New Approaches to Anticoagulation in Atrial Fibrillation · New Approaches to Anticoagulation in...

New Approaches to Anticoagulation in

Atrial Fibrillation

Hugh Calkins M.D.

Nicholas J. Fortuin Professor of Cardiology Professor of Medicine

Director of Electrophysiology

Johns Hopkins Medical Institutions

hcalkins@jhmi.edu

1

Outline

Overview of Atrial Fibrillation

Treatment Strategies

Stroke Risk

Anticoagulation Options

Rate and Rhythm Control

Conclusion

2

Disclosures

Consultant, Research Support, or Honoraria

Biosense Webster, CryoCor, ProRhythm, Ablation

Frontiers,

Medtronic, Boston Scientific, AtriCure, Sanofi

Adventis

3

4

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.

5

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.

6

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.

7 Reproduced 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

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

Years From AF Dx Years After 4 Mo

From AF Dx

Su

rviv

al, %

P<.0001 P<.0001

MN-white expected

Observed

8

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 General

health

Mental

health

index

Emotional

role

Social

functioning

SF

-36 s

cale

*

100

90

80

70

60

50

40

General population1

Recent MI1

AF2

HF1

Impact on QoL: AF vs Other CV Illness

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Pathogenesis of AF

Multiple-wavelet hypothesis1

Focal mechanism with fibrillatory

conduction2

“Autonomic” hypothesis3

1. Moe GK, Abildskov JA. Am Heart J. 1959;58(1):59-70.

2. Konings KT, et al. Circulation. 1994;89(4):1665-1680.

3. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93(5):1043-1065.

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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

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Classification of AF

Recurrent AF* ( 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

*Termination with pharmacologic therapy or direct-current cardioversion does not change the designation.

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

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Treatment

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Treatment Goals and Strategies

Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IA

Class IC

Class III

-blocker

Catheter ablation

Pacing

Surgery

Implantable devices

Pharmacologic • Warfarin

• Aspirin

• Thrombin Inhibitor

Nonpharmacologic • Removal/isolation

LA appendage

Rate control

Pharmacologic • Ca2+ blockers

• -blockers

• Digitalis

• Amiodarone

Nonpharmacologic • Ablate and pace

Prevent Remodeling CCB

ACE-I, ARB

Statins

Fish oil

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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

S2 History of stroke or transient ischemic attack

2

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

16 Gage 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

CHADS2, Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or

transient ischemic attack.

Warfarin

0 5 10 15 20 25 30

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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

www.escardio.org/guidelines

www.escardio.org/guidelines

www.escardio.org/guidelines

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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.

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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

23 Becattini Throm Res 2012

Main Features of New Anticoagulant

Agents

Becattini Throm Res 2012

Clinical Trials and new Anticoagulant Agents

- A Summary -

Becattini Throm Res 2012

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

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

• In patients with atrial fibrillation, 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, as compared with warfarin, 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 versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF)

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

• In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism.

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

Apixaban in Patients with Atrial Fibrillation

(AVERROES)

• In this trial, the factor Xa inhibitor apixaban was shown to reduce the risk of stroke or systemic embolism, as compared with aspirin, without a significant increase in the risk of major bleeding.

• Apixaban is an alternative to aspirin for patients who cannot take warfarin.

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.

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

- compliance issues

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Treatment Goals and Strategies

Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IA

Class IC

Class III

-blocker

Catheter ablation

Pacing

Surgery

Implantable devices

Pharmacologic • Warfarin

• Aspirin

• Thrombin Inhibitor

Nonpharmacologic • Removal/isolation

LA appendage

Rate control

Pharmacologic • Ca2+ blockers

• -blockers

• Digitalis

• Amiodarone

Nonpharmacologic • Ablate and pace

Prevent Remodeling CCB

ACE-I, ARB

Statins

Fish oil

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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

– -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)

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No (or minimal) heart disease

Amiodarone Dofetilide

HF CAD Hypertension

Amiodarone Dronedarone Flecainide

Propafenone Sotalol

Yes

Maintenance of SR

Substantial LVH

No

Dronedarone Flecainide

Propafenone Sotalol

Catheter ablation

Amiodarone Dofetilide

Catheter ablation

Catheter ablation

Amiodarone Catheter ablation

Dofetilide Dronedarone

Sotalol

Amiodarone Dofetilide

Catheter ablation

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.

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Current Efficacy of AF Ablation:

Estimates

Surgical Ablation Single Procedure Multiple

Optimal patient

Less optimal patient

Poor candidate

70%-90%

60%-80%

50%-60%

Catheter Ablation

Optimal patient

Less optimal patient

Poor candidate

60%-80%

50%-70%

40%

80%-90%

70%-80%

40%-60%

Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical ablation of atrial

fibrillation. Heart Rhythm. 2007;4(6):816-861.

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

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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

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Treatment Goals and Strategies

Maintenance of SR

Pharmacologic

Stroke prevention

Nonpharmacologic

Class IA

Class IC

Class III

-blocker

Catheter ablation

Pacing

Surgery

Implantable devices

Pharmacologic • Warfarin

• Aspirin

• Thrombin Inhibitor

Nonpharmacologic • Removal/isolation

LA appendage

Rate control

Pharmacologic • Ca2+ blockers

• -blockers

• Digitalis

• Amiodarone

Nonpharmacologic • Ablate and pace

Prevent Remodeling CCB

ACE-I, ARB

Statins

Fish oil

Conclusions

Atrial fibrillation is common

Atrial fib is an important risk factor for stroke.

Stroke risk can be determined using CHADS

and CHADSvasc

Patients at increased risk of stroke should be

anticoagulated.

Aspirin does little.

The era of new anticoagulants is here and

now.

Thank You

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