Download Investigation of a novel algorithm for synchronized left

Investigation of a novel algorithm for synchronized leftventricular pacing and ambulatory optimization of cardiac
resynchronization therapy: Results of the adaptive CRT trial
David O. Martin, MD, MPH,* Bernd Lemke, MD,† David Birnie, MD, MB, ChB,‡
Henry Krum, MBBS, PhD,§ Kathy Lai-Fun Lee, MD,储 Kazutaka Aonuma, MD, PhD,¶
Maurizio Gasparini, MD,# Randall C. Starling, MD, MPH,* Goran Milasinovic, MD,**
Tyson Rogers, MS,†† Alex Sambelashvili, PhD,†† John Gorcsan III, MD,§§
Mahmoud Houmsse, MD, FHRS,‡‡ Adaptive CRT Study Investigators
From the *Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, †Department of Cardiolgy,
Klinikum Lüdenscheid, Lüdenscheid, Germany, ‡Divison of Cardiology, University of Ottawa Heart Institute, Ottawa,
Ontario, Canada, §Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne,
Australia, 储Cardiology Division, Queen Mary Hospital, University of Hong Kong, Hong Kong, ¶Graduate School of
Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan; #IRCCS Istituto Clinico Humanitas, Rozzano,
Italy, **Referral Pacemaker Center, Clinical Center of Serbia, Belgrade, Serbia, ††Cardiac Rhythm Disease Management, Medtronic,
Mounds View, Minnesota, §§Cardiology Division, Presbyterian University Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania,
and ‡‡Division of Cardiovascular Medicine, Ohio State University Medical Center, Columbus, Ohio.
BACKGROUND In patients with sinus rhythm and normal atrioventricular conduction, pacing only the left ventricle with appropriate atrioventricular delays can result in superior left ventricular and right ventricular
function compared with standard biventricular (BiV) pacing.
OBJECTIVE To evaluate a novel adaptive cardiac resynchronization therapy ((aCRT) algorithm for CRT pacing that provides automatic ambulatory selection between synchronized left ventricular or BiV pacing with dynamic optimization of atrioventricular
and interventricular delays.
METHODS Patients (n ⫽ 522) indicated for a CRT-defibrillator were
randomized to aCRT vs echo-optimized BiV pacing (Echo) in a 2:1
ratio and followed at 1-, 3-, and 6-month postrandomization.
RESULTS The study met all 3 noninferiority primary objectives:
(1) the percentage of aCRT patients who improved in their clinical
composite score at 6 months was at least as high in the aCRT arm
as in the Echo arm (73.6% vs 72.5%, with a noninferiority margin
of 12%; P ⫽ .0007); (2) aCRT and echo-optimized settings resulted in similar cardiac performance, as demonstrated by a high
concordance correlation coefficient between aortic velocity time
integrals at aCRT and Echo settings at randomization (concor-
The trial was sponsored by Medtronic, Mounds View, Minnesota. Dr
Martin serves on a Medtronic advisory board. Dr Lemke has received
honoraria and speaker’s fees from Medtronic and Saint Jude Medical and
speaker’s fees from Boston Scientific. Dr Birnie has received honoraria and
research grants from Medtronic. Dr Krum has received honoraria from
Medtronic. Dr Lee has received research grants from Medtronic. Dr
Aonuma has received honoraria, speaker’s fees, and research grants from
Medtronic. Dr Gasparini has received honoraria and served on advisory
boards for Medtronic and Boston Scientific. Dr Starling has received
dance correlation coefficient ⫽ 0.93; 95% confidence interval
0.91– 0.94) and at 6-month postrandomization (concordance correlation coefficient ⫽ 0.90; 95% confidence interval 0.87– 0.92);
and (3) aCRT did not result in inappropriate device settings. There
were no significant differences between the arms with respect to
heart failure events or ventricular arrhythmia episodes. Secondary
end points showed similar benefit, and right-ventricular pacing
was reduced by 44% in the aCRT arm.
CONCLUSIONS The aCRT algorithm is safe and at least as effective as
BiV pacing with comprehensive echocardiographic optimization.
KEYWORDS Cardiac resynchronization therapy; Fusion pacing; Optimization; LV pacing; Heart failure
ABBREVIATIONS aCRT ⫽ adaptive CRT; AoVTI ⫽ aortic velocity
time integral; AV ⫽ atrioventricular; BiV ⫽ biventricular;
CCS ⫽ clinical composite score; CRT ⫽ cardiac resynchronization
therapy; HF ⫽ heart failure; LV ⫽ left ventricular; RV ⫽ right ventricular; VT/VF ⫽ ventricular tachycardia/ventricular fibrillation
(Heart Rhythm 2012;9:1807–1814) © 2012 Heart Rhythm Society. All
rights reserved.
honoraria from Novartis. Dr Milasinovic has received honoraria from
Medtronic. Dr Gorcsan has consulted for or has received research grants
from Biotronik, Medtronic, St Jude Medical, GE, and Toshiba Medical. T.
Rogers is a statistician employed by Medtronic. A. Sambelashvili is a
scientist employed by Medtronic. Address for reprint requests and
correspondence: Dr David O. Martin, MD, MPH, The Cleveland Clinic
Foundation, 9500 Euclid Avenue, J2-2, Cleveland, OH 44195. E-mail
address: [email protected].
