ashfaq shuaib, md professor of neurology and medicine director university of alberta stroke program...

Ashfaq Shuaib, MD

Professor of Neurology and Medicine

Director University of Alberta Stroke Program

University of Alberta

New Oral Anticoagulants in Stroke Prevention in Atrial Fibrillation

Competing Interests Declaration

• Competing interests– chair the steering committee of the SENTIS trial and

FastFlo Trial and am an advisor to CoAxia. I am also on the steering committee of the DIAS III & DIAS IV trials, Impact-24 trial and the MASCI trial.

• In the past 5 years, I have received speaker fees from:

• Sanofi-Aventis/BMS, BI, Pfizer, Merck, Roche, Servier, AstraZeneca, Bayer

• In the past 5 years, I have served on national and international advisory boards for:

• AstraZeneca, BI, Lundbeck, Bayer, Sanofi-Aventis/BMS, Roche, Pfizer

Key questions addressed today

• Stroke and AF a Case History

• Warfarin and stroke prevention in AF

• NOACs and stroke prevention in AF

• “Flawed” comparison

Case History (three days ago)

• 76 years old male

• AF for 10 years. Initially on warfarin but switched to Dabigatran 110 twice daily due to difficulty maintaining INRs therapeutic

• Hypertension, DM, CHF

• Lower GI bleed. Dabi reduced to once/d

• Presents with L face weekness/dysarthria

• Imaging

Course in hospital

• Hold anticoagulation?

• Further imaging?

• Prevention of recurrent stroke (in-hospital)– ASA ?– iv anticoagulation ?

• When to start oral anticoagulation

• What is the best medication for long term prophylaxis

Atrial Fibrillation is a Major Preventable Cause of Stroke

• AF accounts for 1 in 6 ischemic strokes (1 in 4 in the elderly)– More than 14,000 AF related strokes a year in

Canada– Many times more ‘silent’ strokes

• Strokes caused by atrial fibrillation are generally severe; 1-year mortality is 50%

Also remember….

• AF paroxysmal in up to one third of patients

• The presence of a non-AF identifiable cause does not rule out cardio-embolic stroke secondary to AF

• Many “cryptogenic strokes” may be seconday to AF

Stroke Prevention in AF

• Stroke-risk dependent on presence of “risk factors”. CHAD2 and CHAD-VASc scores

• ASA reduces risk but not significant in patients with previous TIAs or stroke

• ASA+ clopidogrel better than ASA; however increased bleeding risk

• Warfarin very effective in stroke prevention: however TTR problematic

Hart Ann Int Med 1999;131:492

RRR = 64%




• New Oral Anticoagulants and stroke prevention in AF


World Stroke Congress 2010

Seoul, South Korea

Advantages of New Oral Anticoagulants Over Warfarin

Feature Warfarin New Orals

Onset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Interactions Many Few

Monitoring Yes No

Offset Long Short

Disadvantages of New Oral Anticoagulants Over Warfarin

Features Warfarin New Agents

Frequency Once dailyOnce or twice

daily

Monitoring INR Uncertain

Clearance Non-renal Renal 25-80%

Antidote Vit K, FFP, PCC None

Familiarity Extensive Limited

Comparative Pharmacology

Characteristic Rivaroxaban Apixaban Dabigatran

Target Factor Xa Factor Xa Thrombin

Prodrug No No Yes

Bioavailability 80% 60% 6%

Dosing o.d. (b.i.d.) b.i.d. b.i.d. (o.d.)

Half life 7-11 h 12 h 12-17 h

Renal 33% (66%) 25% 80%

Monitoring No No No

Interactions 3A4/P-gp 3A4/P-gp P-gp

Dabigatran and stroke prevention

• RE-LY: probe design (110 and 150 mg Dabigatran vs Warfarin) 18,118 patients

• Both doses of Dabi non-inferior to Warfarin

• Higher dose superior to Warfarin

• Significantly less bleeding, especially ICH

• Higher dose associated with significantly fewer ischemic strokes

Nov 2012

The Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE®) study

Stuart J Connolly, Lars Wallentin, Michael Ezekowitz, John Eikelboom, Jonas Oldgren, Janice Pogue, Paul Reilly, Martina Brueckmann, Salim Yusuf; on behalf of the RELY-ABLE® Steering Committee and Investigators

November 2012

Nov 2012

Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los Angeles, CA, 7 Nov 2012

• Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of products outside the Canadian approved Product Monograph• The content of this slide may contain information not reviewed by Health Canada• Note that there may be discrepancies between the information in this presentation and the final publication

Stroke and ischaemic events: RELY-ABLE®

23

Event

D150

(%/yr)

D110

(%/yr)HR 95% CI

Stroke or SEE 1.46 1.60 0.91 0.69–1.20

All stroke 1.24 1.38 0.89 0.66–1.21

Ischaemic 1.15 1.24 0.92 0.67–1.27

Haemorrhagic 0.13 0.14 0.89 0.34–2.30

Myocardial infarction 0.69 0.72 0.96 0.63–1.45

Pulmonary embolism 0.13 0.11 1.14 0.41–3.15

5851 patients followed for mean of 2.3 yearsD150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratioSEE = systemic embolic event



