Download Combined Cardiac Resynchronization and Implantable

ORIGINAL CONTRIBUTION
Combined Cardiac Resynchronization and
Implantable Cardioversion Defibrillation
in Advanced Chronic Heart Failure
The MIRACLE ICD Trial
James B. Young, MD
William T. Abraham, MD
Andrew L. Smith, MD
Angel R. Leon, MD
Randy Lieberman, MD
Bruce Wilkoff, MD
Robert C. Canby, MD
John S. Schroeder, MD
L. Bing Liem, DO
Shelley Hall, MD
Kevin Wheelan, MD
for The Multicenter InSync ICD
Randomized Clinical Evaluation
(MIRACLE ICD) Trial Investigators
A
N IMPORTANT SUBSET OF PAtients who have chronic heart
failure (HF) also have cardiac dyssynchrony. Delays in
interventricular or intraventricular electrical activation cause marked abnormalities in the sequence of global and
segmental right and left ventricular (LV)
activation and impair mechanical performance.1-3 The ability of new methods of cardiac stimulation to resynchronize ventricular function, improve
overall cardiac performance, and increase exercise capacity has been shown
by the results of several observational
and controlled studies.4-10 The Multicenter InSync Randomized Clinical
Evaluation (MIRACLE), the first ran-
For editorial comment see p 2719.
Context Cardiac resynchronization therapy (CRT) through biventricular pacing is an
effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of
patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown.
Objective To examine the efficacy and safety of combined CRT and ICD therapy in
patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management.
Design, Setting, and Participants Randomized, double-blind, parallelcontrolled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients
with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high
risk of life-threatening ventricular arrhythmias, and in NYHA class III (n=328) or IV
(n=41) despite optimized medical treatment.
Interventions Of 369 randomized patients who received devices with combined CRT
and ICD capabilities, 182 were controls (ICD activated, CRT off ) and 187 were in the
CRT group (ICD activated, CRT on).
Main Outcome Measures The primary double-blind study end points were changes
between baseline and 6 months in quality of life, functional class, and distance covered
during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival,
incidence of ventricular arrhythmias, and rates of hospitalization were also compared.
Results At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (–17.5 [–21 to –14] vs –11.0 [–16
to –7], P=.02) and functional class (–1 [–1 to –1] vs 0 [–1 to 0], P=.007) than controls
but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs
53 m [43-75], P=.36). Peak oxygen consumption increased by 1.1 mL/kg per minute
(0.7-1.6) in the CRT group vs 0.1 mL /kg per minute (–0.1 to 0.8) in controls (P=.04),
although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group
and decreased by 11 seconds (–55 to 12) in controls (P⬍.001). No significant differences were observed in changes in left ventricular size or function, overall HF status,
survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia
termination capabilities were not impaired.
Conclusions Cardiac resynchronization improved quality of life, functional status,
and exercise capacity in patients with moderate to severe HF, a wide QRS interval,
and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD
function.
www.jama.com
JAMA. 2003;289:2685-2694
Author Affiliations and Financial Disclosures are listed
at the end of this article.
Corresponding Author and Reprints: James B. Young,
©2003 American Medical Association. All rights reserved.
MD, Cleveland Clinic Foundation, 9500 Euclid Ave,
Desk F25, Cleveland, OH 44195 (e-mail: youngj@ccf
.org).
(Reprinted) JAMA, May 28, 2003—Vol 289, No. 20 2685
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
Box. Inclusion and Exclusion Criteria
Inclusion
Age ⱖ18 years
Cardiac arrest due to ventricular fibrillation or ventricular tachyarrhythmia, or
spontaneously sustained ventricular tachyarrhythmia, or inducible ventricular fibrillation or sustained ventricular tachyarrhythmia
New York Heart Association functional class III or IV congestive heart failure
Left ventricular ejection fraction ⱕ35%
QRS duration ⱖ130 ms
Left ventricular end diastolic diameter ⱖ55 mm
Stable drug regimen for ⱖ1 month
Exclusion
Estimated survival ⬍6 months
Baseline 6-minute walk test ⬎450 m
Bradycardia requiring pacemaker
Unstable angina, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, cerebral vascular accident, or transient ischemic attack within previous 3 months
⬎2 infusions of inotropic drug per week
Systolic blood pressure ⬍80 mm Hg or ⬎170 mm Hg
Resting heart rate ⬎140/min
Serum creatinine ⬎3 mg/dL (⬎265 µmol/L)
Hepatic enzymes ⬎3-fold upper normal values
Severe lung disease
Chronic atrial arrhythmias, or cardioversion or paroxysmal atrial fibrillation within
previous 1 month
Heart transplant recipient
Severe valvular heart disease
domized, double-blind, controlled trial
of cardiac resynchronization therapy
(CRT) through atrial-synchronized biventricular pacing demonstrated a significant improvement in New York
Heart Association (NYHA) functional
class, an increase in exercise duration,
and improvements in quality of life in
patients with moderate to severe HF and
wide QRS interval. These patients did
not have an indication for pacing or defibrillator therapy.11
Despite increases in survival rates
achieved by new pharmaceutical agents,
such as angiotensin-converting enzyme inhibitors and ␤-blockers, the
5-year mortality following the diagnosis of HF is about 50%, with most of
these deaths occurring suddenly and unexpectedly.12,13 Although an increasing
number of implantable cardioverter defibrillator (ICD) recipients have dilated hearts and marked conduction abnormalities, most reported studies of
2686
CRT excluded patients with standard indications for an ICD. One randomized
study included patients with symptomatic HF with a wide QRS complex interval and indications for an ICD but was
of short duration (3 months) and did not
assess the symptomatic benefit of CRT.14
In these patients, HF often represents the
main factor limiting quality of life and
survival. On the other hand, the improved survival conferred by ICDs is not
limited to patients with life-threatening ventricular arrhythmias15 and includes survivors of myocardial infarction and LV dysfunction without prior
symptomatic ventricular arrhythmias.16 Furthermore, even though ICD
implantation alone decreases HF mortality, it does not appear to ameliorate
symptoms. These observations have
prompted development of implantable
devices that combine cardiac resynchronization with the electrical treatment of
tachyarrhythmias.17
JAMA, May 28, 2003—Vol 289, No. 20 (Reprinted)
We hypothesized that patients with
moderate to severe HF symptoms, a
wide QRS interval, LV systolic dysfunction, and an established indication for
an ICD would benefit from CRT, and
that CRT would not be proarrhythmic
or compromise ICD therapy.
METHODS
The Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE
ICD) study was a randomized, doubleblinded, parallel-controlled clinical trial
to evaluate the efficacy of CRT in a large
number of patients with moderate to severe systolic HF, ventricular dyssynchrony, and an indication for an ICD.15
More specifically, indications for an ICD
at study entry generally were cardiac arrest (manifest by loss of consciousness) due to ventricular tachycardia or
ventricular fibrillation without a transient, reversible cause; patients having recurrent, poorly tolerated, and sustained ventricular tachycardia that
occurs spontaneously or can be induced. Except for the ICD indication
and the timing of baseline tests described later, the patient inclusion criteria and study design were identical to
those previously reported for the
MIRACLE study.11 Enrollment began
after October 1, 1999, and was completed by August 31, 2001. The investigational review board of each participating institution reviewed and
approved the study protocol, and all patients granted their written informed
consent before entering the trial.
