3038996-1

Atrial fibrillation: Integrating new Atrial fibrillation: Integrating new invasive and pharmacologic therapiesinvasive and pharmacologic therapies

Yong-Mei Cha, MDYong-Mei Cha, MD

Mayo ClinicMayo Clinic

Shenyang Cardiovascular Forum Shenyang Cardiovascular Forum

April 16, 2011April 16, 2011

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Atrial fibrillationAtrial fibrillation 房颤房颤 : Integrating new : Integrating new invasive invasive 联合新的介入性联合新的介入性 and and 及药物治疗及药物治疗

pharmacologic therapiespharmacologic therapies

Yong-Mei Cha, MDYong-Mei Cha, MD

Mayo ClinicMayo Clinic

Shenyang Cardiovascular Forum Shenyang Cardiovascular Forum

April 16, 2011April 16, 2011

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Ablation for paroxysmal AFAblation for paroxysmal AF

• Ablation energy:

RF ablation, Cryoballoon ablation, Ablation using robotic Hanson system or stereotaxis

• Ablation style:

lasso-guided pulmonary vein isolation

wide area circumferential PVI

Pulmonary vein antrum ablation

• End-point: pulmonary vein electrical isolation

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Ablation for paroxysmal AFAblation for paroxysmal AF 阵发性房颤消融阵发性房颤消融

• Ablation energy 消融能量 :

射频消融， RF ablation, 冷冻球囊消融，应用机器人 Hanson 系统或定位系统 Cryoballoon ablation, Ablation using robotic Hanson system or stereotaxis

• Ablation style 消融风格 :

lasso-guided pulmonary vein isolation

wide area circumferential PVI

Pulmonary vein antrum ablation

• End-point: pulmonary vein electrical isolation

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Arctic Front Cryothermal Balloon CatheterArctic Front Cryothermal Balloon Catheter

• 2 balloon diameters:2 balloon diameters:

23 mm & 28 mm 23 mm & 28 mm

• Double balloon safety systemDouble balloon safety system

• Over-the-wire with a Over-the-wire with a bi-directional deflectionbi-directional deflection

• PAF: AF-free rate 80%PAF: AF-free rate 80%

• FreezeAFFreezeAF trial: randomized trial: randomized controlled noninferiority trial controlled noninferiority trial comparing isolation of the comparing isolation of the pulmonary veins with the pulmonary veins with the cryoballoon catheter vs open cryoballoon catheter vs open irrigated radiofrequency irrigated radiofrequency ablation in patients with ablation in patients with paroxysmal atrial fibrillation paroxysmal atrial fibrillation (n=244)(n=244)

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Cryoballoon ablation for AFCryoballoon ablation for AF

• Cryoballoon ablation for AF has been performed in >10,000 patients in more than 200 centers outside of the U.S

• FDA has approved this technology for PAF in US

• In Sustained Treatment of Paroxysmal AF trial (STOP AF), 245 patients were randomized to cryoablation (n=163) and AADs (n=82) groups. PV isolation was achieved in 98% of patients. At 1 year, AF free was 70% by ablation, 7% by drug therapy. PV stenosis 3%, phrenic nerve injury (acute 11%, chronic 2%).

• Uniform cryothermal lesion with less thrombus formation

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Hansen Remote robotic Navigation

• Houses the Artisan Control Catheter

• Catheter tip replicates the hand movements of the physician at the instinctive motion controller

• Portable and easily attaches to the procedure table

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AF ablation using Hansen robotic navigationAF ablation using Hansen robotic navigation

Saliba, Natale, JACC 2008

• 100 patients

• Hanson robotic and Navx

• Artisan sheath and Thermocool catheter

• Procedure time 222 min

• Fluoro time 12 min

• AF free 86% after 1.2 procedures at 15 months

• No major complications

Slovak P JCE 2010

The system is FDA approved for use in mapping in 2007, but largely it is used in off-label procedures for the treatment of AF. Over 2000 ablations were performed worldwide using Hanson system

• 40 patients

• Hanson robotic and Navx

• Thermocool catheter

• Procedure time 163 min

• Fluoro time 64 min

• 2 tamponade

• AF free 86% at 1 year

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Positioning of the balloon ablation catheter and endoscopic views.

