stroke prevention in atrial fibrillation

Stroke Prevention inStroke Prevention inAtrial FibrillationAtrial Fibrillation

A Review of New Study Results

and

An Exploration of their Clinical Implications

• Which of the following items are factors that determine the effectiveness of a therapy?

A) Efficacy

B) Penetration

C) Adherence

D) All of the above

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Question #1 -Question #1

• What percentage of patients with atrial fibrillation are optimally treated with Warfarin (i.e. INR is at target) in the Primary Care setting are?

A) 15%

B) 25%

C) 50%

D) 75%


• What percentage of patients who have a documented history of stroke secondary to atrial fibrillation, and who now present to the hospital with a second stroke, are optimally treated with Warfarin (i.e. INR is at target)?

A) 10%

B) 20%

C) 40%

D) 80%


• True or False: Treating patients with antiarrhythmic medications to prevent recurrences of Atrial Fibrillation help to prevent subsequent strokes.

A) True

B) False


Stroke Prevention inStroke Prevention inAtrial FibrillationAtrial Fibrillation

A Review of New Study Results

and

An Exploration of their Clinical Implications

• Astra Zeneca Canada Inc.

• Boehringer Ingelheim Inc.

• Bristol Myers Squibb Canada

• Sanofi Aventis Pharma Inc.

• Servier Canada Inc.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Disclosures -Disclosures

Years after randomization

CumulativeMortality

(%)

00

1 2 3 4 5

5

10

15

20

25

30

All-cause mortality

Rhythm control

Rate control

P=0.08

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -Mortality in Rate vs. Rhythm Control Patients

-The AFFIRM Study-The AFFIRM Study

• N Engl J Med 2002; 347: 1825-33.

Sinus Rhythm

Antiarrhythmic Use

Warfarin Use

Digoxin Use

0.5 1.0 1.5

Risk Ratio0

pValue

<0.0001

0.0005

<0.0001

0.0005

• N Engl J Med 2002; 347: 1825-33.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -Mortality in Rate vs. Rhythm Control Patients

-The AFFIRM Study-The AFFIRM Study

2.0

Study Year

AFASAK I 1989; 1990

SPAF I 1991

BAATAF 1990

CAFA 1991

SPINAF 1992

EAFT 1993

All trials (n=6)

N=2,900

Relative Risk Reduction(95% CI)


Favors Warfarin Favors Warfarin Favors Placeboor Control

Favors Placeboor Control

100%100% 50%50% 00 -50%-50% -100%-100%

Adjusted-dose warfarin comparedwith placebo or controlAdjusted-dose warfarin comparedwith placebo or control

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy of Warfarin -Efficacy of Warfarin

-Meta-Analysis of Antithrombotic Therapy in A Fib-Meta-Analysis of Antithrombotic Therapy in A Fib

• Ann Intern Med 2007; 146: 857-67.

Study Year

AFASAK I 1989; 1990

SPAF I 1991

EAFT 1993

ESPS II 1997

LASAF 1997

DailyAlternate day

UK-TIA300 mg daily1200 mg daily

1999

JAST 2006

Aspirin trials (n=7)

SAFT 2003

ESPS IIDipyridamoleCombination

1997

All antiplatelet trials (n=8)

Antiplatelet agents compared with placebo or controlAntiplatelet agents compared with placebo or control



Favors Antiplatelet Favors Antiplatelet Favors Placeboor Control

Favors Placeboor Control

100%100% 50%50% 00 -50%-50% -100%-100%N=4,876N=4,876

• Ann Intern Med 2007; 146: 857-67.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy of Anti-Platelet Therapy -Efficacy of Anti-Platelet Therapy


• Adjusted dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%, respectively, with an increase in bleeding

• Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding

• Based on these results, warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk

Warfarin Antiplatelets

• Ann Intern Med 2007; 146: 857-67.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy and Safety of Current A Fib Treatments -Efficacy and Safety of Current A Fib Treatments


05

10152025303540

Safety Outcomes

(n)

ICH Major ECH

WW

AA

WW

AA

-64

-22

-70

-60

-50

-40

-30

-20

-10

0

Risk Reduction in Stroke

(%)

% %

% %

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Anti-Thrombotic Therapy in Atrial Fibrillation-Anti-Thrombotic Therapy in Atrial Fibrillation

-ACC/AHA/ESC Guidelines 2006-ACC/AHA/ESC Guidelines 2006

• Europace 2006; 8: 651-745.

