1. 2 Learning Objectives After taking part in this activity, participants should be better able to:...

2

Learning Objectives

After taking part in this activity, participants should be better able to:– Assess the significant clinical consequences and

burden of AF – Apply new practice guidelines/best practices and

performance measures for the management of AF– Interpret the latest clinical data on rate-control and

rhythm-control strategies for the management of patients with AF

– Demonstrate an evidence-based approach for reducing thromboembolic risk in patients with AF

Faculty Disclosure

The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity.

Faculty and planner disclosure information is included in the handout materials.

4

Epidemiology and Burden of Disease

5

Presentation

Case:65-Year-Old Man With Recent Episodes of Palpitations, Weakness, and Lightheadedness

● A 65-year-old man presents with episodes of palpitations, weakness, and significant lightheadedness

● He describes his symptoms, which have been occurring as often as 3 times each day for about 1 week, as severe and debilitating

6

Medical History/Current Medications


The patient has been diagnosed with diabetes, hypertension, and sleep apnea syndrome, and is taking the following medications:

– Lisinopril 10 mg/d

– Metoprolol 50 mg/d

– Insulin (0.6 U/kg nightly)

7

Physical Findings


● BP: 145/90 mm Hg; HR: 85 bpm● Weight: 180 lb (82 kg); height: 5’10”; BMI: 25.9 m2/kg● Chest auscultation and heart sounds

– Normal S1 and S2, no murmurs– Irregularly irregular rhythm

● Abdominal examination findings: soft and nontender

8

Epidemiology of AF

● Most common sustained cardiac arrhythmia1

● Currently affects 5.1 million Americans2

● Prevalence expected to increase to 12.1 million by 2050 (15.9 million if increase in incidence continues)2

● Preferentially affects men and the elderly1,2

● Lifetime risk of developing AF: ~1 in 4 for adults 40 years of age3

1. Lloyd-Jones D, et al. [published online ahead of print December 17, 2009]. Circulation. doi:10.1161/CIRCULATIONAHA.109.192667.

2. Miyasaka Y, et al. Circulation. 2006;114(2):119-125.3. Lloyd-Jones DM, et al. Circulation. 2004;110(9):1042-1046.

9

AF Is the Leading Cause of Hospitalizations for Arrhythmia

Hospital Days (thousands)

N=517,699 (representing 10% of CV admissions).

Hospital Admissions in US

VT

VF

Unspecified

Sick sinus

Premature beats

Junctional

Conduction disease

Cardiac arrest

AFL

AF

0 200 400 600 800 1000

VF, ventricular fibrillation; VT, ventricular tachycardia.

Adapted from Waktare JE, et al. J Am Coll Cardiol. 1998;81(suppl 5A):3C-15C.

10Reproduced with permission from Miyasaka Y, et al. J Am Coll Cardiol. 2007;49(9):986-992.

Mortality After Diagnosis of AF

4-month HR, 9.62

Post-4 months HR, 1.66

100

80

60

40

20

00 2 4 6 8 10 0 2 4 6 8 10

Years From AF Dx Years After 4 MoFrom AF Dx

Su

rviv

al,

%

P<.0001 P<.0001

MN-white expected

Observed

11Reproduced with permission from Wang TJ, et al. Circulation. 2003;107(23):2920-2925.

Development of AF was associated with increased mortality: HR, 1.6 (95% CI, 1.2-2.1) in men; 2.7 (95% CI, 2.0-3.6) in women

Unadjusted cumulative incidence of first AF after heart failure – Framingham Study

One Fifth of Heart Failure PatientsDevelop AF Within 4 Years

Cu

mu

lati

ve In

cid

ence

of

AF 0.4

0.3

0.2

0.1

080 2 4 6 10

Years

No. at risk 708 323 230 146 92 62

12

Time to cardiovascular death or heart failure hospitalization

AF predicted mortality for both preserved EF and depressed EF groups, and CV death or heart

failure hospitalizations for preserved EF group

Reproduced with permission from Olsson LG, et al. J Am Coll Cardiol. 2006;47(10):1997-2004.

AF Is a Marker for Worse Outcomes in Heart Failure: CHARM Program

0 1 2 3 3.5

0.500.450.400.350.300.250.200.150.100.05

0

Number at riskNo AF & Low EF 3906 3207 2755 1963No AF & PEF 2545 2294 2096 1276AF & Low EF 670 509 417 289AF & PEF 478 399 353 203

AF at baseline (Low EF) <0.40

No AF at baseline (Low EF)AF at baseline (Preserved) LVEF >0.40

No AF at baseline (Preserved)

Preserved EF (PEF):Hazard ratio 1.72(95% CI 1.45 – 2.06)P<.001

Low EF:Hazard ratio 1.29(95% CI 1.14 – 1.46)P<.001

Cu

mu

lati

ve

Dis

trib

uti

on

Fu

nct

ion

13

1. Ware JE, et al. New England Medical Center Health Survey; 1993. 2. Dorian P, et al. J Am Coll Cardiol. 2000;36(3):1303-1309.

aHigher numbers indicate higher QoL.SF-36 = Medical Outcomes Study Short Form 36.

