Section II: Clinical Management of AFib. Section II. Clinical Management of AFib 1. Clinical...

Section II:Clinical Management of AFib

Section II. Clinical Management of AFib

1. Clinical Evaluation of AFib

2. Treatment Options for AFib

• Cardioversion

• Drugs to prevent AFib

• Drugs to control ventricular rate

• Drugs to reduce thromboembolic risk

• Non-pharmacological options

1. Clinical Evaluation of AFib

Clinical Evaluation

• Minimum– History and Physical examination

– Electrocardiogram

– Trans-thoracic echocardiogram

– Blood tests of thyroid, renal and hepatic function

• Discretionary– Six-minute walk test

– Exercise testing

– Holter monitoring or event recording

– Trans-oesophageal echocardiography

– Electrophysiological study

– Chest radiograph

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial FibrillationJ Am Coll Cardiol (2006) 48: 854

Opportunistic Case Finding

• In patients presenting with symptoms commonly associated with AFib:

– breathlessness/dyspnoea

– palpitations

– syncope/dizziness

– chest discomfort

• Manual pulse palpation should be performed to determine the presence of an irregular pulse that may indicate underlying AFib

NICE recommendation: Developed by National Collaborating Centre for Chronic Conditions at the Royal College of Physicians; Atrial fibrillation: full guideline DRAFT (January 2006)

• Restore and maintain sinus rhythm whenever possible

• Prevent thromboembolic events

In order to:

– Reduce symptoms and improve QoL

– Minimize impact of AFib on cardiac performance

– Reduce risk of stroke

– Minimize cardiac remodeling

Primary Therapeutic Aims in AFib


2. Treatment Options for AFib

Treatment Options for AFib

Cardioversion

• Pharmacological

• Electrical

Drugs to prevent AFib

• Antiarrhythmic drugs

• Non-antiarrhythmic drugs

Drugs to control ventricular rate

Drugs to reduce thromboembolic risk

Non-pharmacological options

• Electrical devices (implantable pacemaker and defibrillator)

• AV node ablation and pacemaker implantation (ablate & pace)

• Catheter ablation

• Surgery (Maze, mini-Maze)


Cardioversion

Cardioversion of AFib

• Pharmacological

– Early onset AFib

– Long-standing AFib

• Electrical

– Transthoracic

Cardioversion of AFib

Prompt treatment essential

• Limit duration to minimize cardiac remodelling

• Avoid anticoagulation therapy

– (necessary for arrhythmias that last >48 hours)

• Avoid prolonged hospital recovery

• Improve quality of life

Pharmacological Cardioversion


•More effective in recent-onset AFib

– Class IA-IC-III drugs administered IV

– Class IC favoured in non-cardiopathic patients

– Class III favoured in cardiopathic patients or those with delays in conduction

•Oral loading can be performed with class IC drugs

– Flecainide (200-300 mg)

– Propafenone (450-600 mg)


Recent onset AFib

Oral Loading with Class IC Drugs for Recent Onset AFib

Capucci A, et al. Am J Cardiol (1994) 74: 503

100

60

80

40

20

SR

(%

)

Propafenone 600 mgFlecainide 300 mg Placebo

3 hours 8 hours0

p<0.001 vs. placebo p<0.001 vs. placebo

59

51

18

7872

39

Cardioversion of Paroxysmal AFib with Class IC Drugs

Paroxysmal AFib (<48h), good LVEF

• IV 2 mg/kg + 0.007 mg/kg/min, maintenance

• Oral administration flecainide 300 mgpropafenone 600 mg

• Mean efficacy: 80%

• Mean time of efficacy: 3h

• Proarrhythmia: FLA 1:1 ECG monitoring necessary (<0.5%) with patients in resting

condition

Class IC drugs (propafenone, flecainide)

Risk with Class IC Drugs: Transformation of AFib into Atrial Flutter with 1:1 AV Conduction

Flecainide

Treatment Out-of-Hospital with Class IC Drugs

•Symptomatic, rare episodes of AFib

•Recent onset AFib

•No structural heart disease

•Prior hospital experience

•Good physician-patient relationship

•Resting conditions for at least 4 hours

Pill-in-the-Pocket

• In a selected (no or mild HD), risk-stratified patient population with recurrent AFib not currently taking AADs

– 79% developed ≥ 1 episodes of recurrent AFib during 15 ± 5m follow-up

– Acute oral flecainide or propafenone successfully terminated 94% of episodes within 113 ± 84 min, with side effects in 7% of patients

Alboni P, et al. N Engl J Med (2004) 351: 2384

Pill-in-the-Pocket

0

50

Nu

mb

er

per

mon

th

25

Prior to enrolment During follow-up

Hospitalisation

p<0.001

0

50

25

Calls to ER

45.6

4.9

15

1.6N

um

ber

per

month

p<0.001

Alboni P, et al. N Engl J Med (2004) 351: 2384

Connolly SJ Circulation (1999) 100: 2025

Controldrug n

Primary endpoint

Durationof study

OR of SR with amiodarone p

Cowan et al Digoxin IV 34

Conversion to sinus rhythm

24 h 1.11 NS

Hou et al Digoxin IV 50 24 h 1.30 0.0048

Cotter et al Placebo 80 24 h 1.34 0.029

Galve et al Placebo 100 24 h 1.13 0.532

Donovan et al Placebo 64 24 h 1.05 NS

Donovan et al Flecainide 66 24 h 0.86 NS

Nos et al Verapamil 24 3 h 77% amiod./0% verap <0.001

McAlister et al Quinidine 36 8 h 0.64 0.04

Pilati et al Quinidine 75 24 h 1.09 NS

Kerin et al Quinidine 32 24 h 1.07 NS

Di Biasi et al Propafenone 40 24 h 1.15 NS

Larbuisson et al Propafenone 84 24 h 1.22 NS

Chapman et al Procainamide 26 12 h 0.99 NS

Moran et al Magnesium sulfate 42 24 h 0.64 <0.05

Conversion to SR with AmiodaroneIV (randomized studies)

Amiodarone for Cardioversion of Recent-Onset AFib: Meta-analysis

Khan IA, et al. Int J Cardiol (2003) 89: 239

• Amiodarone IV (3-7 mg/kg ± infusion 0.9-3.0 g/day)

• Amiodarone oral (25-30 mg/kg)

• Time to conversion > 6-8 h

• Amiodarone > 1.5 g/day IV > placebo

• Amiodarone 25-30 mg/kg oral > placebo

• Amiodarone not > other AADs

• Safe in patients with structural cardiopathies and low LVEF

100

80

60

40

20

Con

vers

ion

(%

)

Bolus + infusionBolus only

2-4 h 8 h0

34

55

69

95

Amiodarone Single Oral Administration for Cardioversion of Recent Onset AFib

Peuhkurinen K, et al. Am J Cardiol (2000) 85: 462

100

60

80

40

20

Pati

en

ts in

AFib

(%

)

AmiodaronePlacebo

00

2 4 6 8 10 12 14 16 18 20 22 26

Time to conversion (hours)

24

Flecainide IV vs Amiodarone IV for Cardioversion in Recent-Onset AFib

Donovan KD, et al. Am J Cardiol (1995) 75: 693

32

24

28

16

8

Card

iovers

ion

(%

)

00

1 2 3 4 5 6 7 8

(hours)

