n engl j med
352;15
www.nejm.org april
14, 2005
The
new england journal
of
medicine
1539
original article
The Effect of Cardiac Resynchronization
on Morbidity and Mortality in Heart Failure
John G.F. Cleland, M.D., Jean-Claude Daubert, M.D.,
Erland Erdmann, M.D., Nick Freemantle, Ph.D., Daniel Gras, M.D.,
Lukas Kappenberger, M.D., and Luigi Tavazzi, M.D.,
for the Cardiac Resynchronization — Heart Failure (CARE-HF) Study Investigators*
From the Department of Cardiology, Castle
Hill Hospital, Kingston-upon-Hull, United
Kingdom (J.G.F.C.); the Department of
Cardiology, Hôpital Pontchaillou, Rennes,
France (J.-C.D.); Klinik III für Innere Medi-
zin der Universität zu Köln, Cologne, Ger-
many (E.E.); the University of Birmingham,
Edgbaston, United Kingdom (N.F.); Nou-
velles Cliniques Nantaises, Nantes, France
(D.G.); the Division of Cardiology, Centre
Hospitalier Universitaire Vaudois, Lau-
sanne, Switzerland (L.K.); and Istituto di
Ricovero e Cura a Carattere Scientifico,
Policlinico San Matteo, Pavia, Italy (L.T.).
Address reprint requests to Dr. Cleland at
the Department of Cardiology, Castle Hill
Hospital, University of Hull, Kingston-upon-
Hull, United Kingdom, or at j.g.cleland@
hull.ac.uk.
*The CARE-HF Study investigators are
listed in the Appendix.
This article was published at www.nejm.
org on March 7, 2004.
N Engl J Med 2005;352:1539-49.
Copyright © 2005 Massachusetts Medical Society.
background
Cardiac resynchronization reduces symptoms and improves left ventricular function in
many patients with heart failure due to left ventricular systolic dysfunction and cardiac
dyssynchrony. We evaluated its effects on morbidity and mortality.
methods
Patients with New York Heart Association class III or IV heart failure due to left ventricu-
lar systolic dysfunction and cardiac dyssynchrony who were receiving standard pharma-
cologic therapy were randomly assigned to receive medical therapy alone or with cardiac
resynchronization. The primary end point was the time to death from any cause or an
unplanned hospitalization for a major cardiovascular event. The principal secondary end
point was death from any cause.
results
A total of 813 patients were enrolled and followed for a mean of 29.4 months. The pri-
mary end point was reached by 159 patients in the cardiac-resynchronization group, as
compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent;
hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001). There were
82 deaths in the cardiac-resynchronization group, as compared with 120 in the medi-
cal-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence
interval, 0.48 to 0.85; P<0.002). As compared with medical therapy, cardiac resynchro-
nization reduced the interventricular mechanical delay, the end-systolic volume index,
and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction;
and improved symptoms and the quality of life (P<0.01 for all comparisons).
conclusions
In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization im-
proves symptoms and the quality of life and reduces complications and the risk of death.
These benefits are in addition to those afforded by standard pharmacologic therapy.
The implantation of a cardiac-resynchronization device should routinely be considered
in such patients.
abstract
The New England Journal of Medicine
Downloaded from nejm.org at GLASGOW UNIVERSITY LIBRARY on September 26, 2016. For personal use only. No other uses without permission.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;15
www.nejm.org april
14
,
2005
The
new england journal
of
medicine
1540
espite improvements in pharma-
cologic treatment, many patients with
heart failure have severe and persistent
symptoms, and their prognosis remains poor.
1,2
Such patients commonly have regions of delayed
myocardial activation and contraction, leading to
cardiac dyssynchrony. In a series of trials lasting up
to six months, cardiac resynchronization decreased
symptoms and improved exercise capacity, the qual-
ity of life, and ventricular function.