Baseline score

Physical functioning

Vitality Generalhealth

Mentalhealthindex

Emotionalrole

Socialfunctioning

SF

-36

scal

ea

100

90

80

70

60

50

40

General population1

Recent MI1

AF2

HF1

Impact on QoL: AF vs Other CV Illness

14

AF Is Associated With Increased Thromboembolic Risk

● Major cause of stroke in elderly1

● 5-fold ↑ in risk of stroke1,2

● 15% of strokes in US are attributable to AF3

● Stroke severity (and mortality) is worse with AF than without AF4

● Incidence of all-cause stroke in patients with AF: 5%1

● Stroke risk persists even in asymptomatic AF5

1. Fuster V, et al. J Am Coll Cardiol. 2001;38(4):1231-1266.2. Benjamin EJ, et al. Circulation. 1998;98(10):946-952.3. Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457. 4. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.5. Page RL, et al. Circulation. 2003;107(8):1141-1145.

15

Pathophysiology

16

Pathophysiology of AF?Inflammation

• Left ventricular hypertrophy • Diastolic dysfunction

• Mitralregurgitation Atrial dilatation/stretch

?InflammationStretch-activated channelsDispersion of refractorinessPulmonary vein focal/discharges?

Increased vulnerability to AF?

Compliance

• HTN and/or vascular disease

Adapted with permission from Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.

17

What Happens When AF Persists?

Remodeling explains why “AF begets AF”Remodeling explains why “AF begets AF”

LA and LAA dilatation Fibrosis

Decrease in Ca++ currents Shortening of atrial action

potential Increased importance of

early activating K+ channels: IKur, IKto

StructuralRemodeling

Electro-physiologicRemodeling

18

Classification of AF

Recurrent AFa

(≥2 episodes)

Paroxysmal Persistent

Permanent

• Arrhythmia terminates spontaneously

• AF is sustained ≤7 days

• Arrhythmia does not terminate spontaneously

• AF is sustained >7 days

• Both paroxysmal and persistent AF can become permanent

aTermination with pharmacologic therapy or direct-current cardioversion does not change the designation.Fuster V, et al. Circulation. 2006;114(7):e257-e354.

19

Clinical Evaluation

20

ECG Findings


21

Echocardiogram Findings


● Mild LVH and nl LV function– LV wall thickness 1.3 cm– LA size 4.2

22

What other tests would you perform for this patient at this time?


A. 6-Minute walk or exercise test

B. Holter monitoring/event recording

C. Electrophysiology study

D. Cardiac catheterization

E. Cardiac MRI

F. None

23

Clinical Evaluation for AF Patients:Etiology, AAD Risk, Embolic Risk

● Treatment of AF is dependent on etiologic (cause, severity, reversible/modifiable) as well a patient factors (embolic risk, concomitant disorders)

● Some anatomic or functional disorders pose risks from AAD treatment (eg, organ toxicity and ventricular proarrhythmia)

● At a minimum, an evaluation requires

– History – Echocardiogram

– Physical – Blood chemistries

– ECG – Stress test (if CAD is suspected)

– Chest x-ray (and possibly PFTs) if pulmonary disease is suspectand/or HF is a consideration

● Current guidelines emphasize the prospectively determined CHADS2 risk-scoring system for embolic risk

Fuster V, et al. Circulation. 2006;114(7):e257-e354.

24

Conditions Frequently Associated With Nonvalvular AF1-4

1. Wattigney WA, et al. Circulation. 2003;108(6):711-716.2. Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.3. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):854-906.4. Mozaffarian D, et al. Circulation. 2008;118(8):800-807.

● Hypertension ● Aging● Male sex● Obesity/metabolic syndrome/diabetes● Ischemic heart disease● Heart failure/diastolic dysfunction● Obstructive sleep apnea ● Physical inactivity● Thyroid disease● Inflammation?

25

What is the patient’s diagnosis?


A. Paroxysmal AF

B. Persistent AF

C. Permanent AF

D. Other

26

Would you recommend antithrombotic therapy for this patient at this time?


A. Yes

B. No

27

If so, which risk stratification model would you use to decide on the strategy?


A. ACCP

B. AFI (Atrial Fibrillation Investigators)

C. CHADS2

D. Framingham study

E. SPAF (Stroke Prevention and Atrial Fibrillation) Investigators

F. Other

28

CHADS2 Risk Criteria for Stroke in Nonvalvular AF

Risk Factors Score

C Recent congestive heart failure 1

H Hypertension 1

A Age ≥75 y 1

D Diabetes mellitus 1

S2History of stroke or transient ischemic attack 2

Gage BF, et al. JAMA. 2001;285(22):2864-2870.

29Gage BF, et al. JAMA. 2001;285(22):2864-2870.

Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation Based on the CHADS2 Index

Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation Based on the CHADS2 Index

CHADS2, Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack.

CHADS2, Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack.

Warfarin

55

6565

220220

337337

523523

463463

120120

Patients Patients (N=1733)(N=1733) (95% CI)(95% CI)

66

55

44

33

22

11

00CHADSCHADS22 Score Score

Adjusted Stroke Rate (% per y)Adjusted Stroke Rate (% per y)0 5 10 15 20 25 30

30

If you were stratifying this patient’s risk based on CHADS2, what score would he receive?


