[PPT] - Society: Atrial Fibrillation Guidelines Interactive Workshop ACC PowerPoint Presentation

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John A Cairns, MD, FRCPC, FACC University of British Columbia, Canada jacairns@medd.med.ubc.ca

Canadian Cardiovascular Society:

Atrial Fibrillation Guidelines Interactive Workshop ACC Rockies 2012

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Disclosures: John A Cairns

DSMBs

Chair, AVERROES (apixaban), Chair, SHIELD-2 (azimilide)
Member, ACTIVE Trials (aspirin, clopidogrel, warfarin),

PALLAS (dronedarone) Advisory Boards

Boehringer Ingelheim Canada (Since Nov 2010)
St Jude Medical (Since January 2012)

Research Grants

Medtronic, Astra Zenica

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Atrial Fibrillation Guidelines

Anne Gillis (co chair)
Allan Skanes (co chair)
John Cairns
Stuart Connolly
Jafna Cox
Paul Dorian
Jeff Healey
Laurent Macle
Sean McMurtry
Brent Mitchell
Stanley Nattel
Pierre Pagé
Ratika Parkash
P. Timothy Pollak
Michael Stephenson
Ian Stiell
Mario Talajic
Teresa Tsang
Atul Verma

CCS AF Guidelines 2010 Primary Panel

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Atrial Fibrillation Guidelines

GRADE Approach

Clear separation of 2 issues:

1. Four Categories of Quality of Evidence:
High, Moderate, Low or Very Low
2. Strength of Recommendations : 2 Grades
Strong or Conditional (weak)
Quality of evidence only one factor

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Atrial Fibrillation Guidelines

Guidelines Development : 2009-10
CCS Presentations
CJC Publication: Jan/Feb 2011
CCS website – slide set
pocket guide
webinairs
CME events
Update Process: 2011-12
CJC Publication: Mar/Apr 2012

CCS AF Guidelines Process

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Atrial Fibrillation Guidelines

Stroke Prevention

John Cairns (Chair)
Stuart Connolly
Sean McMurtry
Mario Talajic
Carl van Walraven
Gord Gubitz

Rate and Rhythm

Atul Verma (Chair)
Brent Mitchell
Stanley Nattel
Paul Dorian
Anne Gillis
Ratika Parkash
P. Timothy Pollak
Ian Stiell
Teresa Tsang
Jafna Cox

CCS AF Guidelines 2012 Update Primary Panel

Jeff Healey (co chair) Allan Skanes (co chair)

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Atrial Fibrillation Guidelines

New oral anticoagulants
Predicting risk of stroke
Use of new agents in CAD
Anticoagulation and Chronic

Kidney Disease

New evidence about Dronederone

CCS AF Guidelines 2012 Update What’s New?

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Atrial Fibrillation Guidelines

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Atrial Fibrillation Guidelines

New oral anticoagulants
Predicting risk of stroke
Use of new agents in CAD
Anticoagulation and Chronic

Kidney Disease

CCS AF Guidelines 2012 Update What’s New in Stroke Prevention?

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RELY

Dabigatran for stroke prevention in atrial fibrillation

Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor)

R

Warfarin 1 mg, 3mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 Dabigatran Etexilate 150 mg b.i.d. N=6000

Primary objective: Noninferiority to warfarin
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.
Primary end point: Stroke + systemic embolism

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RR = 0.91, P<0.001, non-inf RR = 0.66, P<0.001 sup mo.

RE-LY Trial. Stroke or Systemic Embolism

Connolly SJ, et al. NEJM 2009;361

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RR = 0.91, P<0.001, non-inf RR = 0.66, P<0.001 sup mo.

RE-LY Trial. Stroke or Systemic Embolism

Connolly SJ, et al. NEJM 2009;361

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Major bleeding rates

Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

RR 0.93 (95% CI: 0.81–1.07) p=0.31 (sup)

2.71 3.11 3.36 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 D110 mg BID D150 mg BID Warfarin

RR 0.80 (95% CI: 0.69–0.93) p=0.003 (sup)

322 / 6,015 375 / 6,076 397 / 6,022

RRR 20% % per year

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Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

Statistics: non-inferiority, >95% power, 2.3% warfarin event rate

INR target - 2.5 (2.0-3.0 inclusive) 20 mg daily 15 mg for Cr Cl 30-49

Atrial Fibrillation

Randomize Double blind / Double Dummy (n ~ 14,000)

Risk Factors

CHF
Hypertension
Age  75
Diabetes

OR

Stroke, TIA or Systemic

embolus

At least 2 required

Monthly Monitoring and adherence to standard of care guidelines

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Primary Efficacy Outcome

Stroke and non-CNS Embolism

Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

1 2 3 4 5 6 120 240 360 480 600 720 840 960

No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization Cumulative event rate (%) Rivaroxaban

Rivaroxaban Warfarin Event Rate 1.71 2.16

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Primary Safety Outcomes

Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P- value Major and non-major Clinically Relevant 14.91 14.52 1.03 (0.96, 1.11) 0.442 Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 Non-major Clinically Relevant 11.80 11.37 1.04 (0.96, 1.13) 0.345

Event Rates are per 100 patient-years Based on Safety on Treatment Population

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Atrial Fibrillation with At Least One Additional Risk Factor for Stroke

Apixaban placebo twice daily + Warfarin (target INR 2-3) Apixaban 5 mg oral twice daily + Warfarin placebo Primary outcome: stroke and systemic embolism Other outcomes: Death, MI, bleeding Stratified by warfarin-naïve status

448 events over anticipated 2 year median follow-up; >90% power to show non-inferiority (apixaban vs warfarin upper bound of 95% CI <1.38)

