Atrial fibrillation

Epidemiology, pathogenesis, diagnosis and treatment

Dr. dr. Hendro Darmawan, MSc, SpJP

RS BMC, 31 October 2012

DR. Dr. H. Hendro Darmawan, MSc, SpJP, FIHA

Pekerjaan :

Direktur Utama RS Bogor Medical Center

Pendidikan :

* Dokter Umum FKUI Jakarta 1980

* Dokter Spesialis Jantung dan Pembuluh Darah FKUI Jakarta 1989

* MSc in Epidemiology, University of Illinois Urbana Champaign, USA 1991

* Doktor Epidemiologi Klinis FKM UI 2007

Organisasi :

* Anggota IDI

* Anggota PERKI

* Anggota American Heart Association, Council of Epidemiology

* Ketua PERSI Cabang Bogor

Disorganised electrical and mechanical

activity that originates in the atria with an

irregular ventricular response

AF is an arrhythmia characterized by

uncoordinated atrial activation, with

consequent deterioration of atrial mechanical

function

Condition in which the normal contractions of

the atria are replaced by a rapid irregular

twitching

Atrial fibrillation

Normal sinus

rhythm

Atrial fibrillation

Atrial fibrillation – ECG

Prevalence of AF

AF is considered highly prevalent1–6

- ATRIA study – prevalence in US population estimated at ~1%:1

Prevalence estimated for AF:1–10

- US: 3.3 million people

- Europe: > 6 million people

- Asia-Pacific: incidence of AF is not known in many Asia-Pacific

countries; prevalence ranges from 770 to 1,634 per

100,000 population

- Latin America: incidence of AF is not known in many Latin

American countries; in Brazil ~1.5 million people are thought to be

living with AF

1. Go AS et al. JAMA 2001;285:2370–2375; 2. Heeringa J et al. Eur Heart J 2006;27:949–953; 3. Frost L et al. Int J Cardiol 2005;103:78–84;

4. DeWilde S et al. Heart 2006;92:1064–1070; 5. Miyasaka Y et al. Circulation 2006;114:119–125; 6. Zhou Z and Hu D. J Epidemiol 2008;18:209–

216; 7. Fuster V et al. Circulation 2006;114:700–752; 8. Zimerman LI et al. Arq Bras Cardiol 2009;92:1–39; 9. ESC Guidelines Eur Heart J 2010;

31:2369-2429; 10.Naccarelli GV et al. Am J Cardiol 2009;104(11):1534-9

Atrial fibrillationEpidemiology

The most prevalent

sustained rhythm disorder

Accounts for 1/3 of

hospitalisations due to

cardiac rhythm

disturbances

Estimated prevalence in

USA 2.2 and worldwide

5.5 million

Arrhythmia-related hospitalisations

in the US

Atrial flutter 4%Paroxysmal

supraventricular

tachycardia 6%

Atrial

fibrillation 34%

Ventricular

fibrillation 2%

Ventricular

tachycardia 10%

Miscellaneous 21%

Conduction

abnormalities 8%

Sick sinus

syndrome 9%

Premature

beats 6%

Bialy D et al. J Am Coll Cardiol 1992;19:41A

Age (years)

Prevalence%

Prevalence of atrial fibrillation increases

with age

0.5

1.8

4.8

8.8

0

2

4

6

8

10

50-59 60-69 70-79 80-89

Wolf PA et al. Stroke 1991;22:983-8

Framingham Study

Atrial fibrillation increases mortality

50

40

30

20

10

0

0 1 2 3 4 5 6 7

Subjects dead in follow-up

(%)

Years of follow-up

Men AF

Women AF

Men no AF

Women no AF

0

0.4

0.8

1.2

1.6

2.0

Adjusted odds ratio

Men Women

95% Cl 1.2–1.8 1.5–2.2

Odds ratio for death

Benjamin EJ et al. Circulation 1998;98:946–52

A

T

R

I

A

L

F

I

B

Alcohol

Thyroid disease

Rheumatic heart disease

Ischaemic heart disease

Atrial myxoma

Lung (pulmonary embolism)

Phaeochromocytoma

Idiopathic

Blood pressure (hypertension)

Other causes are known

What causes atrial fibrillation?

