_____
The New England Journal of Medicine -- March 22, 2001 -- Vol. 344, No. 12
ORIGINAL ARTICLE
Effects of Multisite Biventricular Pacing in Patients with Heart Failure and
Intraventricular Conduction Delay
Serge Cazeau, Christophe Leclercq, Thomas Lavergne, Stuart Walker, Chetan
Varma, Cecilia Linde, Stephane Garrigue, Lukas Kappenberger, Guy A. Haywood,
Massimo Santini, Christophe Bailleul, Philippe Mabo, Arnaud Lazarus,
Philippe Ritter, Terry Levy, William McKenna, Jean-Claude Daubert, for the
Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators
_____
Abstract
Background. One third of patients with chronic heart failure have
electrocardiographic evidence of a major intraventricular conduction delay,
which may worsen left ventricular systolic dysfunction through asynchronous
ventricular contraction. Uncontrolled studies suggest that multisite
biventricular pacing improves hemodynamics and well-being by reducing
ventricular asynchrony. We assessed the clinical efficacy and safety of this
new therapy.
Methods. Sixty-seven patients with severe heart failure (New York Heart
Association class III) due to chronic left ventricular systolic dysfunction,
with normal sinus rhythm and a duration of the QRS interval of more than 150
msec, received transvenous atriobiventricular pacemakers (with leads in one
atrium and each ventricle). This single-blind, randomized, controlled
crossover study compared the responses of the patients during two periods: a
three-month period of inactive pacing (ventricular inhibited pacing at a
basic rate of 40 bpm) and a three-month period of active
(atriobiventricular) pacing. The primary end point was the distance walked
in six minutes; the secondary end points were the quality of life as
measured by questionnaire, peak oxygen consumption, hospitalizations related
to heart failure, the patients' treatment preference (active vs. inactive
pacing), and the mortality rate.
Results. Nine patients were withdrawn from the study before randomization,
and 10 failed to complete both study periods. Thus, 48 patients completed
both phases of the study. The mean (±SD) distance walked in six minutes was
23 percent greater with active pacing (399±100 m vs. 326±134 m, P<0.001),
the quality-of-life score improved by 32 percent (P<0.001), peak oxygen
uptake increased by 8 percent (P<0.03), hospitalizations were decreased by
two thirds (P<0.05), and active pacing was preferred by 85 percent of the
patients (P<0.001).
Conclusions. Although it is technically complex, atriobiventricular pacing
significantly improves exercise tolerance and quality of life in patients
with chronic heart failure and intraventricular conduction delay. (N Engl J
Med 2001;344:873-80.)
_____
The aging of the population has made chronic heart failure an increasingly
important health problem. ( 1
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-1> ) It is the
leading medical cause of hospitalization, and its economic cost continues to
increase. Despite important therapeutic advances with
angiotensin-converting-enzyme (ACE) inhibitors ( 2
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-2> , 3
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-3> ) or
angiotensin II-receptor blockers, ( 4
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-4> )
beta-blockers, ( 5
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-5> ) and
spironolactone, ( 6
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-6> ) the
prognosis of patients with chronic heart failure remains poor. The benefit
of medical treatment is probably short-lived, ( 7
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-7> , 8
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-8> ) merely
delaying the inevitable progression to heart failure that is refractory to
drug treatment. As the disorder progresses, the well-being and exercise
tolerance of patients deteriorate dramatically, and the rates of
hospitalization increase. Nonpharmacologic therapies (such as heart
transplantation and the use of implantable assist devices) are considered
only in the later stages of the disease, ( 8
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-8> , 9
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-9> ) but
access to such therapies is restricted.
It was against this backdrop of limited resources and the need for less
expensive and simpler alternatives that resynchronization therapy by means
of multisite biventricular pacing was proposed. ( 10
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-10> ) The
rationale for this therapy is based on the high (30 to 50 percent)
prevalence of intraventricular conduction delay among patients with heart
failure ( 11
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-11> , 12
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-12> , 13
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-13> ) and on
the resultant poor coordination of ventricular contraction and relaxation,
14 <http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-14> , 15
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-15> , 16
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-16> ) which in
turn enhances the hemodynamic consequences of chronic left ventricular
systolic dysfunction. Short-term studies have shown that atriobiventricular
pacing (with leads in one atrium and each ventricle) significantly improves
hemodynamics by reducing ventricular asynchrony. ( 17
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-17> , 18
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-18> , 19
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-19> , 20
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-20> , 21
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-21> , 22
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-22> , 23
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-23> ) Results
from uncontrolled studies of permanent biventricular pacing ( 24
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-24> , 25
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-25> , 26
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-26> ) show a
sustained improvement in terms of symptoms, exercise tolerance, and
well-being. In contrast, univentricular, right-sided pacing in patients with
sinus rhythm has been found to benefit only a small subgroup of patients.
