Primary Care Update in Medicine

SCHOOL OF MEDICINE AND BIOMEDICAL SCIENCES DEPARTMENT OF MEDICINE

New Management Options for Patients with Atrial Fibrillation

Primary Care Update in Medicine January 31 – February 1, 2013

Anne B. Curtis, MD, FACC, FHRS, FACP, FAHA

Charles and Mary Bauer Professor,

Chair, University at Buffalo Department of Medicine

CEO and President, UB|MD Internal Medicine


• Advisory Board • Sanofi Aventis

• St. Jude Medical

• Biosense Webster

• Janssen Pharmaceuticals

• Bristol Myers Squibb

• Honoraria • Medtronic, Inc.

• St. Jude Medical

• Sponsored Research • Medtronic, Inc.

Disclosures


A 69 year old Caucasian female is referred from her

primary care physician’s office after she presented with

episodic palpitations and was found to have new onset

atrial fibrillation. She has a past medical history of

hypertension that is well controlled with lisinopril 10 mg

daily. There is no history of diabetes mellitus, prior

stroke or transient ischemic attack, or cardiovascular

disease. What are her CHADS2 and the CHA2DS2-VASc

scores?

a) 1 and 1

b) 1 and 2

c) 1 and 3

d) 1 and 4

Pre-Test Question #1.


What anti-thrombotic therapy would you

initiate to prevent a risk of stroke in this

patient?

a) None, her risk for stroke is low

b) Aspirin 325 mg daily

c) Aspirin 325 mg + clopidogrel 75 mg daily

d) Warfarin to maintain a therapeutic INR

between 2 and 3



• A 73 year old patient is referred for preoperative

evaluation for knee replacement surgery because

her ECG showed previously undiagnosed atrial

fibrillation.

• She denies cardiovascular symptoms, but she has

treated hypertension and a history of myocardial

infarction. There is no history of diabetes mellitus,

stroke or TIA, or bleeding problems. She denies illicit

drug or alcohol use.

• Her weight is 92.7 kg, Her serum creatinine is 3.2

mg/dl and estimated creatinine clearance is 14

ml/min; liver function is normal.

• The ECG shows AF with an average ventricular rate

of 75 bpm. Echocardiogram shows left ventricular

hypertrophy and left atrial enlargement.



Which anticoagulation strategy would you

recommend?

• a) Aspirin

• b) Warfarin

• c) Dabigatran

• d) Rivaroxaban


AF Prevalence Is Rapidly Increasing

Miyasaka et al. Circulation. 2006;114:119-125.

0

2

4

6

8

10

12

14

16

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

5.1

5.1 5.5

5.9

6.7

6.1 6.8

7.7

8.9

7.5 8.4

8.4

9.4

11.7

13.1

10.3 11.1

14.1

15.2 15.9

11.7 12.1

Pro

ject

ed

Nu

mb

er

of

Pe

rso

ns

W

ith

AF

(mill

ion

s)

Year

Current age-adjusted AF incidence

Increased age-adjusted AF incidence


The Consequences of AF Thromboembolism

Stroke: 4.5 increased risk

Microemboli: reduced cognitive function

Prothrombotic state

Mortality 2 increased risk independent of comorbid CV disease

Sudden death in HF and HCM

Hospitalizations Most common arrhythmia requiring hospitalization

2-3 increased risk for hospitalization

Impaired Hemodynamics

Loss of atrial kick

Irregular ventricular contractions

HF

Tachycardia-induced cardiomyopathy

Reduced QoL Palpitations, dyspnea, fatigue, reduced exercise tolerance

HCM=hypertrophic cardiomyopathy. Van Gelder et al. Europace. 2006;8:943-949; Narayan et al. Lancet. 1997;350:943-950; Wattigney et al. Circulation. 2003;108:711-716; Wyse et al. Circulation. 2004;109:3089-3095; Favale et al. PACE. 2003;26:637-639.

What Happens When AF Persists?

Structural Remodeling

Electro- physiologic

Remodeling

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


Greater SR Maintenance With Earlier Cardioversion

aP<.02. Dittrich et al. Am J Cardiol. 1989;63:193-197 (B).

1 Month

a

Pat

ien

ts in

SR

(%

)

AF Duration prior to cardioversion

6 Months

100

80

60

40

20

0

>12 months 3-12 months <3 months


Prevention of Stroke


CHADS2 CHA2DS2-VASc

Risk 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

Modification of Stroke Risk

Stratification in AF

Lip GY, Halperin JL. Am J Med 2010;123(6):84-488. Olesen JB, et al. Br Med J 2011;342:d124.

