Session 11 - pri-med.com Files/Syllabus Files... · Session 11 Session 11: Heart to Heart: An AF Outcomes Initiative An Interactive Case-Based Discussion of AF Management Agenda –

Session 11

Session 11: Heart to Heart: An AF Outcomes Initiative An Interactive Case-Based Discussion of AF Management Agenda – Faculty Panels Guidelines, Pathophysiology, and Clinical Considerations for Outcomes-Based Patient Management of AF Improving Therapeutic Options: Will Emerging Options Improve Outcomes? Question-and-Answer Session Learning Objectives

• Stratify patients with atrial fibrillation (AF) and with and without concomitant heart failure for rate vs rhythm control strategies and associate patients with the appropriate treatment options based on guideline recommendations.

• Appropriately risk-stratify and discuss factors involved in anticoagulation treatment decisions for AF patients. Faculty Augustus Grant, MD, PhD Professor of Medicine Vice Dean, School of Medicine Duke University Durham, North Carolina Dr Grant is a professor of medicine at the Duke University Medical Center. He was born in Jamaica, West Indies. He received his undergraduate and medical degrees from the University of Edinburgh in Scotland and immigrated to the United States for his doctorate in pharmacology at the University of California at San Francisco. He completed a medical residency at the University of Manitoba, Canada, and came to Duke University in 1977 as a fellow in cardiology. He joined the faculty in 1980 on completion of his fellowship. In 1986-1987 he was an Alexander von Homboldt fellow at the University of Saarland in Germany. He is certified by the British Medical Council, the American Board of Internal Medicine, and the subspecialty board of cardiovascular disease. Dr Grant is a fellow of the American College of Cardiology and the American Heart Association. He served as the president of the Association of Black Cardiologists from 1992 to 1994. He is a past president of the American Heart Association. He has served on the board of directors of the Heart Rhythm Society and on the board of the Stanley Sarnoff Foundation. He serves on the editorial boards of Circulation and the Journal of Molecular and Cellular Cardiology. He is currently deputy editor of the Journal of Cardiovascular Electrophysiology and a consulting editor to the American Journal of Physiology. He has received numerous awards and belongs to several other professional societies including the Biophysical Society and the American Society for Clinical Investigation. Dr Grant’s research and clinical interests include the mechanism of action of antiarrhythmic drugs, cardiac electrophysiology, and management of patients with cardiac arrhythmias. He has published 103 peer-reviewed manuscripts. Dr Grant assumed the position of vice dean in the Duke University School of Medicine on July 1, 2007. P. Gearoid O’Neill, MD Associate Clinical Professor of Medicine University of California, Davis, School of Medicine Director, Cardiac Electrophysiology Services Mercy General Hospital Sacramento Dr O’Neill is director of the Cardiac Electrophysiology Services at Mercy General Hospital in Sacramento, California. He is also an associate clinical professor of medicine at the University of California in Sacramento. Dr O’Neill received his medical degree from the University College in Galway, Ireland. He completed his residency in internal medicine at Baylor College of Medicine in Houston, Texas, where he also completed fellowships in cardiology, interventional cardiology, and electrophysiology. Dr O’Neill belongs to several professional societies including the American Heart Association and the Heart Rhythm Society, and he is a fellow of the American College of Cardiology. He is a peer reviewer for PACE and has published over 30 manuscripts for several prominent journals. He has also lectured internationally on the subject areas of cardiology and cardiac electrophysiology. Faculty Financial Disclosure Statements The presenting faculty report the following:

Dr Grant is on the speakers bureaus of Boston Scientific Corporation; Medtronic, Inc.; and St Jude Medical, Inc. Dr O’Neill has no financial relationships to disclose. Education Partner Financial Disclosure Statement The content collaborators at the Academy for Healthcare Education, Inc. report the following: Robbin Moisa, MD, has no financial relationships to disclose. Drug List Generic Trade Generic Trade amiodarone Cordarone, Pacerone flecainide Tambocor aspirin various ibutilide Corvert clopidogrel Plavix phenprocoumon Liquamar digoxin Lanoxicaps, Lanoxin propafenone Rythmol disopyramide Norpace quinidine various dofetilide Tikosyn sotalol Betapace, Sorine enoxaparin Lovenox warfarin Coumadin Investigational AVE-0118 idraparinux vernakalant apixaban odiparcil dronedarone ATI-2042 piboserod ximelagatran AZD-7009 rivaroxaban dabigatran azimilide tedisamil aminocyclohexyl ether celivarone CVT-150 ZP-123 (GAP 486) Suggested Reading List ACTIVE Writing Group on behalf of the ACTIVE Investigators; Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005;111(9):1100-1105. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation. 2006;114(7):e257-354. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501. Krahn AD, Manfreda J, Tate RB, et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med. 1995;98(5):476-484. McNamara RL, Tamariz LJ, Segal JB, et al. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography [Review]. Ann Intern Med. 2003;139(12):1018-1033. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114(2):119-125. Waktare JE, Camm AJ. Acute treatment of atrial fibrillation: why and when to maintain sinus rhythm [Review]. Am J Cardiol. 1998;81(5A):3C-15C. Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833.

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1

Affairs of the Heart: An AF Outcomes Initiative

Affairs of the Heart: An AF Outcomes Initiative

2008 Pri-Med Updates for Cardiologists

Gearoid O’Neill, MDAssociate Professor of Medicine

University of California Davis School of Medicine

Director Electrophysiology and Pacing

Mercy General HospitalSacramento, CA

Augustus Grant, MD, PhD Professor of Medicine

Vice Dean School of Medicine

Duke University Durham, North Carolina

IntroductionIntroduction

Augustus Grant, MD, PhD

•• Affects 2.5 million patients in United States and 4.5 Affects 2.5 million patients in United States and 4.5 million in Europemillion in Europe

•• Lifetime risk of AF at age 40 is 1:4Lifetime risk of AF at age 40 is 1:4

•• Associated with increase in aging and chronic heart Associated with increase in aging and chronic heart diseases such as heart failure (HF), hypertension, diseases such as heart failure (HF), hypertension, atherosclerosis, diastolic dysfunctionatherosclerosis, diastolic dysfunction

•• Also associated with inflammation and diabetesAlso associated with inflammation and diabetes

•• May induce May induce hypercoagulablehypercoagulable statestate

Go et al. Go et al. JAMAJAMA. 2001;285:2370. 2001;285:2370--2375; ACC/AHA/ESC 2006 guidelines for the management of patients2375; ACC/AHA/ESC 2006 guidelines for the management of patients with with atrial fibrillation. atrial fibrillation. J Am Coll J Am Coll CardiolCardiol.. 2006;48:8542006;48:854--906; 906; LloydLloyd--Jones et al. Jones et al. CirculationCirculation. 2004;110:1042. 2004;110:1042--1046; 1046; Wyse et al. Wyse et al. CirculationCirculation. 2004;109:3089. 2004;109:3089--3095; Thom et al. 3095; Thom et al. Circulation.Circulation. 2006;113:e852006;113:e85--e151; Peters et al. e151; Peters et al. LancetLancet. . 2002;359:5932002;359:593--603.603.