3-7
The Compar-
ison of Medical Therapy, Pacing, and Defibrillation
in Heart Failure (COMPANION) trial showed that
cardiac-resynchronization therapy alone or com-
bined with an implantable defibrillator reduced the
composite end point of death from any cause or hos-
pitalization during a mean follow-up of 16 months
8
;
however, the decrease in the risk of death was not
significant with cardiac resynchronization therapy
alone (P=0.06). Meta-analyses have left lingering
uncertainty about the effects of cardiac resynchro-
nization on the risk of complications and death.
9,10
We analyzed the effects of cardiac resynchroniza-
tion on the risk of complications and death among
patients who were receiving standard medical ther-
apy for moderate or severe heart failure and cardiac
dyssynchrony.
The Cardiac Resynchronization — Heart Failure
(CARE-HF) trial was a multicenter, international,
randomized trial comparing the effect on the risk
of complications and death of standard pharmaco-
logic therapy alone with that of the combination of
standard therapy and cardiac resynchronization
(without a defibrillator) in patients with left ventric-
ular systolic dysfunction, cardiac dyssynchrony, and
symptomatic heart failure.
11-13
Patients were en-
rolled at 82 European centers; enrollment began in
January 2001 and ended in March 2003. The study
was not blinded. The members of the end-points
committee (see the Appendix), however, were not
aware of patients’ treatment assignments. Patients
in the control group were not scheduled to receive a
device, both for ethical reasons and so that the trial
could assess the entire effect of cardiac resynchro-
nization, including complications associated with
implantation of the device.
11-13
The steering committee (see the Appendix) de-
signed the trial. The Medtronic Corporation funded
the trial and provided a study manager to supervise
its conduct. Data were sent by investigators to core
laboratories or to an independent clinical-research
organization (Quintiles, Dublin) that maintained
the database, issued data-clarification forms, and
assisted by Medtronic employees, verified source
documents. The sponsor had no access to the data-
base and did not participate in the analysis of the re-
sults or the writing of the article. All analyses were
performed by one of the authors with the assistance
of an independent statistician. Three Medtronic rep-
resentatives commented on the manuscript before
its submission. The study was approved by the local
ethics committee of each participating institution
and by appropriate national ethics committees. All
patients provided written informed consent.
patients
Eligible patients were at least 18 years of age, had
had heart failure for at least six weeks, and were in
New York Heart Association (NYHA) class III or IV
despite receipt of standard pharmacologic therapy,
with a left ventricular ejection fraction of no more
than 35 percent, a left ventricular end-diastolic di-
mension of at least 30 mm (indexed to height), and
a QRS interval of at least 120 msec on the electro-
cardiogram. Patients with a QRS interval of 120 to
149 msec were required to meet two of three addi-
tional criteria for dyssynchrony: an aortic preejec-
tion delay of more than 140 msec, an interventric-
ular mechanical delay of more than 40 msec, or
delayed activation of the posterolateral left ventric-
ular wall.
11-13
Patients who had had a major cardiovascular
event in the previous six weeks, those who had con-
ventional indications for a pacemaker or an im-
plantable defibrillator, and those with heart fail-
ure requiring continuous intravenous therapy were
excluded. Also excluded were patients with atrial ar-
rhythmias, since such patients cannot benefit from
the atrial component of resynchronization.
11-13
study procedures
Randomization was stratified according to the
NYHA class and was carried out by Quintiles with
the use of a minimization procedure. Patients who
were randomly assigned to undergo cardiac resyn-
chronization received a Medtronic InSync or InSync
III device, which provided atrial-based, biventricular
stimulation with the use of standard right ventricu-
lar and Attain (Medtronic) left ventricular leads. In-
vestigators were asked to position the left ventricular
lead to pace the lateral or posterolateral left ventric-
ular wall transvenously and provide radiographic
documentation. Backup atrial pacing was set at 60
beats per minute. The interventricular delay was set
d
methods
The New England Journal of Medicine
Downloaded from nejm.org at GLASGOW UNIVERSITY LIBRARY on September 26, 2016. For personal use only. No other uses without permission.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;15
www.nejm.org april
14, 2005
effect of cardiac resynchronization on heart failure
1541
to zero, and the atrioventricular delay was echocar-
diographically optimized.
