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CLINICAL RESEARCH
Heart failure/cardiomyopathy
The effect of QRS duration on cardiac
resynchronization therapy in patients with a
narrow QRS complex: a subgroup analysis
of the EchoCRT trial
Jan Steffel1, Michele Robertson2, Jagmeet P. Singh3, William T. Abraham4,
Jeroen J. Bax5, Jeffrey S. Borer6, Kenneth Dickstein7, Ian Ford2, John Gorcsan III8,
Daniel Gras9, Henry Krum10, Peter Sogaard11, Johannes Holzmeister1,
Josep Brugada12, and Frank Ruschitzka1*
1
Department of Cardiology, Heart Failure Clinic and Transplantation, University Heart Center Zurich, Zurich, Switzerland;
2
Robertson Centre for Biostatistics, University of Glasgow,
Glasgow, UK;
3
Cardiac Arrhythmia Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;
4
Division of Cardiovascular Medicine, Ohio State University
Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, USA;
5
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands;
6
Division of
Cardiovascular Medicine and Howard Gilmanand Ron and Jean Schiavone Institutes, State University of New York Downstate College of Medicine, New York, NY, USA;
7
University of
Bergen, Stavanger University Hospital, Stavanger, Norway;
8
University of Pittsburgh, Pittsburgh, PA, USA;
9
Nouvelles Cliniques Nantaises, Nantes, France;
10
Monash Centre of
Cardiovascular Research and Education in Therapeutics, Melbourne, VIC, Australia;
11
Aalborg University, Aalborg, Denmark; and
12
Cardiology Department, Thorax Institute, Hospital
Clinic, University of Barcelona, Spain
Received 30 April 2015; revised 10 May 2015; accepted 14 May 2015; online publish-ahead-of-print 25 May 2015
See page 1948 for the editorial comment on this article (doi:10.1093/eurheartj/ehv264)
Aims In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS
duration of ,130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred
more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT
is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data
regarding the benefit of patients with a QRS duration of 120–130 ms.
Methods
and results
The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared
data for CRT-ON vs. -OFF in patients with QRS ,120 (n¼661) and QRS 120–130 ms (n¼139). On uni- and multi-
variable analyses, no significant interaction was observed between the two groups and randomized treatment for
the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was
observed in patients with a QRS duration of 120 – 130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18,
95% CI 1.02–4.65; P¼0.044). However, no statistically significant interaction, compared with patients with
QRS ,120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction ¼0.160).
Conclusions In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of
120–130 ms. These data further question the usefulness of CRT in this patient population.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Cardiac resynchronization therapy †Narrow QRS †QRS duration
Introduction
In view of the reduction in morbidity and mortality observed in large
clinical trials, cardiac resynchronization therapy (CRT) has become
an important element of modern day heart failure therapy. Current
guidelines recommend CRT implantation for patients with symp-
tomatic chronic heart failure (CHF), a severely reduced left ven-
tricular ejection fraction (EF ≤35%) and a QRS complex
≥120 ms, based on published landmark studies.
1–4
While patients
with left bundle branch block (LBBB) have a class I indication for
*Corresponding author. Tel: +41 44 255 40 39, Fax: +41 44 255 87 01, Email: frank.ruschitzka@googlemail.com
Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2015. For permissions please email: journals.permissions@oup.com.
European Heart Journal (2015) 36, 1983–1989
doi:10.1093/eurheartj/ehv242
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CRT, class IIa and IIb indications are given to patients with non-LBBB
and a QRS duration ≥150 and 120 – 150 ms, respectively. Although
inclusion criteria of previous landmark trials usually allowed patients
with a QRS duration ≥120 ms to enter the trial, the majority of
individuals had longer QRS durations (≥150 ms). Indeed, recent
meta-analyses have questioned the benefit of CRT in patients
with shorter QRS duration, i.e. a QRS duration of ,130 –
150 ms.
5,6
As such, there is some ambiguity regarding the optimal
cut-off QRS duration for CRT and, specifically, whether patients
at lower end of current recommendations (i.e. with a QRS duration
of 120 – 130 ms) truly benefit from CRT.