Dukkipati S R et al. Circ Arrhythm Electrophysiol 2010;3:266-273

Copyright © American Heart Association

Visual balloon-guided AF ablation

• 27 PAF patients• 100% acute PV isolation• 90% PV isolation in 3-m• 83% patients free of AF• No major complications

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Ablation for Persistent/Permanent AFAblation for Persistent/Permanent AF

• Cornerstone: pulmonary vein isolation

• Atrial substrate modification: lack of end-point

• CFAE ablation

• Additional atrial lines and CS ablation

• Atrial denervation (GP ablation)

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Randomized Trials of AF Ablation and AADsRandomized Trials of AF Ablation and AADs

0

20

40

60

80

100

RAAFT A4 APAF CACAF

AblationAblationDrugDrug

Patients (no.)Patients (no.) 7070 112112 198198 137137

Freedom Freedom from from

recurrent recurrent AF (%)AF (%)

RAAFT: RF ablation vs AADs as first-line treatment of symptomatic AFRAAFT: RF ablation vs AADs as first-line treatment of symptomatic AFCACAF: catheter ablation for the cure of AF studyCACAF: catheter ablation for the cure of AF studyAPAF: randomized trial of circumferential PV ablation vs AAD therapy in PAFAPAF: randomized trial of circumferential PV ablation vs AAD therapy in PAF

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0

20

40

60

80

100

0 6 12 18 24 30

Fir

st r

ecu

rren

ce (

%)

Fir

st r

ecu

rren

ce (

%)

Number at riskNumber at riskOverallOverall 774774 447447 358358 251251 212212 129129

Mayo Clinic ExperienceMayo Clinic Experience

Months after ablationMonths after ablation

0

20

40

60

80

100

0 6 12 18 24 30

Fir

st r

ecu

rren

ce (

%)

Fir

st r

ecu

rren

ce (

%)PAFPAF 428428 268268 215215 156156 133133 8787PersAFPersAF 346346 179179 143143 95 95 79 79 42 42

Months after ablationMonths after ablation

Mid-term

Late

1.3%permo5.8%

permo

BLANKING

Very late

0.9%per mo

Overall

BLANKING

Mid-term

LateVery late

PersAF

PAF

P<0.001

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Randomized Study Comparing the Efficacy Randomized Study Comparing the Efficacy and Safety of Vernakalant to Amiodarone in and Safety of Vernakalant to Amiodarone in

Recent-Onset AFRecent-Onset AF

• Vernakalant blocks atrial-specific K+ and Na+ ion channels, prolonging atrial refractory periods and slowing atrial conduction

• 254 patients with AF <48h were randomized

• Vernakalant 3mg/kg iv in 10min, or

Amiodarone 5mg/kg iv in 60min

• Vernakalant conversion rate 51% in 90min, 54% in 4h

Amiodarone conversion rate 5% in 90min, 22% in 4h

Camm J. JACC 2011

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Camm J. JACC 2011

Efficacy of vernakalant and amiodarone in conversion from AF to sinus rhythm

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HEUZEY J, JCE 2010

A randomized, double-blind study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients

with persistent atrial fibrillation: the DIONYSOS study

• N=504, randomization

• dronedarone 400 bid amiodarone 600mg QD, 200mg QD for 6m

• AF recurrence at 12m dronedarone 63% amiodarone 42%

• dronedarone is less effective than amiodarone, better safety file

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HEUZEY J, JCE 2010

Overall adverse eventsDronaderone 39%Amiodarone 44%

Thyroid events

Neurological events

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OOCC44HH99

OO

II

II

OO (CH(CH22))22 NN

CC22HH55

CC22HH55

Amiodarone (MW=682)Amiodarone (MW=682)

