Atrial Arrhythmia Detection, Prevention and t ial yt ia etectio , eve tio a dTherapy AlgorithmHow Do They Work?y

Muhammad MunawarDepartment of Cardiology and Vascular Medicine, Faculty

of Medicine, University of IndonesiaJakarta, Indonesia

• Why atrial arrhythmia (AF) is important in pacemaker patientsimportant in pacemaker patients

• Atrial arrhythmias (AF) supression y ( ) pworkCli i l i l• Clinical trials

Why atrial fibrillation is important in pacemaker patientpacemaker patient

• AF increase morbidity• StrokeStroke• Heart failure

T h di i d d di th• Tachycardia induced cardiomyopathy• AF increase mortality

Risks of Atrial FibrillationRisks of Atrial Fibrillation

• Stroke• Patients with AF are 5 times more likely toPatients with AF are 5 times more likely to

have a stroke than the general population• Cause of 75 000 cases of stroke annually• Cause of 75,000 cases of stroke annually • 23% of all strokes in the U.S.

SJM CRMD RESEARCH BRUSSELS, BELGIUM

(First Call Research Network on 01-OCT-98) and NationsBanc Montgomery Securities

Risks of Atrial FibrillationRisks of Atrial Fibrillation

• Long-term Mortality Rates Framingham Study61.5% 57.6%

60%

70%

Long term Mortality Rates Framingham Study

50%

60%

30.0%20.9%30%

40%

10%

20%

0%Men Women

No AF

Benjamin EJ et al. Circulation 1998; 98: 946-52.

No AFAF Present

Atrial arrhythmias (AF) suppression work

H th iH th iHypothesis Hypothesis

• Suppression of paroxysmal and possibly persistent AF can be achieved by stimulation at one or moreAF can be achieved by stimulation at one or more sites using a variety of overdrive or PAC responsive algorithmsresponsive algorithms.

• Proposed mechanism(s)Proposed mechanism(s)• Reduced dispersion of refractoriness• Improved atrial homogeneityp g y• Reduction in triggers

Options to Stabilize Options to Stabilize S AFS AFor Suppress AFor Suppress AF

• Alternate sites of stimulationBi t i l ti l ti• Bi-atrial stimulation

• Dual-site atrial stimulation• Bachmann’s bundle or interatrial septump• Low septal pacing• Coronary sinus

• Overdrive algorithms• Elevated base rate• PAC responsive algorithm (ELA)• Consistent Atrial Pacing (Medtronic)• AF Suppression™ (St Jude Medical)• AF Suppression (St. Jude Medical)

Mechanism of AF/AT SuppressionMechanism of AF/AT Suppression

1. Pace conditioning 2. PAC suppression2. PAC suppression3. Post-PAC response4 P t i4. Post-exercise response 5. Post-AF response6. Rate soothing

Mitchell ARJ, Sulke N. Europace 2004; 6: 351

Pace conditioningPace conditioning

• Adjusts the atrial pacing rate to just above the underlying intrinsic rhythm in such a way that the

i i d f l 95% f h iatrium is paced for at least 95% of the time

P diti iPace conditioning

PAC SuppressionPAC Suppression

• aims to reduce the incidence of PACs by increasing the heart rate upon detection of a PAC

Post PAC responsePost-PAC response

• prevents pauses after PACs by controlling the atrial rate in the two beats after a PAC

Post exercise responsePost-exercise response

• Aims to prevent the rapid heart-rate drop that can occur after exercise by enabling a post-exercise rate

Post-exercise Response

Rate soothingRate soothing

• Aims to prevent ATs by overdrive pacing the atrium at a rate that is only just above the sinus rate

Post AF responsePost AF response

AF Suppression Starts

AF Suppression Continues

Atrial Rhythm Classification (ARC)Atrial Rhythm Classification (ARC)ARC differentiates atrial flutter (AFL Region) from atrial fibrillation (AF Region) using Rate, Range, andatrial fibrillation (AF Region) using Rate, Range, and Standard Deviation.

AFib zone therapy

Range Standard Deviation

SVT zone therapy

Deviation

• AFL Region arrhythmias receive SVT zone therapy

• AF Region arrhythmias receive AFib zone therapy

Clinical trials

ADOPT A Clinical TrialADOPT-A Clinical Trial

Pacemaker Implant •ProspectiveSt d Pacemaker ImplantTrilogy DR DAOIntegrity AFx DR