Magnani JW et al. Circulation 2011; 124: 1982-1993

Increased potential

for atrial fibrillation

Increased atrial

pressures

Hypertension

High left

ventricular pressures

Hypertension increases the risk of developing

atrial fibrillation almost two-fold

Slowing of atrialconduction velocity

Impaired ventricular filling

Left atrial enlargement

Left ventricular hypertrophy

Patients with AF have an approximately

fivefold increased risk of ischaemic stroke 2

-year

ag

e-a

dju

ste

d

incid

en

ce o

f str

oke/1

,000

Individuals

with AF*

Individuals

without AF

Risk ratio=4.8

p<0.001

0

10

20

30

40

50

60

Framingham Heart Study (N=5,070)

Wolf PA et al. Stroke 1991;22:983–988

*Patients were untreated with antithrombotic therapy when this study was performed in line with clinical

practice at the time

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

%

AF prevalence

Strokes attributable to AF

Age Range (years)

0

10

20

30

50–59 60–69 70–79 80–89

Framingham

Approximately 5-fold increased risk of stroke

Quantify stroke risk: CHADS2/ CHA2DS2-VASc

AF strokes have worse outcomes

Costly health care ~ $16 billion/year

Lone AF (younger persons without evidence of cardiovascular or

precipitating disease)

Transient AF (caused by reversible disorders)

First detected

ParoxysmalSelf-terminating

PersistentNot self-terminating

Permanent

Recurrent AF

(two or more episodes)

Atrial fibrillation – clinical classification

Fuster V et al. Eur Heart J 2006;27:1979–2030

Classification

Paroxysmal: terminates in < 7 days

Persistent: fails to terminate within 7 days

Permanent: > 1 year

Lone: Individuals without structural heart

disease, < 60 yrs old

Paroxysmal

Self-Terminating

Persistent

Lasts > 7 Days

Permanent

Cardioversion

Failed or Not

Attempted

Normal Sinus Rhythm

Atrial Fibrillation

Paroxysmal AF is as likely to cause stroke as

persistent or permanent AF

Atrial fibrillation – consequences

Loss of atrial systolic function (atrial

contribution to ventricular filling is lost)

Irregular rapid ventricular contractions

Abnormal blood flow and stasis in

the atria

Cardiac output reduced

Formation of intra-atrial thrombus

Rightatrium

Leftatrium

Atrial fibrillation – manifestations

Palpitations

Rapid heartbeat

Sudden pounding in the chest

Dizziness

Syncope

Chest discomfort

Shortness of breath

Symptoms of AF

Strategies for treating atrial fibrillation

Rhythm control (including cardioversion)

OR

Rate control

PLUS

Anticoagulation therapy

Hemodynamic stabilization

Rhythm and rate control approaches

Rhythm control

Cardioversion

(electrical or

pharmacological)

Pharmacological agents

(Class IC and III

antiarrhythmics)

Surgery

(maze procedure, ablation)

Device implantation

(pacemaker)

Rate control

Pharmacological agents

(AV node blockers)

Surgery with device

implantation (ablation plus

pacemaker insertion)

Pacemaker image courtesy of

St Jude Medical, Inc

Rate Control

Medications

- Metoprolol / Esmolol: IV or Oral

- Diltiazem: IV or Oral

- Verapamil: Oral Only

- Digoxin: Patients with hypotension

- Amiodarone: Also for rhythm control

Rhythm Control

Synchronized DC cardioversion

- Emergencies/Hemodynamic instability

- Greater efficacy than medications

Pharmacologic cardioversion

- If AF < 7days – dofetilide, flecainide, ibutilide,

propaferone or amiodarone

- If AF > 7 day – dofetilide or amiodarone

Electrical cardioversion

Recommendations for successful cardioversion:

Antiarrhythmic drugs to maintain normal sinus rhythm

Anticoagulation >3 weeks before and >1 month after chemical or electrical cardioversion, or permanently if necessary

Transoesophageal echocardiogram (TEE) to detect any clot in the left atrial appendage before cardioversion

Successful cardioversion is more likely if the patient:- has no other cardiovascular problems- has normal sized atria- has been in atrial fibrillation for a relatively short period- had factors contributing to atrial fibrillation (e.g., hyper- or

hypothyroidism)

Heart rhythm

in atrial fibrillation

Cardioversion

shock

Normal heart

rhythm

ECGMetal

paddle

Vaughan Williams classification of antiarrhythmic agents

Verapamil, diltiazemCalcium channel blockIV

Ibutilide, sotalol*, dofetilide, amiodarone*

Potassium channel block, increase repolarisation and refractoriness

III

Propanolol, esmolol, atenolol, sotalol*

b-adrenergic blockade, slow sinus rhythm, prolong PR interval

II

Propafenone, flecainide,amiodarone*

Little effect on repolarisation(most potent Na+ channel block)

IC

Lidocaine, tocainideShorten repolarisationIB

Quinidine, procainamide, disopyramide, amiodarone*

Prolong repolarisationIA

Sodium channel blockI

ExamplesActionClass

Antiarrhythmics used for: 1. Conversion of AF

2. Prevention of recurrence of AF

* mixed effects across different classes

Chaudhry GM & Haffajee CI. Crit Care Med 2000;28:N158–64

Patient with diagnosis of atrial fibrillation

Hemodynamically

stable

Control ventricular

rate:

Diltiazem

Cardioversion

Yes No

Spontaneous conversion to sinus rhythm

Assess cause

of atrial

fibrillation

Yes No

Contraindication to cardioversion?

Cont’

•Beta Blockers

•Calcium Channel blockers

•Digoxin

•Amiodarone

Unstable…

•Hypotension

•Confusion

•Angina

•….

Long standing

HTNIschemic heart dz

CHF

Hyperthyroidism

PE

Lung ca

Alcohol

Hypothermia

Electrolytes imbalance

Etc. .

UCLA Family Medicine Department IMG Program Carlos Yoo

Consider long-term

anticoagulation

Cardioversion

Yes No

>48hs<48hs

Start Heparin IV

•Immediate

medical or

electrical cardioversion

•Later elective

cardioversion after

3weeks of warfarin

• Early TEE-guided

cardioversion

Atrial fibrillation persist?

Assess cause of atrial

fibrillation

Yes

No

Cont’

Long standing HTN

Ischemic heart dz

CHF

Hyperthyroidism

PE

Lung ca

Alcohol

Hypothermia

Electrolytes imbalance

Etc. .

Warfarin Aspirin

ESC 2012 guidelines: selection of patients

for OACs

Non-valvular atrial fibrillation Valvular atrial fibrillation

< 65 years and lone AF including women

Stroke risk assessment using CHA2DS2-VASc

0 1 ≥2

Assess bleeding risk (HAS-BLED score);

consider patient values/preferences

New oral anticoagulant;

rivaroxaban, dabigatran

apixaban

Vitamin K antagonistNo antithrombotic therapy

Oral anticoagulant

Yes

Camm AJ et al. Eur Heart J 2012 Slide line preferred; dotted line alternative

Assess stroke risk exclusively with CHA2DS2-VASc and no longer use CHADS2

ESC Guidelines recommend anticoagulation for stroke prevention with CHA2DS2-VASc score of 1 or greater

Preference given to novel, non-monitored anticoagulants: apixaban, rivaroxaban, and dabigatran

