Arnold J. Greenspon M.D.

Professor of Medicine

Jefferson Medical College

Philadelphia, PA

ATRIAL FIBRILLATION 2014:

AN UPDATE

Disclosure of Financial RelationshipsDisclosure of Financial Relationships

Arnold J. Greenspon M.D.

Has no relationships with any entity producing, marketing, re-selling, or

distributing health care goods or services consumed by, or used on, patients.

EpidemiologyScope of the Problem

EpidemiologyScope of the Problem

� More than 2 million patients in the US with AF

� Major impact on the elderly

� Prevalence increase as population ages

� Substantial morbidity due to symptoms

� Associated with stroke, heart, failure, and death

� Most common arrhythmia requiring hospitalization

Atrial Fibrillation Demographics by Age

Adapted from Feinberg WM. Arch Intern Med. 1995;155:469-473.

U.S. population

Population with

atrial fibrillation

Age, yr

<5 5-

9

10-

14

15-

19

20-

24

25-

29

30-

34

35-

39

40-

44

45-

49

50-

54

55-

59

60-

64

65-

69

70-

74

75-

79

80-

84

85-

89

90-

94

>95

U.S. population x 1000 Population with AF x 1000

30,000

20,000

10,000

0

500

400

300

200

100

0

Prevalence of AF in the United StatesPrevalence of AF in the United States

0

2

4

6

8

10

12

14

16

18

Year

Pro

ject

ed N

um

ber

of

Peo

ple

wit

h A

F

(mil

lio

ns)

Miyakasa Y, et al. Circulation. 2006; 114:119-125.

Consequences of Atrial FibrillationConsequences of Atrial Fibrillation

Embolic Hemodynamic

� TIA

� Stroke

� Systemic emboli

� Loss of atrial systole

� Increased heart rate

� Decrease in diastolic time

Management of Atrial FibrillationManagement of Atrial Fibrillation

Control of symptoms

� Rate vs Rhythm

� Role of cardioversion

Stroke Prevention

� Risk assessment

� Role of anticoagulation

Types of Atrial FibrillationTypes of Atrial Fibrillation

Episode of AF

Paroxysmal Persistent Permanent

Atrial Fibrillation: DefinitionsAtrial Fibrillation: Definitions

� Paroxysmal

� AF that terminates spontaneously within 7 days

� Persistent

� AF that requires cardioversion for termination

� Permanent

� Sinus rhythm cannot be restored

Atrial Fibrillation is Associated with StrokeAtrial Fibrillation is Associated with Stroke

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

Str

oke (

%)

AFASAK SPAF BAATAF CAFA SPINAF

Stroke Rates in Placebo-Treated Patients With AF

Ischemic Strokes and AF:More Likely DisablingIschemic Strokes and AF:More Likely Disabling

73

33

58

16

36

16

30

11

Framingham Heart Study

Lin HJ, et al. Stroke. 1996;27:1760-1764.

Prevalence of Stroke vs AgeFramingham Data

Prevalence of Stroke vs AgeFramingham Data

Age Groups

Str

ok

e R

ate

/10

00

Wolf et al. Arch Intern Med. 1987;147:1561-1564.

Anticoagulation in AFStroke Risk Reductions

Anticoagulation in AFStroke Risk Reductions

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

Aggregate

Warfarin Better Control Better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Reduction of stroke

RRR 62%

Reduction of stroke

RRR 62%

Reduction ofall-cause mortality RRR

26%

Reduction ofall-cause mortality RRR

26%

INR Control: Target 2-3How Well Do We Do?

INR Control: Target 2-3How Well Do We Do?

Lancet 2003; 362: 1691-98

JAMA 2005; 293(6): 690-98

Chest 2006; 129: 1155-66

SPORTIF 3 66%

SPORTIF 5 68%

ACTIVE W 65% (previous OAC)

60% (OAC naïve)

RELY 64%

Meta analysis 66%

Randomized Clinical Trials

Community Practice

Meta analysis 57%

Ischemic Stroke andIntracranial BleedingIschemic Stroke andIntracranial Bleeding

Fuster et al. J Am Coll Cardiol. 2001;38:1231-1265; Hylek et al. Ann Intern Med. 1994;120:897-902.

INR

Od

ds R

ati

o

20

15

10

5

1

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

Ischemic stroke

Intracranial bleeding

Issues and Challenges for Stroke Prevention in AF Patients

Issues and Challenges for Stroke Prevention in AF Patients

� Warfarin is effective but difficult to use

� Not all patients take or tolerate warfarin

� Time in therapeutic range often low

� Risk of bleeding

SPAF: Risk vs Benefit of AnticoagulationSPAF: Risk vs Benefit of Anticoagulation

Risk of stroke Risk of bleeding

Stroke and Nonvalvular AFStroke and Nonvalvular AF

PriorStroke/TIA

Age> 75 years

Hypertension Female Diabetes Heart Failure� LVEF

Hart RG et al. Neurology 2007; 69: 546.