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2012.07.009
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Introduction
Cardiac resynchronization therapy (CRT) is an established
therapy for patients with heart failure (HF) symptoms, left
ventricular systolic dysfunction, and a wide QRS.1,2 However, the magnitude of clinical and hemodynamic benefit of
CRT varies significantly among its recipients with no clinical improvement in approximately one third.1 Patient-specific characteristics, such as severity and type of electrical
conduction abnormalities, dyssynchrony, and scar burden,
have been associated with the degree of CRT benefit.3,4
While CRT is most commonly achieved by using biventricular (BiV) pacing, multiple acute5 and randomized
chronic6 studies have demonstrated that left-ventricular
(LV) pacing can be at least as efficacious as BiV pacing. In
patients with sinus rhythm and normal atrioventricular (AV)
conduction, pacing only the left ventricle with appropriate
AV intervals can result in even superior LV5,7 and rightventricular (RV)8,9 function compared with standard BiV
pacing.
Optimization of the AV and interventricular (VV) intervals during BiV pacing is another option to maximize the
positive effects of CRT.10,11 Optimization is usually accomplished by using echocardiography or other modalities.
However, these methods can be resource-intensive, and
only a minority of clinicians routinely optimize AV and VV
delays.
Based on published research,7,8,12,13 a novel adaptive
CRT (aCRT) algorithm14 has been developed to provide
RV-synchronized LV pacing when AV conduction is normal, or BiV pacing otherwise. AV conduction is considered
normal when the Asense to RVsense interval is ⱕ200 ms. The
algorithm also adjusts AV and VV delays on the basis of
periodic automatic evaluation of intrinsic conduction intervals. The algorithm is intended to provide ambulatory CRT
optimization and allow more physiologic ventricular activation and greater device longevity in patients with normal
AV conduction by reducing unnecessary RV pacing. The
aim of the aCRT trial was to determine whether the incorporation of this algorithm into the management of CRT
patients is safe and efficacious when compared with BiV
pacing with echocardiographic AV and VV optimization.
Heart Rhythm, Vol 9, No 11, November 2012
morphology with a duration of ⱖ120 ms while on optimal
medical therapy.
Within 30 days prior to the implant, patients underwent
full echocardiographic evaluation of cardiac function,
global clinical status, Minnesota Living with Heart Failure
Quality of Life assessment, and 6-minute hall walk test.
Patients were then implanted with CRT-defibrillator devices
(Medtronic D224TRK, D284TRK, and D294TRK) according to the centers’ standard practices. Within 2 weeks of the
implant, AV and VV delays optimized by using echocardiography and delays recommended by the algorithm were
determined in all patients. Echocardiographic optimization
required optimal VV delay to produce the greatest aortic
velocity time integral (AoVTI), and subsequent AV optimization was done by using the iterative method.15 Echocardiographic aortic flow was acquired at the echo-optimized
and algorithm-suggested settings. The order of the settings
was randomized by the study center, and the images were
labeled in a manner that ensured that the Echo Core Lab at
the University of Pittsburgh was blinded to the device programming. The patients were then randomized in a 2:1 ratio
to CRT by using the aCRT algorithm vs standard BiV
pacing with echo-optimized AV and VV delays. Clinical
status was assessed at 1-, 3-, and 6-month postrandomization. At 6-month postrandomization, all patients underwent
echocardiographic imaging of cardiac function at the
walk-in device settings and 6-minute hall walk test. Echocardiographic optimization of the AV and VV delays was
performed and aortic flow was assessed at these echooptimized settings. All study procedures were the same for
echo-optimized and aCRT patients. Assessment of global
clinical status and administration of the quality-of-life questionnaire and 6-minute hall walk test were conducted by
clinicians blinded to the randomization assignment.
The study had 3 primary end points. The first end point
was the clinical composite score (CCS) developed by
Packer16 and used in multiple CRT trials1,2 (Figure 1). The
study sought to demonstrate that over 6-month follow-up,
the proportion of patients with improved CCS in the aCRT
Methods
Study design
Details of the algorithm and the aCRT study design have
been published previously.14 Briefly, this was a prospective,
multicenter, randomized, double-blind, noninferiority clinical trial comparing CRT with settings dynamically adjusted
by an investigational aCRT algorithm (aCRT or treatment
arm) with standard BiV pacing with AV and VV settings
optimized by using a standardized echocardiographic protocol (Echo or control arm). The study enrolled patients who
did not have permanent atrial tachyarrhythmias and were
clinically indicated for implantation of a de novo CRTdefibrillator system. The clinical indication was New York
Heart Association functional class III or IV HF symptoms,
left ventricular ejection fraction of ⱕ35%, and QRS of any
Figure 1
Clinical composite score definition. HF ⫽ heart failure;
NYHA ⫽ New York Heart Association.
Martin et al
Adaptive CRT Study Results
arm was at least as high as in the Echo arm. The second end
point required that the concordance correlation coefficient
between the AoVTI values measured for each patient under
echo-optimized and algorithm-recommended programming
exceeded 0.82 both at randomization and at 6-month postrandomization visits. AoVTI is an echocardiographic surrogate of stroke volume, and the objective was to demonstrate that cardiac function was similar when using aCRT vs
echo-optimized settings. The third end point was designed
to demonstrate that the ambulatory adjustments of the CRT
settings provided by the algorithm were safe. If any of the
AV or VV delays, stored by the algorithm in the device
memory, varied by more than 60 ms within a period of 28
days, that period was to be evaluated by an unblinded
subcommittee of the Adverse Event Adjudication Committee for safety events and appropriateness of the variation in
settings. The study sought to show that the proportion of
treatment patients experiencing any inappropriate AV and
VV delay changes within 6 months postrandomization was
⬍5%.