High Risk Moderate Risk Low Risk

Rheumatic Valve

Prior Stroke/TIA

Or

>2 Risk Factors:

•Age >75

•Hypertension

•Diabetes

•Congestive Heart Failure

1 Risk Factor:

•Age >75

•Hypertension

•Diabetes

•Congestive Heart Failure

Age <75

No Additional Risk Factors

Warfarin

INR Range 2.0 – 3.0

Warfarin

INR Range 2.0 – 3.0

Or

Aspirin 75-325mg/day

Aspirin 75-325mg/day

• Efficacy is a necessary but not sufficient condition for the effective prevention of cardiovascular disease and is ideally established through randomized, controlled experimental studies

Effectiveness

Efficacy

Adherence

Penetration

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effective vs. Efficacious Drug Therapy-Effective vs. Efficacious Drug Therapy

Unpredictable response

Routine coagulation monitoring

Slow onset/offset of action

Risk of BleedingComplications

Warfarin therapy has

several limitations

that make it difficult to

use in practice

Numerous drug-drug interactions

Numerous food-drug interactions

Frequent dose adjustments

Narrow therapeutic window

(INR range 2-3)

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation

• Warfarin was #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use”

• Warfarin caused 6% of the 702,000 ADEs treated in the ED/year; 17% required hospitalization

• J Thromb Thrombolysis 2008; 25: 52-60.

International Normalised Ratio (INR)

Target INR

(2.0-3.0)

<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.50

20

40

60

80

Eve

nts

/ 10

00 p

atie

nt

year

s

Intracranial haemorrhageIschaemic stroke

The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range

• N Engl J Med 2003; 349: 1019-26.


-Narrow Therapeutic Window-Narrow Therapeutic Window

INR Above TargetINR Above Target6%6%

Subtherapeutic INR Subtherapeutic INR 13%13%

INR at TargetINR at Target15%15%

No No warfarinwarfarin

65%65%

• Arch Intern Med 2000; 160: 967.


-Adequacy of Anticoagulation in Primary Care-Adequacy of Anticoagulation in Primary Care

• Analyzed 597 patients with a first ischemic stroke who had known atrial fibrillation, were classified as high risk for stroke, and who had no known contraindications to anticoagulation

• Stroke 2009; 40: 235-40.


-Preventable Strokes in Patients with Atrial Fib-Preventable Strokes in Patients with Atrial Fib




61%61%

• Analyzed 323 patients with a second ischemic stroke who had known atrial fibrillation at the time of their first stroke, and who had no known contraindications to anticoagulation

• Stroke 2009; 40: 235-40.


-2-2oo Prevention of Strokes in Patients with A Fib Prevention of Strokes in Patients with A Fib




43%43%

PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)

• N Engl J Med 2009; 360: 2066-78.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence

-The ACTIVE-A Study-The ACTIVE-A Study

PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)

Fall Risk (9.8%)

Hypertension (3.2%)

Previous Bleedingon OAC (5.8%)

EtOHUse

(1.1%)

PUD(0.7%)

Low Plt(2.2%)

NSAIDUse

(1.6%)

• N Engl J Med 2009; 360: 2066-78.



PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)

• N Engl J Med 2009; 360: 2066-78.



PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)

Concerns re: Adherence(0.7%)

Both(22.8%)

CoumadinNot Indicated

(28.6%)

• N Engl J Med 2009; 360: 2066-78.



PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)

• N Engl J Med 2009; 360: 2066-78.



PhysicianJudgement

(50.4%)

BleedingRisk

(23.5%)

PatientPreference

(26.1%)Another 22.8% of

Patients “Not WillingTo Take Coumadin”“Not Willing To Take Coumadin”

is the sole reason in 26.1% of Patients • N Engl J Med 2009; 360: 2066-78.