Patient Selection and Trial Entry
The BOX lists the study inclusion and
exclusion criteria. Eligible patients received a stable and appropriate drug
regimen, which included an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, if tolerated, for at least 1 month. If a patient
was taking a ␤-blocker, it had to have
been initiated at least 3 months before
enrollment. Initiation of ␤-blockade was
not permitted during the trial period.
Patients who met the criteria for entry into the study underwent the following evaluations within 7 days of sys-
©2003 American Medical Association. All rights reserved.
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
tem implantation: estimation of NYHA
functional class18; 6-minute walking
test19; quality of life evaluation using the
Minnesota Living with Heart Failure
Questionnaire20; 2-dimensional Dopplerflow echocardiography, which included measurement of LV ejection fraction, internal LV diastolic dimensions,
end diastolic and systolic volumes, and
degree of mitral regurgitation; plasma
neurohormonal concentrations; and
QRS width on 12-lead surface electrocardiogram. Patients with mild symptoms classified as NYHA.
In patients who agreed to participate, an implant was attempted with the
Model 7272 InSync ICD (Medtronic
Inc, Minneapolis, Minn), a standard
right atrial pacing lead, a standard right
ventricular (RV) pacing/defibrillator
lead, and a choice of several LV transvenous leads (Medtronic Inc) positioned in a coronary sinus tributary. The
InSync ICD delivers atrial-synchronized biventricular pacing for cardiac
resynchronization, antitachycardia pacing through RV or RV and LV leads, and
cardioversion and defibrillation to treat
ventricular tachyarrhythmias delivered through the RV lead only.
Within 7 days of a successful implant, but before randomization, patients underwent a cardiopulmonary
exercise test to measure peak oxygen
·
consumption per unit time (VO2) and
exercise duration. Patients were then
randomly assigned, in blocked groups
for each center, to active CRT, including optimal medical treatment and active ICD therapy (CRT group), or optimal medical treatment and active ICD
therapy (control group) (FIGURE 1). Patients and the physicians from the HF
team, who continued to follow patients after implantation of the CRT/
ICD system but were not involved in
the programming of the device, remained unaware of the randomization
assignment until after the 6-month visit.
For patients in the CRT group, the
device was programmed to a mode that
paced both ventricles simultaneously
following atrial-sensed events at rates
of 130/min or lower. Atrial pacing occurred only for sinus rates of less than
35/min. For patients in the control
group, the device was programmed to
a mode that inhibited atrial or ventricular pacing unless the intrinsic rate was
less than 35/min. Implantable cardioverter defibrillator therapy was activated in all patients.
Patients returned at 1, 3, and 6 months
for full interrogation of the CRT/ICD system, reassessment of quality of life, follow-up 6-minute walking test, estimation of NYHA functional class, and
monitoring of background drug regimen. Echocardiogram, cardiopulmonary exercise testing, and measurements of plasma neurohormones were
repeated at the 6-month visit, after which
the blinded phase of the study was completed and CRT was activated in patients initially randomized to the control group. Standard protocols were used
to perform cardiopulmonary exercise
tests and echocardiograms and to collect plasma neurohormones. Independent core laboratories, unaware of the
patient randomization assignment, interpreted the data.
Statistical Analysis
As in the previously reported MIRACLE
study,11 the 3 primary efficacy end points
of MIRACLE ICD were NYHA functional class, quality of life score, and distance covered during the 6-minute walking test. In addition, several secondary
end points were examined, including
·
peak VO2, treadmill exercise duration,
LV ejection fraction, LV end-systolic and
end-diastolic volumes, LV enddiastolic dimension, severity of mitral regurgitation, QRS duration, neurohormone concentrations, and a clinical
composite response that assigned all randomized patients to 1 of 3 response
Figure 1. Enrollment and Follow-up of Patients in Multicenter InSync Implantable
Cardioverter Defibrillator Randomized Clinical Evaluation
639 Patients Enrolled and Consented to Participation
210 With NYHA Class II Excluded (Separate Study
With Different Primary End Point)
60 Not Randomized
50 Unsuccessful CRT System Implantations
(ICD System Implantations Only)
3 Required Permanent Pacing
2 Deaths
2 Decompensated Heart Failure
2 Unsuccessful Repositioning of Dislodged
Left Ventricular Lead
1 Cardiac Transplantation
369 Randomized
182 Assigned to Receive ICD Plus Optimal Medical
Treatment
187 Assigned to Receive ICD Plus CRT Plus Optimal
Medical Treatment
14 Crossed Over to CRT
11 Worsening Heart Failure
2 Bradycardia
1 Programming Error
15 Died
5 Missed 6-Month Follow-up
10 Crossed Over to ICD Only
2 Ventricular Lead Dislodgement
2 Diaphragmatic Stimulation
6 Programming Errors
14 Died
6 Missed 6-Month Follow-up
2 Cardiac Transplantation
162 Completed 6-Month Follow-up
165 Completed 6-Month Follow-up
162 Included in Primary Efficacy Analysis
182 Included in Adverse Event Analysis
165 Included in Primary Efficacy Analysis
187 Included in Adverse Event Analysis
NYHA indicates New York Heart Association; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator.
©2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 28, 2003—Vol 289, No. 20 2687
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
groups (worsened, improved, or unchanged).
A patient was classified as worsened
if he or she died, was hospitalized due
to worsening HF, permanently discontinued double-blind treatment due to
or associated with worsening HF, permanently discontinued double-blind
treatment because of withdrawal of consent or other administrative reason, had
worsening HF at the time of study discontinuation, demonstrated worsening in NYHA class at last-observationcarried-forward (LOCF) or had
moderate to marked worsening of pa-
tient global assessment score at LOCF.
A patient was said to have improved if
he or she had not worsened (as defined above) and demonstrated improvement in NYHA class at LOCF or
had a moderate to marked improvement in patient global assessment score
at LOCF. Finally, a patient was unchanged if he or she was neither improved nor worsened.21,22 All randomized patients contributed to all analyses
with the following exceptions: only patients with data available at both baseline and follow-up were included in efficacy analyses and all patients
Table 1. Baseline Characteristics of MIRACLE ICD Study Groups*
Mean (SD)
Characteristic
Men, No. (%)
Age, y
NYHA functional class, No. (%)
III
IV
Resting heart rate/min
Blood pressure, mm Hg
Systolic
Diastolic
QRS duration, ms
Isolated right bundle branch block, No. (%)
Left ventricular ejection fraction, %
Left ventricular end diastolic diameter, mm
Left ventricular end systolic diameter, mm
Left ventricular end diastolic volume, mL
Mitral regurgitation, average jet area, cm2
Quality of life score
6-Minute walk, m
·
Peak V O2, mL/kg per minute
Exercise duration, s
Underlying heart disease, No. (%)
Ischemic
Nonischemic
Indication for ICD, No. (%)
Cardiac arrest
Sustained ventricular tachycardia
Induced ventricular fibrillation and sustained
ventricular tachycardia
Baseline medications, No. (%)
ACE inhibitor or ACE inhibitor substitute
Antiarrhythmic
␤-Blocker
Diuretic
Control
(n = 182)
141 (77.5)
67.6 (9.2)
CRT
(n = 187)
142 (75.9)
66.6 (11.3)
163 (89.6)
19 (10.4)
71.3 (12.9)
165 (88.2)
22 (11.8)
71.0 (12.4)
114 (17)
67 (10)
162 (22)
24 (13)
23.9 (6.0)
76.7 (10.4)
240 (87)
311 (96)
7.3 (6.7)
55.2 (22.6)
243 (117)
13.4 (3.8)
113 (18)
66 (11)
165 (22)
25 (13)
24.2 (6.5)
75.6 (9.6)
248 (93)
322 (100)
7.5 (5.9)
56.8 (22.6)
243 (129)
13.3 (3.6)
506 (230)
468 (205)
138 (75.8)
48 (26.4)
119 (64.0)
67 (36.0)
20 (11)
76 (42)
85 (47)
17 (9)
71 (38)
99 (53)
162 (89.0)
60 (33.0)
106 (58.2)
172 (94.5)
173 (92.5)
79 (42.3)
116 (62.0)
174 (93.1)
Abbreviations: ACE, angiotensin-converting enzyme; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; MIRACLE ICD, Multicenter InSync ICD Randomized Clinical Evaluation; NYHA, New York Heart
·
Association; V O2, oxygen consumption per unit time.