The Disease of AF The Disease of AF The Consequences of AFThe Consequences of AFThromboembolismThromboembolism

•• Stroke: 4.5Stroke: 4.5×× increased riskincreased risk•• MicroemboliMicroemboli: reduced : reduced

cognitive functioncognitive function•• Prothrombotic stateProthrombotic state

MortalityMortality•• 22×× increased risk independent increased risk independent

of of comorbidcomorbid CV diseaseCV disease•• Sudden death in HF and HCMSudden death in HF and HCM

HospitalizationsHospitalizations•• Most common arrhythmia Most common arrhythmia

requiring hospitalizationrequiring hospitalization•• 22--33×× increase risk for increase risk for

hospitalizationhospitalization

Impaired Hemodynamics• Loss of atrial kick• Irregular ventricular

contractions• HF• Tachycardia-induced

cardiomyopathyReduced QoL

• Palpitations, dyspnea, fatigue, reduced exercise tolerance

Van Van GelderGelder et al. et al. EuropaceEuropace. 2006;8:943. 2006;8:943--949; 949; NarayanNarayan et al. et al. Lancet.Lancet. 1997;1997;350:943350:943--950; 950; WattigneyWattigney et al. et al. CirculationCirculation. 2003;108:711. 2003;108:711--716; Wyse et al. 716; Wyse et al. CirculationCirculation. 2004;109:3089. 2004;109:3089--3095; 3095; FavaleFavale et al. et al. PACEPACE. 2003;26:637. 2003;26:637--639.639.

CV Events in AF PatientsCV Events in AF Patients

aaRRRR adjusted by all the variables using COX regression analysis.adjusted by all the variables using COX regression analysis.CI=confidence interval.CI=confidence interval.RuigRuigóómezmez et al. et al. IntInt J J CardiolCardiol. 2008. doi:10.106/j.ijcard.2008.04.050.. 2008. doi:10.106/j.ijcard.2008.04.050.

0 2 4 6 8 10

7.4 (5.7-9.8)Chronic atrial fibrillation

4.2 (2.7-6.5)Paroxymal atrial fibrillation

6.4 (5.0-8.3)Atrial fibrillation groupHeart Failure



2.1 (1.6-2.9)Atrial fibrillation groupCoronary Event



3.0 (2.3-4.0)Atrial fibrillation group

Relative Riska

(95% CI)Ischemic Cerebrovascular Event

Age (years)

Prev

alen

ce p

er 1

0,00

0 Pe

rson

s

Hospitalizations for AFNational Hospital Discharge SurveyHospitalizations for AFNational Hospital Discharge Survey

WattigneyWattigney et al. et al. CirculationCirculation. 2003;108:711. 2003;108:711--716.716.

Year1985 1987 1989 1991 1993 1995 1997 1999

0

20

40

60

80

100

120

140

35 to 5455-6465-7475-8485+

2

AF Adversely Affects QoLAF Adversely Affects QoL

aP<.05, patients with AF compared to healthy controls; bP<.05, patients with AF compared to those with CAD.Dorian et al. J Am Coll Cardiol. 2000;36:1303-1309 (B).

Higher scores = better QoL

AF vs CAD vs healthy controls

a

SF-3

6 Sc

ore

a

a a a a a b a

a b

a

0

20

40

60

80

100

General Health Physical Function Social Function Mental Health

AF CAD Controls

AF Prevalence Is Increasing RapidlyAF Prevalence Is Increasing RapidlyAF Prevalence Is Increasing Rapidly

MiyasakaMiyasaka et al. et al. CirculationCirculation. 2006;114:119. 2006;114:119--125.125.

00

22

44

66

88

1010

1212

1414

1616

20002000 20052005 20102010 20152015 20202020 20252025 20302030 20352035 20402040 20452045 20502050

5.15.1

5.15.1 5.55.5

5.95.96.76.7

6.16.16.86.8

7.77.78.98.9

7.57.58.48.4

8.48.4

9.49.4

11.711.713.113.1

10.310.311.111.1

14.114.115.215.2

15.915.9

11.711.7 12.112.1

Proj

ecte

d N

umbe

r of P

erso

ns

Proj

ecte

d N

umbe

r of P

erso

ns

With

AF

(mill

ions

)W

ith A

F (m

illio

ns)

YearYear

Current ageCurrent age--adjusted AF incidenceadjusted AF incidenceIncreased ageIncreased age--adjusted AF incidenceadjusted AF incidence

•• 6666--yearyear--old woman with history of atypical chest old woman with history of atypical chest pain who has had 6 weeks of fatigue, intermittent pain who has had 6 weeks of fatigue, intermittent shortness of breath, and palpitationsshortness of breath, and palpitations

•• AF diagnosed on office ECG; ventricular rate AF diagnosed on office ECG; ventricular rate mean 114 bpmmean 114 bpm

•• Anticoagulated with warfarin, sotalol started and Anticoagulated with warfarin, sotalol started and titrated to 120 mg bid; and cardioverted to SR titrated to 120 mg bid; and cardioverted to SR

•• Intermittent palpitations became more frequentIntermittent palpitations became more frequentand very bothersomeand very bothersome

•• Visit EP for second opinionVisit EP for second opinion

Case 1Case 1 Case 1 — 2nd OpinionCase 1 — 2nd Opinion

• Echo: LVEF 45%; LA 4.5 cm, no LVH

• Recent nuclear stress test with inferior wall reduced uptake

• Performed ECG—AF 107 bpm at rest

• Current symptoms− Palpitations, fatigue, shortness of breath

on exertion

• What do you do?

Your Primary Strategy for Long-termManagement Will Be…Your Primary Strategy for Long-termManagement Will Be…

?

1. Rate control2. Rhythm control

Causes of AF: Expanding Etiologies, Diminishing “Lone AF”Causes of AF: Expanding Etiologies, Diminishing “Lone AF”1. Usual etiologies

− MV disease− Ischemic/infarcted LV− HF− HCM− Hypertension− Alcohol− Hyperthyroidism− Others

2. Other etiologies to consider− Sleep apnea− Obesity− Inflammation− Extreme sports/exercise− Latent hypertension− Genetic factors

Schoonderwoerd et al. Europace. 2008;10:668-673.

3

Permanent

Persistent

Paroxysmal

Reentrant Circuits• APBs• Bradycardia

• Tachycardia• Others

Clinical PerspectiveClinical Perspective

Wyse. Wyse. CirculationCirculation. 2004;109:3089. 2004;109:3089--3095.3095.

Trigger/Initiation

Substrate/Maintenance

Rel

ativ

e Im

port

ance

Duration of AF

ModulatingFactors

Modulating Factors for AFModulating Factors for AF

Wyse. Wyse. CirculationCirculation. 2004;109:3089. 2004;109:3089--3095.3095.