Documented AF + 1 risk factor:

Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + CAD or diabetes

ACTIVE WClopidogrel+ASA vs. Warfarin

Contra-indications to Warfarin or Unwilling

ACTIVE AClopidogrel+ASA vs. ASA

No Exclusion criteria for ACTIVE I

ACTIVE IIrbesartan vs placebo

6500 patients 7500 patients

~9000 patients

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The ACTIVE Program -The ACTIVE Program

0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

Cu

mul

ativ

e H

azar

d R

ates

Years

3.93 %/year

5.64 %/yearRR = 1.45

P = 0.0002

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death-Stroke, Embolism, MI and Vascular Death

-The ACTIVE-W Study-The ACTIVE-W Study

• Lancet 2006; 367: 1903-12.

0.0

0.01

0.02

0.03

0.04

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASACu

mul

ativ

e H

azar

d R

ates

Years

2.4 %/year

2.2 %/year

RR = 1.06

P = 0.67

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Major Bleeding-Major Bleeding


• Lancet 2006; 367: 1903-12.

INR RangePercent patient months

in range

<2.0 20.8

2.0-3.0 63.9

>3.0 15.4

• Lancet 2006; 367: 1903-12.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -INR Control in the ACTIVE-W Study-INR Control in the ACTIVE-W Study


0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

C+A

0.0

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5

OAC

C+A

65% INR in Range <65% INR in Range

Cu

mu

lati

ve H

azar

d R

ates

Years

RR = 1.83

P < 0.0001

RR = 1.11

P = 0.47

• Lancet 2006; 367: 1903-12.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death by INR-Stroke, Embolism, MI and Vascular Death by INR







No Exclusion criteria for ACTIVE I



~9000 patients


832 (6.8%/year)

00 11 22 33 44

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

Cu

mu

lati

ve I

nci

de

nce

Cu

mu

lati

ve I

nci

de

nce

YearsYears

Cum

ulat

ive

Haz

ard

Rat

es0.

00.

10.

20.

30.

4

0 1 2 3 4

Aspirin

Clopidogrel+Aspirin

HR=0.89 (0.81-0.98) p=0.014

3772 3456 3180 2523 11803782 3427 3103 2459 1153

No. at Risk

ASAC+A

Years

ASA

924 (7.6%/year) 11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01)

11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01)

Clopidogrel + ASA

• N Engl J Med 2009; 360: 2066-78.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death-Stroke, Embolism, MI and Vascular Death


296 (2.4%/year)

408 (3.3%/year)

Cu

mu

lati

ve In

cid

ence

Cu

mu

lati

ve In

cid

ence

28% RRR RR=0.72 (95% CI,

0.62–0.83; P=<0.001)

28% RRR RR=0.72 (95% CI,

0.62–0.83; P=<0.001)

0.0

0.05

0.10

0.15

0 1 2 3 4

ASA

Clopidogrel + ASA

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke (All Types)-Stroke (All Types)


• N Engl J Med 2009; 360: 2066-78.

YearsYears

• If 1000 patients were treated with clopidogrel plus ASA over the course of 3 years, this would prevent 28 strokes, 17 of which would be fatal or disabling as well as 6 MIs1

• This would occur at a cost of 20 major (non-stroke) bleeds, including 3 fatal bleeds

Meta-analysis ACTIVE A

OAC vs ASA2 Clopidogrel + ASA vs ASA3

BenefitRelative reduction in

stroke38% 28%

RiskRelative increase in major extracranial bleeding

Relative increase in intracranial bleeding

70%

128%

51%

87%

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin-Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin


• Ann Intern Med 2007; 146: 857-67.

• N Engl J Med 2009; 360: 2066-78.