EchoCRT was a randomized trial evaluating the effect of CRT in
patients with a QRS duration of ,130 ms and echocardiographic
evidence of left ventricular dyssynchrony as previously described
(ClinicalTrials.gov Identifier: NCT00683696).
7
The trial was termi-
nated early due to futility. Moreover, a significant relative increase
in all-cause mortality of 81% was observed in the CRT-ON vs.
-OFF group. As a result of EchoCRT, current guidelines recommend
against the use of CRT in patients with a QRS duration of ≤120 ms.
4
Whether the lack of benefit for CRT applies to the entire EchoCRT
cohort, or whether patients with a longer QRS duration (i.e. 120–
130 ms) may derive a benefit from CRT, is presently elusive. This
is of clinical importance as these patients are currently indicated
to receive CRT, albeit with conflicting results as stated. The current
pre-specified subgroup analysis was therefore conducted to assess
whether QRS duration has an impact on clinical outcome in patients
enrolled in EchoCRT.
Methods
Study design and conduct
The EchoCRT study was an investigator-initiated, international, multi-
centre, randomized, clinical trial. The outcome results of the main trial
have previously been reported, including the complete study protocol.
7
In brief, the trial was designed by the executive committee and spon-
sored by Biotronik, with a support for echocardiographic training and
software provided by GE Healthcare. All study results were inde-
pendently analysed at the Robertson Centre for Biostatistics at the Uni-
versity of Glasgow. Patients were eligible if they had New York Heart
Association (NYHA) class III or IV heart failure; a left ventricular ejec-
tion fraction of 35% or less; a standard indication for an implantable
cardioverter-defibrillator (ICD); optimized medical heart failure ther-
apy; a QRS duration of ,130 ms; a left ventricular end-diastolic diam-
eter of 55 mm or more; and echocardiographic evidence of left
ventricular dyssynchrony as previously defined.
7
A 12-lead electrocar-
diogram obtained using a standard electrocardiograph at a speed of
25 mm/s was used to confirm QRS duration eligibility criteria at base-
line, prior to implant. The 12-lead electrocardiogram was submitted
to the ECG Core Laboratory for independent confirmation. QRS dura-
tions as measured by the independent corelab were used for the current
analysis. As for the main publication,
7
our current analysis comprised all
patients included in EchoCRT (with screening QRS measurements per-
formed by the including centre). In 16 of the included patients, a QRS of
≥130 ms was measured by the independent core lab. Eliminating these
16 patients from the analyses resulted in overall consistent results with
the reported outcomes of the entire cohort.
After implantation of a Biotronik Lumax HF-T CRT-D system, pa-
tients were randomly assigned in a 1:1 ratio to have CRT capability
turned on (the CRT group) or to have CRT capability turned off
(the control group). Device-implanting physicians were aware of the
study-group assignments, but patients, heart failure physicians, and study
personnel completing the follow-up assessments were unaware of the
group assignments.
The study was conducted in accordance with the Declaration of
Helsinki.
Endpoints
The primary efficacy outcome was the combination of death from any
cause or first hospitalization for worsening heart failure.
7
The primary
safety outcome was freedom from CRT-D-related complications at
6 months. The pre-specified secondary outcomes included all hospita-
lizations for worsening heart failure throughout the study; changes in
NYHA classification after 6 months; changes in quality of life (QOL;
as measured by the Minnesota Living with Heart Failure questionnaire
after 6 months); a study-specific score based on the composite outcome
of death, first hospitalization for worsening heart failure (up to
24 months), and change in the score on the Minnesota Living with Heart
Failure questionnaire after 6 months; and all-cause mortality.