Stroke Rates Without AnticoagulationAccording to Isolated Risk Factors

The CHADS2 ScoreStroke Risk Score for Atrial Fibrillation

The CHADS2 ScoreStroke Risk Score for Atrial Fibrillation

Congestive Heart failure 1 32

Hypertension 1 65

Age > 75 years 1 28

Diabetes mellitus 1 18

Stroke or TIA 2 10

Moderate-High risk >2Low risk 0-1

VanWalraven C, et al. Arch Intern Med 2003; 163:936.

Prevalence (%)Score (points)

CHADS2 Score: Targeted TherapyCHADS2 Score: Targeted TherapyCHADS2

Score

Adjusted Stroke Rate†

(95% CI)

CHADS2

Risk Level

0 1.9 (1.2-3.0) Low

1 2.8 (2.0-3.8) Low

2 4.0 (3.1-5.1) Moderate

3 5.9 (4.6-7.3) Moderate

4 8.5 (6.3-11.1) High

5 12.5 (8.2-17.5) High

6 18.2 (10.5-27.4) High

†Expected rate of stroke per 100 patient-years.

Snow et al. Ann Intern Med. 2003;139:1009-1017.

The CHA2DS2-VASc ScoreStroke Risk Score for Atrial Fibrillation

The CHA2DS2-VASc ScoreStroke Risk Score for Atrial Fibrillation

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

Congestive heart failure or LVEF < 35% 1

Hypertension 1

Age > 75 years 2

Diabetes mellitus 1

Stroke/TIA/systemic embolism 2

Vascular Disease (MI/PAD/Aortic plaque) 1

Age 65-74 years 1

Sex category (female) 1

Moderate-High risk > 2Low risk 0-1

Weight (points)

Canadian Cardiovascular SocietyAF Guidelines 2012 Update

Canadian Cardiovascular SocietyAF Guidelines 2012 Update

Increasing stroke risk

CHADS2 = 0 CHADS2 = 1 CHADS2 > 2

No anti-thrombotic

ASA OAC* OAC* OAC

No additionalrisk factors of stroke

Either female sex or vascular disease

Age > 65 y or combination of female sex and vascular disease

*Aspirin is a reasonable alternative in some as indicated by risk/benefit

Assess Thromboembolic Risk (CHADS2)

Risk of Bleeding: HAS-BLED ScoreRisk of Bleeding: HAS-BLED Score

Hypertension (> 160 mm Hg systolic) 1

Abnormal renal or hepatic function 1-2

Stroke 1

Bleeding history or anemia 1

Labile INR (TTR < 60%) 1

Elderly (age > 75 years) 1

Drugs (antiplatelet, NSAID) or alcohol 1-2

High risk (> 4%/year) > 4Moderate risk (2-4%/year) 2-3Low risk (< 2%.year) 0-1

Pisters R, et al. Chest 2010; 138: 1093.

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

Risk Score for Predicting Bleeding inAnticoagulated Patients with Atrial Fibrillation

CHADS2 vs CHADS2-VAScCHADS2 vs CHADS2-VASc

2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace. 2012 Aug 24

� Guideline recommends a shift towards focus on low risk

� No recommendation on composite bleeding stroke risk score

Subclinical AF and Risk of StrokeSubclinical AF and Risk of Stroke

Healey JS, et al. NEJM 2012; 366:120-129

Str

oke o

r S

yste

mic

Em

bolis

m

Years

Atrial tachyarrhythmia > 6 min ≤ 3 months after pacemaker or defibrillator implantation

Progression of Atrial FibrillationProgression of Atrial Fibrillation

Paroxysmal

Self-Terminating

Persistent

Lasts > 7 Days

Permanent

Cardioversion Failed or Not Attempted

Normal Sinus Rhythm

Atrial Fibrillation

Paroxysmal AF is as likely to cause stroke aspersistent or permanent AF

SPAF: The Challenge of Assessing Stroke Risk

SPAF: The Challenge of Assessing Stroke Risk

• Paroxysmal AF is difficult to detect.

• 24h Holter is often insufficient. Prolonged monitoring may

be necessary.

• Many strokes are misclassified as “cryptogenic”.

• The misclassified strokes are really thromboembolic and

warrant anticoagulation.