*All differences between control and CRT groups are not statistically significant, except for ichemic vs nonischemic
underlying heart disease (P = .02).
2688
JAMA, May 28, 2003—Vol 289, No. 20 (Reprinted)
undergoing an implant attempt were included in the adverse event analysis.
SAS software version 8.2 (SAS Institute, Cary, NC) was used to generate
the random allocation sequence. The
method of randomization was not disclosed to participating centers and was
accomplished in blocked groups of 4 for
each to ensure balance of CRT and control assignments at each participating
institution. Randomization occurred
following a successful implant. The randomization assignment for each patient was provided to the unblinded
electrophysiology staff in a consecutively numbered and opaque (folded paper inside an envelope inside a second
envelope) sealed envelope that was
opened at the time of randomization.
The HF staff was blinded to the randomization schedule and each patient’s randomization assignment
throughout the 6-month follow-up visit.
All end points were analyzed according to the intention-to-treat principle.
Data are presented as median changes between baseline and 6 months. Confidence limits for medians were computed using a distribution-free
approach.23 Mean values are presented
as mean (SD). For continuous variables, including NYHA, changes from
baseline to the 1, 3, or 6-month visit in
the control group vs the CRT group and
demographic characteristics were compared with the Wilcoxon rank sum test.
For categorical end points, differences in
the distribution of responses to treatment at 6 months in the 2 groups were
compared by using the Fisher exact test.
Survival curves were constructed according to the Kaplan-Meier method with
time zero being the date of implant, and
differences between curves were examined by the log-rank test statistic. Confidence intervals (CIs) for survival were
computed on the log-log survival scale.24
For the primary efficacy variables, prespecified objectives were considered
reached if differences between the groups
in all 3 end points had Pⱕ.05, if 2 had
Pⱕ.025, or if 1 had Pⱕ.017, by using the
Hochberg criterion.25 The sample size
(112 patients per treatment group) was
estimated on the basis of the assump-
©2003 American Medical Association. All rights reserved.
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
Table 2. Efficacy End Points Analysis Between Baseline and 6 Months
Control Group
Change in quality of life score
Change in NYHA functional class
157
162
Median Change
(95% CI)
Primary*
−11 (−16 to −7)
0 (−1 to 0)
Change in 6-minute walk distance, m
153
53 (43 to 75)
152
55 (44 to 79)
.36
Change in quality of life score
Change in NYHA functional class
163
166
Primary†
−11 (−16 to −6)
0 (−1 to 0)
170
171
−17 (−21 to −13)
−1 (−1 to −1)
.01
.006
Change in 6-minute walk distance, m
163
52 (40 to 74)
166
54.5 (40 to 75)
.32
1.1 (0.7 to 1.6)
55.5 (30 to 79)
.04
⬍.001
End Point
No. of
Patients
CRT Group
No. of
Patients
Median
Change (95% CI)
Control vs
CRT P Value
162
165
−17.5 (−21 to −14)
−1 (−1 to −1)
.02
.007
Secondary
Cardiopulmonary exercise
·
Change in peak V O2 (mL/kg per minute)
Change in exercise duration, s
Echocardiographic LV size and function
Change in end diastolic volume, mL
Change in end systolic volume, mL
Change in ejection fraction, absolute %
Change in end diastolic diameter, mm
Change in end systolic diameter, mm
Change in mitral regurgitant jet area, mm
Change in overall clinical status, No. (%)
Improved
Unchanged
Worsened
Change in QRS duration, ms
Changes in plasma neurohormones, pg/mL
Brain natriuretic peptide
Dopamine
Norepinephrine, ng/dL
Epinephrine
Big endothelin
121
123
0.1 (−0.1 to 0.8)
−11 (−55 to 12)
120
120
133
133
133
67
65
126
−5.7 (−16.2 to 1.8)
−8.2 (−19.1 to 0.6)
1.7 (0.7 to 2.4)
−0.2 (−0.3 to 0)
−0.3 (−0.5 to −0.1)
−0.33 (−0.85 to 0)
132
132
132
70
69
130
−19.9 (−39.7 to −6.3)
−22.2 (−32.8 to −10.7)
2.1 (1.2 to 4.1)
−0.1 (−0.3 to 0.1)
−0.1 (−0.4 to 0.1)
−0.55 (−2.00 to 0)
78 (42.9)
43 (23.6)
98 (52.4)
28 (15.0)
61 (33.5)
0
160
121
117
117
115
119
.06
.06
.12
.81
.53
.58
−68 (−133 to −6)
0
−17 (−54 to 49)
−3 (−8 to 0)
−1.8 (−3.7 to 0.9)
.07
162
61 (32.6)
−20 (−21 to −14)
⬍.001
119
112
113
112
110
−50 (−163 to −6)
0
4 (−12 to 68)
0 (−4 to 0)
−2.5 (−6.0 to 1.3)
.77
.37
.58
.05
.98
·
Abbreviations: CI, confidence interval; CRT, cardiac resynchronization therapy; LV, left ventricular; NYHA, New York Heart Association; V O2, oxygen consumption per unit time.
*Including all patients with data.
†Last-observation-carried-forward analysis, excluding patients who died and those with either no baseline data or no follow-up data at 1, 3, and 6 months.
Figure 2. Median Change in Quality of Life Score and Distance Walked in 6 Minutes
Quality of Life Score
6-Minute Walk Distance
0
100
P = .06
P = .16
P = .02
–10
–15
P = .14
80
Median Change, m
Improvement
–5
Median Change
tion that the study would have 80%
power (2-sided ␣=.017) to detect a difference in NYHA class of 0.75, quality of
life of 13 points, or distance walked in 6
minutes of 50 m. For secondary end
points, P⬍.05 was considered statistically significant. All P values were calculated using 2-sided tests. In an analysis that was not prespecified, potential
clinically relevant covariates were analyzed by using analysis of variance with
randomization assignment, the covariates, and the interactions between the covariates and randomization assignment
as independent variables.
A complication was defined as a sign,
symptom, illness, or other medical event
that was resolved invasively or that re-
60
P = .36
P = .87
40
–20
20
–25
0
Control Group
CRT Group
1
3
Follow-up Month
6
1
3
6
Follow-up Month
Paired median changes from preimplant baseline values with 95% confidence intervals at the 1-, 3-, and 6-month
postrandomization follow-up periods in the control group and the cardiac resynchronization therapy (CRT)
group. P values are comparisons between groups.