7
Statistical analysis
All analyses were performed according to the intention-to-treat
principle. Baseline characteristics were compared with the use of
two-sample t-tests and
x
2
(or Fisher’s exact) tests for continuous and
categorical variables, respectively. Hazard ratios (HRs) for CRT-ON
and -OFF with 95% CIs were calculated with the Cox proportional
hazards models for each QRS duration strata including the stratification fac-
tor of country in the model. Additionally, a multivariable Cox proportional
hazards model was performed to account for differences across rando-
mized treatment groups in baseline characteristics between QRS duration
strata [country, age, gender, QOL score, systolic blood pressure (SBP), is-
chaemic cardiomyopathy, coronary artery bypass grafting, chronic kidney
disease, left ventricular end-diastolic diameter (LVEDD), and qualification
by tissue Doppler imaging (TDI), and/or radial dyssynchrony]. Interactions
between QRS duration strata and treatment (CRT ¼ON and CRT ¼
OFF) were tested for in Cox models that included QRS duration strata
and treatment main effects and interaction terms. Time to event curves
were estimated with the use of the Kaplan– Meier method.
Changes in NYHA class from baseline to 6 months were analysed as a
binary outcome (improved condition vs. no change or deteriorated con-
dition) with the use of a logistic-regression model with adjustment for
country of recruitment. The change in total score on the Minnesota Liv-
ing with Heart Failure questionnaire was analysed with theuse of an ana-
lysis of co-variance with adjustment for the baseline total score and
country of recruitment.
All tests were two sided with a P,0.05 considered to be significant.
SAS version 9.2 was used for all analysis.
Results
Baseline parameters at the time of trial entry are presented in
Table 1. Compared with patients with QRS ,120 ms, patients
with a QRS of 120– 130 ms were older, more frequently males
had larger end-diastolic left ventricular diameters, and more
frequently had underlying ischaemic cardiomyopathy and chronic
kidney disease.
333/661 patients (50%) and 65/139 (47%) of patients with QRS dur-
ation of ≤120 ms and QRS 120 – 130, respectively, were randomized
to CRT-ON. There was no statistically significant interaction regarding
J. Steffel et al.1984
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the primary outcome for CRT-OFF vs. CRT-ON in patients with
QRS ,120 ms when compared with QRS ≥120 ms (Figures 1and
2). In unadjusted analysis, a higher cardiovascular mortality was ob-
served in CRT-ON vs. -OFF in patients with QRS ,120 ms (P,
0.003), which was not observed in patients with QRS ≥120 ms (albeit
without a significant interaction; P-interaction ¼0.153; Figure 2).
On multivariable adjustment (Figure 3), an apparent increase in the
primary endpoint as well as in recurrent CHF hospitalization was ob-
served for patients with a QRS of ≥120 ms, but not with a QRS of
,120 ms (which again, however, was not significant on interaction
analysis). For ‘cardiovascular mortality’ and ‘heart failure mortality’
the absolute low number of events precluded adjusting for all baseline
variables. We therefore performed a limited multivariable analysis,
adjusting only for ischaemic cardiomyopathy, age, and LVEDD. The
results were consistent with the univariable analyses for cardiovascu-
lar mortality (QRS ,120 ms: HR 2.85 (95% CI 1.37– 5.90), P¼
0.0049 vs. QRS ≥120 ms: HR 1.78 (95% CI 0.56– 5.64), P¼0.33,
P-interaction ¼0.23) and heart failure mortality (QRS ,120 ms:
HR 1.86 (95% CI 0.74– 4.68), P¼0.19 vs. QRS ≥120 ms: HR 1.16
(0.12– 11.08), P¼0.90; P-interaction ¼0.40).
...............................................................................................................................................................................
...............................................................................................................................................................................