11
Patients were moni-
tored overnight after receiving the device. If the
initial procedure failed, repeated attempts at im-
plantation were encouraged, and expert assistance
was provided.
follow-up
Patients were evaluated at 1, 3, 6, 9, 12, and 18
months and every six months thereafter, and stan-
dard medications were adjusted as appropriate at
these visits. Investigators were asked to report all
adverse events, which were classified in a blinded
fashion by an end-points committee or, if they were
procedure-related or device-related, by an indepen-
dent expert who was not blinded to the study-group
assignments (see the Appendix).
The protocol required follow-up to continue for
18 months after the last patient had been enrolled,
unless the data and safety monitoring board stopped
the study earlier or fewer than 300 patients had
reached a primary end point at that time, in which
case the trial could be extended. On March 6, 2004,
the board recommended extending the study until
May 2005 without disclosing the reasons. However,
since the prespecified criteria had been met, the
steering committee decided to conclude the study
as planned on September 30, 2004,
11
and imple-
mented, without knowledge of the results, an exten-
sion phase with death from any cause as the (nom-
inal) primary outcome. On February 24, 2005, after
this article had been submitted for publication, the
data and safety monitoring board indicated that the
main reasons for its recommendation were interim
analyses showing a trend toward more cardiovas-
cular events in the first 10 days after randomization
among patients assigned to cardiac resynchroniza-
tion than among those assigned to medical therapy
alone and a trend toward a favorable effect of re-
synchronization on long-term mortality that they
thought might fail to reach significance by the time
of the planned closure date.
end points
The primary end point was a composite of death
from any cause or an unplanned hospitalization for
a major cardiovascular event; only the first event in
each patient was included in this analysis. Data on
patients who underwent elective heart transplanta-
tion were censored seven days after the procedure.
Emergency heart transplantation was counted as a
death.
All hospitalizations were adjudicated in a blind-
ed fashion by the end-points committee. The first
hospitalization with documented worsening heart
failure, myocardial infarction, unstable angina, ar-
rhythmia, stroke, or other major cardiovascular
event (e.g., pulmonary embolism or ruptured aortic
aneurysm) or hospitalization owing to or prolonged
by a serious procedure-related event (e.g., infection,
pericardial hemorrhage, or tension pneumothorax)
was counted in the primary end point. Hospitaliza-
tion with worsening heart failure was defined by the
occurrence of increasing symptoms and the need
for treatment with intravenous diuretics or a sub-
stantial increase in oral diuretics (an increase of at
least 40 mg of furosemide per day, 1 mg of bumet-
anide per day, or 10 mg of torsemide per day) or the
initiation of a combination of a thiazide and a loop
diuretic.
Admissions for symptoms without a document-
ed major cardiac event were not included in the
primary end point, nor were readmissions for lead
displacement, unless it precipitated a cardiac emer-
gency, or admissions for initial implantation of the
device, since this was part of the protocol. To pre-
vent bias in favor of cardiac resynchronization, hos-
pitalizations within 10 days after randomization in
either group did not count toward the primary end
point.
The principal secondary outcome was death
from any cause, which was classified according to
mode and cause.
11
Other secondary end points in-
cluded a composite of death from any cause and un-
planned hospitalization with heart failure and, at
90 days, the NYHA class and the quality of life as as-
sessed by the patient with the use of the Minnesota
Living with Heart Failure questionnaire (scores can
range from 0 to 105, with higher scores reflecting a
poorer quality of life)
14,15
and the European Quality
of Life–5 Dimensions (EuroQoL EQ-5D) instrument
(scores can range from –0.594 to 1.000, with lower
numerical values indicating a poorer quality of life;
negative scores are associated with a quality of life
that is considered worse than death).
