Prevention of Disease Progression by Cardiac Resynchronization Therapy in

Patients With Asymptomatic or Mildly Symptomatic Left Ventricular

Dysfunction: Insights From the European Cohort of the REVERSE
(Resynchronization Reverses Remodeling in Systolic Left Ventricular
Dysfunction) Trial
Claude Daubert, Michael R. Gold, William T. Abraham, Stefano Ghio, Christian
Hassager, Grahame Goode, Tamás Szili-Török, Cecilia Linde, on behalf of the
REVERSE Study Group
J. Am. Coll. Cardiol. published online Sep 30, 2009;
doi:10.1016/j.jacc.2009.08.011

This information is current as of October 6, 2009

The online version of this article, along with updated information and services, is
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 ARTICLE IN PRESS
Journal of the American College of Cardiology Vol. 54, No. 20, 2009
© 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2009.08.011

EXPEDITED PUBLICATION

Prevention of Disease Progression

by Cardiac Resynchronization Therapy
in Patients With Asymptomatic or Mildly
Symptomatic Left Ventricular Dysfunction
Insights From the European Cohort
of the REVERSE (Resynchronization Reverses
Remodeling in Systolic Left Ventricular Dysfunction) Trial

Claude Daubert, MD,* Michael R. Gold, MD, PHD,† William T. Abraham, MD, PHD,‡
Stefano Ghio, MD,§ Christian Hassager, MD, PHD,储 Grahame Goode, MD,¶
Tamás Szili-Török, MD,# Cecilia Linde, MD, PHD,** on behalf of the REVERSE Study Group
Rennes, France; Charleston, South Carolina; Columbus, Ohio; Pavia, Italy, Copenhagen, Denmark;
Blackpool, United Kingdom; Budapest, Hungary; and Stockholm, Sweden

Objectives The aim of this study was to determine the long-term effects of cardiac resynchronization therapy (CRT) in the
European cohort of patients enrolled in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left
Ventricular Dysfunction) trial.
Background Previous data suggest that CRT slows disease progression and improves the outcomes of asymptomatic or
mildly symptomatic patients with left ventricular (LV) dysfunction and a wide QRS complex.
Methods We randomly assigned 262 recipients of CRT pacemakers or defibrillators, with QRS ⱖ120 ms and LV ejection
fraction ⱕ40% to active (CRT ON; n ⫽ 180) versus control (CRT OFF; n ⫽ 82) treatment, for 24 months. Mean
baseline LV ejection fraction was 28.0%. All patients were in sinus rhythm and receiving optimal medical ther-
apy. The primary study end point was the proportion worsened by the heart failure (HF) clinical composite re-
sponse. The main secondary study end point was left ventricular end-systolic volume index (LVESVi).
Results In the CRT ON group, 19% of patients were worsened versus 34% in the CRT OFF group (p ⫽ 0.01). The LVESVi de-
creased by a mean of 27.5 ⫾ 31.8 ml/m2 in the CRT ON, versus 2.7 ⫾ 25.8 ml/m2 in the CRT OFF group (p ⬍
0.0001). Time to first HF hospital stay or death (hazard ratio: 0.38; p ⫽ 0.003) was significantly delayed by CRT.
Conclusions After 24 months of CRT, and compared with those of control subjects, clinical outcomes and LV function were
improved and LV dimensions were decreased in this patient population in New York Heart Association functional
classes I or II. These observations suggest that CRT prevents the progression of disease in patients with asymp-
tomatic or mildly symptomatic LV dysfunction. (REsynchronization reVErses Remodeling in Systolic Left vEntricu-
lar Dysfunction [REVERSE]; NCT00271154) (J Am Coll Cardiol 2009;54:000–000) © 2009 by the American
College of Cardiology Foundation

From the *Département de Cardiologie et maladies vasculaires, CHU, Rennes,
France; †Division of Cardiology, Medical University of South Carolina, Charleston,
South Carolina; ‡Division of Cardiovascular Medicine and the Davis Heart and Lung
Research Institute, The Ohio State University, Columbus, Ohio; §Division of
Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 储Department of
Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Den-
mark; ¶Cardiology Research, Lancashire Cardiac Centre, Blackpool Victoria Hospi-
tal NHS Trust, Blackpool, United Kingdom; #Hungarian Institute of Cardiology,
Budapest, Hungary; and the **Department of Cardiology, Karolinska University
Hospital, Stockholm, Sweden. This study was supported by the Medtronic Bakken
Research Center BV, Maastricht, the Netherlands, and Medtronic, Minneapolis, Min-
nesota. Dr. Daubert receives consulting fees from Medtronic, and St. Jude Medical, and
speaker’s honoraria from Medtronic, Sorin Group, and St. Jude Medical. Dr. Gold reports
consultant and clinical trials with Medtronic, Boston Scientific, and St. Jude Medical. Dr.
Abraham receives research grants and consulting fees from Medtronic, St. Jude Medical,
and Biotronik. Dr. Szili-Török received consulting fees from Medtronic. Dr. Linde
receives research grants, speaker’s honoraria, and consulting fees from Medtronic and
speaker’s honoraria and consulting fees from St. Jude Medical.
Manuscript received May 29, 2009; revised manuscript received July 8, 2009,
accepted August 3, 2009.

