ATRIAL FIBRILLATION

 AF is the most common sustained tachyarrhythmia

leading to substantial morbidity and mortality from
thromboembolism (stroke) and heart failure.
 AF has been considered to be the epidemic of the
new millennium, its incidence increases with age and
with the presence of heart disease
 AF is associated with a 2-fold increase in cardiac
mortality
 It is associated with a 5-fold increased risk of stroke
in the absence of adequate anticoagulation therapy
 The Probability of Developing AF
Increases With Age

12
Prevalence ( % )

10

0
<55 55-59 60-64 65-69 70-74 75-79 80-84 >85
Women Men
Go et al. JAMA. 2001;285:2370-2375
 Leading Circle Reentry Ectopic Foci
50
30
10 1 2 Right Atrium Left Atrium
130 50 Septum
3 Superior
6 4 Vena
Cava
17
30 31
110
Pulmonary
Veins
5 Fossa 6 11
190 110 Ovails

Inferior
Vena
170 Cava Coronary
150 Sinus n = 45 pts
1 2 210

250 6 3 190
210 4
170

230 250
5
230

The Mechanisms Underlying Human AF

Pathophysiology of Atrial Fibrillation
? Inflammation

• LVH
• Mitral •  compliance • Diastolic
stenosis / dysfunction
Atrial dilatation/stretch
regurgitation

  stretch-activated channels ? Inflammation

  dispersion of refractoriness
  pulmonary vein focal/discharges?

Increased vulnerability to atrial pathophysiology of AF

Hypothetical construct of the pathophysiology of AF.

(Gersh et al, 2004)
 Patterns of atrial fibrillation (AF )

First
Firstdetected
detected

Paroxysmal
Paroxysmal Persistent
Persistent
((self-terminating
self-terminating)) (( Not
Notself-terminating
self-terminating))
Episodes Episodes
that last 7 that last
days or less longer than 7
days
Permanent
Permanent
Cardioversion failed
ACC / AHA / ESC Guideline 2006
 Management
Managementof
ofAF
AF

To
Tosuppress
suppress To
Toremove
remove
dysrhythmia
dysrhythmia Prevention precipitating
 Preventionof
of precipitating
factors
thromboembolism factorsand
and
•• Ventricular thromboembolism optimal
Ventricularrate
rate optimal
control treatment
treatmentofof
control
underlying
underlying
••Restorations disease
Restorationsand
and disease
maintenance
maintenance
sinus
sinus rhythm
rhythm

ACC / AHA / ESC Guideline 2006

Thrombus Forms in the Atria
and Embolizes to the Brain
Red Thrombus vs White Thrombus
Cardiogenic Stroke
 Ischemic Stroke

Intrinsic cerebro
vascular disease
20%
20%

80%
80%
Cardiac sources of
embolism and
atheromatous pathology
in the prox. aorta
Thrombus Forms in the Atria
and Embolizes to the Brain

Courtesy of Dr. Joseph Blackshear

AF Increases Stroke Risk by Nearly 5x

Risk ratio =4,8

P < 0,0001
6
Two Year age-adjusted incidence

5
of stroke / 100

4
3
2
1
0
No AF AF

Wolf et al. Stroke. 1991;22:983-988

 Ischemic Stroke Risk
 The annual risk of ischemic stroke in AF is
estimated to be 5-7%.
 In lone AF  stroke risk is 0.5%
 The annualized rate of ischemic stroke
during aspirin treatment was similar in those
with paroxysmal (3.2%) and permanent
(3.3%) AF.
 Those with prior stroke or TIA have a rate of
subsequent stroke of 10% to 12% per year
when treated with aspirin.
• Age
• Age
• Prior stroke / TIA
• Intensity of anticoagulation
• Risk Factors
• Underlying Clinical Disorder
• Underlying Heart Disease

Thrombotic Risk Hemorrhagic Risk

The Benefit
The Benefit and
and Risk
Risk of
of Warfarin
Warfarin Treatment
Treatment
 Adjusted-Dose Warfarin Compared with Placebo

Relative Risk Reduction

(95% CI)

AFASAK I
SPAF
BAATAF
CAFA
SPINAF
EAFT
All Trials (n=5)

100% 50% 0 –50% -100%

Warfarin Better Warfarin Worse

Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in

patients with nonvalvular AF: adjusted-dose warfarin compared with placebo
(Fuster et al, 2001)
 Efficacy of Aspirin in AF
No. of Patient-
Events years Risk Reduction (%)