A. 0

B. 1

C. 2

D. ≥3

31

Clinical Evaluation for Selecting Antithrombotic Therapy

● Consider the following before selecting an anticoagulation strategy:

– Bleeding or thrombotic risk, history of/tendency for injuries

– Concomitant requirement for warfarin or antiplatelet therapy

– Drug compliance history and willingness for dietary compliance

– Concomitant therapies (including prescription drugs, OTCs, herbals)

– Patient activities that risk injury or are contraindications to warfarin

● Perform a clinical evaluation is prior to initiating anticoagulation strategy

● Testing the genetic pattern of warfarin metabolism may be helpful in facilitating the initiation phase of warfarin therapy


32

What antithrombotic strategy would you suggest?


A. Aspirin 80 mg/d

B. Aspirin 325 mg/d

C. Warfarin INR 2-3.5

D. Warfarin INR 1.5-2.5

E. Clopidogrel 75 mg/d + aspirin 80 mg/d

F. Dabigatran 110 mg/bid

33

Treatment

34

Treatment Goals and Strategies

Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IAb Class ICClass III-blocker

Catheter ablationPacingSurgery Implantable devices

Pharmacologic• Warfarin• Aspirin• Thrombin InhibitorNonpharmacologic• Removal/isolation

LA appendage

Rate control

Pharmacologic• Ca2+ blockers-blockers• Digitalis• Amiodarone• Dronedaronea

Nonpharmacologic• Ablate and pace

Prevent RemodelingCCB

ACE-I, ARBStatinsFish oil

a Only in patients with nonpermanent AF; b the antiarrhythmic drug classes are based on the Vaughan Williams classification.

a Only in patients with nonpermanent AF; b the antiarrhythmic drug classes are based on the Vaughan Williams classification.

35

No (or minimal)heart disease

Amiodarone Dofetilide

HFCADHypertension

AmiodaroneFlecainidePropafenone

Sotalol

Yes

Maintenance of SR

Substantial LVH

No

FlecainidePropafenone

Sotalol

Catheterablation

Amiodarone Dofetilide

Catheterablation

Catheterablation

Amiodarone Catheterablation

DofetilideSotalol

AmiodaroneDofetilide

Catheterablation

Rhythm Control Therapies to Maintain Sinus Rhythm

ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines

Reproduced with permission from Fuster V, et al. Circulation. 2006;114(7):e257-e354.

Note: In 2009, the FDA approved dronedarone to reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated CV risk factors, who are in sinus rhythm or who will be cardioverted. Consensus regarding its place in the treatment paradigm is not yet available.

36

Individualized Patient Management

Pharmacologic

AVJ ablation

Pharmacologic

Catheter ablation

Surgical maze+/- valve/CAD surgery

AF chronicity

Paroxysmal

Persistent

Chronic

AF symptoms

Aggravation of HF

Anticoagulation

Risk/benefit

Therapy tolerance

Risk/benefit

ICD or pacer

Rate control

Maintain sinus rhythm

Courtesy of KA Ellenbogen, MD.

37

Rate Control● End point

– Resting and ambulatory ventricular rates similar to those expected in sinus rhythm

– Best assessed with Holter monitoring– Determining pulse on exam and heart rate on

ECG are not sufficient

● Methods– Digitalis: in sedentary patients or CHF– β-blockers and/or CCBs (verapamil, diltiazem): needed in

most active individuals– AVN ablation plus pacemaker: in resistant patients

● Special considerations– Brady-tachy syndrome (pindolol, or pacer plus drugs)– Preexcitation (focus on the BT as well as the AVN)

38

CardioversionDirect Current

– Biphasic is best (can do internal CV if needed)

Intravenous AAD– Ibutilide is best of the available drugs

(2 mg/30 min; have MgSO4 available)– Amiodarone (≥1 g over 24 h)– Procainamide, quinidine– Emerging drugs (eg, vernakalant)

Oral AAD– Oral IC is best (70%-80% by 6-8 h;

mean, <4 h)– Dofetilide (30%-50% by 48 h)

(500 μg bid)– Amiodarone (30 mg/kg), IA are

other alternatives– Emerging drugs

Adapted from Capucci A, et al. Am J Cardiol. 1994;74(5):503-505.

0%

20%

40%

60%

80%

100%

Placebo

3 hours

8 hours

Conversion With Class IC RxConversion Rates From AF to

Sinus Rhythm at 3 and 8 Hours

18%(11/62)

Propafenone600 mg

39%(24/62)

51%(31/61)

72%(44/61)

39

Candidates• Recognized acute and recent onset• No AAD risk markers• Adequate tolerance (no pulmonary edema, syncope, etc)

“Pill in the Pocket”

Acute load on chronic therapy• 2 extra “pill in the pocket” dosing regimens have been used to treat breakthrough episodes (max. daily dose vs substitute bolus dose)a

Alboni P, et al. N Engl J Med. 2004;351(23):2384-2391.

aReiffel JA. Pacing Clin Electrophysiol. 2009;32(8):1073-1084.

Alboni P, et al. N Engl J Med. 2004;351(23):2384-2391.

aReiffel JA. Pacing Clin Electrophysiol. 2009;32(8):1073-1084.