Randomize Double blind (n = 15,000)

Age ≥ 75 years
Prior stroke, TIA or SE
CHF or LVEF ≤ 40%
Diabetes mellitus
Hypertension

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

ARISTOTLE

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Primary Outcome

Stroke (ischemic or hemorrhagic) or systemic embolism

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

No. at Risk

Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 21% RRR

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Major Bleeding

ISTH definition

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at Risk

Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491 31% RRR

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CHA2DS2-VASc

Risk Factor Score

Congestive Heart Failure 1 Hypertension 1 Age ≥ 75 2 Diabetes Mellitus 1 Stroke/TIA/Thrombo- embolism 2 Vascular Disease 1 Age 65-74 1 Female 1 Maximum Score 9

Risk Factor Score

Congestive Heart Failure 1 Hypertension 1 Age ≥ 75 1 Diabetes Mellitus 1 Stroke/TIA/Thrombo- embolism 2 Maximum Score 6

CHADS2

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Validation of CHA2DS2VASc

Olesen et al. BMJ 2011;342:d124

HR P-value event %

CHA2DS2VASc score = 0

1.0 0.69 CHA2DS2VASc score = 1 Heart failure 3.39 <0.001 Hypertension 2.32 <0.0001 Diabetes 3.31 <0.0001 Vascular Disease 2.04 0.002 1.40 Age 65-74 3.07 <0.0001 2.13 Female sex 1.25 <0.10 0.86 HRs for Hospital Admission or Death due to Thromboembolism by 5 years’ Follow-up

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Validation of CHA2DS2VASc

Olesen et al. BMJ 2011;342:d124

HR P-value event %

CHA2DS2VASc score = 0

1.0 0.69 CHA2DS2VASc score = 1 Heart failure 3.39 <0.001 Hypertension 2.32 <0.0001 Diabetes 3.31 <0.0001 Vascular Disease 2.04 0.002 1.40 Age 65-74 3.07 <0.0001 2.13 Female sex 1.25 <0.10 0.86

CHA2DS2VASc score = 2
Vasc dis + Female

2.81 <0.008 1.95 HRs for Hospital Admission or Death due to Thromboembolism by 5 years’ Follow-up

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Atrial Fibrillation Guidelines

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RE-LY Yearly Event Rate (%)

Dabi 110 Dabi 150 Warf Dabi vs warf

MI 0.82 0.81 0.64 HR 1.28, P=0.07 MI, UA, Card arrest

r card death

3.16 3.33 3.41 HR 0.96, P=0.50 Stroke, SEE other card isch events 4.76 4.47 5.10 HR 0.90, P=0.05 Net clin benefit 7.34 7.11 7.91 HR 0.91, P=0.02

Submitted to Circulation - Confidential

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Dabigatran and MI in RE-LY (& other trials)

Uchino K, et al. Arch Intern Med 2012

Mortality OR 0.89; 95% CI: 0.80-0.99

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Dabigatran and MI in RE-LY

Years of Follow-up Cumulative Hazard Rates 0.0 0.05 0.10 0.15 0.20 0.25 0.5 1.0 1.5 2.0 2.5

MI Stroke/SEE/MI/UA/PCI/CABG/ Cardiac arrest/Cardiac death Net clinical benefit

Dabigatran 110 Dabigatran 150 Warfarin

Hohnloser S, et al. Circulation 2012 (in press)

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Phase II and III Trials in ACS

DAPT + new OAC vs DAPT REDEEM, APPRAISE, ATLAS-1 : Similar rates of ischemic outcomes ATLAS-2: Significant reduction of composite

utcome of CV death, MI or stroke (AHA)

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We recommend that patients with atrial fibrillation who are receiving OAC: a) Have their renal function assessed at least annually by the measurement of serum creatinine and calculating eGFR b) Be regularly considered for the need for alteration of OAC drug and/or dose-changes based on eGFR Strong Recommendation Moderate Quality Evidence Strong Recommendation Moderate Quality Evidence

Stroke prevention in non valvular A Fib in patients with chronic kidney disease

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For antithrombotic therapy of CKD patients, therapy should relate to eGFR as follows: a) eGFR 30 > ml/min: We recommend that such patients receive antithrombotic therapy according to their CHADS2 score as detailed in recommendations 3, 4 and 5 above Strong Recommendation High Quality Evidence Stroke prevention in non valvular A Fib in patients with chronic kidney disease b) eGFR 15-30 ml/min and not on dialysis: We suggest that such patients receive antithrombotic therapy according to their CHADS2 score as for patients with normal renal

function. The preferred agent for these patients is warfarin.

Weak Recommendation Low Quality Evidence

Values and Preferences: This recommendation places a relatively higher weight on prevention of ischemic stroke than on bleeding complications associated with antithrombotic therapy. No therapy may be appropriate for some patients with eGFR 15-30 ml/min (not on dialysis) with a stronger preference for avoiding bleeding complications than preventing ischemic stroke.

c) eGFR <15ml/min (on dialysis): We suggest that such patients not routinely receive either OAC (Conditional Recommendation, Low Quality Evidence) or aspirin (Conditional Recommendation, Low Quality Evidence) for stroke prevention in atrial fibrillation.

Values and Preferences: This recommendation places a relatively higher weight on observational data linking warfarin and aspirin use with mortality in patients on dialysis, and relatively lower weight on the potential for these agents to prevent ischemic stroke. Therapy for oral anticoagulation or antiplatelet therapy may be appropriate for some patients with eGFR <15 ml/min (on dialysis) in whom there is a stronger preference for avoiding ischemic stroke.