Although the primary end points are defined at 6-month
follow-up, patients will continue to have follow-up visits
every 6 months until study closure. All adverse events were
reviewed and classified by the Adverse Event Adjudication
Committee,14 which consisted of 2 subcommittees, one
blinded and the other unblinded to the randomization assignment. The trial was conducted in compliance with the
Declaration of Helsinki and the requirements of the local
regulatory authorities and ethics committees of the participating centers. All patients signed informed consent prior to
enrollment.
Statistical analysis and sample size
The first primary end point of CCS improvement at 6-month
follow-up was evaluated by using the Farrington-Manning
Figure 2
Flow diagram for the clinical
composite score (CCS) end point. Data on
CCS were available for all randomized patients, since CCS uses last observation carried forward (LOCF) for missing data
(LOCF was used for 2.3% of the subjects).
For the second primary objective of cardiac performance, the analyzed data included 399 aCRT patients at randomization and 235 aCRT patients at follow-up.
For the third primary objective of changes
in AV and VV delays, data from 314
aCRT patients were analyzed. AV ⫽ atrioventricular; exc ⫽ exclusive; inc ⫽ inclusive; opt. ⫽ optimized; rand. ⫽ randomized.
1809
test of 2 independent proportions with a 12% noninferiority
margin. Assuming that the proportion of improved patients
would be 72% and 70% in the aCRT and Echo arms,
respectively, a total of 470 patients (313 in the aCRT arm
and 157 in the Echo arm) were needed to evaluate the test
with 1-sided alpha level of .025 and power of 0.90. If the
noninferiority hypothesis test was passed, a subsequent test
for superiority of aCRT would be performed at the same
alpha level. For the second primary end point, the minimal
boundary of 0.82 was determined from the data on AoVTI
measurement error17 and Pearson correlation observed in
previous studies.12 The paired concordance correlation coefficient was evaluated by using a z test with 1-sided alpha
of .025 and power of 0.949 separately for the randomization
and 6-month AoVTI measurements to result in the overall
power of 0.90. For the third primary end point, a z test of
proportions was used to evaluate the hypothesis with
1-sided alpha of .025, power of 0.90, assuming that 1.5% or
less of aCRT subjects were expected to experience inappropriate AV or VV delays. The sample size for the trial was
the maximum of the sample sizes for the 3 primary hypotheses, which was 470 patients.
If all 3 primary hypotheses were passed, the secondary
hypothesis that RV pacing percentage would be reduced
from implant to 6-month postrandomization in the aCRT
arm was evaluated by using a 2-sample t test with 1-sided
alpha of .025. If this hypothesis test was passed, all other
secondary end points were evaluated for noninferiority in a
hierarchical fashion by using the same 2-sample t test. The
rest of the secondary end points included changes in LV
end-systolic volume index, left ventricular ejection fraction,
New York Heart Association classification, 6-minute hall
walk distance, and quality of life from baseline to 6-month
postrandomization.14 Following the hierarchical analysis, a
1810
Table 1
Heart Rhythm, Vol 9, No 11, November 2012
Baseline demographics and clinical history of the study patients
aCRT
(n ⫽ 318)
Age (y), mean ⫾ SD
Sex: Men, % (n)
BMI (kg/m2), mean ⫾ SD
NYHA class, % (n)
I
II
III
IV
Qualifying LVEF (%),mean ⫾ SD
Ischemic origin, % (n)
Nonischemic origin, % (n)
QRS duration (ms), mean ⫾ SD
LBBB, % (n)
Hypertension, % (n)
Renal dysfunction, % (n)
COPD, % (n)
CABG, % (n)
Heart valve surgery, % (n)
Atrial fibrillation (paroxysmal, persistent, or permanent), % (n)
ACE inhibitors or ARBs, % (n)
Beta-blockers, % (n)
Previous device, % (n)
Echo
(n ⫽ 160)
65.4 ⫾ 11.2
69 (221)
29.1 ⫾ 5.8
66.2 ⫾ 9.7
68 (109)
30.1 ⫾ 7.1
0 (0)
1 (4)
94 (300)
4 (14)
24.7 ⫾ 6.6
45 (143)
47 (151)
154.3 ⫾ 21.0
75 (240)
64 (202)
22 (70)
15 (48)
24 (76)
4 (13)
18 (56)
86 (274)
91 (289)
23 (72)
⬍1 (1)
⬍1 (1)
96 (153)
3 (5)
24.9 ⫾ 6.5
51 (81)
41 (65)
155.7 ⫾ 21.4
80 (128)
69 (110)
20 (32)
19 (31)
31 (50)
7 (11)
19 (30)
89 (143)
91 (146)
18 (29)
P
.40
.76
.11
.42
.74
.24
.16
.47
.27
.26
.61
.23
.09
.19
.76
0.32
0.89
0.25
ACE ⫽ angiotensin-converting enzyme; aCRT ⫽ adaptive cardiac resynchronization therapy; ARB ⫽ angiotensin-receptor blocker; BMI ⫽ body mass
index; CABG ⫽ coronary artery bypass grafting; COPD ⫽ chronic obstructive pulmonary disease; LBBB ⫽ left bundle branch block; LVEF ⫽ left ventricular
ejection fraction; NYHA ⫽ New York Heart Association; SD ⫽ standard deviation.