20

12

4

p=0.007p=0.001

AmiodaroneFlecainidePlacebo


Long-lasting AFib

Effect of Duration on Efficacy of Pharmacological Cardioversion

Reisinger J, et al. Am J Cardiol (1998) 81: 1450

106 patients with AFib <6 months

100

60

80

40

20

SotalolFlecainide

* p=0.005

Total

52*

23

<24 hours

69*

31

<7 days

44

17

<6 months

0 00

Amiodarone Cardioversion in Persistent AFib

Kochiadakis GE, et al. Am J Cardiol (1999) 83: 61

67 patients with AFib >48 hours

100

60

80

40

20

PlaceboAmiodarone

p<0.001

Total

48

0

LA (mm) >45 <45

32

82

LVEF (%)>50 <50

31

65

AFib (m)>1 <1

30

77

0

A B

Sin

us r

hyth

m (

%)

Conversion of Atrial Flutter or AFib with Ibutilide IV

Stambler BS, et al. Circulation (1996) 94: 1613

100

60

80

40

20

Sin

us r

hyth

m (

%)

p<0.0001

Ibutilide0

Placebo

100

60

80

40

20S

inu

s r

hyth

m (

%)

p<0.0001

AFlutter0

AFib

266 patients

Adverse effects: 8.3% polymorphic ventricular tachycardia

Conversion of Atrial Flutter or AFib with Ibutilide IV

Glatter K, et al. Circulation (2001) 103: 253

Effect “on top” of long-term amiodarone

80

60

40

20

Recovery

of

SR

(%

)

AFlutter0

AFib

70 patients(57 AFib, 13 AFlutter)

Ibutilide 2 mg

39

54

Electrical Cardioversion(transthoracic)

Technical Aspects

• Impedence

•Position of paddles

•Pressure applied to paddles

•Waveform

The efficacy of electrical cardioversion depends on the density of current delivered to the atrial myocardium, which is dependent on:

•Transthoracic Cardioversion of Atrial FibrillationComparison of Rectilinear Biphasic vs Damped Sine Wave Monophasic Shocks

Suneet Mittal, Shervin Ayati, Kenneth M. Stein,David Schwartzman, Doris Cavlovich, Patrick J. Tchou,Steven M. Markowitz, David J. Slotwiner, Marc A. Scheiner,Bruce B. Lerman.

Circulation 2000; 101: 1282-7

Defibrillation Waves

Mittal S, et al. Circulation (2000) 101: 1282

Monophasic wave Biphasic wave

Am

pere

0

20

10

0

4 8 12

msec

Am

pere

0

10

0

-10

4 8 12

msec

30

Cumulative Efficacy of Cardioversion

Mittal S, et al. Circulation (2000) 101: 1282

Monophasic or biphasic shock

100

60

80

40

20

Effi

cacy o

f card

iovers

ion

(%

)

p<0.0001

100 J

21

70 J

68

200 J

44

120 J

85

300 J

68

150 J

91

360 J

79

170 J

94

0

p<0.005

Monophasic Biphasic

•Biphasic vs Monophasic Shock Waveform for Conversion of Atrial FibrillationThe Results of an International Randomized, Double-Blind Multicenter Trial

RL Page, RE Kerber, JK Russel, T Trouton, J Waktare, D Gallik,JE Olgin, P Ricard, GW Dalzell, R Reddy, R Lazzara, K Lee,M Carlson, B Halperin, GH Bardy, for the BiCard Investigators.

JACC (2002) 39: 1956-63

Dermal Injury Dependent on Waveform

Page RL, et al. J Am Coll Cardiol (2002) 39: 1956

60

40

50

30

20

10

BiphasicMonophasic

None(no erythema)

Mild(no tenderness)

Moderate(tenderness)

Severe(blistering)

0

Success of Monophasic (MP) and Biphasic (BP) Waveforms at Cumulative EnergyLevels

Adgey AA & Walsh SJ Heart (2004) 90: 1493

Success of Cumulative Shocks for Different Biphasic Devices

Adgey AA & Walsh SJ Heart (2004) 90: 1493

Electrical Cardioversion

Pharmacological pretreatment and management of recurrence

Failure of Electrical Cardioversion

Van Gelder IC, et al. Am J Cardiol (1999) 84: 147R

100

60

80

40

20

Sin

us r

hyth

m (

%)

02 min

90

50

70

30

10

Immediate recurrent AFibNo conversion

Early recurrent AFibLate recurrence AFib

2 weeks 1 year

cardioversion

Recurrence Following Cardioversion: AFFIRM Study

Raitt MN, et al. Am Heart J (2006) 151: 390

AFFIRM:most recurrences occur within 2 monthsof cardioversion

Time (years)

Pati

en

ts w

ith

AF R

ecu

rren

ce (

%)

0

20

40

60

80

100

0 1 2 3 4 5 6

Log rank statistic = 58.62p<0.0001

Rate control: 563,3 (0) 167,383 (69) 96,440 (80) 42,472 (87) 10,481 (92) 2,484 (95)

Rhythm control: 729,2 (0) 344,356 (50) 250,422 (60) 143,470 (69) 73,494 (75) 18,503 (79)

N, Events (%)

Rate control

Rhythm control

Treatment Arm

Immediate Recurrence of AFib Following Successful Electrical Cardioversion

Authors n ERAF (%) Timing

Bertaglia 90 28 7 days

Bianconi 96 18 24 hours

Botto 156 61 7 days

Daoud 337 9 5 min

De Simone 107 14 7 days

Tieleman 61 36 5 days

Villani 116 7 24 hours

Yu 50 26 1 min

Immediate/Early Recurrence of AFib After Electrical Cardioversion

•Effect of Atrial Fibrillation Duration on Probability of Immediate Recurrence after Transthoracic Cardioversion

H Oral, M Ozadyn, C Sticherling, H Tada, C Scharf, A Chugh, SWK Lai, F Pelosi, BP Knight, SA Strickeberger, F Morady.

JCE 2003; 14: 182-5

Immediate Recurrence of AFib (IRAF) According to the Duration of Arrhythmia

Oral H, et al. J Cardiovasc Electrophysiol (2003) 14: 182

100

70

90

60

40

30

80

50

20

10

1hr

1-24hrs

1-7days

7-30days

31-90days

91-180days

181-365days

>365days

Duration of AFib

48

27

34 45

7236 40

13

0

Pre

vale

nce o

f IR

AF

(%

)

Oral Propafenone Before Electrical Cardioversion in Persistent AFib

Bianconi L, et al. J Am Coll Cardiol (1996) 28: 700

Effect on early recurrence of arrhythmia

70

60

50

40

30

20

10

100

80

90

70

60

Sin

us r

hyth

m (

%)

p<0.01

0

Com

ple

x a

tria

l arr

hyth

mia

(%

)

p<0.002

10 minutes50

10 min 24 min 48 min0

PlaceboPropafenone

18

52

Effect of Pre-treatment with Oral Amiodarone

Capucci A, et al. Eur Heart J (2000) 21: 66

30

18

24

12

6

Con

vers

ion

(%

)

p<0.005

SR before ECV0

GIKAmiodarone

No treatment

100

60

80

40

20C

on

vers

ion

(%

)

p<0.05

SR with cardioversion0

GIKAmiodarone

No treatment

No differences in energy for cardioversion

Chenner KS, et al. Eur Heart J (2004) 25: 144

Stable anticoagulation for 2 weeks

Short-term Amiodarone20 (32%)

