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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
13
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
18
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