hepatic/cardiac/bleeding history)
Routine coagulation tests are not reliable for NOACs
No antidote to date
Regular review
Long term safety