Placebo2 (5%)

Long-term Amiodarone30 (49%)

Short-term Amiodarone29 (47%)

Placebo6 (16%)

Long-term Amiodarone34 (56%)

Sinus Rhythm at 52 weeks

Sinus Rhythm at 8 weeks

Short-term Amiodarone48

Placebo30

Long-term Amiodarone48

Sinus Rhythm

Short- and Long-term Treatment with Amiodarone after Cardioversion Reduces Recurrence

DCCV100

Chemical26

Short-term Amiodarone62

Placebo38

Long-term Amiodarone61

30 32 38 16 10

Protocol violation = 4; Withdrew consent = 7

Randomization172

Effect of Pre-treatment with Ibutilide IV

Oral H, et al. N Engl J Med (1999) 340: 1849

• Successful cardioversion in all patients given ibutilide and in 14/50 patients failing cardioversion alone

• The mean energy for defibrillation was less with ibutilide

• Sustained polymorphic tachycardia in 2/64 (3%) patients treated with ibutilide within 15 minof the infusion

50

30

40

20

10

Pati

en

ts (

%)

0

SR after ECV

SR before ECV

AFib

IBU No IBU

•Pre-treatment with Verapamil in Patients with Persistent or Chronic Atrial Fibrillation Who Underwent Electrical Cardioversion

A De Simone, G Stabile, DF Vitale, P Turco, M Di Stasio,F Petrazzuoli, M Gasparini, C De Matteis, R Rotunno, T Di Napoli.

J Am Coll Cardiol (1999) 34: 810-4

Pre-treatment with Verapamil for Reducing Recurrence post-ECV

De Simone A, et al. J Am Coll Cardiol (1999) 34: 810

60

30

50

20

40

10

1 week

30

0

Recu

rren

ce (

%)

3 months

610

39

1517

PFN + VERPFN

PFN - VER

p=0.01

p=0.04

p=0.02

p=0.04

•Effects of Pre-treatmentwith Verapamil on Early Recurrences after Electrical Cardioversionof Persistent Atrial FibrillationA Randomised Study

E Bertaglia, D D’Este, A Zanocco, F Zerbo, P Pascotto.

Heart (2001) 85: 578-80

Effect of Pre-treatment with Verapamilon Early Recurrence Following ECV

Bertaglia E, et al. Heart (2001) 85: 578-80

A randomised trial (90 patients with amiodarone)60

30

50

20

40

10

0

Recu

rren

ce (

%)

Amio + VerAmio

6 h

NS

7 d

NS

30 d

NS

Follow-up

Effect of Verapamil on Immediate and Early Recurrence after Cardioversion of AFib

• Effectiveness demonstrated

– A De Simone et al (JACC 1999)

– E Daoud et al (JCE 2000)

– GQ Villani et al (AHJ 2002)

– A De Simone et al (AJC 2002)

– GL Botto et al (JACC 2002)

• Not efficacious

– E Bertaglia et al (Heart 2001)

– T Van Noord et al (JCE 2001)

– H Ramanna et al (JACC 2001)

Cardioversion of AFib and Maintenance of SR

Van Gelder IC, et al. Arch Int Med (1996) 156: 2585

100

60

80

40

20

Main

ten

an

ce o

f S

R (

%)

01

90

50

70

30

10

1 ECV, no AADsSerial ECV

Months post-cardioversion

2 3 4 5 6 7 8 9 10 11 12

•Success of Serial External Electrical Cardioversion of Persistent Atrial Fibrillation in Maintaining Sinus Rhythm

E Bertaglia, D D’Este, F Zerbo, F Zoppo, P Delise, P Pascotto.

European Heart Journal (2002) 23: 1522-8

Serial Electrical Cardioversion

90 patients with persistent AFib who hadpreviously undergone at least one successfulelectrical cardioversion

RandomizationCardioversion repeated up to 2 timesin case of recurrent AFib within 1 month of the preceding electrical cardioversion (Group AGG)

or

Recurrences were left untreated (Group CTL)

Bertaglia E, et al. Eur Heart J (2002) 23: 1522

Persistence of Sinus RhythmDuring Long-term Follow-up

0102030405060708090

100

0 7 30 180 365

Group AGG Group CTL

Aggressive repeated ECV beneficial in highly recurrent persistent AFib

days

Bertaglia E, et al. Eur Heart J (2002) 23: 1522

Sin

us r

hyth

m (

%)

2.Treatment Options for AFib

Drugs to Prevent AFib


• Antiarrhythmic drugs– Class I-III antiarrhythmics

• Non-antiarrhythmic drugs– ACE-I, ARBs

– Statins

– PUFA

Rationale for Drug Treatment to Prevent Recurrence

•Suppression of symptoms

•Avoidance of tachycardia-induced cardiomyopathy

•Reduction of thromboembolism

•Prevention of heart failure?

•Decrease of mortality?


Antiarrhythmics

Vaughan Williams Classification

Type lA Disopyramide Procainamide Quinidine

Type IB Lidocaine Mexiletine

Type IC Flecainide Moricizine Propafenone

Type II Beta-blockers Type III Amiodarone Bretylium Dofetilide Ibutilide Sotalol

Type IV Calcium antagonists

•Disopyramide 400-750 mg

•Procainamide 1000-4000 mg

•Quinidine 600-1500 mg

•Flecainide 200-300 mg

•Propafenone 450-900 mg

•Amiodarone 100-400 mg

•Dofetilide 500-1000 mcg

•Sotalol 240-320 mg

Drugs to Maintain SR in Patients with AFib – Recommended Daily Doses

•Even with the most effective AAD, such as amiodarone, long-term efficacy is low

~50% or less at 1 year

Effectiveness of Current AADs

Prevention of Recurrencewith AADs

Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

No. of Events/Total Peto OR (95% Cl)

Drugs studiedNo. of

Studies Antiarrhythmic Control p value

Antiarrhythmicvs ControlClass IADisopyramide hydrochloride 2 40/75 49/71 0.52 (0.27-1.01) 0.05

Quinidine sulfate 7 741/1106 417/518 0.51 (0.40-0.65) <0.001

All class IA 8 781/1118 449/564 0.51 (0.40-0.64) <0.001

Class IBAll: aprindine hydrochloride, bidisomide

2 639/781 453/540 0.84 (0.63-1.13) 0.26

Class IC

Flecainide acetate 3 31/71 56/78 0.31 (0.16-0.60) <0.001Propafenone hydrochloride 5 376/720 276/378 0.37 (0.28-0.48) <0.001

All class IC 9 443/843 342/466 0.36 (0.28-0.45) <0.001

Class IIAll: metroprolol tartrate 1 127/197 140/197 0.74 (0.49-1.13) 0.16

Class III

Amiodarone 4 200/428 209/245 0.19 (0.14-0.27) <0.001

Dofetilide 2 252/431 274/325 0.28 (0.20-0.38) <0.001

Sotalol hydrochloride 9 916/1391 622/815 0.53 (0.44-0.65) <0.001

Dronedarone 1 116/151 43/48 0.45 (0.20-1.02) 0.06

All class III 15 1484/2401 1148/1433 0.37 (0.32-0.43) <0.001

0.10 1 10

Prevention of recurrence in studies comparing AADs with placebo or no treatment

70

40

60

30

10

50

20

Quinidine

Pro

port

ion

wit

hou

t R

ecu

rren

ce (

%)