Step 1Step 1 Step 2Step 2 Step 3Step 3

• Rate control (~100 bpm) to prevent 1:1 flutter

• Short-acting CCB or β-blocker

• Rate control (~100 bpm) to prevent 1:1 flutter

• Short-acting CCB or β-blocker

• Propafenone 600 mg (single dose)

• Flecainide 300 mg (single dose)

• Propafenone 600 mg (single dose)

• Flecainide 300 mg (single dose)

• Observe for effect and tolerance (first episode)

• Observe for effect and tolerance (first episode)

Subsequent events• Treat at home (convenient and inexpensive)• Improves QoL, reduces ER visits/hospitalization, costs

40

Which of the following management goals may not be necessary in every patient with AF?


A. Control of the ventricular rate

B. Reduction of thromboembolism risk (particularly stroke)

C. Restoration and maintenance of sinus rhythm

41

AAD Treatment Goals

● Remember to keep goals realistic!

● AF is rarely life-threatening and is usually recurrent

● Thus, goals should be to:

– Reduce the frequency of recurrences

– Reduce the duration of recurrences

– Reduce the severity of recurrences

– Minimize intolerance and risk of therapy

42

Antiarrhythmic Drugs for AF● Class I:

– Class IC: propafenone (also very weak β-blocker), flecainide (no β-blockade effects)

• Sustained-release propafenone (Rythmol SR) and flecainide are bid;

• Propafenone appears to be less proarrhythmic

– Class IA: disopyramide, quinidine, procainamide• No longer included in the ACC/AHA/ESC algorithm• Disopyramide may be useful in vagally induced AF

● Class III:– Sotalol (class III plus β-blocker)– Dofetilide (pure class III)– Amiodarone (class III plus class I, II, IV)– Dronedarone (similar to amiodarone with different pharmacokinetics

and markedly reduced organ toxic potential)

43

Ventricular Proarrhythmia With AAD

● Torsade de pointes:– A consequence of class III and

IA AAD

– Incidence varies within drug class, and with LVH

– Can be as low as 0.1%-0.4%

● Monomorphic VT:– A consequence of class I AAD

(esp. IC) in SHD (ischemic, impaired cell connections)

– Thus, class I AAD are contraindicated as first-line therapy in SHD patients

● Ventricular fibrillation:– May degenerate from TdP or VT

– May be idiopathic

44

14

12

10

8

6

4

2

0

Adapted from Pritchett EL, Wilkinson WE. Am J Cardiol. 1991;67(11):976-980.

aBased on age, race, and sex-specific mortality rates in the United States in 1980.

Exponential Model

Mo

rtal

ity,

%

CASTEnc + Flec

720272

CASTPlacebo

725286

ComparisonSVA165144

ComparisonExpected*

--

FlecainideSVA23893

FlecainideExpecteda

--

Total N =1 Year N =

Mortality Associated With Flecainide and Encainide for Supraventricular Arrhythmias

Estimated 1-Year Mortality (Point Estimate, 95% CI)

45

What treatment to manage the AF would you suggest at this time?


A. Catheter ablation

B. Flecainide

C. Dronedarone

D. Amiodarone

E. AV node ablation and PPM

46

If dronedarone is chosen, where should treatment be initiated?


A. Inpatient administration is mandatory

B. Outpatient administration is feasible

47

Site of AAD Initiation● Inpatient is mandated for dofetilide

● The recommendations are mixed for sotalol (PI says inpatient, ACC/AHA/ESC guidelines allow outpatient initiation in patients without TdP risk markers who are in NSR)

● The only class IA agent approved for AF is quinidine, with initiation as an inpatient

● Outpatient is allowed for class IC and dronedarone, and is customary for amiodarone (which is not FDA approved for AF), assuming normal SN and normal conduction

48

Judging Antiarrhythmic Efficacy

● In patients with symptomatic AF:

– Reduction or abolishment of symptoms

● In symptomatic and asymptomatic AF patients:

– Normalization of pulse on self-examination twice a day

– Assessment with autotriggered loop recorder (devices that can be patient triggered and can automatically record for programmed criteria, including AF)

– Assessment with pacemaker interrogation

49

Dronedarone vs Amiodarone: Structural and Functional Characteristics

A Much Shorter Half-lifea

Reduces Likelihood of Thyroid Hormone Effects

Reduces Likelihood of

Pulmonary Fibrosis

Overall Effects Slows heart rate Slows ventricular rate in AF Prolongs APD and QT/QTc Similar EP and antifibrillatory effects in

ventricles and atria Reduces effect of EDA in M-cells and PF Reduces intrinsic and drug-induced

heterogeneity of myocardial refractoriness

Negligible proarrhythmia and no anti-torsadogenic potential

No negative inotropy Elimination half-life 1-2 days

= Shared = Dronedarone Blocks Multiple K Channels

Improves LVEFin CHF

Na+ ChannelBlockade

SympatholyticBlockade

Ca++ ChannelBlockade

Anti-ischemic & Antifibrillatory

Zimetbaum PJ. N Engl J Med. 2009;360(18):1811-1813..a1 to 2 days for dronedarone vs 30 to 50 days for amiodarone.

a1 to 2 days for dronedarone vs 30 to 50 days for amiodarone.