• Dabigatran is a reversible oral direct thrombin inhibitor (DTI)

• It blocks the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation

• 6.5% bioavailability

• Rapid onset of action (Peak Plasma concentration at 2 h post-dose)

• ~ 80% renally excreted

• T½ of 12-17 h

• No known drug-drug/food-drug interactions

• Predictable and consistent anticoagulant effects

• No requirement for routine coagulation monitoring

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Pradax (dabigatran): An Oral Direct Thrombin -Pradax (dabigatran): An Oral Direct Thrombin

InhibitorInhibitor

Atrial fibrillation with ≥ 1 risk factorAbsence of contraindications

R

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran etexilate 110 mg bid

N=6000

Dabigatran etexilate 150 mg bid

N=6000

• Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin

• Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up

• N Engl J Med 2009; 361 : 1139-51.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study

-Study Design-Study Design

1) Documented atrial fibrillation and

2) One additional risk factor for stroke:

a) History of previous stroke, TIA, or systemic embolism

b) LVEF less than 40%

c) Symptomatic Heart Failure, NYHA Class II or greater

d) Age of 75 years or more

e) Age of 65 years or more and one of the following additional risk factors: Diabetes mellitus, CAD or Hypertension


-Inclusion Criteria-Inclusion Criteria

• N Engl J Med 2009; 361 : 1139-51.

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 mg vs. warfarin

Dabigatran 150 mg vs. warfarin

Noninferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Ma

rgin

= 1

.46

HR (95% CI)

• N Engl J Med 2009; 361: 1139-51.


-Primary Outcome: Stroke or Systemic Embolism-Primary Outcome: Stroke or Systemic Embolism

0.01

0.02

0.03

0.05

0.04

Cu

mu

lati

ve h

azar

d r

ates

RR 0.91(95% CI: 0.74–1.11)p<0.001 (NI)p=0.34 (Sup)

RR 0.66(95% CI: 0.53–0.82)p<0.001 (NI)p<0.001 (Sup)

Years0 0.5 1.0 1.5 2.0 2.5

0.0

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

RRR34%


-Primary Outcome: Stroke or Systemic Embolism-Primary Outcome: Stroke or Systemic Embolism

• N Engl J Med 2009; 361: 1139-51.

RR 0.40(95% CI: 0.27–0.60)p<0.001 (Sup)

RR 0.31(95% CI: 0.20–0.47)p<0.001 (Sup)

Cu

mu

lati

ve h

azar

d r

ates

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

Years

0.0

0.01

0.02

0 0.5 1.0 1.5 2.0 2.5

RRR60%

RRR69%

• N Engl J Med 2009; 361: 1139-51.


-Intracranial Bleeding-Intracranial Bleeding

Dabigatran110 mg

Dabigatran150 mg

WarfarinP-value

110 vs. WP-value

150 vs. W

Number of patients (n) 6015 6076 6022

Major bleeding 2.71 3.11 3.36 0.003 0.31

- Life threatening- Non-life threatening - Gastrointestinal

1.221.661.12

1.451.881.51

1.801.761.02

<0.0010.560.43

0.0370.47

<0.001

Data represents %/year


-Major Bleeding in the RE-LY Study-Major Bleeding in the RE-LY Study

• N Engl J Med 2009; 361: 1139-51.

Dabigatran 110 mg%

Dabigatran 150 mg%

Warfarin%

Dyspepsia* 11.8 11.3 5.8

Dyspnea 9.3 9.5 9.7

Dizziness 8.1 8.3 9.4

Peripheral edema 7.9 7.9 7.8

Fatigue 6.6 6.6 6.2

Cough 5.7 5.7 6.0

Chest pain 5.2 6.2 5.9

Arthralgia 4.5 5.5 5.7

Back pain 5.3 5.2 5.6

Nasopharyngitis 5.6 5.4 5.6

Diarrhea 6.3 6.5 5.7

Urinary tract infection 4.5 4.8 5.6

Upper respiratory tract infection 4.8 4.7 5.2

*Occurred more commonly on dabigatran p<0.001

• N Engl J Med 2009; 361: 1139-51.