DisopyramidePropafenone Flecainide Amiodarone Sotalol0

Prevention of Recurrence with AADs


Antiarrhythmic Drugs for Maintenance of Sinus Rhythm

Tamariz L, et al. J Am Coll Cardiol 2003: 536A

Meta-analysis of 18 randomized, controlled trials

7

4

6

3

1

5

2

Quinidine

Od

ds R

ati

o

Disopyramide Propafenone Flecainide Amiodarone Sotalol0

Amiodarone > risk of non-cardiac adverse effects

Pati

en

ts w

ith

ou

t A

Fib

(%

)

Roy D, et al. N Engl J Med (2000) 342: 913

Amiodarone to Prevent Recurrence of AFib

Follow-up (days)

0 100 200 300 400 500 600

p<0.001

Sotalol

Propafenone

Amiodarone

0

20

40

60

80

100

CTAF Study: mean follow-up 16 months

AFFIRM Substudy of First Anti-Arrhythmic Drug

AFFIRM Study

AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20

Perc

en

t w

ith

ou

t re

cu

rren

ce

Years

100

0 1 2 3 4 5

Class I Drugs

Amiodarone

0

20

40

60

80

0 1 2 3 4 50

20

40

60

80

100

Amiodarone

Sotalol

Years

222 pts 256 pts

62%

23%

60%

38%

p<0.001p=0.011

Pro

bab

ilit

y o

f re

main

ing

in

SR

Follow-up (days)

1.0

0 200 400 600 800 1000

Sotalol

Placebo

Amiodarone

0

0.2

0.4

0.6

0.8

SAFE-T Investigators

0 200 400 600 800 10000

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f re

main

ing

in

SR

All patients Patients with IHD

Amiodarone

Sotalol

Placebo

Singh BN, et al. N Engl J Med (2005) 352: 1861

Amiodarone and Solatolol Equivalent in Patients with Ischaemic Heart Disease

•Hypothyroidism 7.0%

•Hyperthyroidism 1.4%

•Peripheral Neuropathy 0.5%

•Lung Infiltrates 1.6%

•Liver Dysfunction 1.0%

•Bradycardia 2.4%

Major Adverse Experiences Associated with Early Drug Discontinuation

Amiodarone Trials Meta-analysis Investigators Lancet (1997) 350: 1417

•Gastrointestinal events 4.0%

•Pulmonary events 2.6%

•Ocular events 0.6%

•Other 7.1%

Amiodarone Discontinuations Associated with Major Adverse Events

AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20

•Amiodarone meta-analysis 41% at 2y

•CTAF 18% at 16m

•PIAF 25% at 1y

•AFFIRM 12.3% at 1y

Major Adverse Experiences Associated with Early Drug Discontinuation

Major Adverse Experiences Associated with AADs


No. ofStudies

WithdrawalsPeto OR (95% Cl)

Drugs studied

Antiarrhythmic vs Control

Class IA

Disopyramide hydrochioride 2 3.85 (1.13-13.20)

Quinidine sulfate: higher dose 5 3.58 (2.01-6.40)

Quinidine: lower dose 2 0.81 (0.59-1.10)

Quinidine: all studies 7 1.90 (0.90-4.02)

All class IA 8 2.02 (1.00-4.10)

Class IB

All: aprindine hydrochloride 1 0.66 (0.11-3.95)

Class IC

Flecainide acetate 3 9.14 (1.94-42.90)

Propafenone hydrochloride 5 1.69 (1.09-2.62)

All class IC 9 1.93 (1.27-2.93)

Class II

All: metoprolol tartrate 1 3.16 (1.43-6.99)

Class III

Amiodarone 3,4 5.55 (2.24-13.70)

Dofetilide 1,2 1.61 (0.41-6.23)

Sotalol hydrochloride: PAFAC, SOPAT 2 0.95 (0.68-1.33)

Sotalol: rest of studies 6,7 3.02 (1.65-5.53)

Sotalol: all studies 8,9 1.47 (0.84-2.60)

Azimilide dihydrochloride + Dronedarone 2 2.46 (1.51-4.01)

All class III 14,16 1.63 (1.29-2.07)

0.10 1 10

Proarrhythmia Associated with AADs


No. ofStudies

ProarrhythmiaPeto OR (95% Cl)

Drugs studied

Antiarrhythmic vs Control

Class IA

Disopyramide hydrochloride 2 No Events

Quinidine sulfate: higher dose 5 4.56 (1.20-17.30)

Quinidine: lower dose 2 1.53 (0.64-3.60)

Quinidine: all studies 7 2.10 (1.02-4.33)

All class IA 8 2.06 (1.00-4.26)

Class IB

All: aprindine hydrochloride 1 No Events

Class IC

Flecainide acetate 3 5.97 (1.67-21.30)

Propafenone hydrochloride 5 1.52 (0.33-7.02)

All class IC 9 3.41 (1.28-9.09)

Class II

All: metoprolol tartrate 1 7.96 (2.84-22.30)

Class III

Amiodarone 3, 4 2.65 (0.88-8.00)

Dofetilide 1, 2 3.77 (1.31-10.80)

Sotalol hydrochloride: PAFAC, SOPAT 2 1.42 (0.56-3.60)

Sotalol: rest of studies 6, 7 2.67 (1.44-4.98)

Sotalol: all studies 8, 9 2.20 (1.31-3.69)

Azimilide dihydrochloride + dronedarone 2 3.30 (1.01-10.80)

All class III 14, 16 2.20 (1.31-3.69)

0.10 1 10

Proarrhythmic Profile of AADs

Dysopiramide 1-2% ++ + ++ +Quinidine 2% ++ + ++ +Procainamide 1-2% + + + + +Lidocaina Rare Rare Rare RareMexiletine Rare Rare RareMorizicine Rare + ++ ++ +Propafenone Rare + ++ +++ ++Flecainide Rare + ++ +++ ++Amiodarone <1% + + + +++Ibutilide 4-5% + RareSotalol 2-5% + + + +++

Torsade Atrialde Pointe VF VT * Flutter 1:1 Bradyarrhythmia

* More frequent in pts with structural HD or history of ventricular arrhythmias

Friedman P, et al. Am J Cardiol (1998) 82: 50N

Overall Mortality Associated with AADs


No. ofStudies

No. of Events/Total Peto OR (95% Cl)

p valueDrugs studied Antiarrhythmic Control

Antiarrhythmicvs ControlClass IADisopyramide phosphate 2 2/75 0/71 7.56 (0.47-1.22) 0.16

Quinidine sulfate 7 21/1128 4/548 2.26 (0.93-5.45) 0.07

All class IA 8 23/1203 4/594 2.39 (1.03-5.59) 0.04

Class IBAll: aprindine hydrochloride, bidisomide

2 9/781 3/540 1.89 (0.59-6.03) 0.28

Class IC

Flecainide acetate 3 0/71 0/78 Not estimable NAPropafenone hydrochloride 5 0/720 2/378 0.05 (0.00-1.02) 0.05

