New Oral Anticoagulants (NOACs)Dabigatran and Rivaroxaban

for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation

Dr Dipti Chitnavis/Dr Claire HughesConsultants in HaematologyWest 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, Non-

inferiority 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 dabigatran3.11% per year for high dose dabigatran3.36% 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 Non-

Valvular 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 rivaroxaban2.4% per year for warfarin

ROCKET AF

•Clinically relevant bleeding event rates were:14.9% per year in the rivaroxaban group14.5% 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 efficacyDabigatran 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)

• TTR Warfarin (INR 2-3) 64% (WSH TTR 71.95%)

• Av. Age 71yrs• Rx discontinuation

(Dabigatran>Warfarin)• Exclusions: Previous Hx of

GI bleed

ROCKET (Rivaroxaban)

• 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 dataNOACs 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

• AntidoteNOACs have no specific antidoteWarfarin has specific antidote

• Half-lifeDabigatran: 12-14 hours (normal renal

function)Rivaroxaban: 5-9 hours (young); 11-13 hours

(elderly)Warfarin: 40 hoursRisk 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 difficultyDabigatran: cannot be crushed or

administered by nasogastric tubeRivaroxaban: can be crushedWarfarin: can be crushed; oral solution

available

• Suitability for monitored dosage systems (MDS)Dabigatran and warfarin: not suitableRivaroxaban: suitable

Risk of bleedingDabigatran: 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 bleedingDabigatran 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 15-29ml/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

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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 testsDabigatran

• APTT and TT prolongedNOT ACCURATE MEASURE OF

ANTICOAGULATION

• D-dimers lowered!

• Haemoclot Thrombin Inhibition

• TIMING of test!

Rivaroxaban

• PT prolonged (Do not use INR)NOT ACCURATE MEASURE OF

ANTICOAGULATION

• D-dimers lowered!

• Anti-Xa specific for Rivaroxaban

• TIMING of test!

Management of bleeding on NOACsGeneral 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

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

• 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

• 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