©2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 28, 2003—Vol 289, No. 20 2689
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
sulted in the death of or serious injury
to a patient. The termination of a significant device function was also considered a complication. An invasive procedure was one that penetrated the skin,
including the administration of parenteral fluids or drugs. The clinical events
review committee reviewed and classified adverse events without knowledge
Figure 3. Change at 6 Months in NYHA
Class
100
Control Group (n = 162)
CRT Group (n = 165)
Patients, %
80
60
40
20
0
Improved
No Change
Worsened
The percentage of patients in each group who improved, remained unchanged, or worsened in their
New York Heart Association (NYHA) functional class
at 6 months compared with baseline. CRT indicates
cardiac resynchronization therapy. P = .007 between groups.
Figure 4. Composite Clinical Response at
6-Month Follow-up
of the randomization assignment. Investigators had full access to all data and performed analyses without restrictions or
limitations from the sponsor.
RESULTS
Through August 31, 2001, 639 patients were enrolled in the MIRACLE
ICD study program as detailed in Figure 1. Of those, 210 patients had mild
HF symptoms (NYHA functional class
II) and, by a priori protocol design, had
a separate primary end point and are not
included in this analysis. Sixty NYHA
class III or IV patients underwent an implant attempt but did not proceed to the
randomized therapy phase. A total of 369
patients included in the MIRACLE ICD
study underwent successful implantation and were randomized (control
group, n=182; CRT group, n=187). The
baseline characteristics of the randomized patients, summarized in TABLE 1,
were consistent with patients with moderate to severe HF and candidates for
ICD therapy. Except for a higher percentage of patients with ischemic heart
disease in the control group, the baseline clinical characteristics of the 2
groups were similar.
60
Control Group
Patients, %
50
Crossovers From Randomized
to Alternate Treatment
CRT Group
40
30
20
10
0
Improved
No Change
Worsened
CRT indicates cardiac resynchronization therapy.
P = .07 between groups.
In the control group, 14 patients (8%)
crossed over to CRT before the end of
the randomized phase of the study. Biventricular pacing was activated early
because of worsening symptoms of HF
in 11 patients, bradycardia in 2 patients, and programming errors in 1 patient. In the CRT group, 10 patients
(5%) crossed over from active biventricular pacing to no pacing before the
end of the randomized phase. Biventricular pacing was deactivated due to
LV lead dislodgement in 2 patients, diaphragmatic stimulation in 2 patients,
and programming errors in 6 patients.
Primary Efficacy End Points
The results of the efficacy end points
analyses are summarized in TABLE 2. An
improvement in quality of life was observed in both study groups (FIGURE 2).
However, the median decrease (improvement) in quality of life score between
baseline and the 6-month visit was significantly higher in the CRT group compared with the control group (P=.02).
Similarly, a significantly greater median decrease in NYHA functional class
was measured in the CRT group compared with the control group (P=.007)
(FIGURE 3). A similar increase between
baseline and 6 months in median distance covered during 6-minute walking
test was measured in both groups (Figure 2). When a LOCF analysis for surviving patients was performed, both the
magnitude of changes in the primary end
points and the P values for comparison
between groups were nearly identical to
those previously described in the analysis of paired data at 6 months (Table 2).
The treatment effect on quality of life
score and NYHA functional class was not
influenced by the use of a ␤-blocker, underlying heart disease (ischemic vs
nonischemic), morphology of the QRS
complex (left vs right bundle branch
block), or the baseline duration of the
QRS interval (P⬎.10 for all interactions
Table 3. Appropriate and Inappropriate ICD Treatment by Randomization Assignment and by CRT Treatment Received During 6-Month
Randomization Period*
CRT Treatment Received
Randomization Assignment
Control (n = 182)
Category
Appropriate ICD shocks
Inappropriate ICD shocks
Appropriate: only ATP used
Inappropriate: only ATP used
CRT (n = 187)
No CRT (n = 180)
CRT (n = 189)
No. of
Events
No. (%) of
Patients
No. of
Events
No. (%) of
Patients
P
Value
No. of
Events
No. (%) of
Patients
No. of
Events
No. (%) of
Patients
P
Value
154
59
229
26 (14)
13 (7)
31 (17)
89
18
608
24 (13)
8 (4)
33 (18)
.76
.27
.89
155
49
618
26 (14)
13 (7)
32 (18)
88
28
219
24 (13)
8 (4)
32 (17)
.65
.26
.89
32
8 (4)
35
13 (7)
.37
21
7 (4)
46
14 (7)
.18
Abbreviations: ATP, antitachycardia pacing; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator.
*Note that the difference in numbers between the randomized to CRT and CRT treatment received is due to crossovers. Furthermore, the analysis was for the treatment received
and was performed on 180 patients having no CRT and 189 patients having CRT the majority of the time.
2690
JAMA, May 28, 2003—Vol 289, No. 20 (Reprinted)
©2003 American Medical Association. All rights reserved.
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
Table 4. Complications After Hospital Discharge Through 6-Month Follow-up*
Not Randomized
Randomized
CRT System Not
Implanted (n = 50)
CRT System
Implanted (n = 10)
Control (n = 182)
CRT (n = 187)
LV lead related
ICD system related
No. of
Complications
0
0
No. (%) of
Patients
0
0
No. of
Complications
3
0
No. (%) of
Patients
3 (30)
0
No. of
Complications
14
14
No. (%) of
Patients
13 (7)
13 (8)
No. of
Complications
21
9
No. (%)
of Patients
20 (11)
9 (5)
Procedure related
HF decompensation
Other
1
19
15
1 (2)
12 (24)
12 (24)
3
7
15
2 (20)
3 (30)
5 (50)
13
71
74
11 (6)
40 (22)
44 (24)
10
63
81
10 (5)
36 (19)
45 (24)
Total
35
20 (40)
28
7 (70)
186
80 (44)
184
88 (47)
Complication
Abbreviations: CRT, cardiac resynchronization therapy; HF, heart failure; ICD, implantable cardioverter defibrillator; LV, left ventricular.
*Other refers to a variety of events that were mostly clinically insignificant and small in individual numbers. Totals do not add to 100, because a patient can have more than 1 type
of complication.
At 6 months, patients randomized to
treatment with CRT exercised on the
treadmill for a longer duration than at
baseline, whereas treadmill exercise duration decreased in the control group
(P⬍.001) (Table 2). A higher median
·
increase in peak VO2 was measured in
the CRT than in the control group
(P=.04). By echocardiographic analysis, there was a trend toward greater reductions in LV systolic and diastolic
volumes in the CRT group (P = .06 for
both), although changes in other measures of LV size and function were similar in both groups. Median changes in
plasma neurohormones were similar in
both groups, except for a greater decrease in epinephrine in the control
than the CRT group, a difference of borderline statistical significance (P=.05).
A larger proportion of patients with
CRT improved in their composite clinical response than in the control group
and a smaller proportion worsened during the study period, but this was only
a statistical trend (P = .07) (FIGURE 4).
neous and treated episodes, outcomes
of ICD therapy were recorded for 233
episodes in the control group and 678
episodes in the CRT group. Four episodes (1.7%) were not successfully terminated within the interval determined by device criteria in the control
group vs 1 episode (0.1%) in the CRT
group. These 5 episodes all eventually
terminated spontaneously. There was no
difference between the study groups in
the detection times of ventricular fibrillation episodes. Furthermore, there was
no difference in the number of patients
receiving either appropriate or inappropriate ICD treatment, when comparisons are made by randomization assignment and by whether CRT was activated
(TABLE 3). A total of 15 patients in the
control group and 14 patients in the CRT
group died during the 6-month followup. In each group, 3 of these deaths were
characterized as sudden deaths. Cumulative survival at 6 months was 92.2%
in the control group (95% CI, 87.2%95.3%) vs 92.4% (95% CI, 87.5%95.4%) in the CRT group (log rank
P = .96). Of the 429 enrolled patients
with at least 1 implant attempt, 5 (1.2%)
died within 30 days of their latest implant attempt.
