Atrial fibrillation and stroke

Updated November 2013

1
Nov 2013
Epidemiology and pathogenesis of AF

2
Nov 2013
AF is a common disorder

• Responsible for a third of all hospitalizations for cardiac

rhythm disturbances1
• Estimated prevalence:
– Europe: 4.5 million1
– USA: 5.1 million2
• Affects approximately 2.5% of the US population2
• Nearly one in four people at age 55 years will go on
to develop AF (24% of men and 22% of women)3

1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030;
2. Miyasaka Y et al. Circulation 2006;114:119–25; 3. Heeringa J et al. Eur Heart J 2006;27:949–53
3
Nov 2013
 Prevalence of AF increases with age
2
0 Women
(n=4053)
Men
(n=2590)
1
5
Prevalence (%)

1
0

0
55– 60– 65– 70– 75– 80– >8
59 64 69 74 79 84 5
Age (yrs)

Prevalence at baseline assessed in 6808 participants in a European population-based study

Data from Heeringa J et al. Eur Heart J 2006;27:949–53
4
Nov 2013
AF is an increasingly common disorder

• 20% increase in prevalence expected over next decade

– 6.3 million in 2007 to 7.5 million in 2017 in industrialized
countries* 1
• Increasing prevalence driven by:
– Increased longevity of populations worldwide
– Rising prevalence of chronic heart disease
– Rising prevalence of AF risk factors, e.g. diabetes mellitus
• 60% increase in hospital admissions for AF over the
past 20 years2

*USA, Japan, Germany, Italy, France, UK, and Spain

1. Benyoucef S et al. Atrial fibrillation. 2008; available at: http://www.decisionresources.com; accessed Feb 2010;
2. Friberg J et al. Epidemiology 2003;14:666–72
5
Nov 2013
 Prevalence of AF predicted to more than
double by 2050

16

14
People with AF in the USA (millions)

12

10

6 Projected incidence of AF assuming a

continued increase in age-adjusted
4 incidence as evident in 1980–2000

2 Projected incidence of AF assuming no

further increase in age-adjusted incidence
0
2000 2010 2020 2030 2040 2050
Year
Miyasaka Y et al. Circulation 2006;114:119–25
6
Nov 2013
Normal regulation of heart rate and rhythm
• Contraction is controlled by the sinoatrial node

7
Nov 2013
Normal heart rhythm is disrupted in AF

• Characterized by:
– Rapid (350–600 beats/minute) and irregular atrial activity
– Reduced filling of left and right ventricles
• Conduction of most impulses from atria to ventricles
blocked at the atrioventricular node
• Ventricular rate can be:
– Irregular and rapid (110–180 beats/minute; tachycardia)
– Irregular and slow (<50 beats/minute; bradycardia)
• Cardiac output can be reduced

Goodacre S & Irons R. BMJ 2002;324:594–7

8
Nov 2013
AF begets AF

• AF causes remodelling that contributes to the initiation

and maintenance of AF, including:
– Electrical: shortening of atrial refractory period
– Structural: enlargement of atrial cavities

• Initially, many episodes of AF resolve spontaneously

• Over time, AF tends to become persistent or permanent

due to electrical and structural remodelling

Wijffels MC et al. Circulation 1995;92:1954−68

9
Nov 2013
Consequences of AF

• Formation of blood clots (thrombosis) on the atrial

walls that can dislodge (embolize), leading to stroke
and systemic embolism

• Reduction in cardiac output can precipitate heart

failure, leading to distinctive symptoms such as:
– Peripheral oedema
– Dyspnoea
– Pulmonary oedema
– Fatigue
– Chest pain

10
Nov 2013
Classification of five types of AF:
ESC guidelines 2010 (1)

Classification Definition

First diagnosed First recognized episode of AF, irrespective of duration

or the presence and severity of AF-related symptoms

Paroxysmal AF that is self-terminating, usually within 48 hrs

Persistent AF that persists for >7 days or requires termination by

cardioversion

Long-standing AF that has lasted for ≥1 yr when it is decided to adopt

persistent a rhythm control strategy

Permanent AF Presence of the arrhythmia is accepted by the patient

(and physician)

ESC = European Society of Cardiology

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
11
Nov 2013
Classification of five types of AF:
ESC guidelines 2010 (2)

First diagnosed episode of AF

Paroxysmal
(usually ≤48 hrs)

Persistent
(>7 days or requires CV)

Long-standing
persistent (>1 yr)

Permanent
(accepted)