ModulatingFactors

Endothelial DysfunctionEndothelial Dysfunction• Atherosclerosis

InflammationInflammation•• PericarditisPericarditis•• Cardiac surgeryCardiac surgery•• Interleukin 6Interleukin 6•• CC--reactive proteinreactive protein

ANSANS•• VagalVagal•• AdrenergicAdrenergic

HormonalHormonal•• ThyroidThyroid•• DiabetesDiabetes

MiscellaneousMiscellaneous•• ObesityObesity•• Sleep apneaSleep apnea

Coagulation FactorsCoagulation Factors

Non-Correctable• Genetic factors• Age/senescence

Correctable

Atrial & PV StretchAtrial & PV Stretch•• HypertensionHypertension•• LV dysfunctionLV dysfunction•• Mitral stenosisMitral stenosis•• Aortic stenosisAortic stenosis

What Happens When AF Persists?What Happens When AF Persists?

StructuralRemodeling

Electro-physiologicRemodeling

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

ADP=action potential duration; WL=wavelength; AFCI=AF cycle lengADP=action potential duration; WL=wavelength; AFCI=AF cycle length.th.Allessie et al. Allessie et al. CardiovascCardiovasc ResRes. 2002;54:230. 2002;54:230--246.246.

Three Proposed Positive FeedbackLoops of Atrial Remodeling on AFThree Proposed Positive FeedbackLoops of Atrial Remodeling on AF

ElectricalElectrical

ContractileContractile StructuralStructural

AFAF

AFCI AFCI ↓↓ θθ ↓↓

WL WL ↓↓APD APD ↓↓

CaCa++++

ChannelsChannelsCircuitCircuitSizeSize ZigZig--ZagZag

ConductionConduction

AnisotropyAnisotropy

FibrosisFibrosis

ConnexinsConnexins

Dilatation Dilatation

Compliance Compliance ↑↑

Contractility Contractility ↓↓

CytosolicCytosolic ↓↓CaCa++++ Stretch Stretch

Timeline of AF RemodelingTimeline of AF Remodeling

Prystowsky EN. Prystowsky EN. J J CardiovascCardiovasc ElectrophysiolElectrophysiol. 2008;19:575. 2008;19:575--582.582.

I. Paroxysmal AF Persistent AF: Triggered AF (seconds/minutes)

Normal/Abnormal

AbnormalAbnormal

Normal

II. Paroxysmal AF Persistent AF: Triggered AF - 1°Substrate - 2°(minutes/hours)

III. Persistent AF Cardioversion IRAF:Triggered/Substrate AF

IV. Persistent AF Cardioversion SR:Substrate AF

RALA

RALA

RALA

RALA

Greater SR Maintenance With Earlier CardioversionGreater SR Maintenance With Earlier Cardioversion

aaPP<.02.<.02.DittrichDittrich et al. et al. Am J Am J CardiolCardiol. 1989;63:193. 1989;63:193--197.197.

One Month

a

Patie

nts

in S

inus

Rhy

thm

(%) AF Duration prior to cardioversion

Six Months

100

80

60

40

20

0

>12 months3-12 months<3 months

4

What Are the Goals of AF Therapy?What Are the Goals of AF Therapy?

• Improve survival

• Reduce sequelae− Stroke

• Reduce hospitalizations

• Improve symptoms

• Improve QoL

• Restore atrial function/reverse the remodeling process

Ref

ract

ory

Perio

d (m

s)R

efra

ctor

y Pe

riod

(ms)

00 11 22 33 44 55 66 77 88 99 1010

8080

100100

120120

140140

Refractory Refractory PPerioderiod

Work Work IIndexndex

00

55

1010

1515

Atr

ial W

ork

Atr

ial W

ork

II nde

xnd

ex(m

m(m

m22 H

g)Hg)

Time (days)Time (days)

AFAF

Schotten et al. Schotten et al. CirculationCirculation. 2003;. 2003;107:1433107:1433--1439.1439.

Electrical Remodeling CorrelatesWith Atrial FunctionElectrical Remodeling CorrelatesWith Atrial Function

ConversionConversion SR SR






• Improve QoL


QoL Improvement With Restoration of SR SAFE-T Study: Symptomatic PatientsQoL Improvement With Restoration of SR SAFE-T Study: Symptomatic Patients

SR vs AF comparisons on mean changes in QoL scores from baseline to 8 weeks by presence of AF symptoms. aP=.05; bP=.01; cP=.001. (A) Symptomatic patients. (SR group: n=167; AF group: n=179). SCL=symptom checklist; SF-36=Short Form-36.Singh et al. J Am Coll Cardiol. 2006;48:721-730.

SF-36 physical functionSF-36 role-physical

SF-36 general healthSF-36 vitality

SF-36 body painSF-36 social function

SF-36 role-emotionSF-36 mental health

SCL frequencySCL severity

Specific Activity ScaleAF burden

Negative Change Positive Change

SRAF

c

a

a

-6 -4 -2 0 2 4 6 8 10 12 14

a

b

b

b

QoL Improvement With Restoration of SR SAFE-T Study: Asymptomatic PatientsQoL Improvement With Restoration of SR SAFE-T Study: Asymptomatic Patients

SR versus AF comparisons on mean changes in QoL scores from baseline to 8 weeks by presence of AF symptoms. aP=.05; bP=.01; cP=.001. (B) Asymptomatic patients (SR group: n=116; AF group: n=92). Singh et al. J Am Coll Cardiol. 2006;48:721-730.

-6 -4 -2 0 2 4 6 8 10 12 14

SF-36 physical functionSF-36 role-physical

SF-36 general healthSF-36 vitality

SF-36 body painSF-36 social function

SF-36 role-emotionSF-36 mental health

SCL frequencySCL severity

Specific Activity ScaleAF burden

SRAF

c

a

b

a

Long-term Maintenance of SR Improves Functional Capacity: AFFIRMLong-term Maintenance of SR Improves Functional Capacity: AFFIRM

• Mean New York Heart Association functional class (NYHA-FC) score significantly better at each visit in patients in SR

Chung et al. J Am Coll Cardiol. 2005;46:1891-1899.

Months Years

0.500.450.400.350.300.250.200.150.100.05

0

Mea

n N

YHA

-FC

Sco

re

(Lower NYHA-FC score=less symptomatic)Adjusted P<.0001

Initial 2 4 8 1 1⅓ 1⅔ 2 2⅓ 2⅔ 3 3⅓ 3⅔ 4 4⅓ 4⅔ 5

Current AFNo current AF

5

Incr

ease

in D

urat

ion

(sec

onds

)

SR AF

Maximal Exercise Duration During SR vs AFMaximal Exercise Duration During SR vs AF

Singh et al. J Am Coll Cardiol. 2006;48:721-730 (B).

SAFE-T: Sotalol Amiodarone AF Efficacy Trial

0

20

40

60

80

100

8 Weeks 1 Year

P=.01P=.02






• Improve QoL


Clinical Trials in AF TherapyClinical Trials in AF Therapy

Gearoid O’Neill, MD

Evidence for Survival Benefit of SREvidence for Survival Benefit of SR

Pedersen et al.Pedersen et al. Circulation. Circulation. 2001;104:2922001;104:292--296.296.