16
Death was
given a notional NYHA class of V for the analysis of
changes in functional class. Several echocardio-
graphic and biochemical variables were assessed in
core laboratories, including the severity of cardiac
dyssynchrony, ventricular function, mitral regurgi-
tation, and N-terminal pro–brain natriuretic peptide
(Elecsys, Roche Diagnostics), at baseline and at the
3-month and 18-month follow-up visits. Differenc-
es from baseline in heart rate and blood pressure
The New England Journal of Medicine
Downloaded from nejm.org at GLASGOW UNIVERSITY LIBRARY on September 26, 2016. For personal use only. No other uses without permission.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;15
www.nejm.org april
14
,
2005
The
new england journal
of
medicine
1542
were also compared in the two groups at follow-
up.
11
No data other than NYHA class were imputed
for patients who died.
statistical analysis
All prespecified analyses were conducted according
to the intention-to-treat principle. P values other
than for the primary end point are nominal. The
study had a statistical power
17
of 80 percent to iden-
tify a 14 percent relative reduction or a 5.7 percent-
age point reduction in the rate of events, given a con-
ventional one-sided
a
value of 0.025 and a predicted
number of 300 events.
11
The time to an event was
calculated according to the Kaplan–Meier method
and analyzed with the use of Cox proportional-haz-
ards models, which included baseline NYHA class
as a covariate.
18
Continuous data were analyzed
with the use of mixed models, which included base-
line variables as patient-level covariates and study
centers as random effects.
19
Dichotomous out-
comes were analyzed with the use of nonlinear
mixed models, which included the NYHA class as a
patient-level covariate and study centers as random
effects. The rates of adverse events were compared
between groups by means of Fisher’s exact test.
Analyses were conducted with the use of SAS soft-
ware (version 9.12, SAS Institute). The data and
safety monitoring board conducted two planned in-
terim analyses with the use of nonsymmetric stop-
ping rules.
20
A total of 404 patients were assigned to receive med-
ical therapy alone and 409 to receive medical therapy
plus cardiac resynchronization. The mean duration
of follow-up was 29.4 months (range, 18.0 to 44.7).
By the end of the study, the survival status of all pa-
tients was known, 383 patients had reached the pri-
mary end point, and 202 patients had died.
study population
Baseline characteristics were similar in the two
groups (Table 1). Patients had well-treated moder-
ate or severe heart failure and major left ventricular
systolic dysfunction. Only 43 percent were taking
high doses of diuretics (defined as at least 80 mg of
furosemide, at least 2 mg of bumetanide, or at least
20 mg of torsemide). Beta-blockers were taken at
some time during the study by 85 percent of the pa-
tients in the medical-therapy group and 84 percent
of those in the cardiac-resynchronization group.
Implantation of a device was attempted in 404
of the 409 patients assigned to undergo cardiac re-
synchronization. One patient died before undergo-
ing the procedure, and in four instances, the patient
or investigator decided not to proceed. A cardiac-
resynchronization device was implanted and activat-
ed in 390 patients (95 percent), in 349 on the first
attempt; the device was implanted a median of four
days (interquartile range, two to seven) after ran-
domization. The median duration of hospitalization
for implantation was five days (interquartile range,
two to eight). Before the device could be activated,
six patients had an unplanned hospitalization for
cardiovascular reasons that qualified as a primary
end point. Eight patients assigned to undergo car-
diac resynchronization had a device with an addi-
tional defibrillator function implanted during the
study.
In the medical-therapy group, implantation of
a cardiac-resynchronization device alone was at-
tempted in 43 patients and implantation of a resyn-
chronization device with a defibrillator was attempt-
ed in 23 patients (both approaches were attempted
in 1 patient). The device was activated in 50 patients.