Arrhythmic Events and Survival
Hospital Care Use
During the 6-month randomization period, 47 patients (26%) in the control
group and 42 patients (22%) in the CRT
group experienced at least 1 spontaneous episode of ventricular tachycardia
or fibrillation (P=.47). Of the sponta-
The median duration of the successful
implantation procedures was 2.75 hours
(interquartile range, 2.2-3.6). Between
randomization and the 6-month visit, 78
patients in the control group (42.9%) and
85 patients in the CRT group (45.5%)
with randomization assignment). This
analysis was not preplanned, however,
and may have been underpowered.
Secondary Efficacy End Points
©2003 American Medical Association. All rights reserved.
were hospitalized. The mean (SD) length
of hospital stay was 5.4 days (4.7) in the
control group vs 4.8 days (4.9) in the
CRT group (P=.06). During the 6-month
follow-up, the probability of hospitalization for worsening HF or death from
any cause was 25.9% (95% CI, 19.8%32.5%) for the control group vs 25.7%
(95% CI, 19.6%-32.3%) for the CRT
group (P=.69). The risk of death or allcause hospitalization was 48.3% (95% CI,
40.6%-55.6%) for the control group vs
47.4% (95% CI, 40.0%-54.4%) for the
CRT group (P=.88).
Therapy Compliance
In the control group, 86% of patients
received no RV pacing during the randomization period. In the CRT group,
94% of patients were ventricular paced
for 90% or more of the time during the
randomization period.
Complications
Of the 429 patients undergoing an implant attempt, 120 patients (28%) experienced 159 complications from implant to hospital discharge. Of these 159
complications, 37 (23%) were related to
the LV lead, including 15 coronary sinus dissections and 4 cardiac perforations. Other perioperative complications included HF decompensation in 6
patients, all treated with intravenous
medications; heart block in 3 patients,
all requiring bradycardia pacing support; muscle stimulation in 4 patients,
treated by either a lead repositioning or
lead replacement; pericardial effusion in
(Reprinted) JAMA, May 28, 2003—Vol 289, No. 20 2691
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
2 patients treated with a pericardiocentesis; pericarditis in 1 patient treated with
intravenous medications; hemo/
pneuomothorax in 3 patients treated
with the placement of a chest tube; ventricular tachycardia and ventricular fibrillation in 5 patients, in which 3 patients were treated with external
defibrillation and 2 patients were treated
with intravenous medications; and elevated pacing thresholds or loss of capture in 7 patients, in which 6 patients
were treated with a lead repositioning or
lead replacement and 1 patient had a set
screw tightened in the connector block.
Fifty patients had an unsuccessful
CRT system implant but a successful
placement of an ICD-only system. Of
those 50 patients, 20 experienced a total
of 35 complications from the time of
hospital discharge through 6 months.
Heart failure decompensation was the
most common complication, accounting for 19 events (TABLE 4).
From hospital discharge to the end of
the 6-month randomization period, 175
(46%) of the 379 patients with successful implants experienced 398 complications. The rate of device-related events
was substantially lower than the rates anticipated in the prespecified criteria of the
original study protocol. The frequency
of adverse events unrelated to the device or to HF did not differ significantly
between the 2 groups.
COMMENT
The improvements in quality of life and
NYHA functional class in patients with
moderate to severe HF, LV systolic dysfunction, wide QRS interval, and indications for an ICD were similar to those
observed in comparable patient populations without indications for
ICDs.7,8,10,11 However, the absence of a
positive treatment effect on the
6-minute walking test contrasts with
these earlier trials and with the improvements observed in this study with
the more objective measurements of
·
peak VO2 and treadmill exercise duration. Whether these discrepancies are
due to differences between patient
populations or to the different timing
of the 6-minute walking test (per2692
formed before, instead of after, CRT system implantation) remains uncertain.
Furthermore, although there was a
trend of decreased LV volumes and increased ejection fraction in MIRACLE
ICD (Table 2), these observations were
not as compelling as those in the
MIRACLE study.11 Perhaps this is related to the fact that MIRACLE ICD patients, on the whole, were more ill (ie,
having an ICD indication) with less
chance for morphometric remodeling
benefits that might be associated with
cardiac resynchronization.
Although complications associated
with biventricular pacemaker and ICD
insertion were not trivial, the procedure was generally well tolerated with acceptable morbidity. Of particular interest was the incremental risk associated
with the placement of the LV electrode
and the impact of biventricular pacing
on the incidence of ventricular arrhythmias and ICD functions, because all patients in this study were a priori candidates for an ICD. Of the 19 patients
(4.4%) with either coronary sinus dissection or cardiac perforation, 11 ultimately underwent a successful CRT system implantation procedure, suggesting
that the incremental risk was quite low.
After successful CRT system implantation, 47 patients (12%) underwent LV
lead repositioning or replacement during follow-up, which is comparable with
the rates observed in previously commercialized LV lead models.11,26
In the control group, crossovers to
CRT were prompted by an inability to
medically manage congestive HF in 11
of 14 patients, whereas in the CRT group,
all crossovers to the alternate treatment
were due to programming errors, lead
dislodgment, or diaphragmatic pacing.
This low incidence of crossovers had no
effect on the results of the analyses, which
were performed on an intention-totreat basis.
Small uncontrolled studies have suggested that CRT may prevent ventricular arrhythmias.27-29 However, a larger
randomized crossover study found no
survival benefit conferred by biventricular pacing in HF patients with a
preexistent indication for an ICD.30 In
JAMA, May 28, 2003—Vol 289, No. 20 (Reprinted)
this study, the number of patients experiencing ventricular arrhythmias was
similar in both treatment groups (Table
3). Perhaps the 6-month duration of the
randomization phase was too brief to
allow expression of the full therapeutic effects of CRT. Considerably longer
follow-up has often been required to
demonstrate the benefits in pharmaceutical trials in HF. Another important observation in this trial was that
detection of ventricular arrhythmias and
their successful treatment by the ICD
were unimpeded by the presence of biventricular pacing.
There were no differences in survival
or rates of hospitalization between the
control and the CRT groups. However,
this study was not designed with the
power to detect differences in survival
and the 6-month randomization period
may have been too brief to detect differences in hospitalization rates between the
treatment groups. A meta-analysis of randomized controlled trials of cardiac resynchronization in symptomatic patients has suggested a reduction in
mortality from congestive HF with biventricular pacing strategies.31
Right ventricular pacing was infrequent in the control group, whereas the
CRT group was predominately biventricular paced. The Dual Chamber and
VVI Implantable Defibrillator (DAVID)
trial32 showed that, in patients with lifethreatening ventricular arrhythmias, the
combined risk of death and hospitalization for worsening failure was higher
in patients exposed to dual-chamber
pacing with RV apical stimulation than
in patients left unpaced in their spontaneous rhythm. Although patients in
the control groups of both studies were
treated similarly, only approximately
one third of the patients in the DAVID
trial had a QRS duration of 130 ms or
more and only 12% were in NYHA
functional class III or IV HF and therefore were not eligible for randomization in the MIRACLE ICD trial. Also,
differences in rates of hospitalizations
for HF in the DAVID trial became apparent at 6 months, corresponding with
the duration of the randomized phase
of this study. These results raise the
©2003 American Medical Association. All rights reserved.