Mortality and net benefit: RELY-ABLE®

Event

RELY-ABLE®

D150 (%/yr)

D110 (%/yr)

HR 95% CI

Total mortality 3.02 3.10 0.97 0.80–1.19

Vascular mortality 1.67 1.62 1.03 0.78–1.35

Disabling stroke, life-threatening bleed or death

4.53 4.45 1.02 0.86–1.20

Stroke, systemic embolism, myocardial infarction, pulmonary embolism, major bleed or death

7.36 6.89 1.07 0.94–1.22

24

5851 patients followed for mean of 2.25 yearsD150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio



Conclusions• During 2.3 years of additional treatment after RE-LY®

(total mean follow-up 4.3 years), rates of stroke and major bleeding remain low on dabigatran and are consistent with those seen during RE-LY®

• Dabigatran 150 vs dabigatran 110– Both doses have very low rates of hemorrhagic stroke

over 4+ years– With dabigatran 150, there is a lower rate of ischemic

stroke but a higher rate of major bleeding– Both doses have similar mortality

25Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los

Angeles, CA, 7 Nov 2012


Study limitations• Study medication blinded but warfarin open

label • More MIs in treatment arms (initial publication)• GI intolerance • GI bleeding rates similar to warfarin in elderly• Renal disease increased risk of complications,

especially with higher dose of Dabigatran

Rivaroxaban and stroke prevention

• ROCKET-AF: 20 mg daily vs Warfarin 14,264 patients, double blind

• CHAD2 scores higher than other trials

• 55 % of patients with previous TIA or stroke

• Major bleeding, especially ICH lower with Rivaroxiban

• Rivaroxaban non-inferior to Warfarin

Study limitations

• Non-inferior but NOT superior to Warfarin on ‘intention to treat” analysis

• Once a day dose of Rivaroxaban

• Higher rates of GI bleeding with study drug

• Study end and switch to Warfarin– Time to therapeutic INR (13 vs 3 days)– Higher events in the patients previously on

Rivaroxaban

Apixaban and stroke prevention

• AVERROES (5,599) and ARISTOTLE (18,201) trials

• AVERROES stopped early because of significantly fewer events (stroke and ICH) in apixaban group

• ARISTOTLE: Apixaban superior to Warfarin• Significantly fewer hemorrhages (ICH and

systemic) • Lower mortality

Study limitations

• Patient selection (unable to tolerate warfarin !!!) in AVERROES

• Short follow up period in AVERROES – bleeding risk underestimated ?

• Low stroke risk in AVERROES

• Issues with FDA for AF indication





• Specific stroke prevention sub-groups


For patients with atrial fibrillation, anticoagulation effectively reduces the risk of stroke.

Circulation 2012;125:159-164

Stroke risk in patients with previous TIAs and Stroke

Risk of hemorrhage in patients with previous TIAs and Stroke

Limitations with NOACs

• When to start treatment after acute stroke

• Reversal of anticoagulation

• Treatment of ICH

• Thrombolysis in acute stroke

• Combination with ASA or dual antiplatelets

• Long-term experience lacking

• Compliance cannot be monitored

Antithrombotic guidelines for stroke prevention in AF trial fibrillation

• ACCP 2012

“…we suggest dabigatran 150 mg bid rather than adjusted-dose VKA therapy…”.

• AHA 2012“….newer agents superior to VKA therapy…”

• CCS 2012

“…we suggest…that…most patients should receive dabigatran, rivaroxaban or apixaban

in preference to warfarin...” You JJ, et al. Chest 2012; 141: e531S-575SSkanes AC, et al. Can J Cardiol 2012; 28: 125-136

Characteristic Choice Rationale

Mechanical valve or valvular a.fib Warfarin New agents not studied

Poor compliance Warfarin or nothing Missed doses of greater consequence with shorter-acting new agents

Stable on Warfarin Warfarin Patient preference might mean switching

CrCl < 30 mL/min Warfarin Such patients were excluded from trials with new agents

CrCl of 30-50 mL/min Rivaroxaban or Apixaban

Oral factor Xa inhibitors are less affected by impaired renal function than dabigatran

Dyspepsia or upper GI complaints Rivaroxaban or Apixaban

Dyspepsia in up to 10% given dabigatran

Recent GI bleed and ongoing risk Apixaban More gastrointestinal bleeding with dabigatran (150 mg BID) or rivaroxaban than with warfarin

Recent Acute Coronary Syndrome Rivaroxaban or Apixaban

Small myocardial infarction signal with dabigatran

Poor compliance with BID regimen or desire for once daily

Rivaroxaban Only agent that is once a day

Liver dysfunction with elevated INR Warfarin New agents require hepatic metabolism

Atrial Fibrillation treatment choices

ashfaq shuaib, md professor of neurology and medicine director university of alberta stroke program...

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