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 ARTICLE IN PRESS
2 Daubert et al.
CRT in Mild Heart Failure
Abbreviations Cardiac resynchronization therapy
and Acronyms (CRT), alone or in combination
with an implantable cardioverter-
CRT ⴝ cardiac
resynchronization therapy defibrillator (ICD), is recom-
HF ⴝ heart failure
mended as a class I indication
level of evidence A for patients
ICD ⴝ implantable
cardioverter-defibrillator
presenting in New York Heart
LVEF ⴝ left ventricular
Association (NYHA) heart fail-
ejection fraction ure (HF) functional class III or
LVESVi ⴝ left ventricular
IV, a wide QRS, and left ventric-
end-systolic volume index ular (LV) dysfunction (1,2). In
NYHA ⴝ New York Heart this population, CRT alleviates
Association symptoms and lowers major HF
SAE ⴝ serious adverse morbidity, all-cause mortality
event (3–7), and the risk of sudden
death (8). Cardiac resynchroni-
zation therapy also induces pro-
gressive changes in LV structure and function, consistent
with reverse remodeling, most prominent in patients with
nonischemic heart disease (9,10).
See page XXX
On the basis of these observations and the results of
previous small-size studies of patients in NYHA functional
classes I and II (11,12), we hypothesized that CRT is also
beneficial in mildly symptomatic or asymptomatic patients
with LV dysfunction and markers of cardiac dyssynchrony,
primarily by preventing the progression of disease over the
long term (10). The randomized, double-blind REVERSE
(Resynchronization Reverses Remodeling in Systolic Left
Ventricular Dysfunction) trial was designed to test this
hypothesis (13). The primary end point of the study was the
proportion of patients worsened according to the 12-month
clinical composite response, which was not significantly
different between the actively treated (CRT ON) group and
the control (CRT OFF) group (p ⫽ 0.10). A key secondary
observation made in the first 12 months was a significantly
greater degree of reverse ventricular remodeling in the
actively treated than in the control group (14). All patients
enrolled in the trial participated in the first 12 months of the
study, at which time the North American patients learned
their randomization assignment. However, the European
cohort was prospectively randomized for 24 months. We
report these long-term follow-up results in this article.
Methods
The present report refers to the European cohort of patients
enrolled in the REVERSE trial. Patients eligible for the
trial presented in American College of Cardiology/
American Heart Association stage C (2), NYHA functional
class I (previously symptomatic, currently asymptomatic) or
class II (mildly symptomatic), for at least 3 months before
enrollment. They were in sinus rhythm, with a 120-ms or
longer QRS duration, a LV ejection fraction (LVEF)
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ⱕ40%, and a 55-mm or wider LV end-diastolic diameter,
measured by echocardiography. All patients were being
treated with optimal medical therapy for HF (1) including
stable doses of an angiotensin-converting enzyme inhibitor
or angiotensin II receptor blocker and a beta-adrenergic
blocker for at least 3 months. Patients that were, within 3
months before enrollment, in NYHA functional class III or
IV or were hospitalized for HF were excluded from the
study. Patients in need of permanent cardiac pacing or
presenting with permanent or persistent atrial tachyarrhyth-
mias were also excluded. Other exclusion criteria were
published previously (13). The ethics committee of each
participating center approved the study protocol, and all
patients granted their written informed consent.
Study design and procedures. Patients meeting the study
inclusion criteria underwent a baseline evaluation, including
NYHA functional classification, quality-of–life assessment
by the Minnesota Living with Heart Failure questionnaire
and the Kansas City Cardiomyopathy Questionnaire (15), a
6-min hall-walk test, a 12-lead electrocardiogram for mea-
surement of QRS duration, and a 2-dimensional Doppler-
flow echocardiogram to assess the ventricular structure and
function and the degree of mitral regurgitation. After this
evaluation, the patients underwent implantation of CRT
pacemaker or CRT defibrillator systems, depending on ICD
indication. Patients who had undergone successful implan-
tation were randomly assigned in a 2-to-1 scheme to a CRT
ON or CRT OFF group for 24 months. Randomization
occurred in permuted blocks within each center. The device
of patients assigned to CRT ON was programmed to pace
both ventricles and inhibit atrial pacing, unless the intrinsic
rate was 35 beats/min or less. The pulse generator of
patients assigned to CRT OFF was programmed to inhibit
atrial or ventricular pacing, unless the intrinsic rate was 35
beats/min or less. The atrioventricular delay was optimized
by echocardiography in all patients, regardless of the ran-
