The New England Journal
of Medicine -- March 22, 2001 -- Vol. 344, No. 12
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 Nine patients were withdrawn from the study before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) 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 (2,3) or
angiotensin II-receptor blockers, (4)
beta-blockers, (5)
and spironolactone, (6)
the prognosis of patients with chronic heart failure remains poor. The benefit
of medical treatment is probably short-lived, (7,8)
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, (8,9)
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)
The rationale for this therapy is based on the high (30 to 50 percent)
prevalence of intraventricular conduction delay among patients with heart
failure (11,12,13)
and on the resultant poor coordination of ventricular contraction and relaxation,
(14,15,16)
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. (17,18,19,20,21,22,23)
Results from uncontrolled studies of permanent biventricular pacing (24,25,26)
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. (27,28,29)
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)
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)
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)
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). 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)
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)
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)
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. (34,35)
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 (33,36)
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.
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).
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. 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). 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). 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)
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. (5,6) 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, (21,22,23)
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 (10,18,22)
used an epicardial lead implanted in the left ventricle by thoracotomy or
thoracoscopy, but the transvenous route quickly became the standard procedure.
(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)
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, (38,39)
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, (40,41)
was chosen as the primary end point. The use of this test to assess the effect
of therapy in previous studies (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)
is commonly used for the assessment of patients with heart failure, and its
clinical value has been established. (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. (36,43)
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].
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Edward
E. Rylander,M.D.
D.A.B.F.P. AND D.A.B.P.M.