Table 1 Baseline characteristics
Variable QRS <120 (n5661) QRS 120–130 (n5139) P-value
Age (years) 57.2 (12.82) 61.8 (11.83) ,0.001
Males 466 (70.50%) 110 (79.14%) 0.039
Walking distance (m) 324.9 (121.21) 325.7 (114.40) 0.944
Quality-of-life score 52.3 (24.16) 45.4 (24.05) 0.002
NYHA classification
I 3 (0.45%) 2 (1.44%) *
II 14 (2.12%) 4 (2.88%)
III 624 (94.40%) 128 (92.09%)
IV 20 (3.03%) 5 (3.60%)
BNP (pg/mL)
#
249.0 (92.00, 540.00) 322.0 (120.00, 613.00) 0.288
NT-proBNP (pg/mL)
#
1080.5 (427.00, 2447.0) 1232.0 (609.00, 1870.0) 0.505
Sitting SBP (mmHg) 118.2 (18.93) 122.0 (20.62) 0.035
Sitting DBP (mmHg) 72.8 (11.82) 72.8 (11.98) 0.952
BMI (kg/m
2
) 30.8 (11.61) 31.3 (14.84) 0.656
Ischaemic cardiomyopathy 338 (51.21%) 89 (64.03%) 0.006
Myocardial infarction .3 months ago 252 (38.12%) 65 (46.76%) 0.058
PCI .3 months ago 237 (35.85%) 49 (35.25%) 0.893
CABG .3 months ago 114 (17.25%) 35 (25.18%) 0.029
Hypertension 427 (65.19%) 100 (72.46%) 0.100
Congenital heart disease 14 (2.15%) 2 (1.47%) 1.000
Prior ischaemic stroke or TIA 74 (11.28%) 19 (13.77%) 0.409
Diabetes 264 (40.12%) 52 (37.41%) 0.553
Chronic lung disease 118 (18.04%) 31 (22.30%) 0.243
Chronic kidney disease 80 (12.20%) 26 (18.84%) 0.037
LVEF biplane (%) 27.1 (5.59) 26.8 (5.40) 0.657
LV end-diastolic diameter (mm) 65.8 (7.32) 69.2 (8.09) ,0.001
Qualified by TDI and/or radial dyssynchrony
TDI only 178 (26.97%) 22 (15.83%) 0.012
Radial strain only 152 (23.03%) 31 (22.30%)
TDI and radial strain 330 (50.00%) 86 (61.87%)
ACE inhibitor or ARB 627 (94.86%) 131 (94.24%) 0.769
Aldosterone antagonist 397 (60.06%) 83 (59.71%) 0.939
b-Blocker 640 (96.82%) 134 (96.40%) 0.800
Diuretic agent 571 (86.38%) 121 (87.05%) 0.835
For categorical variables, number and percentage are reported; for continuous variables, mean and SD are reported (except for BNP and NT-proBNP where median and
inter-quartile range are presented).
SBP, systolic blood pressure; DBP, diastolic blood pressure; TIA, transient ischaemic attack; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; BMI,
body mass index; NYHA, New York Heart Association; BNP, brain natriuretic peptide; LV, left ventricular; EF, ejection fraction; TDI, tissue Doppler imaging; ACE, angiotensin
converting enzyme; ARB, angiotensin receptor blocker.
#
BNP: n¼329 and 62; NT-proBNP: n¼308 and 71.
*P-value is not reported due to small numbers.
Effect of QRS duration in EchoCRT 1985
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There was no difference in changes in Minnesota Living with Heart
Failure, NYHA class, BNP/NT-proBNP, or 6 min walking distance
from baseline to 6 months between the two groups (data not shown).
When results were analysed based on four groups of QRS dur-
ation (QRS ,100 ms (n¼236), QRS 100– 109 ms (n¼227),
QRS 110–119 ms (n¼198), and QRS ≥120 ms (n¼139)), a simi-
lar picture was observed (Supplemental material online, Tables S1
and S2). Again, no statistically significant interaction was seen
regarding the primary outcome for CRT-OFF vs. CRT-ON in pa-
tients with QRS ,120 ms when compared with QRS ≥120 ms.
However, some numerical trends towards an increased hazard
were observed for QRS ≥120 ms in uni- and multivariable analysis.
As in the overall study,
7
the primary safety endpoint of CRT-
D-related complications were significantly more frequent in the
CRT-ON when compared with the control group. This difference
was similar in patients with QRS ≤120 ms and QRS 120 –130 ms:
Figure 1 Kaplan – Meier estimates for primary outcome events, stratified by QRS duration. Kaplan– Meier curves for the primary composite
outcome of death from any cause or hospitalization for heart failure in patients randomized to CRT-ON and -OFF, stratified by QRS duration.