2-sample t test for superiority with 1-sided alpha of .025
was performed for each noninferiority hypothesis that was
passed under the terms of the hierarchical analysis.
Additional prespecified analyses included risk of death
or HF hospitalization, and adverse events. The occurrence
of true ventricular tachycardia and ventricular fibrillation
(VT/VF) episodes, collected by the device and adjudicated
by the Episode Review Committee, was compared between
arms.
Results
Study population
the Echo arm. The 95% confidence interval for the difference was ⬃6.9% to 9.1%, and the noninferiority objective
was met with a P value of .0007. Since the lower bound of
the confidence interval did not exceed 0%, superiority was
not demonstrated. Details on the individual components of
the CCS for 6-month postrandomization are provided in
Table 2.
Echocardiographic AoVTI was obtained for both echooptimized and aCRT settings in 399 (83.5%) patients at the
randomization visit and in 235 (73.9%) aCRT patients at the
6-month visit. The main reason for not obtaining the measurements was unreadable echocardiographic images. As
A total of 522 patients were enrolled in 94 sites in the United
States, Europe, Central Asia, Australia, Canada, Japan, and
Hong Kong between November 2009 and December 2010;
478 patients were randomized (318 to the aCRT arm and 160
to the Echo arm). The flow of study patients up to the 6-month
postrandomization is shown in Figure 2. The mean follow-up
duration was 9.7 ⫾ 3.0 months (range 0.2–19.4 months). Both
groups demonstrated similar and acceptable visit compliance
throughout the study, with more than 90% of the visits completed in both aCRT and Echo arms. Baseline demographic
characteristics of the 478 patients who were randomized are
given in Table 1.
Primary end points
Figure 3 shows the proportion of patients who improved,
worsened, or remained unchanged in their CCS at 6-month
postrandomization. In the aCRT arm, 73.6% (234 of 318) of
the patients had an improved CCS vs 72.5% (116 of 160) in
Figure 3
Clinical composite score at 6-mo postrandomization by randomization arm. The proportion of subjects improved, worsened, and
unchanged is shown for the aCRT (light gray bars) and Echo (white bars)
arms. The first primary end point compared the proportion of improved
subjects from baseline to 6-mo postrandomization (noninferiority P ⫽
.0007). aCRT ⫽ adaptive cardiac resynchronization therapy.
Martin et al
Table 2
Adaptive CRT Study Results
1811
Clinical composite response details in the aCRT and Echo groups at 6-mo postrandomization*
% (n)
Clinical composite score
aCRT
Improved
Moderately or markedly improved patient global assessment and improved NYHA class
Improved NYHA class only
Moderately or markedly improved patient global assessment only
Unchanged
Worsened
Death
Hospitalized because of or associated with worsening HF
Crossover due to worsening HF
Moderately or markedly worse patient global assessment and worsened NYHA class
Worsened NYHA class
Moderately or markedly worse patient global assessment
73.6
50.9
14.8
7.9
12.3
14.2
4.1
8.5
0.0
0.3
0.3
0.9
Echo
(234)
(162)
(47)
(25)
(39)
(45)
(13)
(27)
(0)
(1)
(1)
(3)
72.5
46.3
17.5
8.8
16.3
11.3
1.3
10.0
0.0
0.0
0.0
0.0
(116)
(74)
(28)
(14)
(26)
(18)
(2)
(16)
(0)
(0)
(0)
(0)
aCRT ⫽ adaptive cardiac resynchronization therapy; CCS ⫽ clinical composite score; HF ⫽ heart failure; NYHA ⫽ New York Heart Association.
*Note that a subject is indicated only once according to the CCS definition (eg, a subject who died and had a hospitalization for worsening HF is listed only
in the “Death” row).
seen in Figure 4, the paired AoVTI measurements follow
the line of equality closely. The lower confidence bounds
for the concordance correlation coefficient both at randomization and at 6-month postrandomization exceeded the prespecified threshold of 0.82 (P ⬍ .0001); thus, the second
primary objective was met. At randomization, the mean
AoVTI for aCRT and echo-optimized settings was 17.8 ⫾
6.0 and 18.0 ⫾ 6.2 cm, respectively (P ⫽ .18). At 6-month
postrandomization, AoVTI for aCRT and echo-optimized
settings was 17.8 ⫾ 5.2 and 18.0 ⫾ 5.2 cm, respectively
(P ⫽ .20).
Complete daily algorithm data over the entire 6-month
study period were recorded for 301 (94.7%) patients in the
aCRT arm. The reasons for missing or incomplete device
data were that the device was not interrogated after a patient’s death (n ⫽ 6) or after a missed visit (n ⫽ 2) or prior
to exit (n ⫽ 2) or because of human error (n ⫽ 7). Based on
the available device data, no patients had wide ranges of AV
or VV delays (⬎60 ms) in any 28-day period. Thus, the
third primary objective was met. During review of the
adverse events, the unblinded subcommittee of the Adverse
Event Adjudication Committee also reviewed device and
algorithm data for each adverse event and found no adverse
events related to the aCRT algorithm.