-Most Common Side Effects-Most Common Side Effects

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Major Bleeding in the RE-LY Study-Major Bleeding in the RE-LY Study

-The Dabigatran Capsule-The Dabigatran Capsule

DabigatranCapsule

DabigatranPellet

TartaricAcid Core

Seal CoatingDabigatran

Coat

Warfarin vs. Placebo

Warfarin vs. ASA

Warfarin vs. ASA + clopidogrel

Warfarin vs. dabigatran 150

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours warfarin Favours other treatment

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-The Antithrombotic Therapy In Perspective

LessBleeding


Warfarin

1.5 2.0 2.5 3.00.75

0.5

1.5

0.75Dabigatran

ASA+Clopidogrel

PlaceboAspirin

MoreBleeding

LessStrokes

MoreStrokes


Treatment Stroke Risk

(/year)

No Therapy 4.5

ASA 3.7

ASA + Clopidogrel 2.8

Warfarin 1.7

Dabigatran 110 1.5

Dabigatran 150 1.1



(/year)

No Therapy 4.5

ASA 3.7


Warfarin 1.7

Dabigatran 110 1.5

Dabigatran 150 1.1

64%



(/year)

No Therapy 4.5

ASA 3.7


Warfarin 1.7

Dabigatran 110 1.5

Dabigatran 150 1.1

34%



(/year)

No Therapy 4.5

ASA 3.7


Warfarin 1.7

Dabigatran 110 1.5

Dabigatran 150 1.1

76%

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The Natural History of Atrial Fibrillation-The Natural History of Atrial Fibrillation

Cardiovascular Outcomes(Stroke, Death, Hospitalization)

Sinus Rhythm

Asymptomatic A Fib

Symptomatic A Fib

ParoxysmalA Fib

PersistentA Fib

PermanentA Fib

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -A “New” Way to Look at Atrial Fibrillation-A “New” Way to Look at Atrial Fibrillation

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SBP>110mmHgNot on an ATII BlockerNo Proven Indication for an ATII BlockerNo Contraindication for an ATII Blocker



~9000 patients


Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Time to First Stroke, MI or Vascular Death-Time to First Stroke, MI or Vascular Death

-The ACTIVE-I Study-The ACTIVE-I Study

• Presented at the European Society of Cardiology, Barcelona, 2009.

00 11 22 33 44

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

Cu

mu

lati

ve I

nci

de

nce

Cu

mu

lati

ve I

nci

de

nce

YearsYears4.54.5


Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke and Other Thromboembolic Events-Stroke and Other Thromboembolic Events


Irbesartan(n=4,518)

Placebo(n=4,498) Hazard

Ratio 95% CIp

Valuen %/year n %/year

Stroke 380 2.1 411 2.3 0.92 0.80-1.05 0.213

TIA 130 0.7 150 0.8 0.86 0.68-1.09 0.208

Non-CNS Embolism 49 0.3 65 0.4 0.74 0.51-1.07 0.114

Stroke/TIA/Non-CNS Emb 518 2.9 585 3.4 0.87 0.78-0.98 0.024

ICH10%

SAH10%

Lacunar20%

Thromboembolic10%

Cardioembolic20%

Other 5%Other 5%

Unknown25%

Ischemic Ischemic 80%80%

Hemorrhagic Hemorrhagic 20%20%

• Stroke 2006; 37: 2493-8.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Etiology of Stroke in Atrial Fibrillation-Etiology of Stroke in Atrial Fibrillation


• J Am Coll Cardiol 2005; 45: 1832-9.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Prevention of A Fib with ACE-I and ATII Blockers-Prevention of A Fib with ACE-I and ATII Blockers

-A Meta-Analysis-A Meta-Analysis

0.10.1 0.20.2 1.01.0 5.05.0 10.010.0 Favors Treatment Favors Treatment Favors Control Favors Control

ACE-I Treatment Control

VanDenBerg 2/7 711

SOLVD 10/186 45/188

TRACE 22/790 42/787

Ueng 18/70 32/75

CAPP 117/5492 135/5493

STOPH2 200/2205 357/4409

GISSI 665/8865 721/8846

Subtotal 1034/17615 1339/19809



ARB

Madrid 9/79 22/75

ValHeFT 116/2209 173/2200

Charm 179/2769 216/2749

LIFE 179/4417 252/4387

Subtotal 483/9474 663/9411

Total 1517/27089 2002/29220

RR (95% CI)