27 <http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-27> , 28
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-28> , 29
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-29> ) The aim
of this single-blind, randomized, controlled crossover study was to assess
the clinical efficacy and safety of transvenous atriobiventricular pacing in
patients with severe heart failure and major intraventricular conduction
delay but without standard indications for a pacemaker. ( 30
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-30> )
Methods
Selection of Patients
All patients gave their written informed consent before enrollment. All had
severe heart failure due to idiopathic or ischemic left ventricular systolic
dysfunction, an ejection fraction of less than 35 percent, and an
end-diastolic diameter of more than 60 mm. All patients were in sinus rhythm
with a QRS interval of more than 150 msec and without a standard indication
for insertion of a pacemaker. ( 30
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-30> ) Before
study entry, patients had been in New York Heart Association (NYHA) class
III for at least one month while receiving the optimal treatment, including
at least diuretics and ACE inhibitors at the maximal tolerated dose.
The criteria for exclusion were hypertrophic or restrictive cardiomyopathy,
suspected acute myocarditis, correctable valvulopathy, an acute coronary
syndrome lasting less than three months, recent coronary revascularization
(during the previous three months) or scheduled revascularization,
treatment-resistant hypertension, severe obstructive lung disease, an
inability to walk, reduced life expectancy not associated with
cardiovascular disease (less than one year), or an indication for the
implantation of a cardioverter-defibrillator. ( 30
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-30> )
Study Design
The trial involved 15 centers in Europe; the study protocol was approved by
local ethics committees in the six participating countries. Enrollment began
in March 1998 and was completed one year later. The study included a
six-month randomized crossover phase, during which atriobiventricular
(active) pacing was compared with ventricular inhibited (inactive) pacing at
a basic rate of 40 bpm, each for a period of three months in random order
Figure 1
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=F1> ).
Implantation was performed after a one-month observation period to verify
the stability of heart failure (defined as no need to change treatment and
no change in functional class). After implantation, the pacemaker was
programmed to be inactive. Patients were randomly assigned to study groups
within the following two weeks, after the proper performance of the pacing
system had been ascertained. Randomization of the order of treatment
followed a block design with stratification according to study center. The
single-blind, crossover phase (active vs. inactive) then began, followed by
a period during which the pacing system was programmed according to the
preference of the patient (on the basis of the two periods during the
crossover phase). Only the results from the crossover phase are reported
here.
Implantation of Pacemakers
All leads were implanted transvenously. The atrial lead was placed high in
the right atrium. The left ventricular lead was placed in a tributary of the
coronary sinus, according to a previously described method. ( 31
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-31> )
Specially designed electrodes were used. A venogram helped to optimize the
position of the lead. The target site was preferably the lateral wall,
midway between base and apex, but other lateral or posterior sites were also
acceptable. The great cardiac vein or the middle cardiac vein was used only
when other sites were not accessible. The right ventricular lead was
positioned as far as possible from the left ventricular lead. The pacemakers
were triple-output devices that made use of standard dual-chamber
technology, with built-in adapters to synchronize the pacing of the two
ventricles (Chorum 7336 MSP, ELA Medical, Montrouge, France, and InSync
8040, Medtronic, Minneapolis). Results of the implantations were assessed
from the positions of the leads on chest x-ray films and from changes in the
width of the QRS interval on 12-lead surface electrocardiograms.
Programming of Pacemakers
At randomization, the pacemaker was programmed to be either inactive or
active. The basic pacing rate was set at 40 bpm and the upper rate limit at
85 percent of the maximal predicted heart rate according to the age and sex
of the patient. Each patient underwent Doppler echocardiography to determine
the optimal atrioventricular delay (electrical delay between atrial and
ventricular excitation) during atriobiventricular pacing. ( 32
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-32> )
Medication
No modification in medication other than adjustment of the dose of diuretic
was permitted between the time of enrollment and the end of the crossover
phase of the study. Compliance was monitored by means of follow-up
interviews and prescription checks.
Evaluation of Patients
At base line, the time of randomization, and the end of each of the two
periods during the crossover phase, the patients were evaluated according to
the distance walked in six minutes, the quality of life as assessed with use
of the Minnesota Living with Heart Failure questionnaire, ( 33
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-33> ) the NYHA
classification, the need for medication, the need for hospitalization,
12-lead surface electrocardiography, and cardiopulmonary exercise testing.