• Patients with PAF and risk factors need OAC.

SPAF: Challenges for the FutureSPAF: Challenges for the Future

� Better risk-stratification

� Balancing stroke vs bleeding

� Methods to better predict events and guide therapy

� Successful rhythm control over time (?)

� Safer treatments for the highest risk patients

� Role of new anticoagulants

VIIIntrinsic

Pathway

Extrinsic

Pathway

IX

II (prothrombin)

XI

XIIXIIa

XX

VIIaIXa

XIa

II (thrombin)

XXa

AnticoagulantsAnticoagulants

XXa

IIa (thrombin)

Warfarin

II, VII, IX, X

VIIaIXa

XXa

IIa (thrombin)

FIBRINOGENFIBRINOGENFIBRINFIBRIN

Walenga et al. Thromb Res. 1997;86:1-36.

Apixaban

Rivaroxaban

Endoxaban

Major Advances In Oral Anticoagulation for SPAF

Major Advances In Oral Anticoagulation for SPAF

6 Trials of Warfarin vs Placebo1989-1993

RE-LY

(Dabigatran)2009

ROCKET AF

(Rivaroxaban)2010

ARISTOTLE

(Apixaban)2011

ENGAGE AF

(Edoxaban)2013

Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents

Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents

Dabigatran Apixaban Rivaroxaban Edoxaban

Target IIa (thrombin) Xa Xa Xa

Hrs to Cmax 2 1-3 2-4 1-2

CYP metabolism None 15% 32% NR

Bioavailability 7% 66% 80% > 45%

Transporters P-gp P-gp P-gp/BCRP P-gp

Protein binding 35% 87% >90% 55%

Half-life 12-14h 8-15h 9-13h 8-10h

Renal elimination 80% 25% 33% 35%

Linear PK Yes Yes No Yes

Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22

BCRP = breast cancer resistance protein; CYP = cytochrome P450; P-gp = P-glycoprotein

Pivotal AF Trials:Dose ComparisonPivotal AF Trials:Dose Comparison

RE-LY ROCKET-AF ARISTOTLEENGAGE

AF-TIMI 48

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

N 18,113 14,266 18,201 21,105

Dose (mg)Frequency

150, 110bid

20 qd

5bid

60, 30qd

Initial Dose adj* No 20 → 15 mg 5 → 2.5 mg60 → 30 mg

30 → 15 mg

Dose adj (%) 0 21 4.7 > 25

Dose adj* after randomization

No No No Yes

Design PROBE 2 x blind 2 x blind 2 x blind

Connolly SJ et al. N Engl J Med 2009; 361:1139-51

Patel MR et al. N Engl J Med 2011; 365:883-91

Granger CB et al. N Engl J Med 2011; 365:981-92

Ruff CR et al. Am Heart J 2010; 160:635-41

* Dose adjusted in patients with ↓drug clearance

Pivotal AF Trials:Clinical Characteristics

Pivotal AF Trials:Clinical Characteristics

RE-LY

(Dabigatran)

ARISTOTLE

(Apixaban)

ENGAGE AF

(Edoxaban)

ROCKET-AF

(Rivaroxaban)

# Enrolled 18,113 18,201 21,105 14,264

Age (yrs) 72 ±±±± 9 70 [63-76] 72 [64-77] 73 [65-78]

Female 36% 35% 38% 40%

CHADS2 score ≥3 32% 30% 52% 87%

VKA naive 50% 43% 41% 38%

Paroxysmal AF 33% 15% 25% 18%

Prior stroke/TIA 20% 19% 18% / 12% 55%*

Diabetes 23% 25% 36% 40%

Prior CHF 32% 35% 56% 62%

Hypertension 79% 87% 90% 91%

*includes prior systemic embolism

Connolly SJ et al. N Engl J Med 2009; 361:1139-51

Patel MR et al. N Engl J Med 2011; 365:883-91

Granger CB et al. N Engl J Med 2011; 365:981-92

Ruff CR et al. Am Heart J 2010; 160:635-41

Pivotal AF Trials:Results

Pivotal AF Trials:Results

DrugDose (mg)

RE-LY ROCKET-AF ARISTOTLE

Dabigatran110 bid 150 BID

Rivaroxaban20 mg qd

Apixaban5 mg bid

Stroke + SEE non-infer Superior ITT cohort: non-infer.