CV = cardioversion
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
12
Nov 2013
 The risk of stroke is not related with the
type of AF
проследяване от 1 година (%)
Пациенти с ИМИ при

(n=708) (n=1,170) (n=886) (n=1,126)

Nieuwlaat R et al. Eur Heart J 2008;29:1181–1189

Nov 2013
Risk factors for AF (1)

• Advancing age
• Cardiovascular diseases:
– Hypertension
– Diabetes mellitus, insulin resistance, metabolic syndrome
– Myocardial infarction
– Congestive heart failure
– Valvular disease and heart surgery
• Excessive alcohol intake
• Family history of AF
• Male gender

Sawin CT et al. N Engl J Med 1994;331:1249–52;

Kannel WB, Benjamin EJ. Med Clin North Am 2008;92:17–40
14
Nov 2013
Risk factors for AF (2)

• Echocardiographic abnormalities:
– Left atrial enlargement
– Increased left ventricular wall thickness
– Reduced left ventricular fractional shortening
• Thyroid disorders
– Hyperthyroidism increases risk 3-fold
• Inflammation
– E.g. myocarditis, pericarditis, systemic inflammation,
pneumonia
• Sleep apnoea

Sawin CT et al. N Engl J Med 1994;331:1249–52; Kannel WB, Benjamin EF. Med Clin North Am 2008;92:17–40;
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030
15
Nov 2013
Clinical evaluation of patients with AF

• All patients • Selected patients*

– History – Transthoracic
– Physical examination echocardiography
– Electrocardiogram – Coronary angiography
– Holter monitor – Electrophysiology study
– Chest X-ray – Magnetic resonance
tomography
– Transthoracic
echocardiogram
– Blood tests (including
thyroid function)
– Exercise stress test

*For example, patients experiencing AF with exercise, with risk factors, suspected trigger arrhythmia such as
concealed pathway, atrioventricular nodal re-entry tachycardia (AVNRT), arrhythmogenic right ventricular dysplasia
(ARVD), or suspected myocarditis
Adapted from ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354;
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
16
Nov 2013
Signs and symptoms
Cause Sign/symptom
• Irregular heart beat • Irregular pulse
• Palpitations

• Decreased cardiac output • Fatigue

• Diminished exercise capacity
• Breathlessness (dyspnoea)
• Weakness (asthenia)

• Hypotension • Dizziness and fainting (syncope)

• Cardiac ischaemia • Chest pain (angina)
• Increased risk of clot formation • Thromboembolic transient
ischaemic attack, stroke,
systemic embolism

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030
17
Nov 2013
Relevant questions to ask a patient with
suspected or known AF

Does the heart rhythm during the episode feel regular or irregular?

Is there any precipitating factor such as exercise, emotion, or alcohol intake?

Are symptoms during the episodes moderate or severe?

– Severity may be expressed using the EHRA score

Are the episodes frequent or infrequent, and are they long or short lasting?

Is there a history of concomitant disease such as hypertension, coronary heart disease,

heart failure, peripheral vascular disease, cerebrovascular disease, stroke, diabetes, or
chronic pulmonary disease?

Is there an alcohol abuse habit?

Is there a family history of AF?

EHRA = European Heart Rhythm Association

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
18
Nov 2013
Electrocardiogram (2)

Regular rhythm • Normal sinus rhythm

– Normal heart rate
P
– Regular rhythm
– P waves
– Steady baseline

Irregularly irregular rhythm • AF

– Heart rate increased
(tachyarrhythmia)*
– Irregularly irregular rhythm
– No P wave

*Reduced heart rate (bradyarrhythmia) may also be observed

Ashley EA & Niebauer J. Cardiology Explained. Remedica: London 2004;
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
19
Nov 2013
Holter monitor

• Portable ECG device for

continuous monitoring

• Short time period (typically

24 hours) was standard
– Benefits of longer
periods now demonstrated

• Useful for:
– Detecting asymptomatic AF
– Evaluating paroxysmal AF
– Associating symptoms with
heart rhythm disturbance
– Assessing treatment response

ECG = electrocardiogram
Hanke T et al. Circulation 2009;120(11 Suppl):S177–84;
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030
20
Nov 2013
Chest radiography

• When clinical findings suggest

an abnormality, chest
radiography may be used to:
– Evaluate pulmonary pathology
and vasculature
– Detect congestive heart failure
– Assess enlargement of cardiac
chambers secondary to heart
disease or AF
(tachycardiomyopathy)

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030
21
Nov 2013
Transthoracic echocardiography
• Non-invasive