The six-minute-walk test was carried out according to the recommendations of
Guyatt and colleagues and Lipkin et al. ( 34
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-34> , 35
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-35> )
Base-line evaluation included a training test to confirm that the patient
could complete the six-minute-walk test. Each visit included two tests with
an interval of at least three hours between them. The maximal difference
between the two tests was 15 percent, and the value recorded was the mean of
the results of the two tests.
The Minnesota questionnaire ( 33
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-33> , 36
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-36> ) contains
21 questions regarding patients' perception of the effects of heart failure
on their daily lives. Each question is rated on a scale of 0 to 5, producing
a total score between 0 and 105. The higher the score, the worse the quality
of life.
End Points
The primary end point was the distance walked in six minutes. The main
secondary end point was the quality of life. Other secondary end points were
peak oxygen uptake, hospital admissions because of decompensated heart
failure, the patient's preference with regard to pacing (active vs.
inactive) at the end of the crossover phase, and death.
Statistical Analysis
On the basis of previous reports of mortality rates in patients in NYHA
class III, we estimated a 10 percent mortality rate at six months. Moreover,
we expected a 10 percent rate of failure of the implantation of the left
ventricular lead and a 20 percent rate of premature termination because of
loss of left ventricular pacing efficacy or unstable heart failure. We
estimated that there would be a 10 percent increase in the distance walked
in six minutes with active pacing. For a study with a 95 percent confidence
level and 95 percent power, the total target sample needed was estimated to
be 22 patients. For the Minnesota quality-of-life score, a predicted 10
percent reduction with active pacing necessitated a 30-patient sample.
However, considering the estimated mortality and dropout rates, we
determined that a 40-patient sample was needed.
All analyses were based on the intention-to-treat principle. Thus, all
enrolled patients were included in the analysis, but each efficacy end point
could be assessed only in patients with no data missing after the completion
of both crossover phases. Base-line characteristics were assessed with the
use of the chi-square test for dichotomous variables and Student's t-test or
Wilcoxon's nonparametric test for quantitative or categorical variables. The
responses obtained for all criteria assessing clinical efficacy were
compared with the use of the Wilcoxon test and according to a two-period and
two-treatment (two-by-two) crossover design. Period and carryover effects
were checked before the efficacy of treatment was evaluated. Morbidity and
mortality were compared during the first crossover period and were described
for all other phases of the study. The stability of the results was assessed
by a per-protocol analysis, which included only patients without any
deviations from the protocol. The threshold of significance was set at 0.05.
Results
Study Population
Sixty-seven patients (50 men and 17 women) with a mean age of 63 years were
included in the study. Heart failure was of ischemic origin in 25 patients.
All patients were in NYHA class III at the time of enrollment, despite the
use of optimal treatment, including ACE inhibitors or the equivalent in 96
percent of patients, diuretics in 94 percent, digoxin in 48 percent,
amiodarone in 31 percent, beta-blockers in 28 percent, and spironolactone in
22 percent. The main base-line characteristics of the patients are listed in
Table 1
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=T1> .
Implantation
Three patients withdrew from the study before implantation, two because of
unstable heart failure (one of whom subsequently died) and one because of a
preexisting indication for pacing. Implantation of a left ventricular lead
was attempted in 64 patients, with a 92 percent success rate. A lateral
position was reached in 80 percent of the patients, and the mean (±SD)
pacing threshold was 1.4±1.1 V. Early dislodgment occurred in eight patients
and was successfully corrected in five. Overall, 88 percent of the patients
had a functional left ventricular lead at the end of the crossover phase.
Study Dropouts and Randomization
Six additional patients were removed from the study before randomization,
five because of failed implantation of the left ventricular lead and one
because of sudden death while the device was inactive. Therefore, 58
patients were randomly assigned to and equally distributed between two study
groups. There were no significant differences in the main clinical
characteristics between the groups ( Table 1
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=T1> ).
At randomization, the width of the QRS complex had acutely decreased by a
mean of 10 percent with active pacing (157±30 msec, as compared with 174±20
msec during spontaneous rhythm; P<0.002). The optimal atrioventricular delay
was 108±43 msec.
Clinical Results
Results are shown in Table 2
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=T2> .
During the active phase, the mean distance walked in six minutes was 23
percent longer (P<0.001) than during the inactive phase ( Figure 2
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=F2> ). In
the per-protocol analysis, which included 23 patients, the mean distance
walked was 375±83 m during the inactive period, as compared with 424±83 m
during the active period (P<0.004).
The Minnesota score decreased by a mean of 32 percent (P<0.001) with active
pacing ( Figure 3
<http://www.nejm.org/content/figs/2001/0344/0012/0873.asp?section=F3> ).