•Prospective•Patient Blinded•Randomized

StudyDesign

DDDR PacingAF Suppression-ON

DDDR PacingAF Suppression-OFF

Follow-upBaseline, 30, 90, 180 days

D i A

Follow-upBaseline, 30, 90, 180 days

D i ADevice AssessmentQOL

Device AssessmentQOL

Symptomatic AF Episodesvia Event Recorder

Symptomatic AF Episodesvia Event Recorder

ADOPT A Clinical TrialADOPT-A Clinical Trial

Atrial Pacing% Atrial Beats Paced*

Atrial Pacing

AF Suppression OFF 67.9

*p<0 0001

AF Suppression ON 92.9*p<0.0001

ADOPT A Clinical TrialADOPT-A Clinical Trial

S t ti AF B d

4 44%5.0%

Symptomatic AF Burden

2 63%

4.44%

3.19%3 0%3.5%4.0%4.5%

%)

(n = 288) p < 0.05AFs OFF

AFs ON2.63%

1.73%1.37%

1.93%

1 5%2.0%2.5%3.0%

AF

Bur

den

(% AFs ON

0 0%0.5%1.0%1.5%A

0.0%

1-Month 3-Month 6-MonthFollow up

ADOPT A Clinical TrialADOPT-A Clinical Trial

AFs OFF AFs ONAF Burden Reduction

Total Patients 158 130

Patients with AF Days 81 73Patients with AF Days 81 73

Total AF Days 682 421

Total Follow-upDuration (Days)

27,359 22,526

AF Burden 2.493% 1.869%

AF Burden Reduction 25.03%

ADOPT A Clinical TrialADOPT-A Clinical Trial

AF Episode Reduction

9

108.3 ± 4.1

AF Episode Reduction

7

89

odes p = < 0.0001

8.1 ± 4.2 AFs OFF

AFs ON

45

6

AF

Epis

4.3 ± 11.5

2

3

4

Mea

n 3.2 ± 8.5

0

1

6 M th P i t I l t I l t t 6 M th6 Months Prior to Implant Implant to 6 Months

ADOPT A Clinical TrialADOPT-A Clinical Trial

Hospitalizations

100Freedom to first hospitalization (n = 288)

Hospitalizations

96

98

100

zatio

n*

AFs OFF

AFs ON

p= NS

92

94

96

Hos

pita

liz

88

90

92

(%) w

/o H

88 0 30 60 90 120 150 180Duration (Days)

6% Reduction in Hospitalizationsp

ADOPT A Clinical TrialADOPT-A Clinical Trial

100

Freedom from First Cardioversion (n=288)

96

98

over

sion

94

96

/o C

ardi

o

AFs OFFp = 0.0925

90

92

(%) w

/

AFs ON

0 30 60 90 120 150 180(Duration) Days

63% reduction in Cardioversions

ADOPT A Clinical TrialADOPT-A Clinical Trial

• Conclusion • AF Suppression pacing appears to be safe andAF Suppression pacing appears to be safe and

to reduce AF burden in sinus node dysfunction patients with paroxysmal or persistent AF.patients with paroxysmal or persistent AF.

• AF Suppression pacing offers incremental benefit to DDDR pacing alonebenefit to DDDR pacing alone.

AT500™ Pacing System U S Clinical ExperienceU.S. Clinical Experience

Two Large US Trials:g• ASPECT1

n=298 implanted, 277 intention-to-treat analysis (138 septal),35 centers, 6 month follow-up (crossover at 3 months);35 centers, 6 month follow up (crossover at 3 months); Single-blind study,Lead site randomized to RA septal or non-septalIntervention pacing algorithms ON vs. OFF

Primary endpoint: AT/AF frequency• ATTEST2

n=368 implanted 324 in efficacy cohortn=368 implanted, 324 in efficacy cohort,28 centers, 3 month follow-up; Single-blind studyAll therapies ON vs. OFF (Intervention and ATP)

Primary endpoint: AT/AF burden and frequencyPrimary endpoint: AT/AF burden and frequency

1 AT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc. 2 Lee M, Weachter R, Pollak S, et al. For the ATTEST Investigators. JACC 41:In Press 2003

AT500™ Pacing SystemASPECT Trial Design

Enrollment

ASPECT Trial Design

Enrollment(n=298)

Non-Septal Randomization Septal Atrial LeadAtrial Lead

N = 150

Septal Atrial LeadN = 148(Implant)

ON OFFCrossover:

1 month run in

Randomization

ON OFF

Randomization(1 month) (1 month)

ON

OFF

OFF

ON

- 1 month run-in- 3 month periods

for each phase

ON

OFF

OFF

ON

Clinical Follow-up Programming at discretion

of Physicianof Physician

AT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc.

AT500™ Pacing SystemASPECT Trial Results

Rx OFF2

(No changes in device-recorded AT/AF Burden or frequency with specialized algorithms ON vs. OFF)

20

25/d

ay)

10

12 Rx ON

15

20

piso

des /

8

hr/d

ay)

10

5

ency

(ep

6

urde

n(h

5

FFr

eque

2

4

AFB

0

AF

0Septal Non Septal Non SeptalSeptalSeptal Non-Septal Non-SeptalSeptal

Padelletti L, et al. PACE 2002;24(Part II):NASPE Abstract.