All class IC 9 1/843 2/466 0.14 (0.00-1.88) 0.14

Class IIAll: metroprolol tartrate 1 3/197 0/197 7.47 (0.77-72.20) 0.08

Class III

Amiodarone 4 13/428 3/245 1.96 (0.68-5.67) 0.21

Dofetilide 2 83/431 83/325 0.97 (0.67-1.40) 0.88

Sotalol hydrochloride 9 30/1391 5/815 2.09 (0.97-4.49) 0.06Azimilide dihydrochloride + dronedarone

2 10/1042 4/537 1.31 (0.43-3.97) 0.63

All class III 16 136/3292 95/1922 1.19 (0.88-1.61) 0.27

0.10 1 10

Coplen SE, et al. Circulation (1990) 82: 1106

100

40

80

20

60

0

(%)

PlaceboQuinidine

3 month

p<0.001

69

45

6 month

p<0.001

58

33

12 month

p<0.001

50

25

Mortality

p<0.05

17

3

# of patients

Mortality Associated with Class 1A Drugs

Prophylaxis of AFib with quinidine: Meta-analysis of 6 randomized trials

Physician Visits Associatedwith AAD Use Over Time

Fang FC et al. Arch Intern Med 2004; 164: 55-60

Vis

its o

n m

ed

icati

on

(%

)

Visit (years)

1991-1992 1993-1994 1995-1996 1997-1998 1999-2000

Quinidine

Class IC

Amiodarone Hydrochloride

0

2

3

4

5

7

6

1

Rhythm and RateControl Studies

• PIAF, Lancet 2000

• RACE, NEJM 2002

• AFFIRM, NEJM 2002

• PAF-2, Eur Heart J 2002

• STAF, JACC 2003

• HOT-CAFÉ, Chest 2004

TrialAge, y

MeanFollow-up

Thrombo-embolic

complications%

Mortality%

Falk, RH. Circulation (2005) 111: 3141

Rhythm vs Rate Trials

n

AFFIRM 42m

Rate control Rhythm control

20272033

7070

3563

8570

67.5

2124

RACE 27m


256266

6868

1039

96-9986-99

5.57.9

1713

STAF 22m


100100

6566

0NR

NRNR

0.63.1

52.5

PIAF 12m


125127

6160

1056

100100

NRNR

1.61.6

Hot Cafe 20m


101104

6160

NR63.5

74NR

12.9

12.9

Sinus rhythm

(%)Warfarin

(%)

Cu

mu

lati

ve m

ort

ality

(%

)

Rhythm control

Rate control

No. ofdeaths

0

30

25

20

15

5

Rhythm control

Rate control10

Years

357 (13)80 (4) 352 (24)0 175 (9) 314 (18)

210 (11)78 (4) 306 (21)0 148 (7) 275 (16)

0 54321

p=0.08

AFFIRM Investigators N Engl J Med (2002) 347: 1825

AFib Follow-up Investigation of Rhythm Management (AFFIRM)No survival advantage of rhythm over rate (n=4060)

Testa L, et al. Eur Heart J (2005) 26: 2000

Study orsub-category

Rate control(n/N)

Rhythm control(n/N)

Van Den Berg 388/2027 438/2033

SOLVD 1/101 6/104

TRACE 2/125 4/127

Ueng 24/256 32/266

CAPP 97100 9/100

Total (95% CI) 2609 2630

Weight(%)

OR (95% CI Random)

89.86 0.86 (0.74, 1.00)

0.46 0.16 (0.02, 1.38)

0.72 0.50 (0.09, 2.78)

6.72 0.76 (0.43, 1.32)

2.24 1.00 (0.38, 2.63)

100.0 0.85 (0.73, 0.98)

Total events: 424 (Rate control). 489 (Rhythm control)Test for heterogeneity chi-square=2.97; df=4; p=0.56; I2=0%Test for overall effect z=2.24; p=0.03

OR(95% CI Random)

10510.1 0.2 0.5 2

Ratecontrol better

Rhythmcontrol better

Odds Ratio for Combined Endpoint (All-cause Death + Thromboembolic Stroke)

Meta-Analysis of Rhythm Control versus Rate Control Studies

Age at enrollment* <0.0001 1.06 1.04 1.08

Coronary artery disease <0.0001 1.65 1.31 2.07

Congestive heart failure <0.0001 1.83 1.45 2.32

Diabetes <0.0001 1.56 1.22 2.00

Stroke or transient ischemic attack <0.0001 1.54 1.17 2.05

Smoking <0.0001 1.75 1.29 2.39

First episode of AFib 0.0067 1.27 1.01 1.58

Sinus rhythm <0.0001 0.54 0.42 0.70

Warfarin use <0.0001 0.47 0.36 0.61

Digoxin use <0.0001 1.50 1.18 1.89

Rhythm-control drug use 0.0005 1.41 1.10 1.83

UpperCovariate Lowerp HRHR: 99% CL

* per year of age

AFFIRM Investigators Circulation (2004) 109: 1509

AFFIRM On-Treatment Analysis: SR but not AAD Use Associates with Improved Survival

AFFIRM Investigators Circulation (2004) 109: 1509

AFFIRM On-Treatment Analysis:SR Associates with Survival

Implications

In patients with AFib such as those enrolled in the AFFIRM study, warfarin improves survival.The presence of SR but not AAD use is associated with a lower risk of death.

These results suggest that if an effective method for maintaining SR with fewer side effects were available, it might improve survival


Non-antiarrhythmic drugs

Non-antiarrhythmic Drugs to Prevent AFib

•ACE Inhibitors and Angiotensin Receptor Blockers

•Statins

•Polyunsaturated fatty acids (omega-3)


ACE Inhibitors and Angiotensin Receptor Blockers

Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

*Abstract only.ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CHF = congestive heart failure; HTN = hypertension; LVD = left ventricular dysfunction; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NSR = sinus rhythm; Post-MI = post-myocardial infarction

Author/Study, DatePatient Group Drug

No. Randomized

MeanFollow-Up

MeanLVEF HTN (%)

Rate of AFin Control Group (%)

ACE-I trials

Van Den Burg, 1995 AF, CHF Lisinopril 30 84 days n/a n/a 64

Ueng, 2003 AF Enalapril 145 270 days(61-575) 51 32 43

Vermes (SOLVD), 2003 LVD, CHF, NSR Enalapril 374 3.3 yrs 27 20 24

Pizetti (GISSI), 2001 Post-MI, NSR Lisinopril 17,711 42 days n/a 30 8

Pedersen (TRACE), 1999

Post-MI, LVD, NSR Trandolapril 1,577 2-4 yrs 33 22 5

STOP-H2, 1999 HTN Enalapril 10,985 5.0 yrs n/a 100 8

CAPP, 1999 HTN Captopril 6,614 6.1 yrs n/a 100 2

ARB trials

CHARM, 2003* CHF, NSR Candesartan 5,518 3.2 yrs 39 55 8

Madrid, 2002 AF Irbesartan 154 254 days(60-710) 64 42 29

ValHeFT, 2003* CHF, NSR Valsartan 4,409 2 yrs 28 7 8

Wachtell, (LIFE), 2003* HTN, LVH, NSR Losartan 9,193 4.9 yrs n/a 100 6

Characteristics of ARB and ACE-I Studies in AFib

StudyTreatment

(n/N)Control(n/N)