domization assignment, before the final programming (13).
For patients assigned to CRT ON, the atrioventricular
delay remained unchanged from the time of their discharge
from the hospital until the end of the study, unless the LV
lead needed to be revised. The patients were followed at 1,
3, 6, 12, 18, and 24 months.
Blinding procedures. The physicians caring for the pa-
tients and responsible for the management of HF when
patients were hospitalized were unaware of the pacing
mode. Quality-of-life questionnaires, patient global assess-
ments, NYHA functional classification, and 6-min walk
tests were performed by observers unaware of the random
treatment assignment. Device interrogations and program-
ming, 12-lead electrocardiograms, echocardiograms, and
pacemaker follow-ups were performed by unblinded
observers.
The investigators were instructed to report all adverse
events, which were adjudicated by an independent Adverse
Event Advisory/Endpoint Committee unaware of the treat-
ment assignment. An unblinded, independent Data Moni-
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toring Committee reviewed the cumulative adverse events,
hospital stays, and deaths. Crossover from the randomly
assigned to the alternate treatment was disallowed before
the 24-month assessment, except if a patient in either group
developed progression of HF to NYHA functional class III
or IV. Crossovers required prior communications between
the site investigator and a member of the Steering Com-
mittee and were only allowed as a last resort.
Study end points. The primary end point of the study was
the HF clinical composite response, used to classify patients
as worsened, unchanged, or improved (12,16). Patients were
classified as worsened if they: 1) died or were hospitalized
for worsening HF; 2) crossed over to the alternate treatment
or permanently discontinued double-blind treatment due to
worsening HF; or 3) had an increase in NYHA functional
class or a moderate or marked worsening in their overall
clinical status. Patients were classified as improved if they
had not worsened and had a decrease in NYHA functional
class or had a moderate or marked improvement in their
overall clinical status or both. Patients who were neither
worsened nor improved were classified as unchanged.
The prospectively powered secondary end point was left
ventricular end-systolic volume index (LVESVi), measured
as the absolute change between baseline and end follow-up
and compared between the 2 study groups. All European
echocardiographic measurements were made by a single
core laboratory.
Adverse events. At each follow-up evaluation and up to
the 24-month follow-up, all adverse events, whether related
or unrelated to CRT, were recorded. Any event that led to
death or to serious deterioration in the health status—
meaning a life-threatening illness or injury resulting in a
permanent impairment, required hospital stays or prolon-
gation of hospital stay, or medical or surgical intervention—
was classified as a serious adverse event (SAE).
Statistical analysis. The data were analyzed according to
the intention-to-treat principle for all randomized patients.
For the pre-specified analysis of the primary end point,
patients who were improved or unchanged were grouped
and considered to have suffered no progression of HF,
whereas the proportion of patients who worsened in each
study group was compared to ascertain the efficacy of CRT.
For all time-to-event analyses, the Kaplan-Meier method
was used, and groups were compared with log-rank statis-
tics. Time 0 was the date of randomization, and patients
who did not experience an event were censored at the
24-month follow-up or on the date of their exit from the
study. The proportions of patients who suffered at least 1
SAE in each study group were compared with Fisher exact
test. Rates of SAE are reported as the number of SAE
divided by the study sample size. Other between-groups
comparisons were made with Fisher exact test (proportions)
or Student 2-sample t test (means). The HF clinical
composite response (percent of patients worsened) is re-
ported as the observed odds ratio of CRT ON to CRT
OFF, and 95% Wald confidence limits were used. Location
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Daubert et al. 3
CRT in Mild Heart Failure
data are reported as mean ⫾ SD. All p values are nominal,
and all statistical tests were 2-sided. The threshold of
significance was set at 0.05.
Results
Study population. A total of 287 patients were enrolled in
the study at 35 European medical centers, between Decem-
ber 2004 and September 2006. The baseline evaluation was
completed in 277 (Fig. 1). The CRT implants were at-
tempted in 274 and successfully performed in 266 patients,
representing a 97% overall implantation success rate. The
CRT defibrillators were implanted in 68% and CRT pace-
makers were implanted in 32% of patients. The mean
LVEF was 28.0 ⫾ 6.8% and mean left ventricular end-