In 10 instances, a device was successfully implanted
but programmed to provide only standard pacemak-
er or defibrillator functions to avoid crossover. In
five patients, the attempt at implantation was un-
successful. The device was activated in 19 patients
(5 percent) before they reached the primary end
point. Eight of these patients subsequently reached
a primary end point, six of whom died. Of 31 pa-
tients in whom the device was activated after they
had reached the primary end point, 7 subsequent-
ly died.
primary end point
By the end of the study, the primary end point had
been reached in 159 patients in the cardiac-resyn-
chronization group, as compared with 224 patients
who received medical therapy alone (39 percent vs.
55 percent; hazard ratio, 0.63; 95 percent confi-
dence interval, 0.51 to 0.77; P<0.001) (Fig. 1A and
Table 2). There were 384 unplanned hospitaliza-
tions for a major cardiovascular event in the control
group and 222 in the cardiac-resynchronization
group. Death was the primary event in 74 patients,
and hospitalization in 309. Prespecified subgroup
analyses for the primary end point revealed no het-
erogeneity in the effect of cardiac resynchronization
(Fig. 2). Twelve patients in the cardiac-resynchro-
nization group and 10 in the medical-therapy group
results
The New England Journal of Medicine
Downloaded from nejm.org at GLASGOW UNIVERSITY LIBRARY on September 26, 2016. For personal use only. No other uses without permission.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;15
www.nejm.org april
14, 2005
effect of cardiac resynchronization on heart failure
1543
* NYHA denotes New York Heart Association, and ACE angiotensin converting enzyme.
† To convert values for N-terminal pro–brain natriuretic peptide to picomoles per liter, divide by 8.457.
‡ The area was calculated as the area of the color-flow Doppler regurgitant jet divided by the area of the left atrium in sys-
tole, both in square centimeters.
§ A high-dose loop diuretic consisted of furosemide at a dose of 80 mg or more, bumetanide at a dose of 2 mg or more,
or torsemide at a dose of 20 mg or more.
Table 1. Baseline Characteristics of the Patients.*
Characteristic
Medical Therapy Alone
(N=404)
Medical Therapy plus Cardiac
Resynchronization (N=409)
Age (yr)
Median 66 67
Interquartile range 59–72 60–73
Male sex (%) 293 (73) 304 (74)
NYHA class IV (%) 27 (7) 23 (6)
Dilated cardiomyopathy (%) 193 (48) 177 (43)
Ischemic heart disease (%) 144 (36) 165 (40)
Heart disease of other causes (%) 67 (17) 67 (16)
Heart rate (beats/min)
Median 70 69
Interquartile range 61–78 60–78
Systolic blood pressure (mm Hg)
Median 110 110
Interquartile range 100–125 100–125
Diastolic blood pressure (mm Hg)
Median 70 70
Interquartile range 60–80 60–79
N-terminal pro–brain natriuretic peptide (pg/ml)†
Median 1806 1920
Interquartile range 719–3949 744–4288
Left ventricular ejection fraction (%)
Median 25 25
Interquartile range 22–29 21–29
Left ventricular end-systolic volume index (ml/m
2
)
Median 117 121
Interquartile range 94–147 92–151
QRS duration (msec)
Median 160 160
Interquartile range 152–180 152–180
Interventricular mechanical delay (msec)
Median 50 49
Interquartile range 30–66 32–67
Mitral-regurgitation area‡
Median 0.23 0.21
Interquartile range 0.11–0.34 0.12–0.33
Glomerular filtration rate (ml/min/1.73 m
2
)
Median 61 60
Interquartile range 46–73 46–73
Use of an ACE inhibitor or angiotensin-receptor blocker (%) 383 (95) 387 (95)
Use of a beta-blocker (%) 298 (74) 288 (70)
Use of spironolactone (%) 238 (59) 219 (54)
Use of a high-dose loop diuretic (%)§ 177 (44) 175 (43)
Use of digoxin (%) 181 (45) 165 (40)
The New England Journal of Medicine
Downloaded from nejm.org at GLASGOW UNIVERSITY LIBRARY on September 26, 2016. For personal use only. No other uses without permission.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.