Transcript Slide 1

Stroke Prevention
in Atrial Fibrillation
Ravi Marfatia, MD
Pat and Jim Calhoun Cardiology Center, University of
Connecticut School of Medicine, Farmington, Connecticut
A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
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Atrial Fibrillation and Stroke

Atrial fibrillation (AF) is associated with a fivefold
increase in the risk of stroke.1

AF is a major risk factor for thromboembolism.1

Ischemic strokes secondary to AF are associated with
significantly higher morbidity and mortality than
those due to other causes.2

Many clinicians tend to underestimate the riskbenefit ratio of anticoagulant therapy and
overestimate its bleeding risks.

As a result, anticoagulation therapy is given to just
30%–60% of eligible patients with AF.3
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2
Current Guidelines

Current guidelines recommend anticoagulation
therapy with vitamin K antagonists in AF patients at
high risk, vitamin K antagonists or aspirin in those at
intermediate risk, and aspirin alone in those
considered to be at low risk. 4–7

Anticoagulation therapy using vitamin K antagonists
has been shown to be superior to aspirin in reducing
ischemic stroke and systemic thromboembolic
events in intermediate-risk AF patients. 8–10

The benefit of using aspirin to prevent systemic
thromboembolic events in low-risk AF patients is
questionable. 11
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Risk Assessment of Stroke

Atrial Fibrillation Investigators12
» Low risk: Age < 65 years and no risk factors
» Medium risk: Age  65 years and no other risk factors
» High risk: Prior ischemic stroke/transient ischemic attack,
hypertension, diabetes mellitus

Stroke Prevention in Atrial Fibrillation13
» Low risk: No risk factors
» Medium risk: Hypertension
» High risk: Prior stroke, female > 75 years, recent clinical
heart failure, left ventricular fractional shortening  25% on
echocardiography
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Risk Assessment of Stroke

CHADS2 Score (1 point each for congestive heart failure,
left ventricular dysfunction, hypertension, diabetes mellitus,
vascular disease, age = 65–74 years, and female gender and
2 points each for age  75 years and prior stroke or transient
ischemic attack)14
» Low risk: Score = 0 points
» Medium risk: Score = 1–2 points
» High risk: Score = 3–6 points
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Risk Assessment of Stroke

CHA2DS2-VASc Score15
» Low risk: No risk factors
» Medium risk: Heart failure or moderate/severe left
ventricular dysfunction (ejection fraction < 40%), diabetes
mellitus, hypertension, age 65–74 years, female gender,
vascular disease
» High risk: One of the following risk factors: age  75 years,
prior ischemic stroke/transient ischemic attack, systemic
embolism, mitral stenosis, prosthetic heart valve; or
two of the following risk factors: heart failure or
moderate/severe left ventricular dysfunction (ejection
fraction < 40%), diabetes mellitus, hypertension, age
65–74 years, female gender, vascular disease
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Risk Assessment of Stroke

Framingham Heart Study (0–10 points for age, 6 points
for female gender, 0–4 points for systolic blood pressure, 5
points for diabetes mellitus, and 6 points for prior ischemic
stroke/ transient ischemic attack)16
» Low risk: Score = 0–7 points
» Medium risk: Score = 8–15 points
» High risk: Score = 16–31 points
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Risk Assessment of Stroke

American College of Chest Physicians17
» Low risk: No risk factors
» Medium risk: One of the following risk factors: age
 75 years, hypertension, poor left ventricular function or
heart failure, diabetes mellitus
» High risk: One of the following risk factors: history of
ischemic stroke/transient ischemic attack or systemic
embolism; or two of the following risk factors: age
 75 years, hypertension, poor left ventricular function
or heart failure, diabetes mellitus
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Risk Assessment of Stroke

National Institute for Health and Clinical Excellence5
» Low risk: Age < 65 years and no risk factors
» Medium risk: Age  65 years and no risk factors or age
< 75 years and hypertension, diabetes mellitus, or vascular
disease
» High risk: Prior ischemic stroke/transient ischemic attack;
or age  75 years and hypertension, diabetes mellitus, or
vascular disease; or valvular disease, heart failure or
impaired left ventricular function on echocardiography
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Risk Assessment of Stroke

American College of Cardiology/American Heart
Association/European Society of Cardiology4
» Low risk: No risk factors
» Medium risk: Age  75 years, hypertension, heart failure,
diabetes mellitus, left ventricular function  35%
» High risk: History of stroke/transient ischemic attack or
more than one moderate risk factors or mitral stenosis or
prosthetic heart valve
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CHADS2 vs CHA2DS2-VASc

The CHADS2 (congestive heart failure, hypertension,
age  75 years, diabetes mellitus, and previous
stroke/transient ischemic attack) index is the most
commonly used stroke risk-stratifying scheme.14

The CHADS2 index classifies a large proportion of
patients as being at intermediate risk and excludes
other known stroke risk factors (female gender, age
65–74 years, and vascular disease) that could help
identify truly low-risk patients.15,18

The CHA2DS2-VASc index includes these factors, has
a predictive value similar to that of CHADS2, and
improves the identification of low-risk patients.15,19
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11
Assessment of Bleeding Risk

Bleeding is the most important complication of oral
anticoagulant therapy with vitamin K antagonists.20

Because patients have different risk factors, the risk
of bleeding during anticoagulant therapy is not
homogeneous.20