diastolic dimension was 70 ⫾ 9 mm. The mean QRS
duration was 156 ⫾ 23 ms. At the time of study enrollment,
an angiotensin-converting enzyme inhibitor or angiotensin
receptor blocker was being administered to 99.6%, and a
beta-adrenergic blocker was being administered to 93.5% of
patients. Target doses of beta-adrenergic blockers were
administered to 36% of patients, whereas 62% were receiv-
ing at least 50% of the target dose recommended by current
HF guidelines (1). Ultimately, 262 patients were randomly
assigned to CRT ON (n ⫽ 180) versus CRT OFF (n ⫽ 82).
The baseline characteristics of the 2 study groups were
similar (Table 1).
European sample versus remainder of the REVERSE
trial population. In the REVERSE trial, several important
baseline characteristics of the European subgroup differed
from the remainder of the study population (i.e., non-
European participants) (14) (Table 2). Overall, compared
with the non-European sample, the European sample was,
on average, significantly younger with fewer comorbidities.
Thus European patients had a lower mean prevalence of
ischemic heart disease (44% vs. 63%; p ⬍ 0.0001), less
peripheral artery disease, less history of prior myocardial
infarction (34% vs. 55%; p ⬍ 0.0001), and of history of
hypertension (34% vs. 66%; p ⬍ 0.0001). Moreover, Euro-
peans had a smaller body mass index and a longer mean
QRS duration (156 ⫾ 23 ms vs. 151 ⫾ 21 ms; p ⫽ 0.008),
covered a longer mean 6-min walked distance (439 ⫾ 103 m
vs. 363 ⫾ 134 m; p ⬍ 0.0001), and had a smaller proportion
of CRT defibrillators implanted (68% vs. 95%; p ⬍ 0.0001)
compared with the non-European patients.
Effect of CRT on primary and secondary end points.
The difference between the 2 study groups became statisti-
cally significant at the 6-month evaluation and continued to
differ significantly and with a similar amplitude of difference
over the entire follow-up period in favor of the CRT ON
assignment (Fig. 2). At 24 months of follow-up, a worsen-
ing of the HF clinical composite response was observed in
34 of the 180 patients (19%) assigned to CRT ON
compared with 28 of the 82 patients (34%) assigned to CRT
OFF (p ⫽ 0.01). Worsening was attributable to death or
HF hospital stays in 68% of worsened patients in the CRT
 ARTICLE IN PRESS
4 Daubert et al.
CRT in Mild Heart Failure
Figure 1 Study Flowchart
CRT OFF ⫽ control group; CRT ON ⫽ actively treated group.
OFF group. Analyzing the HF clinical composite response
conventionally by using the entire distribution of worsened,
unchanged, and improved (16) yielded a p value of 0.0006 at
24 months in favor of CRT ON.
Paired measurements of LVESVi were available for 187
of the 262 patients (71%). The reasons for missing data are
reported in Table 3. Intraobserver and interobserver vari-
ability for LVESVi in the echocardiographic core laboratory
have been previously published (17). The LVESVi de-
creased by a mean of 27.5 ⫾ 31.8 ml/m2 in the CRT ON
(n ⫽ 136) compared with 2.7 ⫾ 25.8 ml/m2 in the CRT
OFF (n ⫽ 51) group (p ⬍ 0.0001) (Fig. 3). In the CRT ON
group, the decrease in LVESVi was more than twice as
great (36.9 ⫾ 32.4 ml/m2) among patients with nonisch-
emic heart disease as among patients with ischemic heart
disease (16.3 ⫾ 27.3 ml/m2). The measurements of left
ventricular end-diastolic volume index and LVEF revealed
similarly greater changes, consistent with reverse remodel-
ing, in the CRT ON than in the CRT OFF group (Fig. 3).
The main ventricular remodeling effect conferred by CRT
occurred during the first 6 months, with further improve-
ments developing over the following 12 months.
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Subgroup analyses. Subgroup analyses yielded concordant
results (Fig. 4). The improvements in clinical status and LV
function conferred by CRT were significant and similar in
patients with ischemic and nonischemic heart disease. A
trend was observed toward less clinical efficacy conferred by
CRT among patients in NYHA functional class I than in
class II, though the statistical comparison was unreliable
because of an insufficient number of observations. Patients
with a QRS duration longer than or equal to 152 ms tended
to derive more benefit from CRT than patients with a QRS
shorter than 152 ms.
Other secondary end points. The distance covered during
the baseline 6-min hall walk test was consistent with the
clinical status of the study population. The mean changes in
the distance walked at 24 months (⫹29.2 ⫾ 87.3 m with
CRT ON vs. ⫹21.9 ⫾ 90.7 m with CRT OFF; p ⫽ 0.57)
and quality of life ascertained by the Minnesota question-
naire score (⫺8.2 ⫾ 15.5 with CRT ON vs. ⫺7.0 ⫾ 14.6
with CRT OFF; p ⫽ 0.62) did not differ between groups.
Hospital stays and death. During the 24-month follow-
up, 106 of the 262 patients underwent a total of 199 hospital
stays. In the CRT ON group, 40.5% of patients were
 ARTICLE IN PRESS
JACC Vol. 54, No. 20, 2009 Daubert et al. 5
November 10, 2009:000–000 CRT in Mild Heart Failure