Congestive heart failure or LVEF < 35% 1

Hypertension 1

Age > 75 years 2

Diabetes mellitus 1

Stroke/TIA/systemic embolism 2

Vascular Disease (MI/PAD/Aortic plaque) 1

Age 65-74 years 1

Sex category (female) 1

Moderate-High risk > 2

Low risk 0-1

Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

Weight (points)

Risk Profile Class / Level

CHA2DS2-VASc = 0No antithrombotic therapy

I B

CHA2DS2-VASc = 1VKA (INR 2-3)

Or

Dabigatran / Rivaroxaban / Apixaban

IIa A (Favored)

CHA2DS2-VASc ≥ 2VKA (INR 2-3)

Or

Dabigatran / Rivaroxaban / Apixaban

I A (Favored)

CHA2DS2-VASc score and stroke risk in

patients with AF

Item Points

Previous strokeTIA or systemic embolism

2

Age ≥75 years 2

Congestive heart failure*

1

Hypertension 1

Diabetes mellitus 1

Age 65–74 years 1

Female gender 1

Vascular disease 1

CHA2DS2-

VASc

1-year

stroke rate

9 23.64%

8 22.38%

7 21.50%

6 19.74%

5 15.26%

4 9.27%

3 5.92%

2 3.71%

1 2.01%

0 0.78%

*Or moderate-to-severe left ventricular systolic dysfunction (left ventricular ejection fraction ≤40%)

Olesen JB et al. BMJ 2011;342:d124; Camm AJ et al. Eur Heart J 2010;31:2369–2429

Add points

together

Hypertension (> 160 mm Hg systolic) 1

Abnormal renal or hepatic function 1-2

Stroke 1

Bleeding history or anemia 1

Labile INR (TTR < 60%) 1

Elderly (age > 75 years) 1

Drugs (antiplatelet, NSAID) or alcohol 1-2

High risk (> 4%/year) > 4

Moderate risk (2-4%/year) 2-3

Low risk (< 2%.year) 0-1 Pisters R, et al. Chest 2010; 138: 1093.

Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.

Weight (points)

Risk Score for Predicting Bleeding inAnticoagulated Patients with Atrial Fibrillation

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Patients with bleeding on NOAC therapy

Mild bleedingModerate-Severe

bleedingLife-threatening

bleeding

• Delay next dose or discontinue treatment as appropriate

• Mechanical compression• Surgical intervention• Fluid replacement and

hemodynamic support• Blood product transfusion• Oral charcoal • Hemodialysis• ? Prothrombin Complex

Concentrate?(Circulation 2011; 2011: 124: 1573-9)

• Consideration of rFVIIa or PCC

• Charcoal filtration• ? Prothrombin Complex

Concentrate(Circulation 2011; 2011: 124:

1573-9)

► CHA2DS2-VASc has replaced CHADS2 as the predominant assessment tool to predict stroke risk (ESC 2012 AF Guidelines Update).

► HAS-BLED has gained dominance as the most predictive bleeding index. It is best used as a cautionary “yellow flag” rather than as a reason to withhold anticoagulation (ESC 2012).

Warfarin better Control better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

RRR of stroke: 62%

RRR All-cause mortality:

26%

RRR, relative risk reduction.

Hart RG, et al. Ann Intern Med. 1999;131:492-501.

VKAs are associated with major bleeding,

particularly among the elderly

• Consecutive admitted patients with AF who started warfarin were identified from January 2001 to June 2003 and followed for 1 year

• Patients had to be ≥65 years of age, have established care at the study institution, and have their warfarin managed on site