Two simple, clinically practical tools for assessing
the risk of major bleeding in AF patients on oral
anticoagulant therapy—HAS-BLED and ATRIA—
have recently been developed and validated in realworld cohorts of patients with AF.21,22
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HAS-BLED Score

The HAS-BLED bleeding risk-stratification scheme
assigns 1 point each for hypertension, abnormal
renal or liver function, stroke, bleeding, labile INR,
advanced age, and drug or alcohol consumption.21

The maximum score is 9; a patient having a score of
> 3 is considered to be at high risk of bleeding.21

The HAS-BLED score has been shown to have a
consistent predictive accuracy over 1 year among
different AF patient populations.21
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ATRIA Score

The ATRIA bleeding risk-stratification scheme
assigns 3 points to anemia and severe renal disease,
2 points to age  75 years, and 1 point each to
previous hemorrhage or a history of hypertension.22

The maximum score is 10; a patient having a score of
0–3 is considered to be at low risk of bleeding; of 4,
intermediate risk, and of 5–10, high risk.22

Major hemorrhage rates in a large cohort of AF
patients receiving warfarin were 0.8% for those at
low risk, 2.6% for those at intermediate risk, and
5.8% for those at high risk.22
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Warfarin

Warfarin significantly reduces the occurrence of
stroke in patients with AF.23

The optimal benefit of stroke prevention that does
not enhance the risk of hemorrhagic complications
occurs at an INR of 2.0–3.0.24

Multiple food and drug interactions affect patient
response to warfarin, requiring frequent monitoring
via blood tests.17

On average, only about 55% of INR values are within
the therapeutic range on repeated testing.25
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Newer Anticoagulants: Dabigatran

Dabigatran, a direct thrombin inhibitor, is one of two
new oral anticoagulants currently approved by the
FDA for reducing the risk of stroke and systemic
embolism in patients with nonvalvular AF.

Dabigatran’s actions are reversible and more
predictable than those of warfarin.26,27

The activity of dabigatran in the blood can be
detected by prolongation of the thrombin clotting
time or ecarin clotting time.27
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Dabigatran

In the RE-LY trial, high-dose dabigatran (150 mg
twice daily) was superior to warfarin (1.11% vs 1.69%
events per year) and was associated with a similar
rate of major bleeding (3.11% vs 3.36% per year).28

Low-dose dabigatran (110 mg twice daily) was
noninferior to warfarin therapy (1.53% vs 1.69%
events per year) and was associated with a lower rate
of major bleeding (2.71% vs 3.36% per year).28

Both doses of dabigatran also caused significantly
fewer intracranial hemorrhagic complications than
did warfarin (P < 0.001).28
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Dabigatran

Recommended doses are 150 mg twice daily for
patients with a creatinine clearance (CrCl) exceeding
30 mL/min and 75 mg twice daily for those with a
CrCl of 15–30 mL/min.29

Although the 110-mg dose has not been approved for
use in the US, European guidelines recommend 150
mg of dabigatran twice daily for patients with a low
bleeding risk (HAS-BLED score = 0–2) and 110 mg
twice daily for those having a high bleeding risk
(HAS-BLED score  3).

Canadian guidelines recommend dabigatran as an
alternative to warfarin at both doses.
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Newer Anticoagulants: Rivaroxaban

Rivaroxaban, a factor Xa inhibitor, recently was
approved in both the US and Europe to prevent
stroke in patients with nonvalvular AF.

In the pivotal ROCKET AF trial, rivaroxaban was
noninferior to warfarin for stroke prevention.30

The rates of major and clinically relevant non-major
bleeding were similar among patients treated with
rivaroxaban and those given warfarin.31

The rate of intracranial hemorrhage was significantly
lower among patients given rivaroxaban compared
with the rate in the warfarin group (0.49% vs 0.74%;
P = 0.02).31
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Newer Anticoagulants: Apixaban

Apixaban is a factor Xa inhibitor under priority
review by the FDA for reducing the risk of stroke and
systemic embolism in patients with AF.

In the AVERROES trial, which compared apixaban
with aspirin, twice-daily administration of apixaban
significantly reduced the occurrence of stroke and
systemic thromboembolism by 55% (hazard ratio,
0.45; 95% CI, 0.32–0.62; P < 0.001), with no
increased risk of major bleeding relative to aspirin.32

As a result, the trial was terminated early following
a recommendation from the data and safety
monitoring board overseeing the study.
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20
Apixaban

In the phase III ARISTOTLE trial, apixaban resulted
in a similar clinical benefit to that achieved with
warfarin in reducing the risk of ischemic stroke, but
its superiority to warfarin was shown by a 21%
overall reduction of stroke and thromboembolic
events, which was secondary to a 50% reduction in
hemorrhagic stroke.33

Major hemorrhagic complications and all-cause
mortality also were significantly lower in the
apixaban arm than in the warfarin arm (31% and
11%, respectively).33
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21
New Anticoagulants: On the Horizon

Betrixaban and edoxaban are oral factor Xa
inhibitors in the early stages of clinical development.

The EXPLORE-Xa trial is a recently completed phase
II study comparing the use of three blinded doses of
betrixaban (40, 60, and 80 mg) with warfarin for
stroke prevention in patients with nonvalvular AF.34

The ENGAGE AF-TIMI 48 study is a phase III
clinical trial assessing the noninferiority of edoxaban
given at a high (60 mg) and low (30 mg) dose when
compared with warfarin therapy in reducing stroke
and thromboembolic events in high-risk AF patients
(CHADS2 score  2).35
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