Baseline
Table 1 Characteristics of Study Groups
Baseline Characteristics of Study Groups

CRT OFF (n ⴝ 82) CRT ON (n ⴝ 180)

Age, yrs 60.4 ⫾ 11.2 61.7 ⫾ 10.0
Men 85% 79%
New York Heart Association functional class II 84% 83%
Ischemic heart disease 41% 44%
Previous myocardial infarction 35% 33%
Diabetes 17% 14%
History of hypertension 38% 32%
Peripheral vascular disease 2% 7%
Angiotensin-converting enzyme inhibitor 84% 87%
Angiotensin-converting enzyme inhibitor or ARB 100% 99%
Beta-adrenergic blocker 90% 95%
ⱖ50% of target beta-adrenergic blocker dose 62% 62%
100% of target beta-adrenergic blocker dose 35% 37%
Diuretic 87% 84%
Intrinsic QRS duration, ms 157 ⫾ 25 155 ⫾ 22
Left ventricular
Ejection fraction, % 27.8 ⫾ 5.8 28.1 ⫾ 7.2
End systolic volume, cm3 186 ⫾ 58 186 ⫾ 75
End diastolic volume, cm3 257 ⫾ 74 256 ⫾ 91
Interventricular mechanical delay, ms 37.2 ⫾ 35.3 37.9 ⫾ 37.9
Glomerular filtration rate, ml/min 85.9 ⫾ 32.0 83.3 ⫾ 31.6
Heart rate, beats/min 66.5 ⫾ 11.1 65.9 ⫾ 10.0
Supine blood pressure, mm Hg
Systolic 125 ⫾ 18 126 ⫾ 18
Diastolic 73 ⫾ 11 73 ⫾ 11
Body weight, kg 85.4 ⫾ 14.0 80.9 ⫾ 14.9
Body mass index, kg/m2 28.3 ⫾ 4.3 27.5 ⫾ 4.1
Minnesota Living with Heart Failure score 27.2 ⫾ 20.0 24.9 ⫾ 17.3
Kansas City Cardiomyopathy Questionnaire summary score 68.3 ⫾ 21.0 72.9 ⫾ 18.1
6-min hall walk, m 430 ⫾ 103 442 ⫾ 104
CRT-D implanted 72% 66%

Values are mean ⫾ SD or percent of patients in corresponding group.

ARB ⫽ angiotensin receptor blocker; CRT-D ⫽ cardiac resynchronization therapy defibrillator; CRT OFF ⫽ control group; CRT ON ⫽ actively treated group.

hospitalized for any cause versus 41.2% of patients in the
CRT OFF group (hazard ratio [HR]: 0.98, p ⫽ 0.94). The
time to first HF hospital stay was significantly longer in the
CRT ON (7.8% hospitalized) than in the CRT OFF
(18.4%) group (HR: 0.39, p ⫽ 0.01).The absolute rates of
HF hospital stay were 14 of 82 (17.1%) CRT OFF patients
and 13 of 180 (7.2%) CRT ON patients. Time to first HF
hospital stay or death, time to first HF hospital stay, and
time to death from any cause are displayed in Figure 5.
During the 24-month follow-up, 13 patients died.
Deaths were classified as sudden cardiac in 3 patients and
HF-related in 3 patients and due to noncardiovascular causes
in 4 patients. No cause of death was identified in 3 patients.
The 24-month death rate was 5.7% in the CRT ON versus
8.6% in the CRT OFF group (HR: 0.40, p ⫽ 0.09).
Adverse events. The perioperative (0 to 30 days) SAE rate
was 21%, consisting mainly of dislodgments of 13 left
ventricular, 6 right atrial, and 5 right ventricular leads. After
implantation and during the 24-month follow-up, 26 of the
262 device recipients experienced a total of 30 device-related
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SAE. The percentage of patients with SAE in the CRT
ON versus CRT OFF study groups were similar (p ⫽ 0.66).
The rate of SAE between 1 and 12 months was 6%, the
most common SAE being lead dislodgement, particularly of
the LV lead (n ⫽ 9). The rate of SAE between 12 and 24
months was 3%, consisting mainly of right ventricular lead
dysfunction. At the time of study closure, 29 of the 30
post-implant, device-related SAE were resolved.
Follow-up compliance and crossovers. In addition to the
13 deaths, there were 4 exits from the study before 24
months. The 24-month follow-up was completed by the
other 245 patients. During the 24 months, 15 of the 262
patients (5.7%) permanently crossed over from their ran-
domized assignment to the alternate treatment, including 2
patients from CRT ON to CRT OFF due to worsening HF
and upon the patient’s request, respectively, and 13 patients
from CRT OFF to CRT ON, because of worsening HF in
10 and other reasons in 3 patients. Crossover due to
worsening HF occurred at various times during follow-up
from 44 to 603 days after randomization.
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6 Daubert et al. JACC Vol. 54, No. 20, 2009
CRT in Mild Heart Failure November 10, 2009:000–000