Figure 2 Endpoint results by QRS duration. Hazard ratio (95% confidence interval) adjusted for country and P-value from Wald test are pre-
sented. Data for QRS ,120 ms (black) and QRS 120 –130 ms (red) are shown.
J. Steffel et al.1986
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CRT-D system-related complications occurred in 47/333 (14.11%)
and 24/328 (7.32%) patients with CRT-ON vs. CRT-OFF, respect-
ively, in patients with QRS duration of ≤120 ms, and 8/65 (12.31%)
and 5/74 (6.76%) patients with CRT-ON vs. CRT-OFF, respectively,
in patients with QRS duration of 120 – 130 ms.
Discussion
Prior to EchoCRT, several small single-centre studies with soft end-
points had indicated a potential benefit of CRT in patients with a
narrow QRS complex and echocardiographic evidence of dyssyn-
chrony.
8–10
Moreover, several small pilot outcome trials failed to
demonstrate consistent results,
11 –13
underlining the necessity for
EchoCRT, a large, endpoint-driven randomized clinical trial to
adequately assess this issue. The EchoCRT trial was terminated early
due to futility, indicating that CRT did not reduce the occurrence of
first hospitalization for heart failure or death from any cause in this
patient population.
7
Postulating a decreasing benefit of CRT with
decreasing QRS duration, as indicated earlier, our current subgroup
analysis investigated those individuals from EchoCRT most likely to
respond to CRT, i.e. those with the longest QRS complex within the
inclusion criteria. However, our results indicate that the primary
outcome of EchoCRT is consistent in patients with different QRS
durations. There was no signal for a benefit in any subgroup of
QRS duration; particularly, patients with a QRS of 120– 130 ms
did not benefit when compared with patients with a shorter QRS
duration.
Based on the inclusion criteria of published landmark trials, cur-
rent guidelines recommend CRT for patients with symptomatic
CHF, a severely reduced left ventricular ejection fraction (EF ≤
35%) and a QRS complex ≥120 ms.
1–4
However, the majority of
included individuals had longer QRS durations. Indeed, the median
QRS duration in CARE-HF was 160 ms (interquartile range 152–
180);
1
along the same line, 65% of patients included in MADIT-CRT
had a QRS duration of ≥150 ms.
14
Several subgroup analyses have
indicated a more pronounced benefit of CRT in patients with longer
QRS duration. In MADIT-CRT, patients with QRS ≥150 ms
showed a 52% reduction in the primary endpoint with CRT vs.
ICD, while those with a QRS of ,150 had no benefit from CRT
(P-interaction ¼0.001).
14
In a recent individual patient meta-
analysis of CARE-HF, MIRACLE, MIRACLE-ICD, REVERSE, and
RAFT, the effect of baseline QRS duration on the benefit of CRT
when compared with no active device or with a defibrillator alone
was investigated.
5
On multivariable analysis, only QRS duration pre-
dicted the magnitude of effect of CRT on outcomes. Further ana-
lyses indicated an increasing benefit of CRT on all-cause mortality
and on the composite of first hospitalization for HF or death with
increasing QRS duration, with a high probability of a benefit particu-
larly in patients with QRS duration of ≥140 ms.
5
Hence, although
currently indicated in these patients, the benefit of CRT on indivi-
duals at the lower end of the QRS spectrum is elusive at best.
Our current subgroup analysis of EchoCRT confirms and extends
these findings. Indeed, inclusion into EchoCRT was based not only
on QRS duration but also on the presence of echocardiographic
signs of dyssynchrony. Taken together with the aforementioned
clinical trials, the lack of benefit even in this ‘enriched’ cohort strong-
ly speaks against a relevant benefit of CRT in this patient population.
As such, strong evidence is accumulating that patients in this range
Figure 3 Endpoint results by QRS duration (fully adjusted models). Hazard ratio (95% confidence interval) adjusted for country, age, gender,
quality-of-life score, systolic blood pressure, ischaemic cardiomyopathy, coronary artery bypass grafting, chronic kidney disease, left ventricular
end-diastolic diameter, and qualification by tissue Doppler imaging and/or radial dyssynchrony are presented. P-value from Wald test. Data for
QRS ,120 ms (black) and QRS 120 –130 ms (red) are shown.