0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7

15.2

1.9 2.8 4.0 5.9 8.5

12.5 18.2

0 1 2 3 4 5 6 7 8 9

Annual Risk of Stroke (%)

Total Score CHA2DS2-VASc CHADS2

CHADS2

Score

CHA2DS2-VASc Risk

Intermediate High

0 39.5% 21.7%

1 - - - - - 92.7%


*HAS-BLED study has not yet been validated in other data sets; †Score of ≥3 indicates ‘high risk,’ and some caution

and regular patient review is needed following initiation of antithrombotic therapy.

INRs = international normalized ratios.

Camm AJ, et al. Eur Heart J. 2010;31(19):2369-2429. Pisters R. Chest. 2010;138:1093-1100. Lip GY, et al. Am J

Med. 2010;123(6):484-488.

HAS-BLED Bleeding Risk Score*

Maximum 9 points

1 or 2 Drugs or alcohol (1 point each)

D

1 Elderly (age >65 years)

E

1 Labile INRs L

1 Bleeding B

1 Stroke S

1 or 2 Abnormal renal and liver function (1 point each)

A

1 HTN H

Score

Clinical Characteristic Letter

.007 P-Value for Trend

1.56 48 3071 Any Score

0 9

0 8

0 7

0.0 0 2 6

12.50 1 8 5

8.70 4 46 4

3.74 7 187 3†

1.88 14 744 2

1.02 13 1286 1

1.13 9 798 0

Bleeds per 100

Patient-Years

Number of Bleeds

N

Risk Factors/ Score

— — — —

— —


ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. ACTIVE Investigators. Lancet. 2006;367:1903-1912. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-2078.

Antiplatelet Therapy in AF

ACTIVE-W: 6706 randomized patients;

trial stopped

6

4

0

2

Ou

tco

me/Y

ear

(%)

Stroke Vascular Event

Major Bleeding

5

3

1

P = .0003

P = .001 P = .53

Warfarin

Clopidogrel + ASA

ACTIVE-A: 7554 randomized patients;

median follow-up of 3.6 years 8

6

4

0

2 Ou

tco

me/Y

ear

(%)

Stroke Vascular Event

Major Bleeding

7

5

3

1

P = .01

P<.001

P<.001

ASA

Clopidogrel + ASA


Newer Anticoagulants

Ma TKW, et al. Pharmacology and Therapeutic 2010; doi;10.1016/j.pharmthera.2010.09.005

Novel Vitamin K Antagonist

ATI-5923

Activated Factor X Inhibitors

Apixaban

Betrixaban

Edoxaban (DU-176b)

TAK-442

Rivaroxaban

YMI 50

Direct Thrombin Inhibitors

Dabigatran Etexilate

AZD0837

MCC977

Warfarin, dabigatran, and rivaroxaban are FDA approved at the present time.

Extrinsic Pathway Activation Intrinsic Pathway Activation

Factor X Factor X Factor Xa

Prothrombin Thrombin

Fibrinogen Fibrin

Activated Factor X Inhibitors

Direct Thrombin Inhibitors

Warfarin


• Pro-drug converted to dabigatran via hepatic microsomal carboxylesterases

• 7% bioavailability (not meal dependent)

• 80% renally excreted

• T1/2 = 8-10 hours after single dose

(14-17 hours after multiple dosages)

• Related to aPTT (non-linear) and thrombin time and ecarin clotting time (both linear), but not INR

Dabigatran Etexilate: Pharmacokinetics


Stroke Prevention in AF Dabigatran Etexilate vs Warfarin (RE-LY)

*Noninferiority; †Superiority. MI = myocardial infarction; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy.

Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151. Connolly SJ, et al. N Engl J Med. 2011;363:1875-1876.