0.45 (0.13-1.57)

0.22 (0.12-0.43)

0.52 (0.31-0.87)

0.60 (0.37-0.97)

0.87 (0.68-1.11)

1.12 (0.95-1.32)

0.92 (0.83-1.02)

0.72 (0.56-0.93)

0.39 (0.19-0.79)

0.67 (0.53-0.84)

0.82 (0.68-1.00)

0.71 (0.59-0.85)

0.71 (0.60-0.84)

0.72 (0.60-0.85)

• There was no difference in the Number of Patients who converted to Normal Sinus Rhythm from Atrial Fibrillation

• There was no difference in the Number of Patients who progressed from Normal Sinus Rhythm to Atrial Fibrillation

• There was no difference in Hospital Admissions for Atrial Fibrillation

• There was no difference in Cardioversions

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Arrhythmia Outcomes-Arrhythmia Outcomes




Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics


Irbesartan(n=4,518)

Placebo(n=4,498)

Age (mean) 69.5 69.6

% Female 39.2 39.3

Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)

66.019.614.3

64.420.514.9

Sinus Rhythm (%) 18.7 19.6

Heart Failure (%) 32.3 31.6

CHADS Risk Score 1.99 1.97

SBP/DBP (mmHg) 138/83 138/82

Heart Rate 75.3 74.9

0

5

10

15

20

25

30

35

40

Hypertension Diabetes Smoking

Lacunar

Thromboembolic

Cardioembolic

% OfPatients

• Followed 14,448 people who were free of clinical stroke for 13.4 years

• Hypertension is the most powerful predictor for all stroke subtypes

• Stroke 2006; 37: 2493-8.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Population Attributable Fraction for Hypertension -Population Attributable Fraction for Hypertension

-The ARIC Study-The ARIC Study

• European Heart Journal 2007; 28: 752-9.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effect of BP on Stroke in Patients with A Fib-Effect of BP on Stroke in Patients with A Fib

-The SPORTIF Trials-The SPORTIF Trials

110110100100 120120 130130 140140

Mean SBP (mmHg)Mean SBP (mmHg)

0.50.5

00

1.01.0

4.04.0

Eve

nt

Rat

e (%

/Yea

r)E

ven

t R

ate

(%/Y

ear)

150150 160160

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5


Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics


Irbesartan(n=4,518)

Placebo(n=4,498)

Age (mean) 69.5 69.6

% Female 39.2 39.3

Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)

66.019.614.3

64.420.514.9

Sinus Rhythm (%) 18.7 19.6

Heart Failure (%) 32.3 31.6

CHADS Risk Score 1.99 1.97

SBP/DBP (mmHg) 138/83 138/82

Heart Rate 75.3 74.9


Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Medications-Baseline Medications


Irbesartan(n=4,518)

Placebo(n=4,498)

ACE-I (%) 60.2 60.6

Beta-Blockers (%) 54.4 54.6

Diuretic (%) 54.3 54.1

Ca2+ Channel Blocker (%) 27.0 27.2

Alpha-Blocker/Vasodilator (%) 11.9 11.1

Aspirin 58.7 59.3

Warfarin 38.1 37.6

Antiarrhythmics 22.7 23.1

Digoxin 35.1 34.7

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Wading into the Deep End-Wading into the Deep End

Dronedarone

CH3SO2HN O(CH2)3

N

O

O

(CH2)3CH3

(CH2)3CH3

Amiodarone

O(CH2)2

N

O

O

CH2CH3

CH2CH3

(CH2)3CH3

(CH2)3CH3

I

I

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Dronedarone: A New Antiarrhythmic Medication-Dronedarone: A New Antiarrhythmic Medication

Primary Endpoint: composite of all-cause mortality combined Primary Endpoint: composite of all-cause mortality combined with cardiovascular hospitalizationwith cardiovascular hospitalization

Secondary Endpoint: death from any cause, cardiovascular Secondary Endpoint: death from any cause, cardiovascular death, hospitalization for cardiovascular reasonsdeath, hospitalization for cardiovascular reasons

