conflicts of interests · 1. ware je, et al. new england medical center health survey; 1993. 2....

1

Advances in the Management of Atrial Fibrillation

State of the Art in 2013

Hugh Calkins MDJohns Hopkins Medical Institutions

Overview of AFStroke risk and anticoagulationRate controlAntiarrhythmic Drug TherapyCatheter ablationConclusion

Conflicts of Interests

None to declare

2

3

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.

2

4

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.

5

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.

6Reproduced with permission from Miyasaka Y, et al. J Am Coll Cardiol. 2007;49(9):986-992.

AF Increases Mortality

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

3

7

• 15429 subjects enrolled in ARIC study• 5479 subjects enrolled in the CV Health Study

8

AF Is Associated With Dementia

HR 2012

9

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.

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

Baseline score

Physical functioning

Vitality Generalhealth

Mentalhealthindex

Emotionalrole

Socialfunctioning

SF

-36

sc

ale

*

100

90

80

70

60

50

40

General population1

Recent MI1

AF2

HF1

AF Reduces Quality of Life

4

Pathogenesis of AF

AF Results in Atrial Remodelong- 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

• FACM is a specific disease/syndrome supplying substrates for AF and other manifestations.

• The long help concept that “atrial begets atrial fibrillation” does not explain the variable pattern of atrialfibrosis in patients with atrial fibrillation.

• Some patients with new onset of AF have severely scarred atria.

• Other patients with longstanding AF have little fibrosis.• Tachy-brady syndrome is likely a manifestation of FACM.• Outcomes of ablation are impacted significantly by the

extent of FACM.• Stroke risk is related to the extent of FACM.

5

13

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?

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% of Patients With AF

Class I – II Class III – IV

Prevalence of AF Increases With Severity of HF

0

0.1

0.2

0.3

0.4

0.5

0.6

Temporal Relations of AF and CHF andTheir Joint Influence on Mortality

The Framingham Heart Study● 1,470 subjects, new onset AF or CHF● AF only 539, CHF only 549, both 382● AF first 144, CHF first 159, same day 79, ● Mean f/u 5 years

Results:● 41% of CHF patients developed AF● 42% of AF patients developed CHF● In AF subjects, the presence of development of CHF

was associated with a 2 – 3 x increased mortality● In CHF patients, the presence of development of AF

did not impact mortality.

Wang TJ, et al. Circulation. 2003;107:2920-2925.

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16

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

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 3,906 3,207 2,755 1,963No AF & PEF 2,545 2,294 2,096 1,276AF & 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 EF [> 0.40])

No AF at baseline(preserved EF [> 0.40])

Preserved EF:HR 1.72 (95% CI 1.45 – 2.06)P < 0.001

Low EF:HR 1.29 (95% CI 1.14 – 1.46)P < 0.001

Cu

mu

lati

ve

dis

trib

uti

on

fu

nct

ion

Olsson LG, et al. J Am Coll Cardiol. 2006;47:1997-2004.

Year

17

• 30 sheep on high calorie diet studies at 4 and 8 months• 10 controls• CMR, hemodynamic, and EP testing• Histological examination

18

7

19

Treatment

AF Guidelines

21

Treatment Goals and Strategies

Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IA 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

Nonpharmacologic• Ablate and pace

Prevent RemodelingCCB

ACE-I, ARBStatinsFish oil

8

Stroke Risk Stratification in AF1,2

CHADS2 CHA2DS2-VAScRisk Factor Score

Cardiac failure 1

HTN 1

Age ≥75 y 1

Diabetes 1

Stroke 2

Risk Factor Score

Cardiac failure 1

HTN 1

Age ≥75 y 2

Diabetes 1

Stroke 2

Vasc dz (MI, PAD, aortic ath) 1

Age 65-74 y 1

Sex category (female) 1

1. Lip GY, Halperin JL. Am J Med. 2010;123(6):484-488.2. Camm AJ, et al. Eur Heart J. 2010;31(19):2369-2429.

0 1 2 3 4 5 60

5

10

15

20

Str

oke

Rat

e, %

0 1.3 2.2 3.2 4.06.7

9.8

CHA2DS2-VASc Score7 8 9

9.6

15.2

6.7Relationship between CHA2DS2-VASc score and annual risk of stroke

22

ESC 2010 Atrial Fibrillation Guidelines

Indications for Anticoagulation in AF PatientsThe 2012 ESC Guidelines

23

Indications for Anticoagulation in AF PatientsThe 2012 ESC Guidelines

24

9

25

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 2.0-3.0*)

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

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

ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines

26

27

10

28

29

30

SPAF - 1

Circulation. 1991: 84: 527-30

11

Connolly SJ et al. N Engl J Med 2011;364:806-817

Apixaban in Patients with Atrial Fibrillation (AVERROES)

32

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.

Targets of New Anticoagulant Agents

33Becattini Throm Res 2012

12

Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY)

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

• Dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage

• Dabigatran administered at a dose of 150 mg, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage

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

Rivaroxaban vs Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF)

• 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin.

• Rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism.

Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE)

Granger CB et al. N Engl J Med 2011;365:981-992

Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality.

13

New Oral Anticoagulant Agents

37

Which New Agent Should We Recommend ?

● Raise the issue / Pop the question

● Variables to consider:

- coumadin experience

- approach to new drugs

- cost considerations

- h/o GI symptoms

- renal function

- compliance issues

Can We Use These New Agents in Patients on ASA or Clopidogrel?

● Concomitant use of an antiplatelet drug leads to a significant rise in bleeding when combined with any anticoagulant.

● The risk is increased by approximately 50% with a single antiplatelet drug and is doubled when dual antiplatelet therapy is used.

● Concomitant antiplatelet therapy has little impact on the relative advantages of dabigatran and apixaban in comparison with warfarin.

14

40


Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IAb

Class ICClass III-blocker



LA appendage

Rate control

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




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

41

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)

42


Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IAb

Class ICClass III-blocker



LA appendage

Rate control

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




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

15

43

No (or minimal)heart disease

Amiodarone Dofetilide

HFCADHypertension

AmiodaroneDronedaroneFlecainide

PropafenoneSotalol

Yes

Maintenance of SR

Substantial LVH

No

DronedaroneFlecainide

PropafenoneSotalol

Catheterablation

Amiodarone Dofetilide

Catheterablation

Catheterablation

Amiodarone Catheterablation

DofetilideDronedarone

Sotalol

AmiodaroneDofetilide

Catheterablation

Rhythm Control Therapies to Maintain Sinus Rhythm

2011 ACCF/AHA/HRS Focused Update on the Management of AF

Reproduced with permission from Wann LS, et al. Circulation. 2011;123(1):104-123.

44

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

45

Catheter Ablation

16

46Reprinted with permission from Haissaguerre M, et al. N Engl J Med. 1998;339(10):659-666.

Initiation of AF From Pulmonary Vein Focus

What Do We Know About AF Ablation?

•How to perform it.

• How to avoid PV stenosis and phrenic nerve injury.

• How to avoid esophageal injury.

• Results in elimination of symptomatic AF in most patients.

• Improves quality of life.

• More effective than antiarrhythmic drug therapy.

• Associated with a moderate risk of complications.

17

49

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.

Me

ta-a

na

lyze

d P

rop

ort

ion

of

Pa

tie

nts

, %

57% 71% 72% 77%

50Reproduced 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)

0.04 0.20 1.00 5.00 25.00

ADT More Effective CPVA More Effective

Risk Ratio

51

Ablation Catheters

18

0 100 200 300 400 500

Days

0%

20%

40%

60%

80%

100%T

reat

men

t S

ucc

ess

Treatment Success

CRYORF

AF Ablation Outcomes in 2013

Single Procedure Multiple Procedure

Optimal Candidate: 60-80% 70-90%

Moderate Candidate 45-65% 55 – 75%

Poor candidate 35 – 50% 45 – 60%

•Success is defined as freedom from symptomatic AF at 12 months of follow-up.

Complications in 2013

Overall Complication Rate: 1% - 3%

Stroke /TIA – 0.2% - 1%Cardiac perforation / tamponade – 0.2% - 1%Vascular injury / bleeding – 0/5% - 1%Phrenic nerve injusy 0.1% - .3%Atrial esophageal fistula - < 1/1000Gastroparesis – 0.1% - 0.2%Death - < 1/1000

19

• Safety and efficacy of the catheter ablation in:

- very elderly

- heart failure

- long standing persisent AF

• Impact of AF ablation on stroke risk.

• Impact of AF ablation on survival.

• Technical questions.

- optimal ablation strategy for long standing persistent

AF

- relative efficacy of cryo ablation, RF ablation, and laser

ablation

Where Are the Knowledge Gaps?

What is the impact of AF ablation on

stroke and mortality?

• The CABANA Trial

• Prospective randomized clinical trial of 3500 patients to compare catheter ablation with pharmacologic therapy of atrial fibrillation.

• 3500 patients, > 65 years of age or > 1 stroke risk factor

• Endpoints: death and stroke

Indications for AF Ablation in 2013

20

Indications for Catheter Ablation of Atrial Fibrillation

Patient Selection for Ablation

Courtesy of Hugh Calkins, MD.

More Optimal Patient Less Optimal Patient

Variable

Symptoms Highly symptomatic Minimally symptomatic

Class I and III drugs failed 1 0

AF type Paroxysmal Long-standing persistant

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

21

61


Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IA Class ICClass III-blocker



LA appendage

Rate control

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




62

Conclusion

• Atrial fibrillation is an important arrhythmia.• Stroke prevention is the primary goal of treatment.• Anticoagulation is indicated for all patients except the extremely

low risk. • Rhythm control strategies may improve quality of life in

symptomatic patients.• Catheter ablation plays an important role in the treatment of AF.• Selection of antiarrhythmic agents is largely based on side effect

profiles.

63

Thank You

conflicts of interests · 1. ware je, et al. new england medical center health survey; 1993. 2....

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