Survival rates of patients treated with dofetilide (A) placebo (B) who converted or did not convert to SR1.00.80.60.40.20.0Pr

obab

ility o

f Sur

vival (A) Dofetilide Group

0Time (months)

6 12 18 24 30 36 42 48

SRNot SR

1.00.80.60.40.20.0Pr

obab

ility o

f Sur

vival (B) Placebo Group

0Time (months)

6 12 18 24 30 36 42 48

SRNot SR

Evidence BasedEvidence BasedSR vs AF in Clinical TrialsSR vs AF in Clinical Trials

• PIAF Pharmacological Intervention in AtrialFibrillation (pilot)

• STAF STrategies in Atrial Fibrillation (pilot)

• AFFIRM Atrial Fibrillation Follow-upInvestigation of Rhythm Management

• RACE RAte Control versus Electrical Cardioversion for Persistent AtrialFibrillation

• HOT CAFE How to Treat Chronic Atrial Fibrillation)

5 prospective, 5 prospective, randomized,randomized, controlled trials comparingcontrolled trials comparingtwo different treatment strategiestwo different treatment strategies

The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825. 2002;347:1825--1833; Waldo. 1833; Waldo. Am J CardiolAm J Cardiol. 1999;84:698. 1999;84:698--700.700.

Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) StudyAtrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study

• Long-term treatment of chronic and paroxysmal AF• Patients ≥65 years of age or other risk factor

for stroke with − AF ≥6 hours in past 6 months− Not continuous AF for ≥6 months− ≥1 episode documented by ECG in past 12 weeks− ≥1 risk factor for stroke (age ≥65 years)

• Randomized to rate vs rhythm control− Patients required to be able to tolerate AF, therefore,

patients were a relatively asymptomatic group

• Both groups anticoagulated

6

AFFIRM: Primary End Point All-Cause MortalityAFFIRM: Primary End Point All-Cause Mortality

Time (years)

The AFFIRM Investigators. The AFFIRM Investigators. N Engl J MedN Engl J Med. 2002;347:1825. 2002;347:1825--1833.1833.

No. of deathsNo. of deaths Number (%)Number (%)Rhythm:Rhythm: 00 80 (4)80 (4) 175 (9)175 (9) 257 (13)257 (13) 314 (18)314 (18) 352 (24)352 (24)Rate:Rate: 00 78 (4)78 (4) 148 (7)148 (7) 210 (11)210 (11) 275 (16)275 (16) 306 (21)306 (21)

3030

2525

2020

1515

1010

55

00

00 11 22 33 44 55

Cum

ulat

ive

Mor

talit

y (%

)C

umul

ativ

e M

orta

lity

(%) Rhythm controlRhythm control

PP=.08=.08

Rate controlRate control

AFFIRM ResultsAFFIRM Results

AADs are associated with increased events when SR is removed from the analysis. Thus, AAD toxicity is counterbalanced by the improved outcome of SR and offsets the benefit of SR.

Corley et al. Corley et al. CirculationCirculation. 2004;109:1509. 2004;109:1509--1513.1513.

AAD use

Digoxin use

Warfarin use

SRTime dependent

Covariate

.0005

.0007

<.0001

<.0001

P Value

0 0.5 1 1.5 2 2.5

HR 99% CIHR 99% CI

Rhythm Control vs Rate ControlPIAF, STAF, RACE, AFFIRM

Rhythm Control vs Rate ControlPIAF, STAF, RACE, AFFIRM • These trials indicate that both strategies are acceptable

but…

• They do not apply to all patients with AF− Particularly to very symptomatic patients − Young patients for whom exercise tolerance

is important− Patients in whom rate control failed− Patients with paroxysmal AF− Patients with depressed LV function

• The clinician should adapt the therapeutic strategy to each individual patient

Position StatementRate vs Rhythm (ACC/AHA/ESC)Position StatementRate vs Rhythm (ACC/AHA/ESC)

• “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.”

ACC/AHA/ESC 2006 guidelines for the management of patients with ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. atrial fibrillation. J Am Coll J Am Coll CardiolCardiol.. 2006;48:8542006;48:854--906.906.

Rate vs Rhythm and Physician CharacteristicsRate vs Rhythm and Physician Characteristics

• 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

Allen Allen LapointeLapointe et al. et al. Am J Am J CardiolCardiol. 2008;101(8):1134. 2008;101(8):1134--1141.1141.

Your Primary Strategy for Long-termManagement Will Be…Your Primary Strategy for Long-termManagement Will Be…

?

1. Rate control2. Rhythm control

7

Questions Regarding Rate- vs Rhythm-Control Strategies and OutcomesQuestions Regarding Rate- vs Rhythm-Control Strategies and Outcomes• Does the risk of the antiarrhythmic outweigh the

benefit of SR?

• Would a better AAD (more effective, less toxic) change the balance in favor of SR?

• Will ablation change the balance in favor of SR?

SR Might Demonstrate Improved Morbidity and Mortality if More Effective and Safer Antiarrhythmics Were Available.

SR Might Demonstrate Improved Morbidity and Mortality if More Effective and Safer Antiarrhythmics Were Available.

?

1. Strongly agree2. Agree3. Disagree4. Strongly disagree






• Improve QoL


Anticoagulation in AFStroke Risk ReductionsAnticoagulation in AFStroke Risk Reductions

Hart et al. Hart et al. Ann Intern MedAnn Intern Med. 1999;131:492. 1999;131:492--501.501.

Warfarin BetterWarfarin Better Control BetterControl Better

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

100%100% 50%50% 00 --50%50% --100%100%

Reduction of Reduction of strokestroke

RRR 62% RRR 62%

Reduction ofReduction ofallall--cause mortality cause mortality

RRR 26%RRR 26%

All trials=6All trials=6

CHADS2 Risk Stratification SchemeCHADS2 Risk Stratification Scheme

Risk Factors ScoreC Recent CHF 1

H Hypertension 1

A Age ≥75 years 1

D Diabetes mellitus 1S2 History of stroke or transient ischemic

attack (TIA) 2

RocksonRockson et al. et al. J Am Coll J Am Coll CardiolCardiol.. 2004;43:9292004;43:929--935.935.

Stroke Risk in New-Onset AFACP/AAFP GuidelinesStroke Risk in New-Onset AFACP/AAFP Guidelines

Moderate5.9 (4.6-7.3)3

High8.5 (6.3-11.1)4

High12.5 (8.2-17.5)5

High18.2 (10.5-27.4)6

Low1.9 (1.2-3.0)0

Moderate4.0 (3.1-5.1)2

Low2.8 (2.0-3.8)1

CHADS2Risk Level

Adjusted Stroke Rateb

(95% CI)CHADS2

a

Score

aaAssessmentAssessment of the following comorbidities: CHF, hypertension, age of the following comorbidities: CHF, hypertension, age ≥≥75, and diabetes 75, and diabetes (1 point each); history of stroke or TIA (2 points each). (1 point each); history of stroke or TIA (2 points each). bExpected rate of stroke per 100 patient-years.Snow et al. Ann Intern Med. 2003;139:1009-1017.