Comparative
Table 2 Baseline Characteristics
Comparative in the European
Baseline Characteristics and
in the in the Non-European
European Cohorts of the
and in the Non-European REVERSE
Cohorts Trial
of the REVERSE Trial

Europe North America

(n ⴝ 262) (n ⴝ 348) p Value
Age, yrs 61.3 ⫾ 10.4 63.4 ⫾ 11.3 0.02
Men 81% 76% 0.16
New York Heart Association functional class II 83% 82% 0.75
Ischemic heart disease 44% 63% ⬍0.0001
Previous myocardial infarction 34% 55% ⬍0.0001
Diabetes 15% 28% ⬍0.0001
History of hypertension 34% 66% ⬍0.0001
Peripheral vascular disease 5% 11% 0.02
Angiotensin-converting enzyme inhibitor 86% 73% ⬍0.0001
Angiotensin-converting enzyme inhibitor or ARB ⬎99% 95% 0.0003
Beta-adrenergic blocker 94% 96% 0.13
ⱖ50% of target beta-adrenergic blocker dose 62% 59% 0.62
100% of target beta-adrenergic blocker dose 35% 35% 0.93
Diuretic 85% 76% 0.006
Intrinsic QRS duration, ms 156 ⫾ 23 151 ⫾ 21 0.008
Left ventricular
Ejection fraction, % 28.0 ⫾ 6.8 26.2 ⫾ 6.4 0.001
End systolic volume, cm3 186 ⫾ 70 209 ⫾ 85 0.0006
End diastolic volume, cm3 256 ⫾ 86 279 ⫾ 97 0.005
Interventricular mechanical delay, ms 37.7 ⫾ 37.0 30.4 ⫾ 40.3 0.04
Glomerular filtration rate, ml/min 84.1 ⫾ 31.7 87.2 ⫾ 34.0 0.25
Heart rate, beats/min 66.1 ⫾ 10.3 68.2 ⫾ 10.5 0.01
Supine blood pressure, mm Hg
Systolic 125 ⫾ 18 124 ⫾ 19 0.38
Diastolic 73 ⫾ 11 71 ⫾ 11 0.10
Body weight, kg 82.3 ⫾ 14.8 88.5 ⫾ 19.9 ⬍0.0001
Body mass index, kg/m2 27.7 ⫾ 4.2 29.0 ⫾ 5.8 0.001
Minnesota Living with Heart Failure score 25.6 ⫾ 18.2 28.9 ⫾ 22.1 0.05
Kansas City Cardiomyopathy Questionnaire summary score 71.4 ⫾ 19.1 73.4 ⫾ 20.5 0.28
6-min hall walk, m 439 ⫾ 103 363 ⫾ 134 ⬍0.0001
CRT-D implanted 68% 95% ⬍0.0001

The p values compare European and North American patients.

REVERSE ⫽ REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction trial; other abbreviations as in Table 1.

Discussion explanations. First, disease progression in patients present-

The 24-month results of the European cohort of the large
multicenter REVERSE trial show for the first time that
CRT improves the HF clinical composite response, a
measure of clinical outcome (16) as well as LV structure and
function, in patients with asymptomatic or mildly symp-
tomatic LV dysfunction. The CRT ON was associated with
progressive reverse LV remodeling over time, which was
significant at 6 months of follow-up with a further improve-
ment over time and was accompanied by a significant
decrease in morbidity and mortality. Not surprisingly, no
significant improvement in quality of life or increase in
exercise capacity by CRT was observed, an expected out-
come in a cohort of patients with little functional impair-
ment at baseline.
The present results with a twice-as-long follow-up were
superior to those observed in the first phase of the study, in
which no significant difference was observed in the primary
end point between the 2 study groups (14). This significant
and sustained benefit conferred by CRT has several putative
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ing with NYHA functional class I or II is usually slow. Its
prevention or reversal by any treatment modality might
require several years to become apparent (18). In the present
study, the longer follow-up might have contributed to the
highly significant results, manifest as progressive, time-
dependent, therapeutic effects conferred by CRT. It does
not, however, explain how the primary objective was
reached as early as 6 months in the European cohort, in
contrast to the main, much larger, 12-month study (14).
The effect of a different patient population might be an
important factor. The European cohort of the REVERSE
trial was representative of a typical European HF population
with, in particular, a relatively low proportion of ischemic
heart disease, as observed in previous European trials of
CRT with favorable outcomes (7). Although the influence
of underlying heart disease on the long-term outcomes of
CRT systems recipients remains to be confirmed, its major
effect on the rate and time course of reverse remodeling
conferred by CRT has been clearly established (9,10). As a
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November 10, 2009:000–000 CRT in Mild Heart Failure

