Can Adaptive Cardiac

Resynchronization Therapy Reduce Atrial Fibrillation Risk?

David O. Martin, MD, MPH J Harrison Hudnall, BS; Bernd Lemke, MD; Kazutaka Aonuma, MD, PhD;

Henry Krum, MBBS, PhD; Kathy Lai-Fun Lee, MD; Maurizio Gasparini, MD; John Gorcsan III, MD; David Birnie, MD, MB, ChB; Tyson Rogers,

MS; Alex Sambelashvili, PhD

3

Background

•Cardiac resynchronization therapy (CRT) is an effective therapy for many HF patients, yet some do not experience full response

•Atrial fibrillation (AF) is the most common arrhythmia among HF patients and contributes to CRT non-response

•The adaptive CRT (aCRT) algorithm is a novel method for delivering CRT

•We investigated the impact of aCRT on AF risk

Adaptive CRT Pacing Algorithm

4

Assess intrinsic conduction

(every 60 sec)

HR ≤ 100 bpm and normal AV

conduction1

HR > 100 bpm or long AV conduction

AV/VV timing optimized for LV-only pacing2

AV/VV timing optimized for BiV pacing

1Normal if: SAV ≤ 200 ms, PAV ≤ 250 ms

Provides ambulatory CRT optimization

Allows more physiologic ventricular activation

Should improve device longevity by reducing RV pacing

Krum H, et al. Am Heart J. 2012;163:747-52 2Synchronized to intrinsic RV activation

Adaptive CRT Trial Design

Objective: To determine the safety and efficacy of aCRT compared to BiV pacing with echocardiographic AV and VV optimization

Patients:

• LVEF ≤ 35%

• QRS ≥ 120 ms

• NYHA III or IV

• Without permanent AF

Enrollment:

• 94 centers (AUS, CAN, RUS, Europe, HKG, JPN, US)

• Nov 2009 – Dec 2010

• Last patient exited Oct 2012 Follow-up Follow-up

Control (AV/VV Echo Opt)

aCRT

Randomized 2:1

Enrolled (<30 days from Implant)

Double-Blinded

CRT-D Implanted

5 Krum H, et al. (Adaptive CRT Design) Am Heart J. 2012;163:747-52

Methods

•As a pre-specified trial analysis, patient adverse events due to new or worsening AF were compared

•Using Cox regression and log-rank tests, the risk of AF was compared by time to

– at least 48 consecutive hours in AF

– at least 7 consecutive days in AF (persistent)

•Clinical predictors of AF were characterized

•Echo data were measured by a core lab

•Two patients in permanent AF were excluded from AF analyses

6

Baseline Demographics

7

PATIENT CHARACTERISTICS Adaptive CRT

(n=318)

Control

(n=160)

Age (yrs) 65.4 ± 11.2 66.2 ± 9.7

Male 69% 68%

NYHA III* 94% 96%

LVEF 24.7 ± 6.6 24.9 ± 6.5

QRS (ms) 154.3 ± 21.0 155.7 ± 21.4

LBBB 75% 80%

AV Block: 1st

, 2nd

, 3rd

degree 24%, 2%, 4% 21%, 3%, 3%

Ischemic 45% 51%

Beta blockers 91% 91%

ACE-i/ ARB 86% 89%

History of AF 18% (56) 19% (30)

Anti-arrhythmic drug 17% (54) 16% (26)

Oral anti-coagulation 19% (61) 23% (37)

Left Atrium Area (cm2) 23.3 + 6.6 22.8 + 6.4

*6 subjects (4 Adaptive CRT, 2 Control) NYHA I or II at baseline, but documented NYHA III or IV within 30 days of enrollment for 5 of the subjects. One subject had NYHA Class II during screening and at baseline visit.