Days on warfarin

Cu

mu

lati

ve i

ncid

en

ce w

ith

majo

r h

ae

mo

rrh

ag

e

0.10

0.08

0.06

0.04

0.02

0.00

0 100 200 300 400

Age 80 years

Age <80 years

Hylek EM et al. Circulation 2007;115:2689–2696

VKAs have a narrow therapeutic window

• INR below 2 is associated with

an increased risk of ischaemia

• INR above 3 is associated

with an increased risk of

haemorrhagic stroke

1. Amouyel P et al. Eur J Intern Med 2009;20:63–69; 2. Pouyanne P et al. BMJ 2000;320:1036

VKA-related haemorrhage is the leading cause of iatrogenic hospitalization,

accounting for 13% of hospitalizations due to drug-related adverse events2

Ischaemic stroke1 Haemorrhagic stroke1

0 1 2 3 4 5 60

2

4

6

8

10

12

Str

oke r

ate

per

100

pa

tie

nt-

ye

ars

0 1 2 3 4 5 60

2

4

6

8

12

16

Str

ok

e r

ate

pe

r

100

pa

tie

nt-

ye

ars

ObservedPredicted95% CI

ObservedPredicted95% CI

10

14

1) Delayed onset/offset

2) Unpredictable dose response

3) Narrow therapeutic index

4) Drug-drug, drug-food interactions

5) Problematic monitoring

6) High bleeding rate

7) Slow reversibility

VKAs have many drug–drug interactions

Increased INR response Decreased INR response

Coumadine Package Insert US revised January 2010

Despite continued use of warfarin, NOACs are considered by many professional medical organizations to be the “best option” for anticoagulation of SPAF patients:

► ESC 2012 AF Update Guidelines

► ACCP 2012 Guidelines

► Canadian AF Guidelines

“ ”

Targets for anticoagulants

VKA VKA

Inactive Factor

Active Factor

Transformation

Catalysis

X IX

IXa

Thrombin

X

a

Fibrinogen Fibrin

Prothrombin

VIITF VIIa

Clot formation

Initiation

Propagation VKA

Direct Factor Xa inhibitionRivaroxaban

Apixaban

Edoxaban

Betrixaban

Direct Factor IIa inhibitionDabigatran

II

IIa

Piccini JP et al. Curr Opin Cardiol 2010;25:312–320; Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:431–440

Features Warfarin New Agents

Onset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Drug interactions Many Few

Monitoring Yes No

Half-life Long Short

Antidote Yes No

45

Stroke & SEE

Ischemic & Unsp. Stroke

Hemorraghic Stroke

Miller CS, et al. Am J Cardiol 2012;110(3):453-460.

Favors NOACs

Favors Warfarin

13%

55%

Major

ICH

GI

Bleeding

Miller CS, et al. Am J Cardiol 2012;110(3):453-460.

51%

Favors NOACs

Favors Warfarin

• Oral direct thrombin inhibitor

• Twice daily dosing

• Renal clearanceDabigatran

• Direct factor Xa inhibitor

• Once daily (maintenance), twice daily (loading)

• Renal clearanceRivaroxaban

• Direct factor Xa inhibitor

• Twice daily dosing

• Hepatic clearanceApixaban

• Direct factor Xa inhibitor

• Once daily dosing

• Hepatic clearanceEdoxaban

Circulation 2010;121:1523

ESC 2012 guidelines: recommendations for new OACS

• Dabigatran 150 mg bid

• Dabigatran 110 mg bid in:

• ≥ 80 years

• Concomitant use of

interacting drugs

• HAS-BLED ≥ 3

• CrCl 30-49 mL/min

• Peri-cardioversion

• No recommendation in

severe renal impairment

CrCl < 30 mL/min

• Apixaban

• No recommendation in

severe renal impairment

CrCl <30 mL/min

• No recommendation for

cardioversion *

• Approved by FDA on

Dec. 28, 2012 and by

EMA on Nov 20, 2012..