The Primary End Point, the HF Clinical

Figure 2
Composite Response at 6, 12, 18, and 24 Months

The p values compare percent worsened in CRT OFF versus CRT ON at each
time point; n ⫽ 262 European patients at each time point. Error bars are exact
95% confidence intervals. CRT OFF ⫽ control group; CRT ON ⫽ actively treated
group; HF ⫽ heart failure; NYHA ⫽ New York Heart Association. Effect of CRT on LV
Figure 3
Dimensions and Function: Changes in Mean

(A) Left ventricular end systolic volume index (LVESVi), (B) left ventricular end
matter of fact, in the present study the extent of reverse diastolic volume index (LVEDVi), and (C) left ventricular ejection fraction (LVEF)
remodeling among patients with nonischemic heart disease between baseline and 24 months, in each study group. Error bars indicate
95% confidence intervals. At each time point, all patients with data are
after CRT was more than 2 times greater than among
included in the mean calculation. CRT OFF ⫽ control group; CRT ON ⫽ actively
patients with ischemic heart disease. treated group.
The extent of reverse remodeling observed in the present
study was similar to that observed in previous studies of
CRT in patients in NYHA HF functional classes III and IV
(9,10). Importantly, a larger proportion of patients in the

Reasons
Table 3 for Reasons
Missed LVESVi Paired
for Missed Difference
LVESVi Paired Difference

CRT OFF CRT ON Total

Reason for Missed LVESVi Paired Data (n ⴝ 82) (n ⴝ 180) (n ⴝ 262)
Have paired data 51 (62%) 136 (76%) 187 (71%)
No baseline, full echocardiogram not done 1 (1%) 0 (0%) 1 (⬍1%)
No baseline, LVESV on echocardiogram not readable 5 (6%) 14 (8%) 19 (7%)
Died before 24 months 6 (7%) 6 (3%) 12 (5%)
Exited before 24 months 2 (2%) 2 (1%) 4 (2%)
No 24-month, full echocardiogram not done 2 (2%) 1 (1%) 3 (1%)
No 24-month, LVESV on echocardiogram not readable 15 (18%) 21 (12%) 36 (14%)
Total missing 31 (38%) 44 (24%) 75 (29%)

CRT OFF ⫽ control group; CRT ON ⫽ actively treated group; LVESVi ⫽ left ventricular end-systolic volume index.

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 ARTICLE IN PRESS
8 Daubert et al. JACC Vol. 54, No. 20, 2009
CRT in Mild Heart Failure November 10, 2009:000–000

Figure 4 Effect of CRT on the HF Clinical Composite Response Among Pre-Specified Study Subgroups

Analysis of the percentage of patients worsened, according to the HF clinical composite end point, with odds ratios and 95% confidence intervals (CIs). Lower odds
ratios favor CRT ON. An odds ratio of 0.5 means that the likelihood of being worsened with CRT ON is 50% of that with CRT OFF. The subgroups of age, systolic blood
pressure, ejection fraction, end-systolic volume index, QRS width, interventricular mechanical delay, and glomerular filtration rate are divided according to the median
value in the entire study sample, including the U.S. patients. ICD ⫽ implantable cardioverter-defibrillator; other abbreviations as in Figure 2.