50

The ERATO Rate-Reduction Trial

Adapted with permission from Davy JM, et al. Am Heart J. 2008;156(3):527:e1-527.e9.

ERATO: Primary Study End Point

aTreatment effect estimate by ANCOVA

Dronedarone Significantly Decreased Ventricular Rate (24-hour Holter)

70

75

80

85

90

95

Baseline D14

Time

Ven

tric

ula

r R

ate,

bp

m

(Mean ± SEM)

76.2

90.290.6

86.5

Dronedarone 400 mg bidPlacebo

11.7 bpma (P<.0001)

Dronedarone Significantly Decreased Maximal Exercise Ventricular Rate

ERATO: Secondary Study End Point

Baseline D14

Ven

tric

ula

r R

ate

(bp

m)

Du

rin

gM

axim

al E

xerc

ise

129.7

159.6162.4

152.624.5 bpma

(P<.0001)

120

125

130

135

140

145

150

155

160

165

170

(Mean ± SEM)


aTreatment effect estimate by ANCOVA

Time

51

EURIDIS ADONIS

EURIDIS and ADONIS Primary End Point: Patients With First Recurrence of AF/AFL

Results: a significant and consistent reduction in first recurrence of AF/AFL

AF, atrial fibrillation; AFL, atrial flutter.

Adapted with permission from Singh BN, et al. N Engl J Med. 2007;357(10):987-999.


Cu

mu

lati

ve In

cid

ence

0 60 120 180 240 300 360

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Time(days)

Log-rank test results: P=.01 Log-rank test results: P=.002

0 60 120 180 240 300 3600 60C

um

ula

tive

Inci

den

ce

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.0

0.1

Time(days)

52

116.6 117.5

104.6102.3

90

95

100

105

110

115

120

Placebo Dronedarone

EURIDIS and ADONIS: Dronedarone Reduced Ventricular Rate at First AF/AFL Recurrence

Mea

n V

entr

icu

lar

Rat

e (w

ith

TT

M)

n=102 n=188 n=117 n=199

ADONIS EURIDIS

P<.001P<.001

Singh BN, et al. N Engl J Med. 2007;357(10):987-999.TTM, transtelephonic monitoring.

TTM, transtelephonic monitoring.

53

ANDROMEDA Primary End Point: Time to Death or Hospitalization for Worsening HF

Placebon=317

Dronedarone 400 mg bidn=310

No. of patients with end point 40 53

RR 1.38

95% CI (0.92-2.09)

Log-rank’s test result (P value) .12

All-cause mortality: placebo, n=12; dronedarone, n=25; HR, 2.13; P=.03

Køber L, et al. N Engl J Med. 2008;358(25):2678-2687.

54

Athena: Primary Outcome Results

Reproduced with permission from Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

Cumulative Incidences for the Composite of First Hospitalization Due to CV Events or Death From Any Cause

Cumulative Incidences for the Composite of First Hospitalization Due to CV Events or Death From Any Cause

0 6 12 18 24 30

100

75

50

25

0

Cu

mu

lati

ve I

nci

den

ce,

%

Months

Placebo

Dronedarone

P<.001

5555

ATHENA Post Hoc Analysis: Reduction in Stroke

Reproduced with permission from Connolly SJ, et al; for the ATHENA Investigators Circulation. 2009;120(13):1174-1180.

• Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (HR, 0.66; P=.027)

• The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy

• Dronedarone had a greater effect in patients with higher CHADS2 scores

• Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (HR, 0.66; P=.027)

• The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy

• Dronedarone had a greater effect in patients with higher CHADS2 scores

Placebo (n=70, annual rate=1.8%)

Dronedarone (n=46, annual rate=1.2%)

0 6 12 18 24 30

5

4

3

2

1

0

HR=0.66 (95%Cl, 0.46-0.96)P=.027

Cu

mu

lati

ve In

cid

ence

, %

Months

56

Emerging Antiarrhythmic Drugs for AF● Agents under study for sinus rhythm maintenance

– “Atrial-selective” (“atrial-specific”) agents• Vernakalant (Kynapid®) is pending FDA approval (in October

2010, the FDA suspended enrollment of the ACT 5 trial due to patient safety concerns)

• Others

● Agents under study for pharmacologic cardioversion– “Atrial-selective” (“atrial-specific”) agents– Others

● Agents currently marketed for a non-AF indication– Ranolazine (Ranexa®)

● Agents with unconventional anti-arrhythmic mechanisms– Stretch receptor antagonists, sodium-calcium exchanger blockers,

late sodium channel inhibitors, gap junction modifiers

Savelieva I, Camm J. Europace. 2008;10(6):647-665.