WarfarinWarfarin

8

Stroke Risk in AFFIRM Rate and Rhythm Control ArmsStroke Risk in AFFIRM Rate and Rhythm Control Arms

aaEventEvent rates derived from Kaplanrates derived from Kaplan--Meier analysis, Meier analysis, PP=.79.=.79.AFFIRM Investigators. AFFIRM Investigators. N Engl J Med.N Engl J Med. 2002;347:18252002;347:1825--1833.1833.

25 (37)42 (69)AF at time of event

17 (22)23 (36)INR <2.0

44 (57)25 (33)Not taking warfarin

16 (21)23 (31)INR ≥2.0

80 (7.1)77 (5.5)Ischemic strokea

Rhythm Controln (%)

Rate Controln (%)

What If:Same patient (66-year-old woman with AF, HR 107 bpm, symptomatic) has nonischemic cardiomyopathywith EF 28% on ACEI and BB.

What would your approach be?



?

1. Rate2. Rhythm

Risk of AF in HF PatientsRisk of AF in HF Patients

0 10 20 30 40 50

SOLVD (II-III)

V-HeFT (II-III)

CHF-STAT (II-III)

ATLAS (III)

DIAMOND-CHF (II-III)

GESICA (II-IV)

CONSENSUS (IV)

Prevalence of AF (%)

Ehrlick et al. J Cardiovasc Electrophysiol. 2002;13(4):399-405 (B).

In HF, new AF occurs at a rate of 6%-8%/year

Overall, AF is present in >15% of HF patients

Dries et al. J Am Coll Cardiol. 1998;32(3):695-703 (B).

SOLVD: Influence of AF on MortalitySOLVD: Influence of AF on MortalityAll-Cause Mortality (%)

AFSR

0

40

60

80

100

20

3650 770 1095 1460

P<.001

Surv

ival

(%)

Death or Hospitalization for HF (%)

100

3650 770 1095 1460

P<.001

0

40

60

80

20Su

rviv

al (%

)

DaysDays

Effect of AF on Sudden Death in HFMADIT II and AVID Studies – Post-Hoc AnalysisEffect of AF on Sudden Death in HFMADIT II and AVID Studies – Post-Hoc Analysis

Wyse et al. J Interven Cardiol Electrophysiol. 2001;5:276-273; Zareba et al. Heart Rhythm. 2006;3:631-637.

AVIDMADIT IIMADIT II

P<.01

Years

Unadjusted P=.001

0.00.20.40.60.81.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0Years

0.0 0.5 1.0 1.5 2.0 2.5 3.00.00.20.40.60.81.0

Prob

abilit

y of D

eath

Unadjusted P=.004AF

P=.03Sinus 1.0

0.90.80.70.60.50.40.30.20.10.0

Years

Surv

ival

0 41 2 3

Unadjusted P=.01Adjusted P=.02

AF Non-AF

Prob

abilit

y of C

HF

Hosp

italiz

atio

n or

Dea

th

AF-CHF TrialAF-CHF Trial

Atrial Fibrillation and Congestive Heart Failure (AFAtrial Fibrillation and Congestive Heart Failure (AF--CHF) Trial. CHF) Trial. Am Heart JAm Heart J. 2002;144(4):597. 2002;144(4):597--607.607.

Follow-up 2 years, clinic visits every 4 monthsOptimal CHF management with ACEI and BB

Study DesignAF-CHF

Rhythm control Rate control

Antiarrhythmic drug and/or non-pharmacologic therapy in resistant

patients

Cardioversion if needed

Pharmacologic dosing adjustment

AF nodal ablation for patients with inadequate rate control

Randomization (open-label)Eligible patients consent

CHF: NYHA class II-IV and EF ≤35%NYHA I and prior hospitalization for CHF or EF ≤25%

Qualifying AF: One episode ≥6 hours within last 6 monthsOne episode ≥10 min within last 6 months and prior D/C shock

Screening

9

AF-CHF Trial: ResultsAF-CHF Trial: Results• No difference in primary end point of CV death

− 182 (26.7%) rhythm control vs 175 (25.2%) rate control (HR 1.058, P=.59)

• No difference in prespecified secondary end points− Total mortality, worsening CHF, and stroke− Composite of CV death, worsening CHF, and stroke− CV mortality

• 21% crossover from rhythm to rate control− Primarily due to inability to maintain SR

• 10% crossover from rate to rhythm control− Primarily due to worsening HF

• Higher hospitalization rate in rhythm control (46% vs 39% at 1 year; P=.0063)− Mainly due to hospitalization for AF and bradyarrhythmias

(8.5% vs 4.9%; P=.0074)

• Higher rate of cardioversions in rhythm control (39% vs 8%)

Roy. Presented at: American Heart Association 2007 Scientific SeRoy. Presented at: American Heart Association 2007 Scientific Sessions; November 2007; ssions; November 2007; Orlando, FL; Orlando, FL; Roy.http://www.scienceondemand.org/sessions2007/lbct/sessions/Roy.http://www.scienceondemand.org/sessions2007/lbct/sessions/player.html?sidplayer.html?sid=071101PS.07.20603. Accessed May 12, 2008. =071101PS.07.20603. Accessed May 12, 2008.





?

1. Rate2. Rhythm

What If:Patient has nonischemic cardiomyopathy with EF 28% on ACEI and BB.For rhythm control, what AA drug would you use?


?

1. Propafenone2. Quinidine3. Amiodarone4. Sotalol

Maintenance of SR

No (or minimal)heart disease

FlecainidePropafenone

Sotalol

AmiodaroneDofetilide

Catheterablation

Hypertension

SubstantialLVH

No Yes


SotalolAmiodarone


Catheterablation

Catheterablation

Catheterablation

Catheterablation


DofetilideSotalol

CAD HF

Amiodarone

ACC/AHA/ESC 2006 guidelines for the management of patients with ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. atrial fibrillation. J Am Coll CardiolJ Am Coll Cardiol. 2006;48:854. 2006;48:854--906.906.



?

1. Propafenone2. Quinidine3. Amiodarone4. Sotalol

What antiarrhythmic agent would you use in a patient with hypertension?What antiarrhythmic agent would you use in a patient with hypertension?

?

1. Propafenone2. Amiodarone3. Sotalol4. Depends on the degree of LVH

10

Effect of AF on Event Rate in Patients With HF and Preserved EFCHARM Study

Effect of AF on Event Rate in Patients With HF and Preserved EFCHARM Study

CV Death or Hospitalization for HF All-Cause Mortality

Olsson et al. Olsson et al. J Am J Am CollColl CardiolCardiol.. 2006;47:19972006;47:1997--2004.2004.