ACE inhibitor

Van Den Berg 2/7 7/11

SOLVD 10/186 45/188

TRACE 22/790 42/787

Ueng 18/70 32/75

CAPP 117/5492 135/5493

STOP-H2 200/2205 357/4409

GISSI 665/8855 721/8846

Sutotal (95% CI) 1034/17615 1339/19809

Weight(%)

RR (95% CI Random)

1.7 0.45 (0.13, 1.57)

4.8 0.22 (0.12, 0.43)

6.6 0.52 (0.31, 0.87)

7.0 0.60 (0.37, 0.97)

11.4 0.87 (0.68, 1.11)

13.0 1.12 (0.95, 1.32)

14.0 0.92 (0.83, 1.02)

58.7 0.72 (0.56, 0.93)

Test for heterogeneity chi-square=32.58; df=6; p<0.00001Test for overall effect z=-2.53; p=0.01

Effect of Treatment Based on Class of Drug: ACE Inhibitors

28%p=0.01

0 10521

RR(95% CI Random)


StudyTreatment

(n/N)Control(n/N)

Weight(%)

RR (95% CI Random)

ARB

Madrid 9/79 22/75

ValHeFT 116/2209 173/2200

Charm 179/2769 216/2749

LIFE 179/4417 252/4387

Sutotal (95% CI) 483/9474 663/9411

43 0.39 (0.19, 0.79)

11.8 0.67 (0.53, 0.84)

12.5 0.82 (0.68, 1.00)

12.6 0.71 (0.59, 0.85)

41.3 0.71 (0.60, 0.84)

Test for heterogeneity chi-square=5.25; df=3; p=0.15Test for overall effect z=-4.12; p=0.00004

Effect of Treatment Based on Class of Drug: ARBs

29%p=0.00002

0 10521

RR(95% CI Random)


Effect of ACE Inhibitors or ARB Based on Indication

Study Treatment (n/N) Control (n/N)Heart FailureVan Den Berg 2/7 7/11SOLVD 10/186 45/188ValHeFT 116/2209 173/2300Charm 179/2769 216/2749Sutotal (95% CI) 307/5171 441/5148

Weight (%) RR (95% CI Random)

1.7 0.45 (0.13, 1.57)4.8 0.22 (0.12, 0.43)

11.8 0.67 (0.53, 0.84)12.5 0.62 (0.66, 1.00)30.9 0.56 (0.37, 0.85)

Test for heterogeneity chi-square=15.01; df=3; p<0.0018Test for overall effect z=-2.72; p=0.007

44%

HypertensionCAPP 117/5492 135/5493LIFE 178/4417 252/4387STOP-H2 200/2205 357/4409Sutotal (95% CI) 496/12114 744/14/283

11.4 0.87 (0.69, 1.11)12.6 0.71 (0.59, 0.85)13.0 1.12 (0.95, 1.32)37.1 0.88 (0.65, 1.19)


12%

0 10521

RR (95% CI Random)


Effect of ACE Inhibitors or ARB Based on Indication

Study Treatment (n/N) Control (n/N) Weight (%) RR (95% CI Random)

Atrial FibrillationMadrid 9/79 22/75Ueng 15/70 32/75Sutotal (95% CI) 27/149 54/150

4.3 0.39 (0.19, 0.79)7.0 0.60 (0.37, 0.97)

11.4 0.52 (0.35, 0.79)Test for heterogeneity chi-square=1.33; df=1; p=0.31Test for overall effect z=-3.13; p=0.002

48%

Post-Myocardial InfarctionTRACE 22/790 42/787GISSI 665/8865 721/6646Sutotal (95% CI) 27/149 54/150

6.6 0.52 (0.31, 0.87)14.0 0.92 (0.83, 1.02)20.7 0.73 (0.43, 1.26)


27%

0 10521

RR (95% CI Random)



Statins

Lozano HF, et al. Heart Rhythm (2005) 2: 1000

Study DesignMedicationand subjects OR Comments

Statin drugsin protecting against AFib

Retrospective analysis of prospective study database

Statin users vs nonusers in a population of chronic CAD (n=449)

0.48 (CI 0.28-0.83) Effect of statins was independent of changes in serum cholesterol.AFib diagnosed by ECG at routine follow-up visits or with new symptoms onset.

Prevention of AFib recurrence after cardioversion

Retrospective analysis of patients referred for cardioversion

Statin users vs nonusers in a population with persistent lone AFib (n=62)

0.31 (CI 0.10-0.90) Patients on statins had higher cholesterol and were older than nonusers.AFib diagnosed by ECG at routine follow-up visits.

Prevastatin to prevent recurrent AFib after electrical cardioversion

Prospective, open-label, controlled multicenter study

Pravastatin40 mg/day vsno drug 3 weeks prior and 6 weeks cardioversion (n=114)

1.08 (CI not available)

Open-label design, small study, conventional antiarrhythmics also used.

52%

69%

8%

Studies of Statins to Prevent AFib

Effect of Atorvastatin on Reducing AFib Recurrence Post-ECV

Ozaydin M, et al. Am J Cardiol (2006) 297: 1490

Fre

ed

om

fro

m r

ecu

rren

ce

Follow-up (days)

0 30 60 90

Atorvastatin

control

0.5

0.6

0.7

0.8

0.9

1.0

48 patients with AFib lasting >48h and followed for 3m

p=0.01


Polyunsaturated fatty acids(omega-3)

Polyunsaturated Fatty Acids in Preventing AFib

Calò L, et al. J Am Coll Cardiol (2005) 45: 1723

100

60

80

40

20Pati

en

ts f

ree o

f A

Fib

(%

)

00

90

50

70

30

10

Control GroupPUFAs Group

Days after surgery

2 3 4 5 6 7 8 9 10 11 12 181 1716151413

Log-rank p=0.009

Mozzafarian D, et al. Circulation (2004) 110: 3683

AFib-Free Survival According to Fish ConsumptionTuna or other broiled/baked fish

1.0

0.8

Su

rviv

al fr

ee o

f A

Fib

0.60

0.9

0.7

p<0.0001(log-rank test for equalityof survivor functions)

5+/wk

Years

2 4 121086

1-4/wk

1-3/mo

<1/mo

AFib-Free Survival According to Fish ConsumptionFried fish or fish sandwich

1.0

0.8

Su

rviv

al fr

ee o

f A

Fib

0.60

0.9

0.7

p=0.0001(log-rank test for equalityof survivor functions)

<1/mo

Years

2 4 121086

1-3/mo

1+/wk

Mozzafarian D, et al. Circulation (2004) 110: 3683

n-3 Fatty Acid Intake from Fish and Incidence of AFib

Brouwer IA, et al. Am Heart J (2006) 151: 857

• European population-based prospective cohort study among subjects aged 55 years and above (n=6808)

• Dietary intake data available from 5184 subjects without AFib

– In the subsequent 6.4y follow-up period, 312 subjects developed AFib

– Incidence of AFib was not significantly associated with either long-chain fatty acid consumption or fish consumption

Rotterdam study


Drugs to Control Ventricular Rate

Permanent AFib and Ventricular Rate Control

Indications for control of ventricular rate:

• Failure of antiarrhythmic therapy for preventing recurrence

• Alternative treatment to maintain sinus rhythm

Clinical symptoms

ECG Criteria

Hemodynamic data

VR 60 - 80 bpm

At rest

VR 90 - 115 bpm

During moderate exercise

Definitions and Criteria for Rate Control

•Digoxin

•Calcium Antagonists

•Beta-Blockers

•Antiarrhythmic Drugs

Drugs Used for Rate Control


Rate Control Drugs in AFFIRM

•Digoxin 51%

•Beta-blockers 49%

•Calcium antagonists 41%

•AV node ablation 5%

Beasley R, et al. Br Med J (1985) 290: 9

Digoxin in Permanent AFibb

pm

Rest Moderate50

110

170

190

130

90

Strenuous

p<0.05

105

171

161

140150

70

• Heart rate during physical exercise and at various plasma concentrations

72

108

93

83

118

191182

164

SR

Nil

Low

High

Roth A, et al. Circulation 73: 316

Digoxin plus Diltiazemin Permanent AFib

bp

m

Rest Submax Exercise50

110

170

190

130

90

Max Exercise

* p<0.05 vs DG+DL * p<0.05 vs DL 360° p<0.05 vs DG 240

142

101

128

106

170

132

154

136150

70

• Medium and high doses alone or in combinationwith digoxin

86

67

8879

*°

*

*

DG

DG+DL 240

DL 240

DL 360

• Gallopamil 100 mg b.i.d.

• Diltiazem 120 mg b.i.d.

• Verapamil 120 mg b.i.d.

• Digoxin 0.8 – 1.4 µg/ml

Botto GL, et al. Clin Cardiol 21: 837

Study protocol

(7 day administration of slow release formulation)

Calcium Antagonists in Permanent AFib

Calcium Antagonistsin Permanent AFib

bp

m

Median VR Minimum VR50

100

150

175

125

75

Maximum VR

* p<0.001o p<0.01 vs DGX

Holter and walking test

90 91

82 80

5963

59 59

167

149142

137°*

*

DGX

GLL

DLT

VRP

Botto GL, et al. Clin Cardiol 21: 837

DiBianco R, et al. Am Heart J (1984) 108: 1121

Nadolol for Controlof Ventricular Rate

• Effect on heart rate in patients on digoxinb

pm

Resting Low Average

p<0.01

0

50

100

150

200

175

125

75

25

3’ Exercise Max Exercise

Nadolol median dose 87 mg

DGX

NDL

Atwood JE, et al. J Am Coll Cardiol (1987) 10: 314

Beta-blockers for Controlof Ventricular Rate

kg

/min

16

18

24

22

20

• Effect of nadolol on physical exercise capacityS

ec

300

500

450

400

350

Exercise time O2 Consumption

p<0.01 p<0.01

DGX

CLP

DGX

DLT

DiBianco R, et al. Am Heart J (1984) 108: 1121

• Metoprolol 200 mg/d

• Diltiazem 300 mg/d

• Digoxin 0.8 – 1.4 µg/ml

• Placebo

Botto GL, et al. PACE (2000) 23: 649

Randomized, cross-over study with administration for 7-10 days

Randomized, cross-over study with administration for 7-10 days

Modulation of Ventricular Rate

Study protocol

Modulation of Ventricular Rate

Metr

es w

alk

ed

240

260

320

300

280

• Walking test resultsM

ax h

eart

rate

150

155

190

*

185

180

175

170

165

160

o

* p<0.05 vs PLA e DGXo p<.,01 vs PLA e DGX

* p<0.005 vs DGXo p<0.05 vs MTP

**o

*

DGXPlacebo DLT

MTP

Botto GL, et al. PACE (2000) 23: 649

Antiarrhythmic Drugs for Control of Ventricular Rate

•Amiodarone

•Solatolol

CHF-STAT Study: Amiodaronein Permanent AFib

Deedwania PC, et al. Circulation (1998) 98: 2574

bp

m

Baseline 2 w 6 m0

50

100

90

80

70

60

40

30

20

10

12 m

NS p=0.001 p=0.001 p=0.006

Amiodarone (400 mg/d)Placebo


Drugs to Reduce Thromboembolic Risk

Atrial Fibrillation and Stroke

•Anticoagulant therapy is clearly indicated and beneficial in valvular atrial fibrillation.

• In non-valvular atrial fibrillation, major randomized trials have provided useful guidelines for identifying and treating patients at risk.

Major Clinical Trials of Primary Prevention in Non-Valvular AFib

• SPAF1 Stroke Prevention in Atrial Fibrillation

• BAATAF2 Boston Area Anticoagulation Trial for

Atrial Fibrillation

• CAFA3 Canadian Atrial Fibrillation Anticoagulation

• AFASAK4 Copenhagen Investigators

• SPINAF5 Stroke Prevention in Non-rheumaticAtrial Fibrillation

1 Lancet (1989) 1: 1752 N Engl J Med (1990) 323: 1505

3 J Am Coll Cardiol (1991) 18: 349

4 Circulation (1991) 84: 5275 N Eng J Med (1992) 327: 1406

SPAF BAATAF CAFA AFASAK SPINAF

Number of Patients 1330 420 378 1007 571

Drug Used Warfarin ASA Warfarin Warfarin Warfarin ASA Warfarin(INR 2-4.5) 325 mg (PT 1.2-1.5x (INR 2-3) (INR 2.8-4.2) 75 mg (INR 1.2-1.5)

Control)

Embolic Rate (%)

Treatment 2,3 3,6 0,41 3,5 1,5 6,0 4,3Control 7,4 6,3 2,98 5,2 6,2 6,2 0,9

Risk Reduction (%)(95% confidence) 67 42 86 45 53 — 79

Major Bleeding Complications (%)

Treatment 1.5 1.4 0.9 2.5 6.3 0.6 1.5Control 1.6 1.9 0.5 0.5 0.0 0.0 0.9

Major Clinical Trials of Primary Prevention in Non-Valvular AFib

100% 50% 0% -100%-50%

All

Risk reduction

Warfarin betterWarfarin better Warfarin worseWarfarin worse

SPINAF

SPAF

CAFA

BAATAF

AFASAK

Events Pts/y

108

29

23

14

15

27

3691

972

508

478

922

811

Adjusted Dose Warfarin vs Placebo

Atrial Fibrillation Investigators Arch Intern Med (1994) 154: 1449

5

3

2

1

0Control Warfarin

An

nu

al r

isk

of

stro

ke (

%)

1.4%

4

4.5%

Reduction in risk = 68%Reduction in risk = 68%

Reduction in Stroke Risk – Meta-analysis of 5 Trials

Average - 68%

Study Range INR Stroke risk reduction

EAFT 2.5 – 4.0 - 62%

1007 patients > 70 with previous TIA or minor stroke

European Atrial Fibrillation Trial Lancet (1993) 342: 1255

vs placebovs placebo

Secondary Prevention

Primary prevention

AFASAK 75 mg - 18% (ns)

SPAF 325 mg - 44% (p<0.02)

Secondary prevention

EAFT 300 mg - 14% (ns)

Global reduction in risk = 25%(range 14-44%)

Aspirin vs Placebo

Study ASA dose Stroke risk reduction

Warfarin Superior to Aspirin

AFASAK I (1)

AFASAK II (2)

EAFT (9)

PATAF (15)

SPAF II (4)

All trials (n=5)