Differences in how CRT was Delivered between Groups

8

Adaptive CRT Control Difference

Atrial Pacing (%) 28.5 + 32.7 29.4 + 32.8 -0.9% P = 0.78

Ventricular Pacing (%) 95.3 + 6.1 94.3 + 12.0 1.0% P = 0.36

RV Pacing (%) 60.0 + 37.0 94.3 + 12.0 34.3% P < 0.0001

Average duration of subject follow-up was 20.2 + 5.9 months

AF Adverse Events

9

0%

10%

20%

30%

40%

0 6 12 18 24

% P

atie

nts

wit

h a

n A

F A

dve

rse

Eve

nt

Months Since Randomization

Hazard Ratio = 0.39 (95% CI 0.19-0.79) P = 0.01

Control

Adaptive CRT 4.3%

Number at Risk Control 160 149 135 119 35 aCRT 315 292 274 258 85

12.7%

Incidence of AF

10

0%

10%

20%

30%

40%

0 6 12 18 24

% P

atie

nts

wit

h >

48

Ho

urs

of

AT/

AF

Months Since Randomization Number at Risk Control 160 141 126 109 33 aCRT 312 280 260 241 83

Hazard Ratio = 0.54 (95% CI 0.31-0.93) P = 0.03

Adaptive CRT

Control

8.7%

16.2%

11

Risk of ≥48 consecutive hours in AT/AF

Incidence of Persistent AF in Patients without AF History

12

0%

10%

20%

30%

40%

0 6 12 18 24

% P

atie

nts

wit

h P

ers

iste

nt

AT/

AF

(>

7 d

ays

of

dev

ice

det

ecte

d A

T/A

F)

Months Since Randomization

Number at Risk Control 130 117 104 95 30 aCRT 259 241 227 213 72

Hazard Ratio = 0.44 (95% CI 0.19-1.03) P = 0.05

Adaptive CRT

Control

4.1%

8.7%

AF Burden: Hours in AT/AF Per Day

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Adaptive CRT Control Difference

95% CI p-value

All Follow-up (n=472) 0.61 + 2.75 0.73 + 2.65 0.12

(-0.39, 0.63) p = 0.65

Post 1-Year Follow-up, Patient with <1 hour of AT/AF every day in 1st year (n=333)

0.01 + 0.06 0.69 + 2.85 0.68

(0.15, 1.22) p = 0.01

Post 1-Year Follow-up, Patient with ≥1 hour of AT/AF any day in 1st year (n=82)

2.98 + 6.61 3.97 + 6.68 1.00

(-2.18, 4.17) p = 0.87

Incidence of AF by Normal vs Prolonged AV

14

0%

10%

20%

30%

40%

50%

0 6 12 18 24

% P

atie

nts

wit

h >

48

Ho

urs

of

AT/

AF

Months Since Randomization

Prolonged AV: Hazard Ratio = 0.45 (95% CI 0.24-0.85) P = 0.01

Adaptive CRT – Normal AV

Control – Prolonged AV

4.2%

27.4%

Control – Normal AV 7.4%

Adaptive CRT – Prolonged AV 12.8%

Normal AV: Hazard Ratio = 0.60 (95% CI 0.19-1.85) P = 0.37

Number at Risk Control 160 141 126 109 33 aCRT 312 280 260 241 83

Left Atrial Remodeling by Treatment Arm

15

20.621.423.3

20.722.8 21.4

0

10

20

30

40

50

-6 0 6 12 18

Months

Mea

n Le

ft A

tria

l Are

a (c

m2 )

Control (n=160)

Adaptive CRT (n=318)

n

Control 145 145 132

Adaptive CRT 302 275 266

Incidence of AF w/out LA Reverse Remodeling at 6M

16

0%

10%

20%

30%

40%

0 6 12 18

% P

atie

nts

wit

h >

48

Ho

urs

of

AT/

AF

Months Since 6 Month Echo Number at Risk Control 49 41 39 8 aCRT 103 87 80 28

Hazard Ratio = 0.98 (95% CI 0.34-2.88) P = 0.98

Control LA 11.1%

Adaptive CRT LA

10.7%

Incidence of AF with LA Reverse Remodeling at 6M

17

0%

10%

20%

30%

40%

0 6 12 18

% P

atie

nts

wit

h >

48

Ho

urs

of

AT/

AF

Months Since 6 Month Echo Number at Risk Control 75 69 58 18 aCRT 153 146 137 38

Hazard Ratio = 0.26 (95% CI 0.09-0.69) P = 0.004

Adaptive CRT LA

Control LA

4.2%

15.5%

Conclusions

•Patients receiving Adaptive CRT experienced a 46% reduced incidence of AF compared to conventional CRT

•The largest effect was seen in patients without prior history of AF and in those who experienced left atrial reverse remodeling by six months

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