Secondary end points
Since all primary hypotheses were satisfied, the prespecified
hierarchical analysis was conducted on the secondary end
points. Ventricular pacing percentage data were collected
via device interrogations. A total of 314 of the 318 patients
in the aCRT group and all 160 patients in the control group
had at least 1 interrogation following randomization. The
percentage of ventricular pacing through 6 months in the
aCRT arm was 95.5% ⫾ 5.7% (range 35.6%–100.0%) as
compared with 95.1% ⫾ 10.5% (range 2.9%–100.0%) in
the Echo arm. In the Echo arm, virtually all ventricular
pacing was BiV, whereas in the aCRT arm BiV pacing
accounted for a median of 50.9% of all ventricular pacing,
the rest being LV-only pacing. Figure 5 shows the distribution of LV-only and BiV pacing in the aCRT patients.
Depending on a patient’s intrinsic AV conduction, percent
LV-only pacing could range from 0.0% to 97.9%. Forty-
Figure 4
Comparison of cardiac performance at the aCRT and Echo-optimized settings at randomization and 6-mo follow-up. The second primary end
point compared echocardiographic aortic velocity time integral (AoVTI) at the settings calculated by the aCRT algorithm and settings obtained using
echocardiographic optimization protocol for all subjects at randomization (left panel) and only aCRT subjects at 6-mo postrandomization (right panel).
aCRT ⫽ adaptive cardiac resynchronization therapy; CCC ⫽ concordance correlation coefficient.
1812
Heart Rhythm, Vol 9, No 11, November 2012
Figure 5
Distribution of LV-only and biventricular pacing
in the aCRT arm. Percentage of total ventricular pacing consists of percent adaptive BiV pacing (light gray) and percent
LV-only pacing (dark gray) and is displayed as 1 stacked bar
for each patient. aCRT ⫽ adaptive cardiac resynchronization
therapy; LV ⫽ left ventricular.
seven percent of aCRT patients experienced LV-only pacing at least 50% of the time. Patients with aCRT had, on
average, a 43.8% absolute reduction in RV pacing over 6
months postrandomization compared with control patients.
Table 3 lists the results for the remaining secondary end
points. Both arms demonstrated an improvement from baseline to 6-month postrandomization, and the differences between the aCRT and Echo arms were within the corresponding noninferiority margins for all secondary end points.
Superiority testing did not reach significance for any of
these end points.
Additional analyses
Death and HF hospitalizations at 6-month follow-up are
presented in Table 2. Further examination of all follow-up
data available at the time of the 6-month analysis data lock,
Table 3
which includes follow-up after the 6-month visit, was done.
There were a total of 18 deaths and 71 HF hospitalizations
(46 patients) in the aCRT arm and 7 deaths and 34 HF
hospitalizations (21 patients) in the Echo arm. At the mean
follow-up of 9.7 months, the mortality rate was 7.5% in the
aCRT arm and 8.8% in the Echo arm and the rate of first HF
hospitalization was 18.6% in the aCRT arm and 16.1% in
the Echo arm. Neither mortality (log-rank P ⫽ .47) nor first
HF hospitalization (log-rank P ⫽ .61) rates were significantly different between the arms.
There was no difference in time to first occurrence of
VT/VF between the aCRT and Echo arms (log-rank P ⫽
.87). The rate of VT/VF per patient-year was 1.68 in the
aCRT arm and 0.88 in the Echo arm and was not significantly different (generalized estimating equations [GEE]
Structural and functional secondary end points
aCRT (n ⫽ 318)
n
Mean ⫾ SD
Echo (n ⫽ 160)
n
Mean ⫾ SD
Difference (95% CI)
P* (margin)
2
LVESVi (mL/m )
Baseline
6-mo postrandomization
Paired difference at 6 mo
LVEF (%)
Baseline
6-mo postrandomization
Paired difference at 6 mo
NYHA
Baseline
6-mo postrandomization
Paired difference at 6 mo
6-min walk distance (m)
Baseline
6-mo postrandomization
Paired difference at 6 mo
MLWHF QOL
Baseline
6-mo postrandomization
Paired difference at 6 mo
291
268
250
71.7 ⫾ 28.3
63.5 ⫾ 31.9
⬃8.3 ⫾ 23.3
140
137
123
74.0 ⫾ 30.9
64.7 ⫾ 32.7
⬃10.5 ⫾ 24.2
2.3 ⬃(2.8 to 7.4)
⬍.0001 (15)
291
268
250
29.6 ⫾ 9.2
33.6 ⫾ 10.4
3.9 ⫾ 10.0
140
137
123
30.3 ⫾ 8.4
32.9 ⫾ 10.1
2.9 ⫾ 9.8
1.0 ⬃(1.2 to 3.1)
0.0009 ⬃(2.5)
⬍.0001 (0.3)
318
296
296
3.0 ⫾ 0.2
2.0 ⫾ 0.8
⬃1.0 ⫾ 0.8
160
153
153
3.0 ⫾ 0.3
2.2 ⫾ 0.8
⬃0.8 ⫾ 0.8
⬃0.15 (0.3 to 0.0)
312
288
284
276.8 ⫾ 127.5
325.5 ⫾ 130.4
42.4 ⫾ 103.3
156
146
142
277.7 ⫾ 137.8
311.4 ⫾ 152.0
29.0 ⫾ 123.0
13.4 ⬃(8.9 to 35.7)
286
263
261
48.5 ⫾ 24.1
28.2 ⫾ 22.0
⬃19.3 ⫾ 20.7
142
139
135
46.3 ⫾ 23.6
28.4 ⫾ 23.0
⬃17.6 ⫾ 23.8
⬃1.7 ⬃(6.3 to 2.8)
0.0002 ⬃(30)
0.002 (5.1)
aCRT ⫽ adaptive cardiac resynchronization therapy; CI ⫽ confidence interval; LVEF ⫽ left ventricular ejection fraction; LVESVi ⫽ LV end-systolic volume
index; MLWHF ⫽ Minnesota Living With Heart Failure; NYHA ⫽ New York Heart Association; QOL ⫽ quality of life; SD ⫽ standard deviation.