†P<.001

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Stroke/Systemic Embolism

Major Bleed Intracranial Hemorrhage

Pe

rce

nt/

Year

Dabigatran 110 mg is not FDA approved for this indication; for informational purposes only

MI

Dabigatran 150 mg

Warfarin INR 2.0-3.0

Dabigatran 110 mg P = .003

*P<.001

P<.001

P<.001

P=.09

Avg TTR: 67%


Warfarin (INR 2.0 to 3.0, target 2.5)* Dabigatran †

Any high-risk factor or more than 1 moderate-risk factor (Previous stroke, TIA or embolism, mitral stenosis, and Prosthetic heart valve*)

Aspirin 81 to 325 mg daily, or Warfarin (INR 2.0 to 3.0, target 2.5) Dabigatran†

One moderate-risk factor (Age ≥75 yrs, HTN, CHF, LVEF ≤35%, and diabetes)

Aspirin, 81 to 325 mg daily No risk factors

Recommended Therapy Risk Category

ACCF/AHA/HRS 2011 Focused Update to the Guidelines for Antithrombotic Therapy to

Prevent Stroke

*If mechanical valve, target INR >2.5. †Dabigatran is useful as an alternative to warfarin in patients with AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant

valve disease, severe renal failure, or advanced liver disease. LV = left ventricular; INR = international normalized ratio; TIA = transient ischemic attack.

Fuster V, et al. J Am Coll Cardiol 2006;48:e149-e246. Wann SL, et al. Heart Rhythm. 2011;8:e1-8.

ESC Guidelines use CHA2DS2-VASc, rather than CHADS2, risk stratification,

with score ≥2 requiring warfarin or dabigatran.


Characteristics of New and Investigational Oral Anticoagulants

Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban

Mechanism of action

Thrombin inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

T1/2 14-17 hours 5-9 hours 12 hours 19-24 hours 6-12 hours

Regimen BID QD, BID BID QD QD

Peak to trough

~7x 12x (QD) 3-5x ~3x ~3x

Renal excretion of absorbed drug

~80% 36%-45% 25%-30% ~15% 35%

Potential for drug interactions

P-glycoprotein inhibitor

CYP3A4 substrate and P-glycoprotein inhibitor


Not substrate for major CYPs


T1/2 = half-life; CYP3A4 = cytochrome P450 3A4. Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397. Piccini JP, et al. Curr Opin Cardiol. 2010;25(4): 312-320.


ROCKET AF:

Primary Efficacy and Safety Outcomes

*P<0.001 for noninferiority of rivaroxaban vs warfarin; †Superiority. Event rates are per 100 patient-years. Based on safety on treatment or ITT through site notification populations.

Patel MR, et a. N Engl J Med. 2011. Published online August 30, 2011.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

On Treatment ITT Major Bleeding IntracranialBleeding

Eve

nt

Rat

e /

10

0 P

t-Yr

s

Rivaroxaban*

Warfarin

Safety

†P=0.02

†P=0.12

†P=0.58

P=0.02

Stroke and Non-CNS Embolism

Rivaroxaban was recently approved by the FDA for stroke prevention in AF.


ARISTOTLE Trial: Efficacy and Safety Results

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Eve

nt

Rat

e /

10

0 P

t-Yr

s

Apixaban**

Warfarin

P=0.01

P=0.047 P < 0.001

*Net clinical outcomes: Stroke, system embolism, or major bleeding. **Apixaban is not FDA approved. Granger CB, et al. N Engl J Med. 2011. Published online August 30, 2011.

Stroke or Systemic Embolism

Death from Any Cause

ISTH Major Bleeding

Intracranial Bleeding

Net Clinical Outcomes*

P < 0.001

P < 0.001


“Before choosing rate control as a long-term strategy,

the clinician should consider how permanent AF is

likely to affect the patient in the future. RACE…and

AFFIRM…do not necessarily apply to younger patients

without heart disease or to patients whose dependency

upon sinus rhythm is likely to change appreciably over

time. This makes it important to ensure that a window of

opportunity to maintain sinus rhythm is not overlooked

early in the course of management of a patient with

atrial fibrillation.”

Rate vs Rhythm Control ACC/AHA/ESC

Fuster et al. J Am Coll Cardiol. 2006;48:854-906.


AFFIRM: Primary Endpoint All-Cause Mortality

Time (years)

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833 (A).

No. of deaths Number (%)

Rhythm: 0 80 (4) 175 (9) 257 (13) 314 (18) 352 (24)

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

30

25

20

15

10

5

0

0 1 2 3 4 5

Cu

mu

lati

ve M

ort

alit

y (%

) Rhythm control

P=.08

Rate control


AFFIRM: “On-Treatment” Post Hoc

SR

Warfarin

Digoxin

AADs

0.54 (0.42-0.70; P<.0001)

0.47 (0.36-0.61; P<.0001)

1.50 (1.18-1.89; P<.0001)

1.41 (1.10-1.83; P=.0005)

-54%

-47%

+50%

+41%

SR Is Associated With Better Survival

0 0.5 1 1.5 2

Other significant variables in model: age, CAD, CHF, smoking, stroke/TIA, LVEF, mitral regurgitation.