Relative RiskReduction (95% CI)

100 -1000Warfarin better

(%)Warfarin worse

(%)

Warfarin comparedwith aspirin

-5050

AFASAK I (1)

SPAF I (3)

EAFT (9)

ESPS II (14)

LASAF (13)

UK-TIA (16)

All trials (n=6)

Relative RiskReduction (95% CI)

100 -1000Aspirin better

(%)Aspirin worse

(%)

Aspirin comparedwith placebo

-5050


SPAF Investigators Lancet (1994) 343: 634

Discontinued = 31Lost to follow-up = 0

Primary events = 11Deaths = 34

Completed without primary event = 478

1044 eligible patients randomised

Fixed, low dose warfarin plus aspirin (n = 521)

INR assessed at 1m and 2m then every 3m

Discontinued = 41Lost to follow-up = 0

Primary events = 44Deaths = 35

Completed without primary event = 442

Adjusted dose warfarin (n = 523)

Weekly INR control until stable, then monthly

SPAF III - Adjusted-dose vs. Low-intensity, Fixed-dose warfarin + ASA


Combination therapy

Adjusted-dose warfarin

Cu

mu

lati

ve

ev

en

t ra

te (

% p

er

ye

ar)

20

18

16

14

12

10

8

6

4

2

0

0 365 730

Days from randomization

521

523

378

397

265

273

166

173

61

65

Combination therapy

Warfarin therapy

Number at Risk

SPAF III – Stroke Rate

0 0-5 1 21-5

Major haemorrhage

Adjusted dose warfarin better

Stroke, MI,Vascular death

Vascular death

All disabling strokes

Disabling ischaemic stroke

Primary events

Combination therapy better


SPAF III – Relative Risk

AFASAK 2 - Copenhagen Investigators

677 patients with permanent AFib

Warfarin fixed-dose 1.25 mg

Warfarin fixed-dose 1.25 mg +

ASA 300 mg

ASA 300 mg Warfarin dose variable (INR 2.0-3.0)

Cumulative incidence of primary events – 12m follow-up 5.8 % 7.2 % 3.6 % 2.8 %

1.0 1.5 2.0 4.52.5

SPAF III(adjusted)

INR range (2.0-3.0) recommended by 4th ACCP Consensus on Antithrombotic Therapy

EAFT

SPINAF

CAFA

BAATAF

AFASAK

Warfarin – INR range

3.0 3.5 4.0

SPAF I + II

SPAF III(fixed)

2.8-4.2

2.0-4.5

1.5-2.7

2.0-3.0

1.4-2.8

2.5-4.0

1.2-1.5

2.0-3.0

Primary Prevention Trials – Anticoagulation Ranges

2 INR 3

Cli

nic

al e

ven

ts

Thromboembolic HaemorrhagicTherapeutic window

Optimal Anticoagulation Ranges

Connolly SJ, et al. J Am Coll Cardiol (1991) 18: 349Ezekowitz MD, et al. N Engl J Med (1992) 327: 1406

SPAF II Lancet (1994) 343: 687Connolly SJ, et al. Lancet (1994) 343: 1509

Petersen P, et al. Lancet (1989) 171SPAF Circulation (1991) 84: 527

BAATAF N Engl J Med (1990) 323: 1505EAFT Lancet (1993) 342: 1255

60 65 70 8575Median age (y)

2

1

Intr

acra

nia

l hae

mo

rrh

age

(%

/y)

80

Oral anticoagulant

AspirinSPAF II (>75)

SPINAF(>70)

4 trials(>75)

AFASAKEAFT

BAATAF

SPINAF

CAFASPAF I

SPAF II(<75)

Intracranial Haemorrhage in Trials – Influence of Age


Drugs to Reduce Thromboembolic Risk

Risk stratification

Clinical risk factors

Echocardiographic risk factors

Thromboembolic Risk Stratification

Advanced age (> women)

Hypertension

Cardiac insufficiency

Previous TIA

(Diabetes)

Clinical Risk Factors

Left atrial dilatation

Left ventricular systolic dysfunction

Transthoracic Echocardiographic Risk Factors

Thrombus – atrium and/or left atrial appendage

Dense spontaneous echo contrast

Reduced blood flow in left atrial appendage

Dilatation of left atrial appendage

Septal aneurysm

Complex aortic plaque

Trans Esophageal Echocardiographic Risk Factors

HIGH RISK MODERATE RISK LOW RISK

1 major risk factor NO major risk factor No major or

> 1 moderate risk factor 1 moderate risk factor minor risk factors

Major Risk FactorsAge > 75 Previous stroke or systemic embolismHistory of arterial hypertensionCardiac insufficiency o ventricular dysfunctionMitral valve diseaseProsthetic valve replacement

Minor Risk FactorsAge 65 - 75 Diabetes mellitusIschaemic cardiopathy with normal ventricular function sinistra

adapted from the 6th ACCP Consensus Conference on Antithrombotic Therapy, Chest (2001) 119 (Suppl): 194S

Risk Stratification in Patients with AFib

Antithrombotic Therapy Recommendations

Female gender Age greater thanor equal to 75 y

Previous stroke, TIA or embolism

Age 65 to 74 y Hypertension Mitral stenosis

Coronary artery disease Heart failure Prosthetic heart valve*

ThyrotoxicosisLV ejection fraction

35% or lessDiabetes mellitus

Moderate-risk factorsLess validated or weakerRisk factors

*If mechanical valve, target international normalized ratio (INR) greater than 2.5. INR = international normalized ratio; LV = left ventricular; TIA = transient ischemic attack

High-risk factors

No risk factors Aspirin, 81 to 325 mg daily

One moderate-risk factor Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5)

Any high-risk factor or morethan 1 moderate-risk factor Warfarin (INR 2.0 to 3.0, target 2.5)*

Risk category Recommended therapy

Contraindications of Oral Anticoagulants

• GI haemorrhage

• Uncontrolled arterial hypertension

• Pregnancy

• Alcoholism

• Severe hepatic insufficiency

• Vascular malformations that can lead to risk of haemorrhage

• Coagulopathies

• Recent surgical interventions – eyes or CNS

• Previous severe haemorrhage during anticoagulation therapy

• Severe neoplastic disease

Cardioversion and Anticoagulation Recommendations

Naccarelli GV, et al. Am J Cardiol (2000) 85: 36D

Cardioversion

Heparin + warfarin 24 h

Warfarin(INR 2.0-3.0)

3-4 weeks+

Cardioversion

NegativePositive

Warfarin3-4 weeks

TEE

AFib > 48 hours


Non-Pharmacologic Treatment Options

SurgeryElectrophysiologicalDevices

Pacemaker(single or dual chamber)

Internal atrialdefibrillators

Catheter ablation

AV node ablation

Non-Pharmacological Treatment Options for AFib

Maze procedure

Modified Maze

(mini-Maze)


Management of AFib - Summary

• Maintenance of sinus rhythm should be the primary objective of treatment whenever possible– sinus rhythm correlates with improved survival

• Current antiarrhythmic drug therapies, however, are not highly effective in maintaining SR and generally have poor outcomes– high recurrence rates– adverse effects and high discontinuation rate

• A potentially curative therapy for AFib is desirable

Section II: Clinical Management of AFib. Section II. Clinical Management of AFib 1. Clinical...

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