AF at Baseline (Low EF)No AF at Baseline (Low EF)AF at Baseline (Preserved)No AF at Baseline (Preserved)

Preserved EF (PEF):Hazard ratio 1.72(95% Cl, 1.45-2.06)P<.001

Low EF:Hazard ratio 1.29(95% Cl, 1.14-1.46)P<.001

0.50

0.40

0.30

0.20

0

0.10

0.05

0.15

0.25

0.35

0.45

0 1 2 3 3.5Year

Cum

ulat

ive D

istrib

utio

n Fu

nctio

n

AF at baseline (Low EF)No AF at baseline (Low EF)AF at baseline (Preserved)No AF at baseline (Preserved)

Preserved EF (PEF):Hazard ratio 1.80(95% Cl, 1.46-2.21)P<.001

Low EF:Hazard ratio 1.38(95% Cl, 1.21-1.59)P<.001

0.40

0.30

0.20

0

0.10

0.05

0.15

0.25

0.35

0.45

0 1 2 3 3.5Year

Cum

ulat

ive D

istrib

utio

n Fu

nctio

n

Maintenance of SR



Sotalol


Catheterablation

Hypertension

SubstantialLVH

No Yes


SotalolAmiodarone


Catheterablation

Catheterablation

Catheterablation

Catheterablation


DofetilideSotalol

CAD HF

Amiodarone


What antiarrhythmic agent would you use in a patient with hypertension?What antiarrhythmic agent would you use in a patient with hypertension?

?

1. Propafenone2. Amiodarone3. Sotalol4. Depends on the degree of LVH

At What Point Do You Consider Ablation?At What Point Do You Consider Ablation?

?

1. Never in HF2. Only after all drugs have failed and patient

remains symptomatic3. In patients who failed one drug but are

symptomatic4. As a first line management

Maintenance of SR



Sotalol


Catheterablation

Hypertension

SubstantialLVH

No Yes


SotalolAmiodarone


Catheterablation

Catheterablation

Catheterablation

Catheterablation


DofetilideSotalol

CAD HF

Amiodarone


Success Rates With AblationWorldwide SurveySuccess Rates With AblationWorldwide Survey

0102030405060708090

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. Cappato et al. Circulation.Circulation. 2005;111:11002005;111:1100--1105.1105.

Rat

es (%

)R

ates

(%)

Range of Follow-up (months)Range of FollowRange of Follow--up (months)up (months)

11

Ablation vs AAD Therapy: Metaanalysis of Clinical TrialsAblation vs AAD Therapy: Metaanalysis of Clinical Trials

14/9973/99Pappone et al

13/5356/69Jais et al.

84/345254/348Total*

30/6863/69Stabile et al.

20/7722/37Wazni et al.

3/159/15Krittayaphong et al.

Recurrence in Ablation Group at

1 Year (n/N)

Recurrence in AAD Group at1 Year (n/N)Study

* * PP<0.001 for the comparison of AAD group to ablation group.<0.001 for the comparison of AAD group to ablation group.Nair et al. Nair et al. J J CardiovascCardiovasc ElectrophysElectrophys. 2008 [. 2008 [EpubEpub ahead of print].ahead of print].

Improvement in LV Function/Dimensions After Ablation in AF Patients With CHFImprovement in LV Function/Dimensions After Ablation in AF Patients With CHF

Plotted values are means ±SD. P values, which are for the comparison with baseline data, were determined with the use of Fisher’s least-significant-difference test. The numbers of patients included at each time point were as follows: 0 month, 58; 1 month, 55; 3 months, 48; 6 months, 40; 12 months, 34.Hsu et al. N Engl J Med. 2004;351:2373-2383.

PP<.001<.001PP<.001<.001PP<.001<.001PP<.001<.001

PP<.001<.001PP<.001<.001PP<.001<.001PP<.001<.001

PP=.001=.001PP=.001=.001PP<.001<.001PP<.001<.001P=P=.001.001PP=.02=.02PP=.03=.03PP=.001=.00175757070

60605555

0045455050

6565

LV E

ndLV

End

-- Dias

tolic

Di

asto

lic

Diam

eter

(mm

)Di

amet

er (m

m)

00 11 33 66 1212MonthMonth

LV E

ndLV

End

-- Sys

tolic

Sy

stol

ic Di

amet

er (m

m)

Diam

eter

(mm

) 5555

0030303535404045455050

00 11 33 66 1212MonthMonth

7070

6060

5050

4040

3030

002525

3535

4545

5555

6565

LV E

jectio

n LV

Ejec

tion

Frac

tion

(%)

Frac

tion

(%)

00 11 33 66 1212MonthMonth

4040

25252020

00

3535

LV F

ract

iona

l LV

Fra

ctio

nal

Shor

teni

ng (%

)Sh

orte

ning

(%)

00 11 33 66 1212MonthMonth

3030

1515

Complication Rates for Catheter AblationComplication Rates for Catheter Ablation

0.05

1.22

0.01 0.020.16 0.11

0.530.42

0.01 0.030

0.5

1

1.5

Cappato et al. Cappato et al. Circulation.Circulation. 2005;111:11002005;111:1100--1105.1105.

Perip

roced

ural

Perip

roced

ural

deathdeath

Tampo

nade

Tampo

nade

Sepsi

s, ab

scesse

s, or

Sepsi

s, ab

scesse

s, or

endo

cardi

tis

endo

cardi

tisPn

eumoth

orax

Pneu

mothora

xHem

othora

x

Hemoth

orax

Perm

anen

t diap

hragm

atic

Perm

anen

t diap

hragm

atic

paral

ysis

paral

ysis

Femora

l pseu

doan

eurys

m

Femora

l pseu

doan

eurys

mArt

eriove

nous

fistula

e

Arteri

oveno

us fist

ulae

Valve

damag

e

Valve

damag

eAo

rtic dis

sectio

n

Aortic

disse

ction

Patie

nts

(%)

CABANA TrialCABANA Trial

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

RecentRecent--onset AFonset AFeligible for ablation eligible for ablation or drug therapy or drug therapy ≥≥65 years old or65 years old or<65 years with <65 years with ≥≥1 1 risk factor for CAD risk factor for CAD or strokeor stroke

Primary AblationPrimary Ablation(technique at(technique at

operator discretion)operator discretion)

Drug TherapyDrug Therapy(rate or rhythm control(rate or rhythm control[at operator discretion][at operator discretion]with anticoagulation)with anticoagulation)

ContinuedContinuedAnticoagulationAnticoagulation

DiscontinuedDiscontinuedAnticoagulationAnticoagulation

Indications for Catheter AF AblationIndications for Catheter AF Ablation

• Symptomatic AF refractory or intolerant to at least one Class I or III 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 et al. Heart Rhythm. 2007;4:1-46.

Management After AblationManagement After Ablation

• Heparin (UFH or LMWH) as bridge to warfarin

• Warfarin for all patients for ≥2 months

• Use of warfarin >2 months following ablation based on patient’s risk factors for stroke and not presence or type of AF− Discontinuation of warfarin therapy postablation

generally not recommended for CHADS2 score ≥2

Calkins et al. Heart Rhythm. 2007;4:1-46.

