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
Topics
• Trials Summary
• Trials Issues
• Advantages and Disadvantages of NOACs
compared to Warfarin
• Effect on Coagulation Tests
• Cardioversion/ Invasive Procedures
• Management of Bleeding
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, Noninferiority Trial
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
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
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
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.
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 NonValvular Atrial Fibrillation
ROCKET AF
• Designed to determine whether rivaroxaban was
non-inferior to dose adjusted warfarin (target INR of
2.0 -3.0) 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
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
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.
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.
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
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%)
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; longterm safety data available
• Antidote
NOACs have no specific antidote
Warfarin has specific antidote
• Half-life
Dabigatran: 12-14 hours (normal renal
function)
Rivaroxaban: 5-9 hours (young); 11-13 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%)
• 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
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
• 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
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 1529ml/min; caution advised if eGFR 40-50
– Warfarin is not contra-indicated in renal
impairment
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
• 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
Cardioversion
Patients can stay on dabigatran and
warfarin while being cardioverted
No data on rivaroxaban in cardioversion
Invasive procedures-elective
• Discontinuation may be required depending
on bleeding risk/ type of procedure.
• Timing of discontinuation depends on CrCl
• SPCs provide specific information
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
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
Effects on coagulation tests
Dabigatran
Rivaroxaban
• APTT and TT prolonged
• PT prolonged
NOT ACCURATE MEASURE OF
ANTICOAGULATION
(Do not use INR)
NOT ACCURATE MEASURE OF
ANTICOAGULATION
• D-dimers lowered!
• D-dimers lowered!
• Haemoclot Thrombin
Inhibition
• TIMING of test!
• Anti-Xa specific for
Rivaroxaban
• TIMING of test!
Management of bleeding on NOACs
General non-pharmacological measures
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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
Management of bleeding on NOACs
-specific measures
Dabigatran
• 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
Rivaroxaban
• PCC (Octaplex/Beriplex),
APCC (FEIBA) or rVIIa if
ongoing life-threatening
Advantages of NOACs
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Standard dosing
No routine monitoring
No food interaction
Fewer drug interactions (Appendix 6 of the WSCCG
Guidelines)
• Monitored dosage system possible (Rivaroxaban)
NPSA requirements for Warfarin
(VKAs) & NOACs
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Counselling
Alert Card
Patient support
Regular review of anticoagulation
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