OOCC44HH99

OO

OO (CH(CH22))22 NN

CC44HH99

CC44HH99

SR 33589B/Dronedarone (MW=593)SR 33589B/Dronedarone (MW=593)

CHCH33SOSO22NHNH

HCIHCI

Patel C: Circulation, 2009

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DronedaroneDronedarone• A derivative of amiodarone, blocking IA derivative of amiodarone, blocking INaNa , I , ICa-LCa-L, I, IKrKr

channels and beta adrenergic receptorschannels and beta adrenergic receptors

• Metabolized primarily by cytochrome P-450 (CYP) 3A4 Metabolized primarily by cytochrome P-450 (CYP) 3A4 and excreted in the bile with minimal renal excretion and excreted in the bile with minimal renal excretion

• Fewer drug interactions; concurrent use of medications Fewer drug interactions; concurrent use of medications that inhibit CYP3A4 can increase exposure to the drug that inhibit CYP3A4 can increase exposure to the drug

• Does not contain iodine and have no thyroid or Does not contain iodine and have no thyroid or pulmonary toxicitypulmonary toxicity

• Half-life 27-31 hours, shorter than amiodaroneHalf-life 27-31 hours, shorter than amiodarone

• A 10-15% increase in serum creatinine is related to A 10-15% increase in serum creatinine is related to inhibition of tubular secretion of creatinine by the drug inhibition of tubular secretion of creatinine by the drug and does not represent a decrease in the glomerular and does not represent a decrease in the glomerular filtration ratefiltration rate

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RR of AF Recurrence with RR of AF Recurrence with Dronedarone Versus PlaceboDronedarone Versus Placebo

StudyStudy

DAFNEDAFNE

EURIDISEURIDIS

ADONISADONIS

ATHENAATHENA

Pooled (FE)Pooled (FE)

DronedaroneDronedarone

35/5435/54

150/411150/411

154/417154/417

779/1,732779/1,732

1,118/2,6141,118/2,614(43%)(43%)

PlaceboPlacebo

43/4843/48

95/20195/201

89/20889/208

950/1,741950/1,741

1,177/2,1981,177/2,198(54%)(54%)

Weight (%)Weight (%)

44

1010

1010

7676

100100

Relative riskRelative risk(95% CI)(95% CI)

0.72 (0.58-0.90)0.72 (0.58-0.90)

0.77 (0.64-0.94)0.77 (0.64-0.94)

0.86 (0.71-1.06)0.86 (0.71-1.06)

0.82 (0.77-0.86)0.82 (0.77-0.86)

0.82 (0.77-0.87)0.82 (0.77-0.87)

RR (log scale)RR (log scale)

0.10.1 11 1010Cochran’s Q = 1.9, P=0.6Cochran’s Q = 1.9, P=0.6II22 = 0%, 95% CI (0-85%) = 0%, 95% CI (0-85%)

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All-Cause MortalityAll-Cause Mortality

StudyStudy

DAFNEDAFNE

EURIDISEURIDIS

ADONISADONIS

RATORATO

ANDROMEDAANDROMEDA

ATHENAATHENA

Pooled (RE)Pooled (RE)

DronedaroneDronedarone

0/760/76

2/4112/411

9/4179/417

1/851/85

25/31025/310

116/2,327116/2,327

153/3,600153/3,600(4.3%)(4.3%)

PlaceboPlacebo

0/660/66

0/2010/201

5/2085/208

1/891/89

12/31712/317

139/2,301139/2,301

157/3,208157/3,208(4.9%)(4.9%)

Weight (%)Weight (%)

11

22

1313

22

2626

5555

100100

Relative riskRelative risk(95% CI)(95% CI)

0.87 (0.02-43.2)0.87 (0.02-43.2)

1.96 (0.09-43.2)1.96 (0.09-43.2)

0.90 (0.30-2.65)0.90 (0.30-2.65)