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
question of a treatment-limiting effect
of RV added to LV stimulation vs a duration of follow-up too brief for the
demonstration of differences in survival and rehospitalization.
The major limitation of the
MIRACLE ICD trial is that it was not
designed or powered to detect a mortality or morbidity difference between
control and CRT groups and the follow-up was relatively short.
In conclusion, CRT without interfering with ICD functions improved the
quality of life, functional capacity, and
cardiopulmonary exercise test performance of patients with moderate to severe HF, a wide QRS interval, and lifethreatening ventricular arrhythmias.
These therapeutic effects were observed in the context of appropriate preexistent and continuing vigorous medical management of these patients.
Author Affiliations: Cleveland Clinic Foundation,
Cleveland, Ohio (Drs Young and Wilkoff ); University of Kentucky, Lexington (Dr Abraham); Emory University School of Medicine, Atlanta, Ga (Drs Smith and
Leon); Harper Hospital, Detroit, Mich (Dr Lieberman); Texas Cardiac Arrhythmia, Austin (Dr Canby);
Stanford University Medical Center, Stanford, Calif (Drs
Schroeder and Liem); and Baylor University Medical
Center, Dallas, Tex (Drs Hall and Wheelan). Dr Abraham is now with Ohio State University, Columbus.
Financial Disclosures: Dr Young is a consultant to
Medtronic as chairman of the MIRACLE ICD Steering Committee. Drs Abraham and Smith receive research grant support and speaker’s honoraria from
Medtronic. Dr Leon is a consultant to and receives research grants from Medtronic. Dr Lieberman is a consultant, receives research, and honoraria from
Medtronic. Dr Wilkoff receives honoraria and lecture
and research support from Medtronic. Dr Liem is a consultant for Medtronic. Dr Wheelan is a consultant for
and owns public stock in Medtronic.
Author Contributions: Dr Young, as coprincipal investigator of this study, had full access to all of the data in
this study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
Study concept and design: Young, Abraham.
Acquisition of data: Young, Abraham, Smith, Leon,
Lieberman, Wilkoff, Canby, Schroeder, Liem, Hall,
Wheelan.
Analysis and interpretation of data: Young, Abraham,
Leon, Wilkoff.
Drafting of the manuscript: Young, Abraham.
Critical revision of the manuscript for important intellectual content: Young, Abraham, Smith, Leon,
Lieberman, Wilkoff, Canby, Schroeder, Liem, Hall,
Wheelan.
Statistical expertise: Abraham.
Obtained funding: Abraham.
Administrative, technical, or material support: Young,
Abraham, Leon, Schroeder, Liem, Hall.
Study supervision: Young, Abraham, Smith, Leon,
Lieberman, Canby, Schroeder.
Clinical Events Review Committee: James B. Young,
MD, William T. Abraham, MD, Angel R. Leon, MD,
Anthony S. Tang, MD.
Echocardiography Core Lab: University of Pennsylva-
nia, Philadelphia: Martin St John Sutton, MD, Ted Plappert.
Cardiopulmonary Exercise Core Lab: University of
Cincinnati, Cincinnati, Ohio: Lynne Wagonner, MD,
Paul Zengel, MS.
Investigators and Institutions Participating in the
MIRACLE ICD Trial: Study Centers and Investigators:
Albany Medical Center, New York, NY: Ferdinand Venditti, MD; Marti DelManzo, ACNP, Mark Guilzon, MD,
James O’Brien, MD, Edward Philbin, MD, Ian Santoro, MD, Amar Singh, MD, Guillermo Sosa-Suarez, MD,
George Vassolas, MD, Tina Omorogbe, RN; Arizona
Heart Institute, Phoenix: Thomas Mattioni, MD, Marwan Bahu, MD, Renzo Cataldo, MD, David Riggio, MD,
Sue Welch, RN; Baptist Memorial Hospital, Memphis, Tenn: Eric E. Johnson, MD, Frank McGrew, MD,
Mark A. Coppess, MD, Barbara Hamilton, RN; BarnesJewish Hospital, St Louis, Mo: Mitchell Faddis, MD, Joe
Rogers, MD, Jane Chen, MD, Gregory Ewald, MD,
Marye J. Gleva, MD, Michael H. Kim, MD, Bruce D.
Lindsay, MD, Judy Osborn, RN; Bayfront Medical Center, St Petersburg, Fla: Robert Sheppard, MD, Elizabeth Floden, RN; Baylor University Medical Center, Dallas, Tex: Kevin Wheelan, MD, Shelley Hall, MD, Thomas
P. Bevridge, MD, Johannes J. Kuiper, MD, Jerold S. Shinbane, MD, Peter J. Wells, MD, Sue Bruce, RN; Beth Israel Deaconess Medical Center, Boston, Mass: Mark
Josephson, MD, Beverly Lorrel, MD, James P. Morgan, MD, Panagiotis Papageorgiou, MD, Carl Rasmussen, MD, Peter Zimetbaum, MD, Mary Jane McDonald,
RN; Brigham and Women’s Hospital, Boston, Mass:
Lynne Warner-Stevenson, MD, Kristin Ellison, MD,
Lawrence Epstein, MD, William Stevenson, MD, Michael Sweeney, MD, Nancy Sweitzer, MD, Kathleen
Corrigan, RN; Cardiology of Tulsa, Tulsa, Okla: R. Doug
Ensley, MD, Wayne Adkisson, MD, Gerhard Muelheims, MD, Carole Stromme, RN; Cedars-Sinai Medical Center, Los Angeles, Calif: Steven Khan, MD, PengSheng Chen, MD, Donna Gallick, MD, Eli S. Gang, MD,
Jeffrey Goodman, MD, Walter Kerwin, MD, William
Mandel, MD, C. Thomas Peter, MD, Charles Swerdlow, MD, Linn Defensor, RN; Christ Hospital, Oak Lawn,
Ill: Marc A. Silver, MD, Pierre Abi-Mansour, MD, Adarsh
Bhan, MD, Thomas Bump, MD, John Burke, MD,
Muhyaldeen Dia, MD, Mahoj Duggal, MD, Bohdan
Fedirko, MD, Bassam Habbal, MD, Harish Patil, MD,
A. Thomas Petropulos, MD, Roberto Wayhs, MD, Diane Braun, RN; Christiana Care Medical Center, Newark, Del: Henry Weiner, MD, Raymond Miller, MD, Joseph Pennington, MD, Brian Sarter, MD, Michael
Stillabower, MD, Alexander Vigh, MD, Lynne Bittner,
RN; Cleveland Clinic Foundation, Cleveland, Ohio:
Bruce Wilkoff, MD, James Young, MD, Corinne BottSilverman, MD, Lon W. Castle, MD, Mina K. Chung,
MD, Garrie J. Haas, MD, Robert E. Hobbs, MD, Fredrick J. Jaeger, DO, Karen B. James, MD, Suzanne R. Lutton, MD, Andre Natale, MD, Mark J. Niebauer, MD,
Steve Pavia, MD, Gustavo Rincon, MD, Walid Saliba,
MD, Robert A. Schweikert, MD, Randall C. Starling, MD,
Patrick J. Tchou, MD, Mohamad H. Yamani, MD, Juliet Pryce, RN; Crawford Long Hospital, Atlanta, Ga:
Angel Leon, MD, Andrew L. Smith, MD, David B.