Effect of QRS duration in EchoCRT 1987
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of QRS duration may not be the optimal candidates for CRT and
may possibly derive harm from it. Indeed, in our multivariable ana-
lysis, patients with a QRS duration of 120 – 130 ms showed an in-
creased hazard for the combined primary endpoint (although this
needs to be interpreted with caution in view of the negative inter-
action P-value and relatively small sample size). It is conceivable that
limited power due to low number of events and premature termin-
ation of the trial contributed to the lack of statistical significance of
some of the results, which may have turned out significant with a
higher number of included patients and events.
Patients with left bundle branch block have been shown to have a
higher probability to profit from CRT than those with non-specific
intra-ventricular conduction disorder or right bundle branch
block.
15
As a result, patients with LBBB have a class I indication
for CRT (level of evidence A for QRS ≥150 ms and B for QRS
120– 150 ms). In contrast, a class IIa indication is given to patients
with non-LBBB and a QRS duration of ≥150 ms, while only a class
IIb indication is given to patients with non-LBBB and a QRS of
120–150 ms (both level of evidence B). As EchoCRT was primarily
performed in patients with a narrow QRS complex, presence or ab-
sence of bundle branch block (or bundle branch block ‘pattern’) was
not assessed. In view of the trends observed in our current analysis,
it appears unlikely that patients with a QRS duration of 120 –130 ms
and LBBB may have derived a substantial benefit from CRT.
Modern echocardiographic techniques including speckle tracking
radial strain as well as TDI were used in EchoCRT,
7
which had been
shown to be associated with beneficial outcomes in patients with a
wide QRS complex.
16 –18
It can only be speculated whether use of
other, novel echocardiographic parameters of dyssynchrony would
allow for better distinction of patients likely to respond to CRT. Sev-
eral such parameters, including assessment of ‘apical rocking’, have
recently been brought forward.
19,20
In the absence of an adequately
powered randomized clinical trial, however, these findings should
be viewed as hypothesis generating at best, and not as a base for clin-
ical decisions regarding CRT implantation, particularly for patients
with a narrow QRS complex. Experience from the past pilot studies
cited above serves as a clear and present reminder that such hypoth-
eses may eventually be proven wrong if assessed in an endpoint-
driven clinical trial.
Since initiation of the EchoCRT trial, various studies have indi-
cated an increased likelihood of benefit for CRT in patients in
whom placement of the LV electrode wastargeted to the site of lat-
est mechanical or electrical activation of the left ventricle.
21
From
our current data, it cannot be excluded that such a strategy may
have resulted in a benefit of CRT in patients with a QRS duration
of 120– 130 ms or even shorter. Further endpoint-driven rando-
mized trials are necessary to prove or dismiss the concept of
targeted LV lead placement in this particular patient population.
Our data are consistent with other large-scale clinical trials and
meta-analyses,
5,14
indicating a lack of benefit (and potential harm)
for CRT in ‘borderline’ QRS duration of 120 – 130 ms. As a result,
an adaptation of current clinical guidelines recommending CRT
for patients presenting with a QRS complex ≥120 ms may be
viewed as self-evident. Looked upon purely from a clinical trial point
of view, this may be problematic as it implies adaptation of guidelines
based on subgroup analyses rather than clinical trial inclusion cri-
teria. However, data from several carefully and independently
conducted randomized clinical trials all point into the same direc-
tion, indicating a solid base for a guideline adaptation. Interestingly,
an ESC CRT Survey conducted in 2009 in 13 countries reported
that 19% of patients receiving a CRT had a QRS duration of
,130 and 9% had a QRS duration of ,120 ms.
22
It should not
be forgotten that CRT by itself may be associated with harm, which
if not counterbalanced by clear clinical benefit may result in a worse
outcome. Also in EchoCRT, the rate of adverse effects was substan-
tially higher in patients randomized to CRT-ON, mainly driven by
lead-related problems.