12

At What Point Do You Consider Ablation?At What Point Do You Consider Ablation?

?

1. Never in HF2. Only after all drugs have failed and patient

remains symptomatic3. In patients who failed one drug but are

symptomatic4. As a first line management

New Approaches to TreatmentNew Approaches to Treatment

Augustus Grant, MD, PhD






• Improve QoL


New AAD Development: Possible MechanismsNew AAD Development: Possible Mechanisms• BB with class I or III effects• Amiodarone congeners• Atrial-selective antiarrhythmic drugs

− IKur and IKAch blockers− Atrio-selective Na channel blockers− 5-HT4–receptor antagonists

• Stretch-activated channel blockers• ACEIs/ARBs• NCX (Na/Ca exchanger) inhibitors• Anti-inflammatories (statins)• Gap-junction conduction facilitation

BhaktaBhakta et al. et al. Expert Expert OpinOpin TherTher Targets. Targets. 2007;11(9):11612007;11(9):1161--1178.1178.

Electrophysiologic RemodelingElectrophysiologic Remodeling

Normal

0 100 200 300 400

ICaIKur

IKr

IKs

Ito

Remodeled

ICa

IKur

IKrIKs

Ito

IKAch

0 100 200 300 400msms

Vernakalant (RSD1235)Vernakalant (RSD1235)

• Unique ion channel–blocking profile− Frequency- and voltage-dependent INa block− Early activating K+ channel block − Blocks IKACh

• Rate-enhanced activity on conduction

• Atrial-selective APD/ERP prolongation

• Activity confirmed in several species

• No adverse hemodynamic effects

• Novel aminocyclohexyl ether drug

VernakalantVernakalant is an investigational drug; not yet approved by FDA.is an investigational drug; not yet approved by FDA.BeatchBeatch et al. et al. Circulation.Circulation. 2003;108(suppl IV):IV85.2003;108(suppl IV):IV85.

13

0

10

20

30

40

50

60 Placebo Vernakalant

Vernakalant: ACT IIIVernakalant: ACT III

VernakalantVernakalant is an investigational drug; not yet approved by FDA.is an investigational drug; not yet approved by FDA.TdPTdP==torsadestorsades de pointes.de pointes.Adapted from Roy et al. Presented at: Heart Rhythm Society; May Adapted from Roy et al. Presented at: Heart Rhythm Society; May 5, 2006; New Orleans, LA. 5, 2006; New Orleans, LA.

4%

52%

Term

inat

ion

of A

F (%

)

4%

P=.001 41%

P<.001

AF Duration 3 h-7 d

AF Duration 3 h-45 d

Conversion of recentConversion of recent--onset AF (3 honset AF (3 h--7 d): 52% vs 4% (7 d): 52% vs 4% (PP<.001) <.001) 88--min median time to conversionmin median time to conversionNo drugNo drug--related related TdPTdP seenseen

n=86

n=84

n=118

n=121

Oral Vernakalant—Phase 2b (Interim Analysis)Oral Vernakalant—Phase 2b (Interim Analysis)

01%52%>90 daysa500 mg BID (110)

00%NSNS300 mg BID (108)

12%NSNS150 mg BID (110)

11%39%59 daysPlacebo (118)Death

Related SAEs% SR

Time to Recurrence

VernakalantVernakalant is an investigational drug; not yet approved by FDA.is an investigational drug; not yet approved by FDA.No No TdPTdP cases or drugcases or drug--related deaths.related deaths.NS=not significant.NS=not significant.aaPP<.05 (2<.05 (2--tailed).tailed).HofmanHofman. Fierce Biotech Web site. . Fierce Biotech Web site. http://www.fiercebiotech.com/presshttp://www.fiercebiotech.com/press--releases/cardiomereleases/cardiome--announcesannounces--positivepositive--interiminterim--phasephase--2b2b--resultsresults--oraloral--vernakalantvernakalant--andand--engagesengages--mm--00. Accessed May 8, 2008.. Accessed May 8, 2008.

Do Multichannel Agents Have Advantages Over Specific Channel Agents as Related to Atrial Remodeling?

Do Multichannel Agents Have Advantages Over Specific Channel Agents as Related to Atrial Remodeling?

?

1. Yes2. No

Dronedarone Dronedarone

• Amiodarone-like compound lacking the iodine moiety

• Similar electrophysiologic properties− Blocks IKr; IKur; IKs; IKAch; ICa; Ito; INa

− Beta-blockade as well

• No evidence of thyroid or pulmonary toxicity

• 24-hour half-life

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Dale et al. Dale et al. Ann Ann PharmacotherPharmacother. . 2007;41(4):5992007;41(4):599--605; 605; AltomareAltomare et al. et al. British J PharmBritish J Pharm. 2000;130:1315. 2000;130:1315--1320.1320.

Dronedarone Heart Rate ControlERATO StudyDronedarone Heart Rate ControlERATO Study

Effect on Resting HR Effect on Exercise HR

Davy et al. Am Heart J. 2008;156:527.e1-e9.

100

90

80

70

60 P<.0001

5

-5

-10

-15

Hear

t Rat

e (bp

m)

Change from Baseline (bpm

)

0

Placebo Dronedarone 400 mg bid

170

150

110100

80Day 0 Day 14 Day 14 –

Day 0

P<.0001

5

-15

-25Hear

t Rat

e (bp

m)

Change from Baseline (bpm

)

-10

160

140

120130

90

0-5

-20

-35-30

Day 0 Day 14 Day 14 –Day 0

Dronedarone: TrialsDronedarone: Trials

• EURIDIS (EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenanceof Sinus rhythm)

• ADONIS (American-Australian trial with DronedarONein atrial fibrillation or flutter patients for the maIntenanceof Sinus rhythm)

• ANDROMEDA (ANtiarrhythmic trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse)

• ATHENA (A Trial with dronedarone to prevent Hospitalization or dEath in patieNts with Atrial fibrillation)

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Dale et al. Dale et al. Ann Ann PharmacotherPharmacother. . 2007;41(4):5992007;41(4):599--605. 605.

14

Primary End Point: Patients With Adjudicated First Recurrence of AF/AFLPrimary End Point: Patients With Adjudicated First Recurrence of AF/AFL

Dronedarone 400 mg bidDronedarone 400 mg bidPlaceboPlacebo

EURIDISEURIDIS ADONISADONIS

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Singh et al. Singh et al. N N EnglEngl J MedJ Med. 2007;357:987. 2007;357:987--999.999.

Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

00 6060 120120 180180 240240 300300 360360

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.8


PP=.01=.01PP=.002=.002


Cum

ulat

ive

Inci

denc

eC

umul

ativ

e In

cide

nce

00 6060 120120 180180 240240 300300 360360

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.8

Pooled Tolerability and Safety DataEURIDIS and ADONISPooled Tolerability and Safety DataEURIDIS and ADONIS

•• No evidence of proarrhythmia; in particular, no case of No evidence of proarrhythmia; in particular, no case of TdPTdP reported reported during 12during 12--month followmonth follow--upup

•• No detection of No detection of dysthyroidiesdysthyroidies (systematic hormonal monitoring)(systematic hormonal monitoring)

Incidence of Incidence of TreatmentTreatment--EmergentEmergentAdverse Events (Adverse Events (TEAEsTEAEs)) PlaceboPlacebo

Dronedarone Dronedarone 400 mg 400 mg bidbid

(n=409)(n=409) (n=828)(n=828)

Patients with any AEPatients with any AE 65.8%65.8% 69.8%69.8%

Patients with any SAEPatients with any SAE 24.4%24.4% 19.8%19.8%

DeathsDeaths 0.7%0.7% 1%1%

Patients who permanently Patients who permanently discontinued study drug following discontinued study drug following any TEAEany TEAE

7.1%7.1% 9.7%9.7%

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Singh et al. Singh et al. N N EnglEngl J MedJ Med; 2007;357:987; 2007;357:987--999.999.

ATHENAPrimary OutcomeATHENAPrimary Outcome

Time to first cardiovascular hospitalization or death

Patients at riskPlacebo 2327 1858 1625 1072 385 3Dronedarone 2301 1963 1776 1177 403 2

0

10

20

30

40

50

0 6 12 18 24 30

Cum

ulat

ive

Inci

denc

e (%

) HR=0.76P<.001

Months

Placebo

Dronedarone

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Mean followMean follow--up 21 up 21 ±± 5 months.5 months.HohnloserHohnloser. Presented at: The Heart Rhythm Society; May 2008; San Francisc. Presented at: The Heart Rhythm Society; May 2008; San Francisco, CA.o, CA.

ATHENAFatal OutcomesATHENAFatal Outcomes

20

26

17

63

53

116

Dronedarone(n=2301)

0.84

0.55

0.95

0.71

1.10

0.84

Hazard Ratio

0.47-1.52

0.34-0.88

0.49-1.85

0.51-0.98

0.74-1.62

0.6-1.08

95% CIOutcomePlacebo (n=2327) P Value

All death 139 .18

Non-CV death 49 .65

CV death 90 .03

Cardiac nonarrhythmicdeath 18 .89

Cardiac arrhythmic death 48 .01

Vascular noncardiac 24 .57

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Hohnloser. Presented at: The Heart Rhythm Society; May 2008; SanHohnloser. Presented at: The Heart Rhythm Society; May 2008; San Francisco, CA.Francisco, CA.

ATHENANonFatal OutcomesATHENANonFatal Outcomes

First hospitalization for

.5420.51-1.420.852732Syncope

.0300.51-0.970.706289ACS

13

112

335

675

734

Dronedarone(n=2301)

1.09

0.86

0.63

0.75

0.76

Hazard Ratio

0.50-2.39

0.67-1.1

0.55-0.72

0.67-0.82

0.69-0.8495% CIOutcome

Placebo (n=2327) P Value

Primary outcome 917 <.001

CV reasons 859 <.001

AF 510 <.001

CHF 132 .221

Ventricular arrhythmia or nonfatal cardiac arrest

12 .828

Dronedarone is an investigational drug; not yet approved by FDA.Dronedarone is an investigational drug; not yet approved by FDA.Hohnloser. Presented at: The Heart Rhythm Society; May 2008; SanHohnloser. Presented at: The Heart Rhythm Society; May 2008; San Francisco, CA.Francisco, CA.

ATHENAPrimary Outcome in Important Clinical SubgroupsATHENAPrimary Outcome in Important Clinical Subgroups

0.71 (0.58-0.86)1359No0.78 (0.69-0.87)3269Yes

Beta-blocking agents0.79 (0.66-0.95)1412No0.74 (0.66-0.83)3216Yes

ACE/ARB0.78 (0.70-0.86)4004≥450.66 (0.47-0.92)36135-450.68 (0.44-1.03)179<35

LVEF (%)0.76 (0.68-0.86)3263No0.75 (0.64-0.88)1365Yes

Congestive HF0.77 (0.65-0.92)1853No0.76 (0.67-0.85)2732Yes

Structural heart disease0.76 (0.68-0.85)3473No0.74 (0.61-0.91)1155Yes

Presence of AF/AFL0.77 (0.67-0.89)2169Female0.74 (0.64-0.85)2459Male

Sex0.75 (0.65-0.87)1925≥750.76 (0.67-0.87)2703<75

Age (years)HR (95% CI)NCharacteristic

Dronedarone Better

Placebo Better

0.1 101

.41

.59

.30

.83

.85

.85

.65

.93

P

Dronedarone is an investigational drug; not yet approved Dronedarone is an investigational drug; not yet approved by FDA; by FDA; Hohnloser. Presented at: The Heart Rhythm Hohnloser. Presented at: The Heart Rhythm Society; May 2008; San Francisco, CA.Society; May 2008; San Francisco, CA.

15

ATHENA Post-Hoc AnalysisStroke ReductionATHENA Post-Hoc AnalysisStroke Reduction

Connolly SJ. ATHENA: The effect of dronedarone on cardiovascular outcomes and stroke in patients with atrial fibrillation. European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany. Clinical trials update 3. http://www.theheart.org/viewArticle.do?primaryKey=901685. Accessed September 4, 2008

1.79 2.05

0.54

5.52

6.70

5.06

3.80

0.36

1.371.19

0

2

4

6

8

Stroke Stroke orTIA

FatalStroke

Stroke,ACS, or CV

Death

Stroke,ACS, or

All-causeDeath

DronedaronePlacebo

Ann

ual R

ate

P=.027P=.020

P=. 247

P<.001P=.002

34% Risk Reduction of Stroke

Note: Investigators were encouraged to maintainanticoagulation according to published guidelines

ARS QuestionWill new antiarrhythmic agents shift the therapeutic choice in favor of rhythm control?

ARS QuestionWill new antiarrhythmic agents shift the therapeutic choice in favor of rhythm control?

?

1. Yes2. No

ARS QuestionShould the AFFIRM study be repeated utilizing new antiarrhythmic agents?

ARS QuestionShould the AFFIRM study be repeated utilizing new antiarrhythmic agents?

?

1. Yes2. No

ARS QuestionShould an AFFIRM-like study be performed utilizing ablation for rhythm control?

ARS QuestionShould an AFFIRM-like study be performed utilizing ablation for rhythm control?

?

1. Yes2. No

SummarySummary

• AF is a common disease that is increasing in prevalence

• There are significant consequences to AF, including stroke, HF, sudden death, other CV mortality

• Atrial electrical and structural remodeling take place early and progress, making return to SR more difficult with longer duration of AF

• New agents have properties that are designed to work more effectively in remodeled atria

• Current guidelines provide algorithms for antiarrhythmic use in specific clinical conditions

• New agents may provide antiarrhythmic options with improved outcomes for managing AF

Documents

Session 11 - pri-med.com Files/Syllabus Files... · Session 11 Session 11: Heart to Heart: An AF Outcomes Initiative An Interactive Case-Based Discussion of AF Management Agenda –