The AFFIRM Investigators. Circulation. 2004;109:1509-1513.

Risk Ratio


• Duration and patterns of AF

• Type and severity of symptoms

• Associated cardiovascular disease

• Potential for changes in cardiac function

over time

Clinical Considerations for Management

Strategy of Rate Versus



• Assessed patient and physician characteristics

associated with the choice of rate or rhythm control

strategy in hospital

• 155,731 hospitalizations from 464 hospitals

• 48% rhythm control

• 52% rate control

• Care by a noncardiologist and increasing age >65

years were associated with lower odds of rhythm vs

rate control (OR 0.33, 95% CI, 0.31 - 0.36 for family,

general, and internal medicine vs cardiology)

• Warfarin use was greater in the rhythm control group

compared with the rate control group

Rate vs Rhythm and Physician Characteristics

Lapointe et al. Am J Cardiol. 2008;101(8):1134-1141.


Rate Control


• Beta blockers

• Metoprolol

• Carvedilol

• Atenolol

• Calcium channel blockers

• Diltiazem

• Verapamil

• Digoxin

Agents for Heart Rate Control Nonacute and Chronic Maintenance



• Adequate rate control is critical to avoid

tachycardia-mediated cardiomyopathy

• 60-80 beats per minute at rest AND

• 90-115 beats per minute with exertion

• Criteria vary with age

• May be evaluated using 24-hour Holter

recording

What Is Adequate Rate Control?



• 614 patients with permanent AF

• Lenient rate control: resting heart rate <110 bpm (97.7%

met target)

• Strict rate control: resting heart rate <80 bpm and heart rate during moderate exercise <110 bpm (67% met

target)

• Primary outcome: composite of death from CV

causes, hospitalization for heart failure, and

stroke, systemic embolism, bleeding, and life-

threatening arrhythmic events

• Incidence of primary outcome at 3 years

• Lenient: 12.9%

• Strict: 14.9%

RACE II

Van Gelder IC et al., NEJM 2010;362:1363-73


• The mean (±SD) resting heart rate at the end of

dose-adjustment:

• Lenient control: 93±9 bpm in the

• Strict-control: 76±12 bpm (P<0.001)

• At the end of the follow-up period:

• Lenient-control: 85±14 bpm

• Strict-control group: 76±14 bpm (P<0.001)

RACE II

Van Gelder IC et al., NEJM 2010;362:1363-73


Rhythm Control


Pharmacologic Management of Patients With

Recurrent Paroxysmal Atrial Fibrillation Sinus Rhythm Maintenance

Recurrent Paroxysmal AF

Minimal or no symptoms

Anticoagulation and rate control

as needed

Disabling symptoms in AF

Anticoagulation and rate control

as needed

AAD therapy No drug for prevention of AF

AF ablation if AAD treatment fails Fuster et al. J Am Coll Cardiol. 2006;48:854-906.


A Safety-Driven Approach

*Within each box, drugs are listed alphabetically and not in order of suggested use. ACCF/AHA/HRS = American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society; CAD = coronary artery disease; ESC = European Society of Cardiology; LVH = left ventricular hypertrophy; NYHA = New York Heart Association. Wann LS, et al. Circulation. 2011:123:104-123. Camm AJ, et al. Eur Heart J. 2010:31;2369-2429.

2011 ACCF/AHA/HRS Guidelines: Antiarrhythmic Approaches to Maintain SR in Patients with Recurrent PAF or Persistent AF*

HF

Amiodarone Dofetilide

Maintenance of SR


Catheter ablation

Dronedarone Flecainide

Propafenone Sotalol

No (or minimal) heart disease


Propafenone Sotalol

Amiodarone

No Yes


Catheter ablation

Catheter ablation

HTN

Substantial LVH

CAD

Catheter ablation

Amiodarone Catheter ablation

Dofetilide Dronedarone

Sotalol


• Flecainide 300 mg orally (200 mg for <70 kg)

• Propafenone 600 mg orally (450 mg for <70 kg)

• Treatment was successful in 534 episodes

(94 percent)

• Time to resolution of symptoms was 113±84

minutes

• Among the 165 patients with recurrences,

the drug was effective during all the arrhythmic

episodes in 139 patients (84 percent)

Outpatient Treatment of Recent-Onset Atrial

Fibrillation with the “Pill-in-the-Pocket”

Approach

Alboni, P. et al., N Engl J Med 2004;351:2384-91.