7
Other potentially harmful effects have
been related to the additional risk of infection, as well as a poten-
tially increase proarrhythmic effect due to an increase in transmural
dispersion of repolarization.
23
As such, CRT implantation in non-
suitable patients may not only result in a neutral effect due to lack
of benefit, but may negatively affect clinical outcome.
Limitations
Although pre-specified, this subgroup analysis of EchoCRT should
by definition be interpreted as hypothesis generating. Randomiza-
tion was not stratified by QRS duration leaving the possibility of un-
measured residual confounding. As the trial’s primary endpoint was
negative, any subgroup analyses need to be interpreted with caution.
Moreover, the trial was terminated prematurely, further reducing
the statistical power of any subgroup analysis. The number of pa-
tients included with QRS 120– 130 ms was too small to meaningfully
perform further subgroup analyses; as such, it cannot be assessed
with confidence if patients with a QRS of 120–130 ms and positive
prognostic characteristics for response (women, non-ischaemic pa-
tients, etc.) may have profited from CRT.
Conclusion
In this pre-specified subgroup analysis of EchoCRT, no benefit of
CRT was evident in patients with a QRS duration of 120 – 130 ms.
Our data further question the usefulness of CRT in this specific pa-
tient population. Together with the consistent data from other
large-scale randomized trials, these findings may have important im-
plication for further guidance regarding the optimal QRS duration
cut-off for CRT.
Supplementary material
Supplementary material is available at European Heart Journal online.
Conflict of interest: J.S. reports consultant and/or speaker fees
from Amgen, Astra-Zeneca, Bayer, Biotronik, Biosense Webster,
Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb,
Daiichi-Sankyo, Cook Medical, Medtronic, Novartis, Pfizer, Roche,
Sanofi-Aventis, Sorin, and St. Jude Medical and is co-director of
CorXL. He reports grant support through his institution from Bayer
Healthcare, Biotronik, Daiichi-Sankyo, Medtronic, and St. Jude Med-
ical. J.P.S. reports grants and personal fees from Biotronik, grants and
personal fees from Boston Scientific, grants and personal fees from
Medtronic, grants from St. Jude Medical, personal fees from Sorin
Group, personal fees from CardioInsight, personal fees from Respi-
cardia Inc. during the conduct of the study. W.T.A. reports grant
J. Steffel et al.1988
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support and personal fees from Biotronik during the conduct of the
study; and grant support and personal fees from Medtronic and
St. Jude Medical outside the submitted work. J.J.B. reports grant sup-
port from GE Healthcare, Biotronik, Boston Scientific, Medtronic,
Lantheus, Servier, and Edwards Lifesciences outside the submitted
work. J.S.B. reports personal fees from Biotronik during the conduct
of the study; and personal fees from Servier, Cardiorentis, ARMGO,
Novartis, and Celladon outside the submitted work. K.D. reports
personal fees from Biotronik during the conduct of the study; and
personal fees from Medtronic, Sorin, and Boston Scientific outside
the submitted work. I.F. reports grant support from Biotronik during
the conduct of the study; grant support and personal fees from Ser-
vier, and Medtronic, and personal fees from RESMED outside the
submitted work. J.G. has received research grant support from Bio-
tronik, Medtronic, and GE. D.G. reports personal fees from Medtro-
nic, St. Jude Medical, Boston Scientific, and Biotronik outside the
submitted work. H.K. reports personal fees from Biotronik outside
the submitted work. P.S. has received consultant fees from Biotro-
nik, speaker fees from GE HealthCare, and research grants from
Biotronik, GE Health Care, Bayer, and EBR systems. J.H. reports
grant support from St. Jude Medical and grant support and personal
fees from Biotronik during the conduct of the study; and other sup-
port from Cardiorentis outside the submitted work. J.B. has nothing
to disclose. F.R. reports personal fees from Biotronik during the
conduct of the study; and personal fees from Servier, Cardiorentis,
and St. Jude Medical outside the submitted work.
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