On Rx cohort: SuperiorSuperior

ICH Superior Superior Superior Superior

Bleeding Lower similar similar Lower

Mortality similar P = 0.051 similar Superior: P = 0.047

Ischemic stroke similar Lower similar similar

Mean TTR 64% 55% 62%

Stopped drug 21% 23% 23%

WD consent 2.3% 8.7% 1.1%

TTR = time in therapeutic rangeWD consent = withdrawal of consent, no further data available

Novel Oral Anticoagulant: EfficacyNovel Oral Anticoagulant: Efficacy

Stroke

Ischemic Stroke

HemorraghicStroke

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

Favors NOACs

Favors Warfarin

13%

55%

Novel Oral Anticoagulant: : Safety Novel Oral Anticoagulant: : Safety

Major

ICH

GI

Bleeding

Favors NOACs Favors Warfarin

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

51%

Novel Oral Anticoagulant: BleedingNovel Oral Anticoagulant: Bleeding

Fatal Bleeding

Major Bleeding

GI Bleeding

40%

20%

30%

Favor NOAC FAVOR Warfarin

Adam SS et al: Ann Int Med 2012;157:796-807

AVERROES: Comparison of Apixaban and Aspirin

AVERROES: Comparison of Apixaban and Aspirin

Stroke or Systemic Embolic Event

Major Bleeding

HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)

Connolly SJ, et al. N Engl J Med 2011 (epub)

Aspirin

Apixaban

P < 0.001

0 3 6 9 12 18

0.05

0.04

0.03

0.02

0.01

0.00

Aspirin

Apixaban

P < 0.001

0 3 6 9 12 18

0.020

0.015

0.010

0.005

0.000

Summary of SPAF GuidelinesSummary of SPAF Guidelines

� The CHADS2-VASc is probably best for identifying low-

risk patients

� The HAS-BLED score assesses bleeding risk.

� Correct the correctable

� HAS-BLED>3- caution and regular review advised

� NOACs offer better efficacy, and convenience

compared to VKAs

� No data to recommend one over the other

� Efficacy of ASA is weak

� Risk of bleeding same as OAC

Atrial Fibrillation: ManagementAtrial Fibrillation: Management

Rate control Rhythm control

Why Are There No New Drugs for Rhythm Control??

Why Are There No New Drugs for Rhythm Control??

Antiarrhythmic Drugs=

Poisons with beneficial side effects

Definition:

Drugs for Rhythm ControlDrugs for Rhythm Control

� Class I Drugs- Na+ Blockers (slow conduction)

� IA Quinidine or Disopyramide

� IC (avoid in pts with CAD, CM)

� Flecainide 100-225mg bid

� Propafenone 150-225 mg tid or bid

� Class III Drugs- K+ Blockers (prolong repolarization)

� Sotalol 80-160 mg bid (may not be tolerated in CHF)

� Dofetilide 0.125-0.500 mg bid (may be used in CHF, but must watch QTc, K+, creatinine)

� Dronedarone 400 mg BID (avoid CHF or permanent AF)

� Amiodarone 100-200 mg daily (drug of choice in pts with CHF)

Canadian Trial of Atrial Fibrillation (CTAF):

Rhythm Control

Canadian Trial of Atrial Fibrillation (CTAF):

Rhythm Control

Rate of recurrence lowest with amiodarone

Roy D, Talajic M, Dorain P et al: N Eng J Med 2000;342:913

AFFIRM: Rate control versus Rhythm controlAFFIRM: Rate control versus Rhythm control

Wyse DG, Waldo AL, DiMarco JP, et al: N Eng J Med 2002;3347:1825

p=0.058

Mortality

Rhythm or Rate Control in AF

Rate

Control

Rhythm

Control P-value

PIAF 1 (0.8%) 2 (1.6%) ns

STAF 8 (8%) 4 (4%) ns

AFFIRM 306 (26%) 356 (27%) .058

RACE 18 (7.0%) 18 (6.7%) ns

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Rhythm Control Worse

Rhythm Control Better

AFFIRM(n=4060)

1.28 (0.95 – 1.72)

RACE(n=522)

2.25 (1.88 – 5.75)

STAF(n=200)

3.01 (0.35 – 25.30)

PIAF(n=252)

4.92 (0.58 – 41.50)

TOTAL(n=5034)

1.36 (1.03 – 1.78)

2.2P=.04

2.4

Cerebrovascular Events

Rhythm or Rate Control in AF

Relationship between NSR, Treatment, and Survival in AFFIRM: AFFIRM substudyRelationship between NSR, Treatment, and Survival in AFFIRM: AFFIRM substudy