Efficacy of AADs in AF Trials

*At 6 months; †Mean follow-up 7 months. CTAF = Canadian Trial of Atrial Fibrillation; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; DAFNE = Dronedarone Atrial Fibrillation Study after Electrical Cardioversion; EURIDIS = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; ADONIS = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter for the Maintenance of Sinus Rhythm; DIONYSOS = Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Dronedarone vs Amiodarone for at Least 6 Months for the Maintenance of Sinus Rhythm in Patients with AF. Courtesy of G Naccarelli, MD. Roy D, et al. Am J Cardiol. 1997;80:464-468. Singh BN, et al. N Engl J Med. 2005;352(18):1861-1872. AFFIRM Investigators. J Am Coll Cardiol. 2003;42:20-29. Touboul P, et al. Eur Heart J. 2003;24:1481-1487. Singh BN, et al. N Engl J Med. 2007;357(10):987-999. Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605.

100

80

60

40

20

100

Pati

en

ts i

n S

R a

t 1 Y

ear

(%)

CTAF SAFE-T AFFIRM DAFNE* EURIDIS* ADONIS EURIDIS/ ADONIS Pooled

DIONYSOS†

Dronedarone

Sotalol

Amiodarone

Class IC

Placebo

• De-iodinated amiodarone

analog

• Predictable

pharmacokinetics (T1/2 of

13-19 hrs; BID dosing)

• Hepatically cleared

• Low incidence of side

effects

• Low proarrhythmia (safe

to use as outpatient)

• No evidence of thyroid or

pulmonary toxicity but

rare cases of serious

hepatotoxicity

Dronedarone

Dronedarone

CH3SO2HN

O(CH2)3N

O

O

(CH2)3CH3

(CH2)3CH3

Amiodarone

O(CH2)2N

O

O

CH2CH3

CH2CH3

(CH2)3CH3

(CH2)3CH3

I

I

Kathofer S, et al. Cardiovasc Drug Rev. 2005;23(3):217-30. Hynes BJ, et al. Future Cardiol. 2005;1(2):135-144. US Food and Drug Administration. http://www.fda.gov/drugs/drugsafety/ucm240011.htm. Accessed March 10, 2011.


• Na channel blocker (10X stronger than amiodarone)

• Antiadrenergic effect (non-competitive βRc binding)

• Potassium channel blocker (IKr; IKs; IAch-Ado; IK1); (IAch-Ado 100X

stronger than amiodarone)

• Calcium channel blocker (ICa-L)

• Special considerations and contraindications

• Contraindicated in Class IV HF or lesser HF with recent

decompensation

• Potential liver toxicity/hepatic function impairment

• Drug interactions similar to amiodarone, except no significant

interaction with warfarin

• Exposure to dabigatran is higher when it is administered with

dronedarone

• Should not be used in permanent AF

Dronedarone: Pharmacological Effects

Patel C, et al. Circulation. 2009;120:636-644. Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2011.


ATHENA Primary Outcome: First

Cardiovascular Hospitalization or Death

Patients at Risk

Mean follow-up 21± 5 months. RRR = relative risk reduction. Hohnloser SH, et al. N Engl J Med. 2009;360:668-678.

Months

Components of End Point (as First Event)

Placebo (n=2327) n (%)

Dronedarone 400 mg BID (n=2301) n (%)

CV hospitalization 856 (36.8) 669 (29.1)

Death from any cause 57 (2.4) 58 (2.5)

Cu

mu

lati

ve In

cid

ence

(%

)

0

10

20

40

50

30

6 12 18 24 30 0

24% RRR Dronedarone

Placebo

HR=0.76 (95% CI: 0.68-0.83)

P<0.0001

Placebo 2327 1858 1625 1072 385 3

Dronedarone 2301 1963 1776 1177 403 2

Primary End Point: Reduction in CV Hospitalization or Death From Any Cause (Entirely Attributable to Effect on CV Hospitalization)


Analysis up to study discontinuation

Placebo (n=317)

Dronedarone 800 mg/d (n=310)

12 Number of patients who died 25

Relative risk (relative to placebo) 2.13

95% CI 1.071, 4.247

P value .02717

ANDROMEDA:

Study Primary Endpoint

• Primary endpoint

• The primary composite endpoint was all-cause mortality

or hospitalization for heart failure vs placebo

• Results

CI = confidence interval. Kober L, et al. NEJM 2008;358;2678-87.