All NOACs are recommended for SPAF in patients at risk of

stroke (CHA2DS2-VASc≥2) in preference over a VKA

• Rivaroxaban 20 mg od

• Rivaroxaban 15 mg od

with:

• HAS-BLED ≥3

• CrCl 30-49 mL/min

• No recommendation in

severe renal impairment

CrCl < 30 mL/min

• No recommendation for

cardioversion*

Camm AJ et al. Eur Heart J 2012; od=once daily; bid=twice daily*based on lack of published data

Properties of an ideal oral anticoagulant

Once

daily

No

significant

food

interactions

Predictable

response

No routine

coagulation

monitoring

Fixed

dosing

Wide

therapeutic

window

IDEAL

Warfarin

Rivaroxaban

Dabigatran

Apixaban

ESC 2012 guidelines: ASA/DAPT

• Antiplatelet therapy for SPAF should be limited to patients who

refuse/cannot take VKAs/NOACs

– Consider in patients who refuse OAC and at low bleeding risk

• DAPT (ASA/clopidogrel) or

• less effectively ASA

• No evidence for the decrease in total or CV mortality with ASA (or

antiplatelet drugs) in SPAF

• Antiplatelet therapy (including ASA monotherapy) carries a similar

risk of major bleeding and ICH as OAC, particularly in the elderly

Camm AJ et al. Eur Heart J 2012; DAPT=dual antiplatet therapy; ICH=intracranial haemorrhage

ROCKET AF

Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition

Compared with Vitamin K Antagonism for Prevention of

Stroke and Embolism Trial in Atrial Fibrillation

ROCKET AF - Rivaroxaban vs

warfarin – Study design

RivaroxabanN=7131

WarfarinN=7133

Primary endpoint: stroke or non-CNS systemic embolism

INR target: 2.5

(2.0–3.0 inclusive)20 mg od

(15 mg od for CrCl 30–49

ml/min)

Atrial fibrillation

Randomized

double blind

Monthly monitoring

Adherence to standard-of-care guidelines

*Enrolment of patients without prior stroke, TIA or systemic embolism and only two factors capped at 10%

Risk factorsStroke, TIA or

systemic embolism OR

• CHF • Hypertension

• Age 75 • Diabetes

At least 2

or 3

required*

Patel MR et al. N Engl J Med 2011;365:883–891

N= 14,264

Number of subjects at risk

Rivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496

Warfarin 7,004 6,327 5,911 5,542 4,461 3,478 2,539 1,538

ROCKET AF

Rivaroxaban vs warfarin – Results: Efficacy- PPP

PPP=Per-protocol population – as treated = all ITT patients without major predefined protocol violations

Days since randomization

Warfarin

Rivaroxaban

HR 0.79 (0.66, 0.96)p<0.001 (non-inferiority)

0 120 240 480 600 7200

1

2

3

4

5

6

840360

Cu

mu

lati

ve e

ven

t ra

te (

%)

Stroke or systemic embolism

Patel MR et al. N Engl J Med 2011;365:883–891

ROCKET AF

Rivaroxaban vs warfarin – Conclusions

• Based on the prespecified primary efficacy outcome:

– A once-daily fixed-dose regimen of rivaroxaban was non-inferior to warfarin for

prevention of stroke or non-CNS systemic embolism

– Rivaroxaban was superior to warfarin while patients were taking study drug

– A sensitivity analysis in the ITT population that followed all patients in the trial until

completion showed a benefit for rivaroxaban, but did not reach superiority

• Safety:

– Similar overall incidence of bleeding and adverse events

– Increase in gastrointestinal bleeds but fewer intracranial haemorrhages and less

fatal bleeding with rivaroxaban

• Implication:

– Rivaroxaban, administered once daily, has demonstrated non-inferiority to

warfarin in the prevention of stroke or systemic embolism, with similar overall

bleeding and fewer intracranial haemorrhages and fatal bleeds

Patel MR et al. N Engl J Med 2011;365:883–891

KEY POINTS

► VKA is a very effective for SPAF but related to some limitations that can lead to underuse by both patient and physician.

► Novel Oral Anticoagulants offer favourable risk–benefit profile compare to VKA, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin.

• Rivaroxaban, administered once daily, has demonstrated non-inferiority to warfarin, both in primary and secondary prevention of stroke or systemic embolism with similar overall bleeding and fewer intracranial haemorrhages and fatal bleeds