AT500™ Pacing SystemASPECT Trial Results

Patients w/septal leads had 47% fewer symptomatic AT/AF episodes ON vs. OFF

Symptomatic frequency reduction in Septal Arm

h)

OFF ON

p=0 01

Patients w/septal leads had 47% fewer symptomatic AT/AF episodes ON vs. OFF

AT s/m

ont h

8p=0.01

p=0.89O

MAT

IC A

epis

ode

4

SYM

PTO

UEN

CY

(

S

FREQ

U

0SEPTAL NON

SEPTALAT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc.

AT500™ Pacing SystemClinical ResultsClinical Results

• ASPECT1,2,3

• No change in frequency or burden of AT/AF episodes when prevention algorithms were enabledSignificant reduction in frequency of symptomatic AT/AF• Significant reduction in frequency of symptomatic AT/AF episodes when the atrial lead was placed in the septum

• Significant reduction in frequency of premature atrial i ( ) i b h l d l l dcontractions (PACs) in both septal and non-septal lead

placement groups• Patients with non-septal lead placement and high frequencyPatients with non septal lead placement and high frequency

PACs may represent a responder group for intervention algorithms

1 AT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc. 2 f S C 2002 2 68 ( S #6 9)2 Padeletti L, Pererfellner H, Adler S, et al. PACE 2002, Part II;24:687 (NASPE Abstract #659)3 Harvey M, Holbrook R, Young M, et al. JACC 2003; 41:Abstract #1017-5

AT500™ Pacing SystemATTEST Trial Design

Enrollment

ATTEST Trial Design

Class I / II Indications for Dual

Chamber Pacing

EnrollmentBrady + AT/AF

(n=368)+ At least 1 episode of paroxysmal or persistent AT/AF

(n 368)

Randomization

Prevention &

persistent AT/AF documented by ECG in last year

and 1 symptomatic

(at 1 month)

Prevention & ATP TherapiesON vs. OFF

and 1 symptomatic episode in past

3 monthsON

3 mosOFF3 mos

Clinical Follow-upProgramming at discretion of physicianProgramming at discretion of physician

AT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc.

AT500™ Pacing SystemATTEST Trial Results

18000

20000(ATP Did Not Significantly Alter Episode Duration)

14000

16000

18000

Therapies ON

odes

10000

12000

14000Therapies OFF

of E

piso

6000

8000

10000

umbe

r o

2000

4000Nu

0 1-10 10-60 1-4 4-12 12-24 24-72 >72min min hr hr hr hr hr

Episode DurationEpisode Duration Lee M, Weachter R, Pollak S, et al. For the ATTEST Investigators. JACC 41:In Press 2003AT500 FDA P980035/S13/A3; Data on file, Medtronic, Inc.

AT500™ Pacing SystemClinical ResultsClinical Results

• ATTEST1

• 99.9% (99.7% GEE) Positive Predictive Value for detection of AT/AF episode (based upon Investigator review)

• 54% (41% GEE) ATP therapy success rate for device-defined AT( ) py• Median % of atrial pacing was 98% ON vs. 75% OFF group• No incidence of ventricular pro-arrhythmia • No significant reduction in AT/AF burden, total frequency orNo significant reduction in AT/AF burden, total frequency or

symptomatic AT/AF frequency ON vs. OFF

Note: Median % of ventricular pacing was 97% in the ONNote: Median % of ventricular pacing was 97% in the ON group while only 30% of patients were diagnosed with AVB, suggesting high level of RV-pacing may have minimized affect of the atrial therapiesminimized affect of the atrial therapies.

1 Lee M, Weachter R, Pollak S, et al. For the ATTEST Investigators. JACC 41:In Press 2003

SAFE Study DesignSAFE Study DesignIMP

Week6-8 M6 M12 M18 M24

Septal Position + DAO = ON

Septal Position + DAO =OFF

RRAA Position + DAO = ON

RAA Position + DAO = OFF

Prospective, parallel, randomized, multiProspective, parallel, randomized, multi--center studycenter study

The problem of successful of AF suppressionThe problem of successful of AF suppression

• Anti-arrhythmias to be used• The sites of atrial pacingThe sites of atrial pacing• Progression of computer technology

Ch i i t ti t• Choosing appropriate patients• Maybe DDD pacemaker for bradycardia has little

effect for AT/AF supression• Detrimental effect of apex RV ventricular

pacing (‘ventricular pro-arrhythmic pacing’)

ConclusionConclusion

• The AF suppression technology in pacemaker patient is still being progress

• There are clearly groups of patients who benefit from AF suppression algorithm but there are alsofrom AF suppression algorithm but there are also many who do not

• Reduced ventricular pacing is also very important• Reduced ventricular pacing is also very important