Peak oxygen uptake increased by a mean of 8 percent (P<0.03). No significant
carryover and period effects were noted.
Because of the crossover design, hospitalizations were analyzed in the first
period only. Three hospitalizations for heart failure occurred during active
pacing, as compared with nine during inactive pacing (P<0.05).
Patients' Preferences
At the end of the crossover phase, the patients -- who had no knowledge of
the order of treatment -- were asked which three-month period they had
preferred. Forty-one (85 percent) preferred the period corresponding to the
active-pacing mode (P<0.001), two (4 percent) preferred the period
corresponding to the inactive-pacing mode, and five (10 percent) had no
preference.
Safety
Ten patients did not complete the two crossover periods, including five who
did not complete the first period. One withdrew his consent at the time of
randomization. Two had uncorrectable loss of left ventricular pacing
efficacy. During inactive pacing, one patient had severe decompensation
leading to a premature switch to active pacing. One patient died suddenly
after 26 days of active pacing.
During the second crossover period, five additional patients dropped out,
including three for worsening heart failure. The only instance of
decompensation with active pacing was attributed to rapidly progressive
aortic stenosis. One patient died from acute myocardial infarction a few
hours after a premature switch to active pacing because of severe
decompensation. Another patient had decompensation as persistent atrial
fibrillation occurred during inactive pacing. One patient died suddenly two
hours after switching from inactive to active pacing. Finally, one patient
withdrew from the study because of lung cancer. The total number of deaths
was three during the six-month crossover phase of the study.
Discussion
This study shows that ventricular resynchronization significantly improves
exercise tolerance and the quality of life in patients with severe heart
failure who have sinus rhythm and major intraventricular conduction delay
but who do not have a standard indication for the implantation of a
pacemaker.
To be included, patients had to have been in NYHA class III for at least one
month. The purpose of this criterion was to select patients whose condition
was stable enough for them to withstand a 7.5-month study, including a
6-month crossover phase. Earlier, uncontrolled studies ( 24
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-24> ) showed
that despite clinical improvement, mortality remained high in patients in
class IV whose condition was unstable, as compared with the much lower
mortality in patients who were in class III at the time of implantation.
Optimal medical therapy principally involved two classes of drugs: ACE
inhibitors (or angiotensin II-receptor blockers) and diuretics, prescribed
at the maximal tolerated doses in 98 percent of patients. Conversely,
beta-blockers and spironolactone were prescribed to many fewer patients,
since these two drugs were not recognized as effective treatments for severe
heart failure when the study protocol was approved. ( 5
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-5> , 6
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-6> ) No
changes in treatment were permitted between the time of inclusion and the
end of the crossover phase. We were therefore able to conclude that any
clinical changes noted during the crossover periods were induced by the
pacing modes, by the natural history of the disease, or by both.
Ventricular asynchrony was assessed by electrocardiography and defined as a
QRS interval of more than 150 msec during the intrinsic conduction. This
empirical choice was later supported by studies of acute hemodynamic
changes, ( 21
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-21> , 22
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-22> , 23
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-23> ) which
showed that atriobiventricular or atrial-left ventricular pacing had
beneficial effects, mostly in patients with an intrinsic QRS interval of
more than 150 msec.
Cardiac-resynchronization therapy requires simultaneous stimulation of both
ventricles, in synchrony with atrial activity. The main technical difficulty
is to ensure reliable left ventricular pacing. Early attempts at permanent
biventricular pacing ( 10
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-10> , 18
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-18> , 22
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-22> ) used an
epicardial lead implanted in the left ventricle by thoracotomy or
thoracoscopy, but the transvenous route quickly became the standard
procedure. ( 31
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-31> ) After
catheterization of the coronary sinus, the transvenous approach permits
insertion of the lead into an epicardial vein over the left ventricular free
wall; experience with the procedure and improvements in lead technology have
dramatically increased the success rate of implantation. The optimal site of
implantation, however, remains to be determined. Results from short-term
studies ( 37
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-37> ) suggest
that the lateral wall, midway between base and apex, is optimal. In our
study, this target location was reached in 80 percent of the patients.
Finally, the reliability of the transvenous route was confirmed, because 88
percent of the patients had a functional lead in the left ventricle at the
end of the second crossover period.
This trial was designed primarily to assess the clinical efficacy of
multisite biventricular pacing. To that end, a crossover design was chosen.