Covariate p-value H.R. 99% CI

Sinus rhythm <0.0001 0.53 0.39-0.72

Warfarin use <0.0001 0.50 0.37-0.69

Digoxin use 0.0007 1.42 1.09-1.86

AAD use 0.0005 1.49 1.11-2.01

Time-Dependent Co-variates Associated with Survival

AFFIRM Investigators: Circulation 2004;109:1509-1513

Toxicity of antiarrhythmic drugs counterbalances the benefits of SR

AF Clinical Trials: Rhythm vs Rate Control

� Mortality is similar, regardless of treatment strategy

� Lenient control (mean rate<110 bpm) as good as

strict control (mean rate <80 bpm)

� RACE II: NEJM 2010;362:1363

� Anticoagulation in patients at high risk for stroke is

important, regardless of rate or rhythm treatment

strategy

What AFFIRM did not answer:

� Is NSR associated with an

improved outcome in high-risk,

symptomatic patients?

� Is NSR preferable in young

patients?

� Is rhythm control superior if

patients receive OAC?

The management cascade for patients with AFCardioversion, TEE and anticoagulation

AF = atrial fibrillation; DCC = direct current cardioversion; LA = left atrium; LAA = left atrial appendage; OAC = oral anticoagulant;SR= sinus rhythm; TEE= transesophageal echocardiography.AF = atrial fibrillation; DCC = direct current cardioversion; LA = left atrium; LAA = left atrial appendage; OAC = oral anticoagulant;SR= sinus rhythm; TEE= transesophageal echocardiography.

Eur Heart J 2013;31:2369-2429

TEE

Recent onsetConventional strategyTEE strategy

Standard OAC or TEE

Choose antiarrhythmic drugaccording to underlying pathology

Eur Heart J 2013;31:2369-2429

(?)

Treatment of AF:Non-pharmacologic Options

Treatment of AF:Non-pharmacologic Options

� Rate control

� Ablate and pace

� Surgical

� Cox-MAZE procedure

� Radiofrequency catheter ablation

� Pulmonary vein isolation

� Extended LA ablation

Cox J L Europace 2003;5:S20-S29

Surgical procedure for AF: Standard Maze-III Surgical procedure for AF: Standard Maze-III

Angiogram of a Left Inferior Pulmonary Vein Depicting the Source and Exit of Ectopic Activity.

Haïssaguerre M et al. N Engl J Med 1998;339:659-666.

Initiation of Focal AFInitiation of Focal AF

Haissaguerre et al. NEJM 1998;389:659-66

AF Ablation: Targeting and isolating pulmonary veinsAF Ablation: Targeting and isolating pulmonary veins

Ames A , Stevenson W G Circulation 2006;113:e666-e668a

Electroanatomic map with an integrated computed tomographic image of the left atrium and pulmonary veins (viewed from the back) showing the lesion set created for ablation of paroxysmal

atrial fibrillation.

Calkins H Circulation. 2012;125:1439-1445

AF Ablation: Creating PVIAF Ablation: Creating PVI

Tung R et al. Circulation 2012;126:223-229

Ablation of Persistent AF: Additional lesions requiredAblation of Persistent AF:

Additional lesions required

Tung R et al. Circulation 2012;126:223-229

Efficacy of Antiarrhythmic Drugs versus Catheter AblationEfficacy of Antiarrhythmic Drugs versus Catheter Ablation

Me

ta-a

na

lyze

d p

rop

ort

ion

o

f p

ati

en

ts (

%)

Drugs (N=34 studies) Ablation (N=63 studies)

Treatment

success

Recurrent

AF

Single-

procedure

success

off AAD

Multiple-

procedure

success

off AAD

Single-

procedure

success

on AAD or

uncertain

Multiple-

procedure

success

on AAD or

uncertain

Patients

requiring

repeat

ablation

0

10

20

30

40

50

60

70

80

90

Calkins H: Circ Arrhy Electrophysiol 2009;2:349

N= 6589 N=6936

AF Ablation ComplicationsAF Ablation Complications� Mortality

� Death overall 0.7%

� Procedure-related 0%

� Vascular access <1%

� Periprocedural events

� TIA/Stroke 0.5%

� Cardiac tamponade 0.8%

� Pericardial effusion 0.6%

� PV stenosis 1.6%

� LA-esophageal fistula 0%

� Total= 4.9%

Calkins H: Circ Arrhy Electrophysiol 2009;2:349

SummarySummary

� AF is a common disorder whose incidence is expected to rise dramatically

� Stroke prevention is a critical component of management in patients with AF

� Anticoagulation is underutilized

� Even when utilized, current anticoagulant characteristics limit the ability to maintain patients within target range

� Emerging anticoagulant agents without some of these limitations may improve stroke prevention

� Rate control vs rhythm management based on clinical assessment

� AF ablation is a Rx option for highly symptomatic patients