57

Preventing Thromboembolism

58

Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those with lone AF or contraindications

The antithrombotic agent should be chosen based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient

Preventing ThromboembolismI IIa IIb III

A

A



For patients at high risk of stroke,a chronic oral anticoagulant therapy with a vitamin K antagonist (INR 2.0 to 3.0) is recommended, unless contraindicated

Anticoagulation with a vitamin K antagonist is recommended for patients with >1 moderate risk factorb

For patients at high risk of stroke,a chronic oral anticoagulant therapy with a vitamin K antagonist (INR 2.0 to 3.0) is recommended, unless contraindicated

Anticoagulation with a vitamin K antagonist is recommended for patients with >1 moderate risk factorb

A

aFactors include prior stroke, TIA, or systemic embolism, rheumatic mitral stenosis, mechanical heart valve.bAge ≥75 years, hypertension, diabetes mellitus, HF, or impaired LV systolic EF.

aFactors include prior stroke, TIA, or systemic embolism, rheumatic mitral stenosis, mechanical heart valve.bAge ≥75 years, hypertension, diabetes mellitus, HF, or impaired LV systolic EF.

A

59

INR should be determined at least weekly during initiation of therapy and monthly when stable

Aspirin, 81-325 mg daily, is recommended in low-risk patients or in those with contraindications to oral anticoagulation

For patients with mechanical heart valves, the target intensity of anticoagulation should be based on the type of prosthesis, maintaining an INR of at least 2.5

Antithrombotic therapy is recommended for patients with atrial flutter as for AF

Long-term anticoagulation is not recommended for primary stroke prevention in patients <60 years without heart disease (lone AF)

Preventing Thromboembolism (cont)I IIa IIb III

A

A

B

C


C


60

Risk Stratification for AF: Antithrombotic Therapy

Risk Category Recommendation

Low Risk

No moderate-risk factors

CHADS2 = 0

Aspirin, 81-325 mg a day

Moderate Risk

One moderate-risk factor

CHADS2 = 1

Aspirin, 81-325 mg a day or warfarin (INR 2.0-3.0)

High Risk

Any high-risk factor or ≥2 moderate-risk factors

CHADS2 = ≥2

Warfarin (INR 2.0-3.0a)

aINR 2.5-3.5 for prosthetic valves. What to do about “weaker” risk factors?



Currently Available Antithrombotic Agents

Warfarin

Low–molecular-weight heparin

Unfractionated heparin

Aspirin

Aspirin + clopidogrela

Dabigatran

a Not currently FDA approved.61

62

Limitations of Warfarin

Limitations Consequences

Slow onset of action Overlap with parenteral anticoagulant

Genetic variation in metabolism Variable dose requirements

Multiple food and drug interactions Frequent coagulation monitoring

Narrow therapeutic window Frequent coagulation monitoring

Hirsh J. N Engl J Med. 1991;324(26):1865-1875.Bates SM, Weitz JI. Br J Haematol. 2006;134(1):3-19.

Courtesy of PR Kowey, MD.

The ACTIVE Studies

63

ACTIVE-W1

– Compared warfarin (INR, 2-3) vs clopidogrel 75 mg/d + ASA (75-100 mg/d) in high-risk AF patients

– 6706 patients randomized– 1.28 years of follow-up– Primary end point: stroke, systemic embolus, MI, vascular death– Study stopped early due to superiority of warfarin

ACTIVE-A2

– Compared clopidogrel 75 mg/d + ASA (75-100 mg/d) vs ASA alone in high-risk AF patients who could not or would not take warfarin

– 7554 patients randomized– Same primary end point– 3.6 years of follow-up– Stroke occurred in 296 (2.4%/y) patients on clopidogrel + ASA and in 408 patients

(3.3%/y) on ASA alone (RR, 0.72; P<.001). However, major bleeding occurred in 251 (2.0%/y) patients on clopidogrel + ASA and in 162 (1.3%/y) patients on ASA alone (RR, 1.57; P<.001)

1. ACTIVE Investigators. Lancet. 2006;367(9526):1903-1912.2. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-

2078.

Aspirin alone is recommended for patients unable to take oral anticoagulants

The combination of clopidogrel plus aspirin carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin (new recommendation)

64

Recommendations for Atrial FibrillationI IIa IIb III

A

B

Furie KL, et al. Stroke. [published online October 21, 2010]. doi: 10.1161/STR.0b013e3181f7d043.

AHA/ASA 2010 Guidelines for the Prevention of Stroke in Patients With Stroke or TIA

65

RE-LY: Study Design

Primary objective: noninferiority to warfarin Minimum 1-year follow-up, maximum of 3 years and mean of

2 years of follow-up Primary end point: stroke or systemic embolism

Nonvalvular atrial fibrillation at moderateto high risk of stroke or systemic embolism

(at least 1 additional risk factor)

R

Warfarin1 mg, 3 mg, 5 mg

(INR, 2.0-3.0)n=6000

Dabigatran Etexilate 110 mg bid

n=6000

Dabigatran Etexilate 150 mg bid

n=6000

Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

RE-LY: Primary Outcome

66Reproduced with permission from Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361(12):1139-1151.