The excess in mortality was primarily related to an excess of heart failure related deaths.


PALLAS Study Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy

• Hypothesis

• Dronedarone would reduce major vascular events in

high-risk permanent atrial fibrillation

• Methods/Inclusion criteria

• Patients > 65 years of age

• > 6-month history of permanent atrial fibrillation

• Risk factors for major vascular events

• Patients randomized to dronedarone 400 mg bid vs.

placebo

• Coprimary outcomes

• Stroke, MI, systemic embolism or CV death

• Unplanned CV hospitalization or death Connolly, SJ et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011; DOI: 10.1056/NEJMoa1109867. Published Nov 14, 2011. Accessed Nov 15, 2011.


PALLAS Trial:

Dronedarone in Permanent AF

Connolly, SJ et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011; DOI: 10.1056/NEJMoa1109867. Published Nov 14, 2011. Accessed Nov 15, 2011.

8.2

25.3

4.7 4.4

8.3

23.2

3.6

12.9

2.4 1.9

4.6

10.7

0

5

10

15

20

25

30

Stroke, MI,Systemic

Embolism, orCVD

Death orUnplanned CVHospitalization

Death Stroke Hospitalizationfor HF

HF Episode orHospitalization

Rat

e p

er

10

0 P

atie

nt-

Year

s

Dronedarone

Placebo

P=0.002

P<0.001

P=0.049

P=0.02

P<0.001

After PALLAS enrolled 3236 patients, the study was stopped for safety reasons.

P=0.02


CATHETER ABLATION


A Safety-Driven Approach

ACCF/AHA/HRS = American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society; CAD = coronary artery disease; ESC = European Society of Cardiology; LVH = left ventricular hypertrophy; NYHA = New York Heart

Association. Wann LS, et al. Circulation. 2011:123:104-123. Camm AJ, et al. Eur Heart J. 2010:31;2369-2429.

2011 ACCF/AHA/HRS Guidelines: Catheter Ablation is Still “Second Tier” Therapy

HF


Maintenance of SR


Catheter ablation


Propafenone Sotalol

No (or minimal) heart disease


Propafenone Sotalol

Amiodarone

No Yes


Catheter ablation

Catheter ablation

HTN

Substantial LVH

CAD

Catheter ablation

Amiodarone Catheter ablation

Dofetilide Dronedarone

Sotalol


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

• Symptomatic AF refractory or intolerant to at least

1 Class I or III AAD

• Selected symptomatic patients with HF and/or

reduced ejection fraction

• As an alternative to device implantation to support

AAD therapy in bradycardic patients

• Presence of an LA thrombus is a contraindication to

catheter ablation of AF

• Discontinuation of anticoagulation is not an

indication for ablation

Indications for Catheter AF Ablation


APAF = Ablation for Paroxysmal Atrial Fibrillation; CACAF = Catheter Ablation for the Cure of Atrial Fibrillation. Nair GM, et al. J Cardiovasc Electrophysiol. 2009;20(2):138-144.

Meta-Analysis of

Catheter Ablation vs Drug Therapy

Risk Lower Upper Study Name Ratio Limit Limit Z P Risk Ratio and 95% CI

Thai study 0.333 0.112 0.995 -1.970 .049

Natale et al 0.204 0.078 0.531 -3.259 .001

APAF study 0.187 0.113 0.307 -6.606 .000

CACAF study 0.483 0.366 0.638 -5.142 .000

Haissaguerre et al 0.258 0.161 0.416 -5.573 .000

Morady et al 0.618 0.387 0.987 -2.016 .044

0.331 0.217 0.505 5.131 .000

Statistics for Each Study

Favors Ablation

Favors Medical Therapy

0.1 0.2 0.5 1 2 5 10


Success Rates With Ablation Worldwide Survey

0

10

20

30

40

50

60

70

80

90

100

0-3 4-6 7-9 10-12 13-18 19-24 >24

Success without AADs Success with AADs Overall success

Cappato et al. Circulation. 2005;111:1100-1105(B).