*P value for noninferiority between aCRT and Echo arms.
Martin et al
Adaptive CRT Study Results
P ⫽ .46). There were 3 patients (2 aCRT, 1 Echo) who had
VT/VF episode counts exceeding 3 standard deviations
from the mean. The 2 aCRT patients had 19 and 128
episodes, whereas the Echo patient had 19 episodes. To
account for these outliers, a sensitivity analysis was performed by substituting the number of episodes
in the outliers with the median number of episodes (2)
among the rest of the subjects with VT/VF. After this
adjustment, the aCRT group had 0.53 events per patientyear vs 0.66 events per patient-year in the Echo group.
The odds of an improved CCS were compared between
aCRT and Echo arms for typically considered subgroups
(Figure 6). For left ventricular ejection fraction and QRS
duration, the subgroups were defined by the quartiles and
subgroup analyses tested for a linear trend. The analysis
demonstrated comparable results across subgroups.
We also analyzed the subgroup of patients in sinus
rhythm with normal AV conduction and left bundle branch
block before randomization, as one would expect this subgroup to benefit from LV fusion pacing the most. Within
this subgroup (n ⫽ 219; 45.8%), there were no significant
differences between the arms in baseline demographics and
total percent atrial and ventricular pacing, but the aCRT
patients received LV-only pacing 64.0% ⫾ 32.8% of the
time. In this subgroup, more aCRT patients improved in
CCS compared with the Echo arm (80.7% vs 68.4%; P ⫽
Figure 6 Improved clinical composite score by subgroups. CRT ⫽
cardiac resynchronization therapy; LBBB ⫽ left bundle branch block;
LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart
Association.
1813
.04), with an odds ratio of 1.94 for improved CCS (95%
confidence interval 1.03–3.65).
Discussion
The aCRT trial evaluated a novel pacing algorithm for CRT.
The design of the algorithm was based on the hypothesis
that CRT benefit can further be increased through (1) avoidance of RV pacing and greater recruitment of intrinsic
conduction in patients with normal conduction into the right
ventricle and (2) dynamic adjustment of AV and VV delays
based on the electrical conduction intervals. The aCRT
algorithm resulted in a 44% absolute reduction in the percentage of RV pacing. The trial demonstrated that optimization provided by the aCRT algorithm is safe and noninferior to echocardiographic optimization with respect to
clinical, structural, and functional improvement at 6-month
postrandomization.
Among patients with intact AV conduction, LV dysfunction, and a narrow QRS, it is well accepted that RV pacing
is to be avoided as it results in a higher incidence of HF,
presumably due to iatrogenic ventricular dyssynchrony
caused by RV pacing.18 One can speculate that substituting
intrinsic RV activation with RV-paced activation may also
be unnecessary in patients with left bundle branch block and
LV dysfunction. Multiple acute studies proposed incremental superiority of appropriately timed LV pacing over simultaneous BiV pacing in the CRT subpopulation with
sinus rhythm and intact AV conduction5. For instance, van
Gelder et al7 compared invasive hemodynamic measurements under simultaneous BiV pacing and LV-only pacing
at a variety of AV delays in 34 CRT patients who had sinus
rhythm and intact AV conduction. The authors found that
LV-only pacing produced a higher maximum LV pressure
rise (dP/dtmax) than BiV pacing, but only when LV pacing
was timed to fuse with intrinsic ventricular activation.
RV pacing may also have deleterious effects on RV
function. In an acute hemodynamic study using 17 CRT
patients with sinus rhythm and intact AV conduction, Lee et
al8 found that BiV pacing suppressed RV dP/dtmax, whereas
LV pacing synchronized to preempt intrinsic conduction did
not. To evaluate the mechanism of this further, Varma et al9
used electrocardiographic mapping to assess ventricular activation by using RV-only, LV-only, and BiV pacing at
optimized AV intervals in 14 CRT recipients. RV pacing,
whether alone or as part of BiV pacing, produced RV
activation delays, which were avoided with LV pacing.
The previous studies suggested that LV fusion pacing is
most likely to benefit patients with left bundle branch block
and normal AV conduction.7 In the present trial, this patient
subgroup primarily received synchronized LV pacing and
demonstrated a higher improvement in CCS with the aCRT
algorithm. Further investigation of clinical outcomes over longer follow-up is needed to support the benefit of synchronized
LV pacing.