67

RE-LY: Bleeding EventsDabigatran

110 mg

Dabigatran

150 mgWarfarin

Dabigatran 110 mg vs Warfarin

Dabigatran 150 mg vs Warfarin

AnnualRate

AnnualRate

AnnualRate

RR95% CI

P ValueRR

95% CIP Value

Major 2.7% 3.1% 3.4%0.80

0.69-0.93.003

0.930.81-1.07

.31

Life- threatening (major)

1.2% 1.5% 1.8%0.68

0.55-0.83<.001

0.810.66-0.99

.04

Gastro- intestinal (major)

1.1% 1.5% 1.0%1.10

0.86-1.41.43

1.501.19-1.89

<.001

Minor 13.2% 14.8% 16.4%

0.79

0.74-0.84 <.0010.91

0.85-0.97.005

Major or minor

14.6 16.4% 18.2%0.78

0.74-0.83<.001

0.91

0.86-0.97.002

Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361(12):1139-1151.

Emerging Anticoagulants for Stroke Prevention in AF

Direct factor Xa inhibitors– Apixaban (AVERROES, ARISTOTLE)– Betrixaban (EXPLORE Xa)– Edoxaban (ENGAGE AF–TIMI 48)– Rivaroxaban (ROCKET AF)

Vitamin K antagonists– Tecarfarin

Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397. 68

69

Scheduled Follow-up Visit at 4 Weeks


● The patient continues to take dronedarone as prescribed

● His ECG shows sinus rhythm without other abnormalities

● He reports no side effects from the medication; however, he continues to experience episodes of AF 2 to 3 times per week that last several hours at a time, and complains of severe palpitations and fatigue during the AF episodes

70

What treatment would you now suggest?


A. Catheter ablation

B. Flecainide

C. Dofetilide

D. Amiodarone

E. AV node ablation and PPM

71

Surgical and Catheter Ablation

72

Indications for Surgical Ablation● Symptomatic AF patients undergoing other cardiac surgery

● Selected asymptomatic AF patients undergoing cardiac surgery in whom the ablation can be performed with minimal risk

● Symptomatic AF patients who prefer a surgical approach, have failed 1 or more attempts at catheter ablation, or are not candidates for catheter ablation

HRS/EHRA/ECAS 2007 Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation

Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816-861.

Best results are obtained in patients with paroxysmal AF who are young and otherwise healthy

73

Patient Selection for Ablation

Courtesy of Hugh Calkins, MD.

Variable

Symptoms Highly symptomatic Minimally symptomatic

Class I and III drugs failed 1 0

AF type Paroxysmal Long-standing persistent

Age Younger (<70 years) Older (70 years)

LA size Smaller (<5.0 cm) Larger (5.0 cm)

Ejection fraction Normal Reduced

Congestive heart failure No Yes

Other cardiac disease No Yes

Pulmonary disease No Yes

Sleep apnea No Yes

Obesity No Yes

Prior stroke/TIA No Yes

74Reprinted with permission from Haissaguerre M, et al. N Engl J Med. 1998;339(10):659-666.

Initiation of AF From Pulmonary Vein Focus

75

Reprinted with permission from Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

AF Is a Complex Arrhythmia

LSPVLSPVRSPVRSPV

LIPVLIPV

Vein and ligament of Marshall

Vein and ligament of Marshall

RIPVRIPV

IVCIVC

SVC

76

Surgical and Minimally Invasive Surgical Ablation

77Reprinted with permission from Sundt TM 3rd, et al. Cardiol Clin. 1997;15(4):739-748.

Cox-Maze Procedure

In a trial of 190 patients, 1987-1997: 92% had freedom from AF and were off AAD agents

78

Heart rate control:When pharmacologic therapy is insufficient or associated with side effects

When rate cannot be controlled pharmacologically or tachycardia-mediated cardiomyopathy is present

Should not be attempted without prior trial of medication

Rhythm control:Reasonable alternative to pharmacologic therapy to prevent recurrent AF in symptomatic patients with little or no LA enlargement

Recommendations for Catheter AblationI IIa IIb III

B

C

C

C



79

Indications for Catheter Ablation

● Symptomatic AF refractory or intolerant to at least 1 Class 1 or 3 antiarrhythmic medication

● In rare clinical situations, it may be appropriate as first-line therapy

● Selected symptomatic patients with heart failure and/or reduced ejection fraction

● Presence of a left atrial thrombus is contraindication to catheter ablation of AF

Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816-861.

HRS/EHRA/ECAS 2007 Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation

80

Efficacy of Catheter Ablation in Patients With AF

31 (2,800)

34 (3,481) 52 (4,786)

42 (3,562)

0

15

30

45

60

75

90

Single-proceduresuccess off AAD

Multiple-proceduresuccessoff AAD

Single-proceduresuccess

on/off med

Multiple-proceduresuccess

on/off med

Adapted with permission from Calkins H, et al. Circ Arrhythmia Electrophysiol. 2009;2(4):349-361.

Met

a-an

alyz

ed P

rop

ort

ion

of

Pat

ien

ts, %

57% 71% 72% 77%

81

Catheter Ablation of the AV Junction

Advantages– Simple

– Highly effective

– Safe

– Allows a reduction in medication

– Reduces symptoms

But:– Does not prevent AF

– Does not restore a normal heart rhythm

– Requires placement of a pacemaker

– Does not lower the risk of stroke

82Reproduced with permission from Noheria A, et al. Arch Intern Med. 2008;168(16):581-586.