1.05 (0.07-16.4)1.05 (0.07-16.4)

2.13 (1.09-4.16)2.13 (1.09-4.16)

0.84 (0.66-1.07)0.84 (0.66-1.07)

0.95 (0.76-1.18)0.95 (0.76-1.18)

RR (log scale)RR (log scale)

0.010.01 11 100100Cochran’s Q = 6.7, P=0.24Cochran’s Q = 6.7, P=0.24II22 = 26%, 95% CI (0-69%) = 26%, 95% CI (0-69%) 0.10.1 1010

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Selected Adverse Events and Laboratory Abnormalities Selected Adverse Events and Laboratory Abnormalities in Patients Receiving Dronedarone in the ATHENA Trialin Patients Receiving Dronedarone in the ATHENA Trial

Dronadarone (%)Dronadarone (%) Placebo (%)Placebo (%) PP

BradycardiaBradycardia 3.53.5 1.21.2 <0.001<0.001

QT-interval prolongationQT-interval prolongation 1.71.7 0.60.6 <0.001<0.001

Interstitial lung diseaseInterstitial lung disease 0.20.2 0.20.2 1.01.0

DiarrheaDiarrhea 9.79.7 6.26.2 <0.001<0.001

NauseaNausea 5.35.3 3.13.1 <0.001<0.001

Abnormal liver function testAbnormal liver function test 0.50.5 0.60.6 0.840.84

HypothyroidismHypothyroidism 0.50.5 0.30.3 0.230.23

HyperthyroidismHyperthyroidism 0.30.3 0.30.3 1.001.00

RashRash 3.43.4 2.02.0 0.0060.006

Serum creatinine increaseSerum creatinine increase 4.74.7 1.31.3 <0.001<0.001

Premature discontinuationPremature discontinuation 12.712.7 8.18.1 <0.001 <0.001 of study drug because of of study drug because of an adverse eventan adverse event

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Dronadarone: SummaryDronadarone: Summary

• It was approved by the FDA for the treatment of It was approved by the FDA for the treatment of atrial atrial fibrillation and atrial flutterfibrillation and atrial flutter

• It is now available as 400 mg tablets, bid It is now available as 400 mg tablets, bid

• FDA did not approve dronedarone for reducing deathsFDA did not approve dronedarone for reducing deaths

• It is It is contraindicatedcontraindicated in patients with in patients with NYHA class IV heart NYHA class IV heart failure, or NYHA class II-III with a recent decompensation failure, or NYHA class II-III with a recent decompensation heart failure;heart failure; patients given dronedarone had a >2-fold patients given dronedarone had a >2-fold increase in mortalityincrease in mortality

• Dronedarone has Dronedarone has modestmodest antiarrhythmic efficacy, half as antiarrhythmic efficacy, half as effective compared with amiodaroneeffective compared with amiodarone

• Dronedarone reduces heart rate in patients with AF/AFLDronedarone reduces heart rate in patients with AF/AFL

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SummarySummary

• Antiarrhythmic drug efficacy: 10-65% of patients are maintained in SR in 1-5 years.

• Catheter ablation success rate is 80% for PAF, 60-70% for persistent AF (up to 50% patients need >1 procedure) and complication rate 6%. Ablation technology continue evolving.

• Many patients require combined ablation and drug therapy to maintain sinus rhythm, achieving synergistic effect.

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SummarySummary 总结总结

• Antiarrhythmic drug efficacy 抗心律失常药物疗效 : 10-65% of patients are maintained in SR in 1-5 years.10-65% 患者在 1-5 年内维持窦性心律。

• Catheter ablation success rate is 80% for PAF, 对于阵发性房颤导管消融的成功率为 80% ， 60-70% for persistent AF (up to 50% patients need >1 procedure) and complication rate 6%. Ablation technology continue evolving. 持续性房颤为 60-70%（）

• Many patients require combined ablation and drug therapy to maintain sinus rhythm, achieving synergistic effect.