DeLurgio, MD, Jonathan Langberg, MD, Fernando
Mera, MD, Ann Britz, RN, Sheila Heeke, RN; EMH Regional Medical Center, Elyria, Ohio: Stephen L. Moore,
DO, Thomas B. Edel, MD, Kenneth J. Bescak, MD,
Lynette Barr, RN; Florida Heart Group, Orlando: Kerry
M. Schwartz, MD, Scott Pollak, MD, J. Craig Barnett,
MD, Leonard S. Dreifus, MD, Joel D. Greenberg, MD,
H. B. Karunaratne, MD, Mark Milunski, MD, George
Monir, MD, Michael A. Nocero, MD, Arsenio Rodriquez, MD, Cary L. Stowe, MD, Carol Stastny, RN,
Jackie White, RN; Genesis Medical Center, Davenport, Iowa: Blair Foreman, MD, Michael Giudici, MD,
Kent J. VonWhy, MD, Maureen Burke, RN; Good Samaritan Hospital, Downers Grove, Ill: Matthew O. Nora,
MD, Raymond N. Kawasaki, MD, Robert M. Kinn, MD,
Elaine Enger, MS; Hackensack University Medical Cen-
©2003 American Medical Association. All rights reserved.
ter, Hackensack, NJ: John Zimmerman, MD, Taya
Glotzer, MD, Glauco Radoslovich, MD, Tisha Arakelian, RN; Hamot Medical Center, Erie, Pa: James D.
Maloney, MD, Jeffrey L. Dakas, MD, Jean B. Moubarak, MD, Theresa Kisiel, RN; Harper Hospital, Detroit, Mich: Randy Lieberman, MD, Jack O’Connell, MD,
Anna Mick, NP, Marc Meissner, MD, Amy Skaleski, NP;
Henrico Doctor’s Hospital, Richmond, Va: Robert
Sperry, MD, James Thompson, MD, Joseph Evans, MD,
F. Roosevelt Gilliam, MD, Paula Furcron, RN; Hospital
of St. Raphael, New Haven, Conn: Mark H. Schoenfeld, MD, Thomas J. Donohue, MD, Mark L. Blitzer,
MD, Eugene A. Caracciolo, MD, Christopher Clyne, MD,
Andre Ghantous, MD, Eric M. Grubman, MD, Constantin B. Marcu, MD, Mark A. Marieb, MD, Jeanine
L. May, RN; Huntington Memorial Hospital, Pasadena, Calif: Mayer Rashtian, MD, Mark R. Myers, MD,
David Y. Mok, MD, L. Caroline LaLonde, NP; Iowa Heart
Center, Des Moines: W. Ben Johnson, MD, William J.
Wickemeyer, MD, Steven J. Bailin, MD, Robert H. Hoyt,
MD, Randolph R. Rough, MD, Denise M. Sorrentino,
MD, Loline Voegtlin, RN; JFK Hospital, Atlantis, Fla:
Robert Fishel, MD, Norman Erenrich, MD, Jamie Kosik,
RN; LDS Hospital, Salt Lake City, Utah: Brian G. Crandall, MD, Dale G. Renlund, MD, Steven Horton, MD,
Abdallah Kfoury, MD, Jeffrey Osborn, MD, David O.
Taylor, MD, Stephanie Vrable-Moore, MD, Frank G.
Yanowitz, MD, Imran Zubair, MD, Megan Louie, RN;
Lahey Clinic Foundation, Burlington, Mass: Roy M.
John, MD, William H. Gaasch, MD, Al Levin, MD, David
T. Martin, MD, Farouk Pirzada, MD, Kim Howlett, RN;
Lancaster Heart Foundation, Lancaster, Pa: Seth Worley, MD, Roy S. Small, MD, Halbert J. Feinberg, MD,
Douglas C. Gohn, MD, Nicholas Mandalakas, MD, Lisa
D. Rathman, CRNP, Jill Repoley, CRNP, Susan Deck,
RN; Lee Memorial Hospital, Fort Myers, Fla: M. Erick
Burton, MD, William M. Miles, MD, Michael D. Danzig, MD, Joseph P. O’Bryan, MD, Mary Barr, RN; London Health Sciences Centre, London, Ontario: Raymond Yee, MD, Peter Pflugfelder, MD, Dennis Humen,
MD, Bonnie Spindler, RN; Mayo Clinic Foundation,
Rochester, Minn: Paul Friedman, MD, Alfredo Clavell,
MD, Brooks Edwards, MD, Raul E. Espinosa, MD, Stephen Hammill, MD, David Hayes, MD, David Holmes,
Jr, MD, Margaret Lloyd, MD, Michael D. McGoons, MD,
Michael Osborn, MD, Robert F. Rea, MD, Cindy Truex,
RN; Medical College of Virginia, Richmond: Mark
Wood, MD, Hari Baddigan, MD, Henry Clemo, MD,
Kenneth Ellenbogen, MD, Raphael Gaytar, MD, Charles
Joyner, MD, Richard Shepard, MD, Shirley Constantine, RN, Kim Hall, RN; Mercy Hospital, Sacramento,
Calif: Gearoid O’Neill, MD, John Chin, MD, Stephen
Stark, MD, Raye Bellinger, MD, Jack Casas, MD, Roy
Kaku, MD, Daniel Vanhamersveld, MD, Mark Winchester, MD, Larry Wolff, MD, Deirdre Oman, RN, Anne
Skadsen, RN; Montreal Heart Institute, Montreal, Quebec: Bernard Thibault, MD, Marc Dubuc, MD, Anique
Ducharme, MD, Pierre Gagné, MD, Peter Guerra, MD,
Normand Racine, MD, Denis Roy, MD, Mario Talajic,
MD, Christine Villemaire, RN; New York University
Medical Center, New York: Larry Chinitz, MD, Neil Bernstein, MD, Douglas Holmes, MD, Eileen McAleer, MD,
Aileen Ferrick, RN; Ohio State University Medical Center, Columbus: Charles Love, MD, Phil Binkley, MD,
Shaun Harper, MD, Robert Hoover, MD, Samer Khouri,
MD, Carl Leier, MD, Steve Nelson, MD, Alan Nichols,
MD, Karen Donovan, RN; Our Lady of Lourdes, Haddonfield, NJ: Kent Volosin, MD, Lewis L. Horvitz, MD,
Nader N. Ghaly, MD, Steve Fox, MD, Steven DaTorre, MD, William F. Fearn, MD, Marvin Grossman,
MD, Jeffrey Kramer, MD, Matthew J. Sandler, MD, Dilip
Viswanath, MD, Stephen Weinberg, MD, Tamara
Brunker, RN, Michelle Cole, RN, Sherry James, RN; Our
Lady of the Lake Hospital, Baton Rouge, La: Henry Patrick, MD, Brian Gremillion, MD, D. Joseph Deumite,
MD, Steven Gremillion, MD, Becky Ash, RN; Presbyterian Hospital, Oklahoma City, Okla: Mark Harvey,
MD, Dwayne Schmidt, MD, Philip Bentley Adamson,
(Reprinted) JAMA, May 28, 2003—Vol 289, No. 20 2693
ICD AND CARDIAC RESYNCHRONIZATION IN HEART FAILURE
MD, Karen J. Beckman, MD, M. Timothy Hauser, MD,
Dwight Wells Reynolds, MD, Tammy Jo Ramsey, RN,
Genne Straughn, RN; Providence Hospital, Mobile, Ala:
Stephanie Grosz, MD, Eliyya G. Abbud, MD, Kenneth
M. Burnham, MD, Dale Scott Kirby, MD, Fabio M. Leonelli, MD, Patricia Hall, RN; Riverside Methodist Hospital, Columbus, Ohio: John D. Hummel, MD, Steven
J. Kalbfleisch, MD, Ralph Augostini, MD, Dennis Calnon, MD, Emile Daoud, MD, Karanvir Grewal, MD, Rajesh Malik, MD, Raul Weiss, MD, Stacy Williams, RN;
Rush-Presbyterian-St Luke’s Medical Center, Chicago, Ill: Richard Trohman, MD, Elaine Winkel, MD,
John Barron, MD, Alain Heroux, MD, Walter Kao, MD,
Salpy Pamboukian, MD, Jonathan Sahu, MD, Mitchell
Saltzberg, MD, Peter Santucci, MD, Jeanine Murphy,
RN; Sacred Heart Medical Center, Spokane, Wash: Donald Chilson, MD, Bryan Fuhs, MD, Harold Goldberg,
MD, Dean Hill, MD, Michael Kwasman, MD, Tim Lessmeier, MD, Terry Scanlan, RN; Santa Rosa Hospital,
Santa Rosa, Calif: Peter Chang-Sing, MD, John J.