DDronedarone 400 mg BIDronedarone 400 mg BID PlaceboPlacebo

4,628 patients 4,628 patients >>75 years with atrial fibrillation or 70-75 years with atrial fibrillation 75 years with atrial fibrillation or 70-75 years with atrial fibrillation and at least one additional cardiovascular Risk Factor* prior to randomization. and at least one additional cardiovascular Risk Factor* prior to randomization. Double blind. Randomized. Placebo controlled. International multicenter. Mean Double blind. Randomized. Placebo controlled. International multicenter. Mean

follow-up 21 months. follow-up 21 months.

RR

12-30 mos. follow-up12-30 mos. follow-up

• *Risk Factor=Htn, diabetes, prior stroke/TIA, LA ≥50 mm, LVEF <40%

• N Engl J Med 2009; 360: 668-78.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Study Design-Study Design

-The ATHENA Study-The ATHENA Study

Months0

10

20

40

50

30

Cum

ulat

ive

Inci

denc

e (%

)

6 12 18 24 300

Placebo on top of standard therapy*

Dronedarone 400mg bid on top of standard therapy*

HR=0.76

p<0.001

24% reductionin relativerisk

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Cardiovascular Hospitalization or Death-Cardiovascular Hospitalization or Death


• *Standard therapy may have included anti-thrombotic therapy and/or rate control agents and/or other cardiovascular agents such as ACE-I statins

• N Engl J Med 2009; 360: 668-78.

Reason for first CV hospitalisation

Placebon=2327

Dronedarone n=2301 HR 95% CI p value

Any reason 859 675 0.74 0.67; 0.82 <0.001

Atrial Fibrillation 510 335 0.63 0.55; 0.72 <0.001

CHF 132 112 0.86 0.67; 1.10 0.22

ACS 89 62 0.70 0.51; 0.97 0.03

Syncope 32 27 0.85 0.51; 1.42 0.54

Ventricular arrhythmia or cardiac arrest

12 13 1.09 0.50; 2.39 0.83

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Cardiovascular Hospitalization-Cardiovascular Hospitalization


• N Engl J Med 2009; 360: 668-78.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effect of Dronedarone on Stroke-Effect of Dronedarone on Stroke


• HR=0.48 if CHAD>1, but no benefit if CHADS<1

• 60% of patients were on Warfarin

• Circulation 2009; 120: 1174-1180.

Months

5

3

2

1

00

Cum

ula

tive

Inc

iden

ce (

%)

Placebo on top of standard therapy*

Dronedarone (DR) 400mg bid on top of standard therapy*

34% reduction in relative risk

HR=0.66p=0.027

4

126 18 3024

• While Warfarin has been proven to be an efficacious therapy for the prevention of stroke in atrial fibrillation, its effectiveness is limited by poor adherence as a result of both physician and patient related factors

• Novel strategies have been developed to potentially replace Warfarin, including combination antiplatelet therapy and oral direct thrombin inhibitors, which are both safe and effective

• Antiarrhythmic medications may be making a resurgence in the prevention of stroke in atrial fibrillation

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Conclusions -Conclusions

• Dosing: Currently Dabigatran is only available in the 110mg formulation and should be

dosed at 110mg po bid for Stroke Prevention in Atrial Fibrillation Should not use if the CrCL<30mL/min (80% Renally Excreted) When switching from Warfarin to Dabigatran, the Warfarin should be held, and

the Dabigatran should be started when the INR falls below 2 Aspirin, Plavix or Aggrenox may be used concomitantly with Dabigatran

• Surgical Considerations: Dabigatran should be discontinued at least 24 hours prior to elective surgical

procedures Dabigatran should be resumed as soon as it is clinically feasible post procedure

• Bleeding: Dabigitran has a half-life of 12-17 hours FFP may be used to help control bleeding Can use aPTT or Thrombin Time to monitor effect Dabigatran is dialyzable

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Practical Aspects to Dabigatran Administration-Practical Aspects to Dabigatran Administration

stroke prevention in atrial fibrillation

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