• Used to identify:
– Atrial thrombi
– Atrial and ventricular size
and functioning Thrombus in
– Ventricular hypertrophy left atrium
– Pericardial disease
– Valvular heart disease

Asinger RW. Echocardiography 2000;17:357−64; ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:
e257–354 & Eur Heart J 2006;27:1979–2030; lower image from Lazraq M et al. Arch Cardiovasc Dis 2008;101:679−80
22
Nov 2013
Transoesophageal echocardiogram
• Ultrasound transducer positioned
close to the heart

• High-quality images of cardiac

structure and function
– Particularly the LAA, the most
common site of thrombi in AF
Thrombus in
• Not routinely used but useful for: left atrium
– Cardioversion
– Accurate assessment of stroke risk
– Detection of low flow velocity
(‘smoke’ effect)
– Measurement of LAA flow velocity
– Sensitive detection of atrial thrombi

LAA = left atrial appendage

Agmon Y et al. J Am Coll Cardiol 1999;34:1867–77; Seward JB et al. Mayo Clin Proc 1993;68:523–51;
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; lower
image from Lazraq M et al. Arch Cardiovasc Dis 2008;101:679–80; Manning WJ et al. N Engl J Med 1993;328:750–5
23
Nov 2013
TEE: visualization of thrombus in LAA

• TEE for assessment of rheumatic

mitral stenosis
• Warfarin treatment suspended for
5 days before procedure
• Medium-sized thrombus visible
in LAA

• Repeat TEE performed 6 weeks

after restarting warfarin
• Clear LAA, indicating that
thrombus was freshly formed
after the temporary suspension
of warfarin treatment

LAA = left atrial appendage; TEE = transoesophageal echocardiogram;

Lairikyengbam SKS et al. Heart 2008;94:1593
24
Nov 2013
Laboratory tests

• Routine blood tests should be carried out at least

once in patients with AF

• Important parameters to assess include:

– Thyroid function
– Renal function
– Hepatic function
– Serum electrolytes
– Complete blood count

Krahn AD et al. Arch Intern Med 1996;156:2221–4;

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030
25
Nov 2013
Thrombogenic tendency in AF

• Complex and multifactorial pathogenesis

• Patients with AF show extensive abnormal changes in:

– Atrial wall
– Blood stasis
– Blood constituents

• Thus, through fulfilment of Virchow’s triad, AF could

drive a prothrombotic or hypercoagulable state

Watson T et al. Lancet 2009;373:155–66

26
Nov 2013
Components of Virchow’s triad for thrombogenesis
in AF

vWF = Von Willebrand factor

Watson T et al. Lancet 2009;373:155–66
27
Nov 2013
Stroke is the leading complication of AF

• AF is associated with a 5-fold higher stroke risk overall1

• AF doubles the risk of stroke when adjusted for other
risk factors2
• Without prevention, approximately 1 in 20 patients will
have a stroke each year3
– 7% of patients will experience brain ischaemia* each year4
• Responsible for nearly a third of all strokes,5 and the
leading cause of embolic stroke6

*Stroke, transient ischaemic attacks and clinically ‘silent’ strokes

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. ACC/AHA/HRS focused update guidelines: Fuster V et al. Circulation
2011;123:e269–357; 3. Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449–57;
4. Carlson M. Medscape Cardiol 2004;8; available at http://www.medscape.org/viewarticle/487849;
accessed Feb 2010; 5. Hannon N et al. Cerebrovasc Dis 2010;29:43–9;
6. Emmerich J et al. Eur Heart J 2005;7(Suppl C):C28–33
28
Nov 2013
Stroke risk is evident in subclinical AF
• Subclinical AF* is associated with a 2.5-times greater risk of
ischaemic stroke or systemic embolism
– 4.2% vs 1.7% with no arrhythmia (P=0.007)

0.08 Risk of ischaemic stroke or systemic embolism

0.06 Subclinical atrial

Cumulative hazard

tachyarrhythmias present

0.04

0.02
Subclinical atrial
tachyarrhythmias absent
0
0 0. 1. 1.5 2.0 2.
5 0Years of follow-up 5
*Subclinical atrial tachyarrhythmias detected by implanted devices (n=2580)
Healey JS et al. N Engl J Med 2012;366:120–9
29
Nov 2013
Ischaemic stroke results from different
pathologies affecting arteries supplying the brain