Catheter Ablation of AF: Meta-analysis of 4 Randomized Clinical Trials

Source Risk Ratio (95% CI)

% Weight

Pappone et al, 2006 3.86 (2.65-5.63) 37.5

Stabile et al, 2006 6.43 (2.91-14.21) 18.1

Wazni et al, 2005 4.22 (2.14-8.32) 22.0

Krittayaphong et al, 2003 2.00 (1.02-3.91) 22.4

Overall (95% CI) 3.73 (2.47-5.63)

0.040.04 0.200.20 1.001.00 5.005.00 25.0025.00

ADT More EffectiveADT More Effective CPVA More EffectiveCPVA More Effective

Risk RatioRisk Ratio

83

NaviStar® ThermoCool® Diagnostic/Ablation Catheter

● Steerable, multi-electrode, deflectable● 3.5-mm tip and 3 ring electrodes● 6 saline ports in the tip for irrigation and cooling (open irrigation)● A location sensor and a temperature sensor incorporated into the tip● Approved by the FDA on February 6, 2009, for treatment of AF

84

Days Into Effectiveness Follow-up

ThermoCool® Catheter vs AAD:Time to Chronic Failures

Ablation 103 69 69 66 63 62 61 54 52 37 15 3 2

AAD 56 39 29 19 16 13 11 10 7 2 0 0 0

Effectiveness cohort, N=159. Circles in the graph represent 14 censored catheter ablation subjects.

Number of subjects at risk:

Wilber D. Presented at: American Heart Association 2008 Scientific Sessions; November 11, 2008; New Orleans, LA.

16% AAD (n=56)

64% Ablation (n=103)

Fre

edo

m F

rom

AF

Rec

urr

ence

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210 240 270 300 330 360

P<.001

85

Catheter Ablation and Follow-up Visit at 3 Months


● The patient undergoes successful catheter ablation● On follow-up 3 months post-catheter ablation, he is in

AF and reports that AF recurred about 3 weeks following the ablation procedure and has been present constantly since that time

● He complains of continued palpitations and fatigue ● An ECG confirms the presence of AF

86

What treatment would you now suggest?


A. Repeat catheter ablation

B. MiniMaze procedure

C. DCC

D. Pharmacologic cardioversion

E. Amiodarone

F. AV node ablation and PPM

87

DCC and Follow-up Visit at 6 Months Post-Catheter Ablation


● The DCC was successful in restoring sinus rhythm● At a 6-month follow-up visit after the catheter ablation,

the patient reports 1 episode of AF each month lasting approximately 20 minutes

88

At this point, what treatment would you suggest?


A. Repeat catheter ablation

B. MiniMaze procedure

C. DCC

D. Pharmacologic cardioversion

E. Dronedarone

F. AV node ablation and PPM

G. Clinical follow-up

89

Possible “Upstream” Treatments and Mechanisms for AF Prevention

ACEIs/ARBs Statins Glucocorticoids Physical activity Omega-3 fatty acids

Courtesy of CJ Pepine, MD.

Inflammation Oxidative stress RAAS activity Endothelial function

Autonomic nervous system activity

Plaque stability Atrial remodeling Stabilize left atrial endocardium

Atrial fibrillation

2010 ESC Guidelines for the Management of

Atrial Fibrillation

90

2010 Guidelines for the Management of AFThe Task Force for the Management of AF of the

European Society of Cardiology (ESC)a

New recommendations

● Addition of “long-standing persistent AF” as a patient category

● Introduction of the EHRA symptom score for arrhythmias

● Establishment of better risk profiles to assess who will benefit most from new anticoagulants to prevent stroke

– CHA2DS2-VASc score (refinement of CHADS2 score)

– HAS-BLED (new score for assessing bleeding risk)

91

a Developed together with the European Heart Rhythm Association (EHRA) and endorsed by the European Association for Cardio-Thoracic Surgery (EACTS).

Camm AJ, et al. Eur Heart J. 2010;31:2369-2429.



Changes from the previous ACC/AHA/ESC 2006recommendations

● New guidance in the area of rate control

● Advice on how to use the antiarrhythmic drug dronedarone

● Formal indications for the use of ablation therapy

● Recommendations on “upstream” therapies to prevent the deterioration of AF

● Advice on certain “special situations”

92

2010 Guidelines for the Management of AF (cont)

The Task Force for the Management of AF of the European Society of Cardiology (ESC)a





www.escardio.org/guidelines

111

Question-and-Answer Session

112

AF Performance Improvement Outcomes Study

● NCME has partnered with Harvard Clinical Research Institute (HCRI) to evaluate the impact of this educational activity

● The goal of the study is to:

– help each participating hospital gain perspective on how their institution manages AF

– directly assess improvements in patient outcomes

● Data will be collected via a secure online Web site

● Baseline data will be collected representing a period prior to the grand rounds lecture, and then one year as a follow up

● Study closely aligns with QI programs your hospital is already involved in (eg, reporting to Joint Commission and CMS)

● $500 honorarium will be provided to each participation institution

● To sign up for the study complete the enrollment form provided to your CME coordinator or send an e-mail message to [email protected]

113

Thank you for participating!

1. 2 Learning Objectives After taking part in this activity, participants should be better able to:...

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Transcript of 1. 2 Learning Objectives After taking part in this activity, participants should be better able to:...