Rat

es

(%)

Range of followup (months)


Effect of AF Ablation on LVEF and Chamber Size in Patient with and without Concurrent

Heart Disease and Rate Control

Hsu LF, et al. NEJM 2004; 351: 2373-2383.

LV E

nd

-Dia

sto

lic D

iam

ete

r (m

m)

Months

Ejection Fraction

LV ED Diameter

LV E

ject

ion

Fra

ctio

n (

%)

Months

70

65

60

55

50

45

40

35

30

25

0

0 1 3 6 12

0 1 3 6 12

LV E

ject

ion

Fra

ctio

n (

%)

Months

LV E

ject

ion

Fra

ctio

n (

%)

Months

70

65

60

55

50

45

40

35

30

25

0

0 12

0

Heart Disease

70

65

60

55

50

45

40

35

30

25

0

12

Rate Control

P < 0.001 P < 0.001 P < 0.001

P < 0.001

P=0.001 P=0.03 P=0.02 P=0.001

P < 0.001

P < 0.001

No Concurrent Heart Disease

Concurrent Heart Disease

P < 0.001

P < 0.001

Inadequate Rate Control

Adequate Rate Control

75

70

65

60

55

50

45

0


Complication Rates for Catheter Ablation

0.05

1.22

0.01 0.02

0.160.11

0.53

0.42

0.01 0.03

0

0.5

1

1.5Cappato et al. Circulation. 2005;111:1100-1105(B).

Pat

ien

ts (

%)


CABANA Trial

Packer. Presented at: 2005 Scientific Sessions of the American Heart Association; November 13-16, 2005; Dallas, TX(Ai).

Recent-onset AF

eligible for ablation

or drug therapy

65 years old or

< 65 years old with

1 risk factor for

CAD or stroke

Primary Ablation

(technique at

operator discretion)

Drug Therapy

(rate or rhythm control

[at operator discretion]

with anticoagulation)

Continued

Anticoagulation

Discontinued

Anticoagulation


• AF is a common disease that is increasing in

prevalence.

• Atrial electrical and structural remodeling takes

place early and progresses, making the return to

SR more difficult with longer duration of AF.

• Newer anticoagulants provide more options for

stroke prophylaxis in patients with AF

• Decisions about rate and rhythm control in AF

depend on the frequency of episodes and the

severity of patients’ symptoms.

• Catheter ablation is curative in many patients who

have failed antiarrhythmic drug therapy.

Summary


A 69 year old Caucasian female is referred from her

primary care physician’s office after she presented with

episodic palpitations and was found to have new onset

atrial fibrillation. She has a past medical history of

hypertension that is well controlled with lisinopril 10 mg

daily. There is no history of diabetes mellitus, prior

stroke or transient ischemic attack, or cardiovascular

disease. What are her CHADS2 and the CHA2DS2-VASc

scores? a) 1 and 1

b) 1 and 2

c) 1 and 3

d) 1 and 4

• CHADS2 score of 1: Hypertension

• CHA2DS2-VASc score of 3: hypertension, female, and

age between 65 to 74 years

Post-Test Question #1.


What anti-thrombotic therapy would you

initiate to prevent a risk of stroke in this patient?

a) None, her risk for stroke is low

b) Aspirin 325 mg daily

c) Aspirin 325 mg + clopidogrel 75 mg daily

d) Warfarin to maintain a therapeutic INR

between 2 and 3

Although her CHADS2 score is 1, her CHA2DS2-

VASc score is 3. This gives her a stroke risk of

3.2%, that is best minimized with warfarin.



• A 73 year old patient is referred for preoperative evaluation for

knee replacement surgery because her ECG showed previously

undiagnosed atrial fibrillation.

• She denies cardiovascular symptoms, but she has treated

hypertension and a history of myocardial infarction. There is no

history of diabetes mellitus, stroke or TIA, or bleeding problems.

She denies illicit drug or alcohol use.

• Her weight is 92.7 kg, Her serum creatinine is 3.2 mg/dl and estimated creatinine clearance is 14 ml/min; liver function is

normal.

• The ECG shows AF with an average ventricular rate of 75 bpm.

Echocardiogram shows left ventricular hypertrophy and left

atrial enlargement.



Which anticoagulation strategy would you

recommend?

a) Aspirin

b) Warfarin

c) Dabigatran

d) Rivaroxaban

Both dabigatran and rivaroxaban are cleared

by the kidneys and should be avoided when

creatinine clearance is less than 15 ml/min.

Primary Care Update in Medicine

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