Haemorrhagic
Haemorrhagic (8%)
(8%)1
1 All strokes

Ischaemic
Ischaemic (92%)
1,2
(92%)1,2
25%
25% large
large artery
artery 5%
5% unusual
unusual
atherosclerotic
atherosclerotic (e.g.
(e.g. dissections,
dissections,
stenosis 2,3
stenosis2,3 arteritis)2,3
arteritis)2,3

25%
25% small
small artery
artery 25%
25% cryptogenic
cryptogenic 20%
20% major-risk
major-risk
disease
disease (lacunar
(lacunar (no
(no known cause)
known 2,3
cause)2,3 source
source cardiogenic
cardiogenic
stroke) 2,3
stroke)2,3 embolism 2,3
embolism2,3

See
See slide
slide notes
notes for
for further
further details
details of
of stroke
stroke subtype
subtype definitions
definitions

1. Andersen K et al. Stroke 2009;40:2068–72; 2. Adams HP et al. Stroke 1993;24:35–41;

3. Hart RG et al. Lancet Neurol 2014;13:429–38
30
Nov 2013
Most strokes associated with AF are ischaemic
Types of stroke in patients with AF

Haemorrhagic
(8%)

Ischaemic stroke
(n=5810)

Haemorrhagic stroke
(n=484)

Ischaemic
(92%)

Based on data collected in the Danish National Indicator Project for 39 484 patients hospitalized for stroke
(including 6294 patients with AF)
Andersen KK et al. Stroke 2009;40:2068–72
31
Nov 2013
Ischaemic stroke in AF likely to result in persistent
disability or death

Outcomes of first ischaemic stroke in high-risk patients with AF (n=597)

60

60%
50
Proportion of patients (%)

40

30

20
20%
10

0
Persisting disability Death
Modified Rankin scale ≥2
Gladstone DJ et al. Stroke 2009;40:235–40
32
Nov 2013
Nov 2013
Fang et al. The American Journal of medicine 2007; 120:700-705 Nov 2013
Importance of assessing stroke risk in AF

• Antithrombotic therapy reduces the risk of stroke but

also carries a risk of bleeding complications

• Stroke risk reduction greatest in patients at highest risk

– High-risk patients benefit from intensive antithrombotic
treatment

• Risk of major bleeding is similar regardless of stroke risk

– Low-risk patients may not gain sufficient benefit from oral
anticoagulant therapy to outweigh the risk of bleeding and need
for close monitoring

van Walraven C et al. JAMA 2002;288:2441–8; van Walraven C et al. Arch Intern Med 2003;163:936–43
35
Nov 2013
 Stroke risk assessment with CHADS2

CHADS2 criteria Score

0
Congestive heart failure 1
1 Hypertension 1
Age ≥75 yrs 1
2 Diabetes mellitus 1
CHADS2 score

Stroke/transient ischaemic 2
3 attack

0 5 10 15 20 25 30
Annual stroke rate (%)*

Gage BF et al. JAMA 2001;285:2864–70

36
Nov 2013
Assessing stroke risk: CHA2DS2-VASc

CHA2DS2-VASc criteria Score Adjusted

Total Patients
stroke rate
score (n=7329)
(%/year)*
CHF/LV dysfunction 1
0 1 0.0
Hypertension 1 1 422 1.3
2 1230 2.2
Age ≥75 yrs 2
3 1730 3.2
Diabetes mellitus 1 4 1718 4.0
5 1159 6.7
Stroke/TIA/TE 2
6 679 9.8
Vascular disease 1 7 294 9.6
8 82 6.7
Age 65–74 yrs 1
9 14 15.2
Sex category (i.e. female gender) 1
*Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk,
based on Hart RG et al. 2007
CHF = congestive heart failure; LV = left ventricular; TE = thromboembolism; TIA = transient ischaemic attack
Lip G et al. Chest 2010;137:263–72; Lip G et al. Stroke 2010; 41:2731–8;
Camm J et al. Eur Heart J 2010;31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67
37
Nov 2013
Risk factors for ischaemic stroke
Multivariate hazard ratios
(95% CI)
Age (years) –
<65 1.0 (reference)
65–74 2.97 (2.54–3.48)
≥75 5.28 (4.57–6.09)
Female sex 1.17 (1.11–1.22)
Previous ischaemic stroke 2.81 (2.68–2.95)
Intracranial bleeding 1.49 (1.33–1.67)
Vascular disease (any) 1.14 (1.06–1.23)
Myocardial infarction 1.09 (1.03–1.15)
Previous CABG 1.19 (1.06–1.33)
Peripheral artery disease 1.22 (1.12–1.32)
Hypertension 1.17 (1.11–1.22)
Heart failure (history) 0.98 (0.93–1.03)
Diabetes mellitus 1.19 (1.13–1.26)
Thyroid disease 1.00 (0.92–1.09)
Thyrotoxicosis 1.03 (0.83–1.28)