This design, which makes every patient his or her own control, is probably
ideal for the initial evaluation of such a therapeutic intervention, whereas
parallel trials that require a large study population are better suited to
the assessment of treatments that have shown promise in earlier crossover
trials and to the evaluation of long-term morbidity and mortality. A
potential downside of the crossover design is that the treatments
administered during the first period may have a carryover effect in the
second period. In this study, analysis revealed the absence of any
significant carryover effect for the main selected end points. Another
methodologic issue is the possible influence of study dropouts on results,
but a per-protocol analysis found a significant difference in the primary
end point in favor of active pacing.
Exercise tolerance (as indicated by the six-minute-walk test) was chosen as
the primary end point. Peak oxygen uptake, measured during cardiopulmonary
exercise testing, has been considered as a reference measurement in patients
with heart failure, ( 38
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-38> , 39
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-39> ) which
can be used to assess the maximal exercise tolerance. However, this variable
only remotely reflects the functional impairment endured during activities
of daily life. Furthermore, peak oxygen uptake can be interpreted only by a
sophisticated technique whose reproducibility must be ascertained -- a fact
that may restrict its practical use in multicenter trials. Therefore, the
distance walked in six minutes, which correlates with the peak oxygen
uptake, ( 40
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-40> , 41
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-41> ) was
chosen as the primary end point. The use of this test to assess the effect
of therapy in previous studies ( 42
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-42> ) showed
that the minimal variation required to confirm with 99 percent confidence
that a real change has occurred is 10 percent. This threshold of 10 percent
was used in our study to determine the sample size. In fact, we observed a
mean global difference of 23 percent in favor of active pacing.
The Minnesota questionnaire introduced by Rector et al. ( 33
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-33> ) is
commonly used for the assessment of patients with heart failure, and its
clinical value has been established. ( 36
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-36> ) The
quality-of-life score from this questionnaire was defined as the main
secondary end point in this study. The mean global difference in this score
observed between the two pacing modes was 32 percent. The magnitude of
improvement for both the distance walked in six minutes and the
quality-of-life score was greater than that previously seen in drug trials
of the same duration and with similar patients. ( 36
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-36> , 43
<http://www.nejm.org/content/refs/2001/0344/0012/0873.asp#ref-43> )
In contrast, the results with respect to mortality and morbidity should be
interpreted with caution in this relatively small study, which had limited
follow-up. The significantly lower number of hospitalizations with
atriobiventricular pacing during the first crossover period is encouraging,
but it involves only a short time. Mortality was 7.5 percent (5 of 67
patients) during the 7.5 months of the protocol, but randomized studies
involving a large number of patients and extended follow-up will be
necessary to reach conclusions regarding the morbidity and mortality
associated with atriobiventricular pacing.
In conclusion, our results support the therapeutic value of ventricular
resynchronization in patients who have severe heart failure and major
intraventricular conduction delay. Atriobiventricular pacing significantly
improved symptoms, exercise tolerance, and the quality of life and was
associated with a reduced number of hospitalizations for decompensated heart
failure. However, further studies are needed to assess the long-term
clinical effect of this therapeutic approach.
Supported by ELA Recherche, Medtronic and the Swedish Heart and Lung
Association and by a grant from the Swedish Medical Research Council
(B96-11626-01).
During the study, Drs. Cazeau, Kappenberger, and Daubert were paid
consultants for Medtronic, and Dr. Cazeau was also a paid consultant for ELA
Recherche. Dr. Bailleul is an employee of ELA Recherche who was temporarily
on leave during the study period.
We are indebted to the European Society of Cardiology, owner of data from
the MUSTIC study; and to the Centre Hospitalier Universitaire de Rennes,
promoter of the study in France.
Source Information
From InParys, Saint-Cloud, France (S.C.); the Centre Cardio-Pneumologique,
Centre Hospitalier Universitaire, Rennes, France (C. Leclercq, J.-C.D.),
Hopital Broussais, Paris (T.L.); Harefield Hospital, Harefield, United
Kingdom (S.W.); St. George's Hospital, London (C.V.); Karolinska Hospital,
Stockholm, Sweden (C. Linde); Hopital Cardiologique du Haut Leveque,
Bordeaux, France (S.G.); Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland (L.K.); Derriford Hospital, Plymouth, United Kingdom (G.A.H.);
Ospedale San Filippo Neri, Rome (M.S.); and ELA Recherche, Le Plessis
Robinson, France (C.B.). Address reprint requests to Dr. Daubert at the
Departement de Cardiologie et Maladies Vasculaires, Centre
Cardio-Pneumologique, Hopital Pontchaillou-Centre Hospitalier Universitaire,
35033 Rennes CEDEX, France, or at [log in to unmask]
<mailto:[log in to unmask]> .
_____
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Edward E. Rylander,M.D.
D.A.B.F.P. AND D.A.B.P.M.
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