The present trial compared the aCRT algorithm to BiV
pacing with echocardiographic optimization, utilized in
multiple CRT trials and recommended by the American
1814
Society of Echocardiography.15 Although the clinical benefit of echocardiographic optimization was not demonstrated in 1 multicenter trial,19 smaller studies have suggested a positive impact on clinical condition10 or exercise
tolerance.11 In contrast to previous device optimization trials,19, 20 the control arm in the present study had both AV
and VV delays optimized by using a mandatory standardized protocol.
Electrocardiographic CRT optimization algorithms have
previously been proposed and evaluated.19,20 However, these
algorithms reside in a device programmer and provide only
in-office optimization, which may be insufficient, since optimal settings may change with time and patient activity.21 The
aCRT algorithm is unique in that it permits dynamic AV and
VV optimization with the option of synchronized LV pacing.14
Based on bench-testing, the algorithm itself has negligible
impact on battery life. The synchronized LV-pacing option
should improve the longevity of the device and may benefit
patients with normal AV conduction. Interestingly, the recent
GREATER-EARTH trial,6 which utilized a cross-over design
to compare LV pacing with BiV pacing, showed that 17.1% of
the nonresponders to BiV pacing improved with LV pacing.
Our findings suggest that the aCRT algorithm may offer clinicians and patients enhanced options to improve response to
CRT.
Study limitations
The specific echocardiographic optimization approach chosen for the treatment arm may be no better than other
optimization methods or no optimization at all. The study
was conducted in a population of New York Heart Association HF class III and IV patients without permanent atrial
tachyarrhythmias, and so the results cannot be generalized
to patients with permanent atrial fibrillation or to less symptomatic patients. Longer-term follow-up is needed to confirm the safety of the algorithm with respect to mortality and
hospitalizations. Inappropriate AV and VV delay changes
caused by the aCRT algorithm were defined as changes of at
least 60 ms. It is possible that smaller variations could have
an adverse impact on clinical condition. Missing device
interrogation data from aCRT patients (5.3% of the patients
had at least 1 interrogation missing) could have had safetyrelated information.
Conclusions
The aCRT algorithm was safe and at least as effective as
BiV pacing with comprehensive echocardiographic optimization across a variety of primary and secondary end points.
Supplement
A complete list of primary investigators in the Adaptive
CRT Clinical Trial is available online.
Heart Rhythm, Vol 9, No 11, November 2012
References
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Adaptive CRT Study Results
Appendix
The authors would like to congratulate the achievements
and acknowledge the contributions made by the following primary investigators in the Adaptive CRT Clinical
Trial: Dr. Vikram Nangia, Aurora Sinai Medical Center,
USA; Dr. Peter Wells, Baylor Jack and Jane Hamilton Heart
and Vascular Hospital, USA; Dr. Andrew Merliss, BryanLGH Heart Institute, USA; Dr. Irfan Khan, Buffalo Heart
Group LLC, USA; Dr. James Stone, Cardiology Associates
of North Mississippi, USA; Dr. David Rodak, Spartanburg
Regional Healthcare System, USA; Dr. Sung Lee, Washington Adventist Hospital, USA; Dr. Simon Milstein, Central Minnesota Heart Center, USA; Dr. David Martin,
Cleveland Clinic Foundation, USA; Dr. Thomas Svinarich,
Colorado Heart and Vascular, PC, USA; Dr. Daniel Lustgarten, Fletcher Allen Health Care, USA; Dr. Robert Sorrentino, Georgia Health Sciences University, USA; Dr. John
McKenzie, Glendale Memorial Hospital & Health Center,
USA; Dr. Jonathan Hobson, Heart & Vascular Institute of
Florida, USA; Dr. Jeffrey Scott Allison, Heart Center Research LLC, USA; Dr. Van De Bruyn, Heart Clinic Arkansas PA, USA; Dr. Timothy Lessmeier, Heart Clinics Northwest PS, USA; Dr. W. Ben Johnson, Iowa Heart Center PC,
USA; Dr. Satish Goel, Jacksonville Heart Center, USA; Dr.
Martin Emert, Kansas University Medical Center Research
Institute Inc, USA; Dr. Robert Lerman, LA Cardiology
Associates, USA; Dr. Muqtada Chaudhry, Lahey Clinic
Hospital Inc, USA; Dr. Steven Klein, LeBauer Cardiovascular Research Foundation, USA; Dr. Michael Imburgia,
Louisville Cardiology Medical Group PSC, USA; Dr. Michael Gold, Medical University of South Carolina, USA;
Dr. Liaqat Zaman, Michigan Cardiovascular Institute, USA;
Dr. Brian Ramza, Mid America Heart Institute, USA; Dr. J.
Russell Bailey, Mid Carolina Cardiology, USA; Dr. David
Bello, Mid Florida Cardiology, USA; Dr. Blair Foreman,
Midwest Cardiovascular Research Foundation, USA; Dr.
Raymond Kawasaki, Midwest Heart Foundation, USA; Dr.
John Lobban, Morgantown Internal Medicine Group, USA;
Dr. Jay Curwin, Morristown Memorial Hospital, USA; Dr.
Gioia Turitto, New York Methodist Hospital, USA; Dr.