Hunter, MD, Lorri Martinez, RN; St Luke’s Medical Center, Milwaukee, Wis: T. Edward Hastings, MD, Masood Akhtar, MD, Zalmen Blanck, MD, Peter Chapman, MD, Ryan L. Cooley, MD, Sanjay Deshpande, MD,
Anwar Dhala, MD, Jeffery D. Hosenpud, MD, Charles
Lanzarotti, MD, Jasbir Sra, MD, Vicken R. Vorperian,
MD, Samuel L. Wann, MD, Jule Wetherbee, MD, Carol
Gilbert, RN; St Michael’s Hospital, Toronto, Ontario:
David Newman, MD, Paul Dorian, MD, Victoria Korley, MD, Sally Thorne, RN; St Paul Heart Clinic, St Paul,
Minn: Stuart Adler, MD, Alan Bank, MD, David Dunbar, MD, Michael Garr, MD, Gregory Granrud, MD,
Thomas Johnson, MD, R. Dent Underwood, MD, Pierce
Vatterott, MD, Linda Nelson, RN, Joy Gilliam, RN; St
Paul Hospital, Vancouver, British Columbia: John
Yeung, MD, Jim Abel, MD, Brett Heilbron, MD, Andrew Ignasewski, MD, Charles Kerr, MD, Neil Lewis,
MD, Hilton Ling, MD, Mary Jo Race, RN; St Vincent’s
Hospital, Jacksonville, Fla: Jay R. Patterson, MD, Steven
Nauman, MD, Paul Bednarzyl, MD, Carlos Leon, MD,
J.Timothy Walsh, MD, Alicia Disney, RN; St Vincent’s
Medical Center, Indianapolis, Ind: David P. Rardon, MD,
Keith B. Allen, MD, Nancy A. Branyas, MD, Richard I.
Fogel, MD, David A. Heimansohn, MD, Eric N. Prystowsky, MD, John J. Schier, MD, Regina Margiotti,
CMA, CCRC; St Vincent’s Hospital, Portland, Ore:
Daniel S. Oseran, MD, Ranae M. Ratkovec, MD, S. Anthony Garvey, MD, Blair D. Halperin, MD, Ronald R.
Petersen, MD, Polly Luthro, RN; Stanford University
Medical Center, Stanford, Calif: Bing Liem, MD, John
S. Schroeder, MD, Sung Chun, MD, Michael B. Fowler,
MD, Jennifer Han, MD, R. Hardwin Mead, MD, Ruey
J. Sung, MD, Randy Vagelos, MD, Linda Ottoboni, RN;
Sunrise Hospital, Las Vegas, Nev: Eric Pena, MD, Rahul Doshi, MD, Pamela Ivey, MD, Jeanette Nee, MD;
Terrebonne General Medical Center, Houma, La:
Richard Abben, MD, Peter Fail, MD, Donnie Scott,
CRNP, Jill Trosclair, RN; Texas Cardiac Arrhythmia, Austin: Robert C. Canby, MD, Touissaint Smith, MD, Michael Attas, MD, Thomas Baldacchino, MD, Russell
Burns, MD, Gregory Buser, MD, Edward Chafizadeh,
MD, Mary Beth Cishek, MD, David Dick, MD, G. Joseph Gallinghouse, MD, David Hayes, MD, Rodney Horton, MD, David Ivans, MD, Thomas Lundeen, MD, Jean
Muller, MD, Erol Ozdil, MD, Randy Randall, MD, John
Robert Randall, DO, George Rebecca, MD, Paul Roach,
MD, Eric Tiblier, MD, Thomas Tracey, MD, Paolo Venegoni, MD, Michael Watkins, MD, Ken Wigley, MD,
James Williams, MD, Jason D. Zagrodzky, MD, Debbie Cardinal, RN; Tulane University Medical Center,
New Orleans, La: James McKinnie, MD, Frank W. Smart,
MD, John Pigott, MD, Dwight Stapleton, MD, Hector
Ventura, MD, Suzanne Bowers, RN; Union Memorial
Hospital, Baltimore, Md: David J. Schamp, MD, Thomas
Guarnieri, MD, Russell Hillsley, MD, Barbara Spink, RN;
University of Alabama, Birmingham: G. Neal Kay, MD,
Andrew E. Epstein, MD, Vance J. Plumb, MD, Rosemary Bubien, RN; University of Cincinnati, Cincin-
2694
nati, Ohio: Jefferson Burroughs, MD, Lynne E. Wagoner, MD, Theodore Chow, MD, Richard Henthorn,
MD, Russell Hoffman, MD, Santesh Menon, MD, Edward J. Schloss, MD, Theodore J. Waller, MD, John H.
Wilson, MD, Russell Hoffman, RN; University of Kentucky, Lexington: William Abraham, MD, Julie Griffin,
PA-C, John Gurley, MD, Sumant Lamba, MD, Terrance Ross, MD, Robin Trupp, RN; University of Ottawa Heart Institute, Ottawa, Ontario: Anthony S. Tang,
MD, Martin Green, MD, Gwen Ewart, RN; Wake Medical Center, Raleigh, NC: Randolph A. S. Cooper, MD,
Robert Lee Jobe, MD, James R. Foster, MD, Sameh Mobarek, MD.
Funding/Support: Medtronic Inc provided funding for
this study and is the manufacturer of the dualchamber biventricular pacing ICD system used in the trial.
Role of the Sponsor: The Medtronic MIRACLE-ICD
operations team, which included Jeffrey Cerkvenik,
Cole Hannon, Michael Hill, Ven Manda, Doug Smith,
Shelley Thomas, and Lorry Witte, had the responsibility for initial study design, ensuring the integrity of
day-to-day study operations, data collection, data management, and statistical analysis in conjunction with
the coprincipal investigators, William Abraham, MD,
and James B. Young, MD. The study sponsor also participated in the preparation and review of the manuscript for accuracy.
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