CABG = coronary artery bypass graft

Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
38
Nov 2013
Assessing bleeding risk: HAS-BLED

HAS-BLED risk criteria Score

Hypertension (SBP >160 mmHg) 1

Abnormal renal or liver function (1 point each) 1 or 2

Stroke 1

Bleeding (history or predisposition) 1

Labile INRs (e.g. <60% TTR) 1

Elderly (e.g. age >65 yrs) 1

Drugs or alcohol 1 or 2
(1 point each; includes antiplatelets and NSAIDs)

INR = International normalized ratio; NSAID = non-steroidal anti-inflammatory drug; SBP = systolic blood pressure;
TTR = time in therapeutic range
ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429
39
Nov 2013
ESC 2012 focused update:
choice of antithrombotic therapy in AF (1)
Atrial fibrillation = CHA2DS2-VASc 0

Valvular AF*
Yes = CHA2DS2-VASc 1

No (i.e. nonvalvular) = CHA2DS2-VASc ≥2

Yes
<65 years and lone AF (including females)
= best option
No
Assess risk of stroke = alternative option
CHA2DS2-VASc score

0 1 ≥2

Oral anticoagulant therapy

Assess bleeding risk

(HAS-BLED score)
Consider patient values and
preferences

No antithrombotic
therapy NOAC VKA

*Includes rheumatic valvular disease and prosthetic valves; ESC = European Society of Cardiology;
NOAC = novel oral anticoagulant; VKA = vitamin K antagonist
Camm AJ et al. Eur Heart J 2012;33:2719–47
Disclaimer: Dabigatran etexilate, rivaroxaban, and apixaban are approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Edoxaban is not 40
approved for stroke prevention. Please check local prescribing information for further details Nov 2013
 ASA is not associated with a significant reduction
in thromboembolic risk in most AF trials
Primary prevention Secondary prevention
AS
A
Placeb
7 RRR: RRR: 25 o
16% 42% RRR: RRR:
6 P=NS P=0.02 17% 33%
20 P=0.12 P=0.16
Annual rate (%)

Annual rate (%)

4 15
RRR: –
3 8% RRR:
68% 10
P=NS
P=0.05
2
5
1

0 0
AFASAK SPAF LASAF LASAF EAFT ESPS II (BID)
n=1107 n=1330 (OD) (QOD) n=1007 n=429
75 mg 325 mg n=285 n=285 300 mg 25 mg ASA
ASA ASA 125 mg 125 mg ASA ASA
ASA

BID = twice daily; NS = not significant; ASA = acetylsalicylic acid; OD = once daily; QOD = every other day;
RRR = relative risk reduction
Albers GW et al. Chest 2001;119:194S–206S
41
Nov 2013
VKAs have a narrow therapeutic window
2
0
Therapeutic
range
1
Strok
5
e

1 Intracranial bleed
Odds
ratio

1
0
1 2 3 4 5 6 7 8
International normalized ratio
VKAs = vitamin K antagonists
ACCF/AHA/HRS focused update guidelines: Fuster V et al. Circulation 2011;123:e269-e367;
Wann LS et al. Circulation 2011;123:104–23 & Circulation 2011;123:1144–50
42
Nov 2013
 At a
glance

AF and stroke: epidemiology

• AF is an increasingly common disorder
– Prevalence set to double by 20501
• Stroke is the leading complication of AF
– 5-fold increase in stroke risk2
– Risk persists in asymptomatic/paroxysmal AF3,4
• Most AF-related strokes are ischaemic5
• Factors increasing stroke risk include:6
– Previous stroke or TIA
– Advancing age
– Hypertension
– Diabetes mellitus
• Assessing stroke risk is important to guide antithrombotic therapy

TIA = transient ischaemic attack

1. Miyasaka Y et al. Circulation 2006;114:119–25; 2. Savelieva I et al. Ann Med 2007;39:371–91;
3. Hart RG et al. J Am Coll Cardiol 2000;35:183–7; 4. Flaker GC et al. Am Heart J 2005;149:657–63;
5. Andersen KK et al. Stroke 2009;40:2068–72; 6. Gage BF et al. JAMA 2001;285:2864–70
43
Nov 2013