REVERSE trial were treated with beta-adrenergic blockers
for at least 3 months before randomization than in these
previous trials, and a larger proportion of patients received
target doses, with no changes in doses allowed during the
randomization phase, unless medically necessary. This sug-
gests that CRT has prominent effects on ventricular remod-
eling, above and beyond the effects of drugs prescribed for
the management of HF. This observation, along with the
higher survival associated with reverse LV remodeling (but
not symptomatic improvement) reported by another study
over 2 years (19), is consistent with the improvement in
clinical outcomes observed in this study.
The mortality and hospital stay rates in the asymptomatic
or mildly symptomatic patient population of the RE-
VERSE trial were low, as expected. On average, the
patients were also younger, had a shorter mean QRS
duration, and were more rigorously managed at baseline
according to current HF guidelines (1) than in previous
trials. A clearly decreased morbidity and a trend toward a
decreased mortality, attributable to CRT, were nevertheless
observed in this study. Although the REVERSE trial was
not designed to examine morbidity or mortality, our obser-
vations suggest that, in the long term, they might both be
lowered by CRT in patients presenting in NYHA func-
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tional class I or II. The long-term effects of CRT on
mortality and HF-related clinical events are currently being
studied by the RAFT (Resynchronization/Defibrillation in
Ambulatory Heart Failure) trial (20) and MADIT CRT
(Multicenter Automatic Defibrillator Implantation Trial–
Cardiac Resynchronization Therapy) trial (21).
The benefits conferred by CRT in a patient population
similar to that of the REVERSE trial must be balanced
against its risks. Because most patients in the REVERSE
trial were candidates for the primary preventive implanta-
tion of an ICD (22), the added risk associated with the
addition of a CRT system was related to the LV lead, which
was 11% at 24 months with most complications occurring
during the 12 first months. Furthermore, the implant
success rate was very high, reflecting the progress made in
implantation techniques and lead design since earlier studies
of CRT devices (3–5).
Study limitations. Complete blinding is not feasible in
device trials. In the present double-blind study, all precau-
tions were taken to limit potential bias due to blinding
procedure. Most importantly, different staff members eval-
uated the device and patients outcome, including the elec-
trocardiograms and echocardiograms. Still, we cannot
exclude that some situations—like examining the electro-
 ARTICLE IN PRESS
JACC Vol. 54, No. 20, 2009 Daubert et al. 9
November 10, 2009:000–000 CRT in Mild Heart Failure

cardiogram while evaluating the patient—would have

disclosed whether patients were programmed to CRT
ON or CRT OFF and might have created the potential
for bias. The present analysis was conducted in the
European cohort of the study. Because there were some
important differences in baseline demographic data be-
tween European and non-European patients, we cannot
exclude that our results are in part explained by a
population effect. Thus, our conclusions are mainly
appropriate for a European NYHA functional class I/II
HF population. The REVERSE trial was planned to
enroll mildly symptomatic or asymptomatic HF patients
with LV dysfunction. However, relatively few NYHA
functional class I patients (17% of the entire study
population) were recruited. Accordingly, this article more
accurately reports on the results of CRT in patients with
NYHA functional class II HF. The relatively high
proportion of missing echocardiographic data is a com-
mon observation in studies with centralized analysis
(9 –11). In the present study, there are 2 main reasons for
the imbalance in paired data: deaths (7% CRT OFF vs.
3% CRT ON) and nonreadable 24-month echocardio-
graph (18% CRT OFF and 12% CRT ON). Missing
echocardiographic data were more common in the CRT
OFF group than in the CRT ON group, but a sensitivity
analysis revealed that the results would be the same even
if we assumed outcomes in favor of CRT OFF over CRT
ON for the missing patients.

Conclusions
Over a 24-month follow-up, CRT improved the clinical
status, reduced the risk of first HF hospital stay or death,
and reversed LV remodeling, in a large European popula-
tion of patients in NYHA functional classes I or II.

Acknowledgments
The authors wish to acknowledge the 73 centers that
contributed to this study, the echocardiographic core labo-
ratory, the Data Monitoring Committee and Adverse Event
Advisory Committee, as well as the Swedish Heart and
Lung Foundation (Online Appendix).

Reprint requests and correspondence: Dr. Claude Daubert,

Service de cardiologie et maladies vasculaires, Centre cardio-
pneumologique, Hôpital Pontchaillou-CHU, Rennes, 35033,
France. E-mail: jean-claude.daubert@chu-rennes.fr.
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Key Words: biventricular stimulation y cardiac resynchronization
therapy y heart failure y randomized controlled trial y reverse cardiac
remodeling.
APPENDIX
For centers and committee members,
please see the online version of this article.
Prevention of Disease Progression by Cardiac Resynchronization Therapy in
Patients With Asymptomatic or Mildly Symptomatic Left Ventricular
Dysfunction: Insights From the European Cohort of the REVERSE
(Resynchronization Reverses Remodeling in Systolic Left Ventricular
Dysfunction) Trial
Claude Daubert, Michael R. Gold, William T. Abraham, Stefano Ghio, Christian
Hassager, Grahame Goode, Tamás Szili-Török, Cecilia Linde, on behalf of the
REVERSE Study Group
J. Am. Coll. Cardiol. published online Sep 30, 2009;
doi:10.1016/j.jacc.2009.08.011
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