Jonathan Lowy, North Cascade Cardiology, USA; Dr. Sree
Karanam, Northern Indiana Research Alliance, USA; Dr.
Eric Putz, Northwest Cardiovascular Institute, USA; Dr.
Jack Collier, Oklahoma Cardiovascular Research Group,
USA; Dr. Jay Simonson, Park Nicollet Institute, USA; Dr.
Brad Mikaelian, Pikes Peak Cardiology, USA; Dr. Steven
Compton, Providence Alaska Medical Center, USA; Dr.
Luis Pires, Saint John Hospital and Medical Center, USA;
Dr. J. Timothy Walsh, Saint Vincent’s Ambulatory Care
Inc, USA; Dr. Manish Wadhwa, San Diego Arrhythmia
Associates, USA; Dr. John Herre, Sentara Norfolk General
Hospital, USA; Dr. Robert Canby, Texas Cardiac Arrhythmia Research, USA; Dr. Keith Bruce, The Chattanooga
Heart Institute, USA; Dr. Mahmoud Houmsse, The Ohio
State University Medical Center, USA; Dr. John Sims and
Dr. Robert Carney, Tyler Cardiovascular Consultants, USA;
1814.e1
Dr. Alan Bank, United Heart and Vascular Clinic, USA; Dr.
Mark Borganelli, University of Mississippi Medical Center,
USA; Dr. Walter Clair, Vanderbilt University, USA; Dr.
Richard Shepard, Virginia Commonwealth University
Health System, USA; Dr. Jim Cheung, Weill Medical College of Cornell University, USA; Dr. Darryl Elmouchi,
West Michigan Heart, USA; Dr. F. Heath, Aalborg Sygehus, Denmark; Dr. A. Kypta, Allgemeines Krankenhaus der
Stadt Linz, Austria; Dr. P.T. Mortensen, Århus Universitetshospital Skejby, Denmark; Dr. F. Voss, Barmherzige
Brüder Trier e.V. - Krankenhaus der Barmherzigen Brüder
Trier – Akademisches Lehrkranken, Germany; Dr. T. Lawo,
Berufsgenossenschaft liche Universitätsklinik Bergmannsheil GmbH, Germany; Dr. L.H.R. Bouwels, Canisius-Wilhelmina ziekenhuis, the Netherlands; Prof. G. Milasinovic,
Clinical Center of Serbia, Republic of Serbia; Dr. M.E.
Landolina, Fondazione IRCCS Policlinico San Matteo, Italy; Prof. S. Faerestrand, Helse Bergen HF – Haukeland
Universitetssjukehus, Norway; Dr. M. López Gil, Hospital
Universitario 12 de Octubre, Spain; Prof. D.V. Kovacevic,
Institut za Kardiovaskularne Bolesti Vojvodine, Republic of
Serbia; Prof. M. Gasparini, IRCCS Istituto Clinico Humanitas - Humanitas Mirasole Spa, Italy; Dr. J. Hörnsten, Karolinska Universitetssjukhuset, Sweden; Prof. Z. Perisic, Klinicky Centar Niš, Republic of Serbia; Prof. H. Nägele,
Krankenhaus Reinbek St. Adolf Stift, Germany; Dr. M.
Scheffer, Maasstad Ziekenhuis - Lokatie St. Clara, the Netherlands; Prof. B. Lemke, Märkische Gesundheitsholding
GmbH & Co. KG – Klinikum Lüdenscheid, Germany; Dr.
A. Brandes, Odense Universitetshospital, Denmark; Dr. E.
Kongsgård, Oslo Universitetssykehus, Rikshospitalet, Norway; Dr. C. Hassager, Rigshospitalet, Denmark; Dr. A.
Hersi, The College of Medicine & King Khalid University
Hospital, King Saud University, Saudi Arabia; Dr. V.A.
Kuznetsov, Tyumen Cardiology Center, Russia; Dr. M.A.
Aydin, Universitäres Herzzentrum Hamburg GmbH (UHZ),
Germany; Dr. R. Borgquist, Universitetssjukhuset i Lund,
Sweden; Dr. W. Mullens, Ziekenhuis Oost Limburg – Campus St.-Jan, Belgium; Dr. Vince Paul, Royal Perth Hospital,
Australia; Dr. Michael Kilborn, Royal Prince Alfred Hospital, Australia; Dr. John Hayes, St. Andrew’s Hospital,
Australia; Dr. Bruce Walker, St Vincent’s Hospital Sydney,
Australia; Dr. Russell Denman, The Prince Charles Hospital, Australia; Prof. Prashanthan Sanders, Royal Adelaide
Hospital, Australia; Dr. Raymond Yee, London Health Sciences Centre - University Campus, Canada; Dr. Yaariv
Khaykin, Newmarket Electrophysiology Research Group,
Canada; Dr. Glen Sumner, University of Calgary Libin
Cardiovascular Institute, Canada; Dr. David Birnie, University of Ottawa Heart Institute, Canada; Dr. Anthony Tang,
Victoria Cardiac Arrhythmia Trials Inc, Canada; Dr. Shiro
Kamakura, National Cerebral and Cardiovascular Center,
Japan; Dr. Kazutaka Aonuma, Tsukuba University Hospital,
Japan; Dr. Hung-Fat Tse, Queen Mary Hospital, Hong
Kong.