AFASAK 35 807

SPAF 65 1457

EAFT 130 838

Combined* 230 3102

100 50 0 -50 -100
Aspirin Better Aspirin Worse
*Total risk reduction for all 3 studies combined is 21%
 Warfarin compared with Aspirin in AF
Relative Risk Reduction
( 95% CI )

AFASAK I ( 432 )
AFASAK II ( 439 )
EAFT ( 403 )
PATAF ( 443 )
SPAF II ( 440 )
All Trials ( n = 5 )
100% 50% 0 -50% -100%
Risk reduction
( combined ) is 31% Warfarin better Warfarin worse
( 95% CI 13% to 49% )
ACC / AHA / ESC Guideline 2006
 62
60 Warfarin

Aspirin
50
Risk Reduction %/year

40

20 22

10

Warfarin Aspirin

A meta- analysis of antithrombotic therapy to prevent stroke in

atrial fibrillation
(Hart et all, 1999)
 Predicting Stroke Risk in AF:
Multivariate Analysis of Pooled Data

Clinical risk factors Relative risk

Previous stroke or TIA 2.5 x
History of hypertension 1.6 x
Diabetes 1.7 x
Increasing age (per decade) 1.4 x

ACC / AHA / ESC Guideline 2006

 20

Ischemic Stroke
15 Intracranial bleeding
Odds ratio

10

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

International Normalized Ratio

Adjusted odds ratios for ischemic stroke and intracranial bleeding in

relation to intensity of anticoagulation.
(Hylek & Singer, 1994; Oden et all., 2006)
Annual rates of major hemorrhage during anticoagulant
5 Major bleeding rate ( %/y )

2
Average = 1,2 %/y
1

0
AFASAK SPAF BAATAF CAFA SPINAF
Patients with nonvalvular atrial fibrillation
Mean age was 69 years
Major hemorrhage : - require hospitalization
- require transfusion or surgical
- permanently disabling or fatal
ACC / AHA / ESC Guideline 2006
 Antithrombotic therapy for patients with atrial fibrillation

Risk category Recommended therapy

High-risk patients (approximately > 6 major Warfarin (INR 2.0 to 3.0, target
thrombo-embolic events/100 patients/year) 2.5)a
Previous stroke, TIA or systemic embolism
Mitral stenosis
Prosthetic heart value
Intermediate-risk patients (approximately 2 – Aspirin, 81 to 325 mg daily, or
6 major thrombo-embolic events/100 warfarin (INR 2.0 to 3.0, target
patients / year) 2.5)
Age > 75 years
Hypertension
Heart failure
Left ventricular ejection fraction < 35%
Diabetes mellitus
Low-risk patients (approximately < 2 major Aspirin, 81 to 325 mg daily
thrombo-embolic events / 100 patients/year)
Female gender
Age 65-74 years
Coronary artery disease
Thyrotoxicosis
a
If mechanical valve, target international normalized ratio (INR) greater than 2,5.

(Fuster et al., 2006)

 Warfarin Therapy

 Warfarin reduces strokes by 62% compared with

no treatment.
 Compared with aspirin, warfarin reduces the risk
of stroke by 45% and cardiovascular event by
29%.
 The absolute rate increase of major bleeding with
warfarin is 1.2 events per 100 patient-years
 Around 50 % of AF patients with additional stroke
risk factors and without contraindication do not
receive warfarin.
 Number Needed to Treat
• Warfarin
Primary prevention :
1 stroke over 37 patients per year
Secondary prevention :
1 stroke over 12 patients per year
• Aspirin
Primary prevention :
1 stroke over 67 patients per year
Secondary prevention :
1 stroke over 40 patients per year
 The ACTIVE W Trial
0.05
RR=1.72 (1.24-2.37).p-0.001

0.04
Cumulative hazard rates

0.03
Clopidogrel + aspirin

0.02

0.01 Oral anticoagulation therapy

0
0 0.5 1.0 1.5
Years
Number at risk
Clopidogrel
3335 3168 2419 941
* Aspirin

Oral 3371 3232 2466 930

anticoagulation
therapy

Cumulative risk of stroke

The treatment of anticoagulation should
still be made on an individual basis after
the following :

 Appropriate stratification of their

thromboembolic and hemorrhagic risk.
 Verification of the patient’s comprehension of
the disease and its treatment.
 Assessment of their ability to manage their own
health care and to comply with therapy and
 in conjunction with their treatment preferences

(Poli et all, 2005)