Download Implantable Defibrillators for the Prevention of Mortality in Patients

REVIEW
Implantable Defibrillators for the Prevention
of Mortality in Patients
With Nonischemic Cardiomyopathy
A Meta-analysis of Randomized Controlled Trials
Akshay S. Desai, MD, MPH
James C. Fang, MD
William H. Maisel, MD, MPH
Kenneth L. Baughman, MD
S
EVERAL RANDOMIZED CLINICAL
trials have demonstrated that implantable cardioverter defibrillators (ICDs) reduce mortality in
high-risk subgroups of patients with
coronary artery disease.1-7 However,
nearly 10% to 15% of instances of sudden cardiac death occur in patients with
left ventricular dysfunction but no evidence of prior myocardial infarction.
While sudden cardiac death in patients
with prior myocardial infarction is
thought mainly to be the result of reentrant ventricular arrhythmias originating from the subendocardial surface of
infarcted myocardium, the mechanism
of sudden cardiac death in patients with
nonischemic cardiomyopathy (NICM) is
less understood.8 Identification of patients with NICM at high risk for sudden death is complicated by the inadequate predictive accuracy of both
electrophysiologic studies and noninvasive tests in this patient population.9,10
Nosingleprospectiverandomizedcontrolled trial of ICD therapy in NICM has
demonstrated convincing evidence of
mortality reduction. Observational studies suggest that up to 30% of deaths in patients with NICM are sudden.11 Mortality in medically treated patients with
See also Patient Page.
Context Implantable cardioverter defibrillator (ICD) therapy is effective in primary
and secondary prevention of sudden cardiac death among patients with prior myocardial infarction and depressed ejection fraction. However, conclusive evidence of survival benefit in patients with nonischemic cardiomyopathy (NICM) is still lacking.
Objective To determine whether ICD therapy reduces all-cause mortality in patients with NICM.
Data Sources MEDLINE (1966-2004), EMBASE (1991-2004), the Cochrane Central
Register of Controlled Trials (through first quarter, 2004), reports presented at scientific
meetings (2003-2004), and bibliographic review of secondary sources. Search terms included defibrillator, randomized controlled trials, clinical trials, and sudden death.
Study Selection Eligible studies were prospective randomized controlled trials of
ICD or combined cardiac resynchronization therapy and defibrillator (CRT-D) vs medical therapy enrolling at least some individuals with NICM and reporting all-cause mortality as an outcome. Of 675 potentially relevant articles screened initially, 8 reports
of randomized trials enrolling a total of 2146 patients with NICM were included.
Data Extraction Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, primary end point, mortality of ICD
cohort, and mortality of control cohort.
Data Synthesis Five primary prevention trials enrolling 1854 patients with NICM
were identified; pooled analysis suggested a significant reduction in total mortality among
patients randomized to ICD or CRT-D vs medical therapy (risk ratio [RR], 0.69; 95%
confidence interval [CI], 0.55-0.87; P = .002). Mortality reduction remained significant even after elimination of CRT-D trials. Two of the 3 secondary prevention trials
presented subgroup estimates for ICD efficacy in NICM. Pooled analysis of these secondary prevention trials (n=256 patients with NICM) indicated an equivalent but nonsignificant mortality reduction with ICD therapy (RR, 0.69; 95% CI, 0.39-1.24; P=.22).
Analysis of all 7 trials combined demonstrated a statistically significant 31% overall
reduction in mortality with ICD therapy (RR, 0.69; 95% CI, 0.56-0.86; P=.002).
Conclusion ICD therapy appears to significantly reduce mortality in selected patients with NICM.
www.jama.com
JAMA. 2004;292:2874-2879
NICM and a prior history of syncope may
exceed30%12 at2years,whilethosetreated
with an ICD experience a high frequency
ofappropriatedevicetherapies.13 Twoprimary prevention trials14,15 have demonstrated a trend toward reduced mortality
Author Affiliations: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Mass.
Corresponding Author: Akshay S. Desai, MD, MPH,
Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (adesai
@partners.org).
2874 JAMA, December 15, 2004—Vol 292, No. 23 (Reprinted)
©2004 American Medical Association. All rights reserved.
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IMPLANTABLE DEFIBRILLATORS AND MORTALITY
in the subgroup of ICD-treated patients
with NICM, but they failed to achieve statistical significance. Two additional small
randomizedcontrolledtrialsofICDinprimary prevention among patients with
NICM showed no benefit over therapy
with antiarrhythmic drugs.16,17
The appropriate role of ICD therapy
in the NICM population remains unclear. We performed a systematic review and meta-analysis of randomized
controlled trials of ICD therapy for prevention of all-cause mortality in NICM.
METHODS
Search Strategy
All prospective randomized controlled
trials of ICD vs medical therapy enrolling patients with NICM were identified using a 2-level search strategy. First,
public domain databases including
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials
were searched using Web-based search
engines (PubMed, OVID). Second, relevant studies were identified through a
manual search of secondary sources including references of initially identified articles and a search of reviews, commentaries, and proceedings from
national cardiology meetings from 20032004. All references were downloaded
for consolidation, elimination of duplicates, and further analysis.
The MEDLINE database was searched
from January 1966 to April 2004. MeSH
keywords included defibrillators, implantable; randomized controlled trials; and
clinical trials. A previously developed
MEDLINE research methodology filter18 designed to retrieve scientifically
strong studies of treatment was also used
with the keyword defibrillator and optimizing for a sensitive rather than specific search. The Cochrane Library and
Central Register of Controlled Trials
(current through the first quarter of
2004) was searched using OVID exploding keywords including defibrillator, clinical trial, randomized clinical trial, and sudden death. The EMBASE database was
searched from January 1991 to the second quarter of 2004 using OVID, exploding keywords including defibrillator, clinical trial, and sudden death.
Study Selection
Studies considered for inclusion met the
following criteria: the design was a prospective randomized controlled clinical trial; the study population was patients with resuscitated cardiac arrest,
those with documented or symptomatic sustained ventricular tachyarrhythmia, or those with depressed left ventricular function deemed to be at high
risk for developing lethal cardiac arrhythmia; patients were randomly assigned to ICD vs medical therapy; and
main outcomes included all-cause mortality, cardiac death, or arrhythmic mortality. A QUOROM19 flow diagram of
the study selection process is illustrated in FIGURE 1.
Because the detailed, final results of
SCD-HeFT are not yet published, we relied on the preliminary results as reported by the investigators at a recent
national cardiology meeting.14
Quality Assessment
and Data Abstraction
All qualifying studies were assessed for
adequate blinding of randomization,
completeness of follow-up, and objectivity of the outcome assessment. Blinding of the intervention was not used for
quality assessment because the intervention (ICD implantation) was surgical.
Data regarding detailed inclusion criteria, ICD device type, duration of followup, rates of crossover, all-cause mortality, and arrhythmic death were abstracted
(as available) from each individual study.
Statistical Analysis
We conducted a meta-analysis of summary statistics from the individual trials
because detailed, patient-level data were
not available for all trials. For each study,
data regarding all-cause mortality in both
the ICD and control groups were used
to generate risk ratios (RRs) and 95% confidence intervals (CIs). A priori, the decision was made to analyze the primary and
secondary prevention trials separately
due to anticipated heterogeneity in the
baseline clinical risk of these populations. Study-specific estimates were combined using inverse variance-weighted
averages of logarithmic RRs in both fixed-
©2004 American Medical Association. All rights reserved.
Figure 1. QUOROM Flow Diagram for the
Meta-analysis
675 Potentially Relevant
Publications Screened
459 Excluded Based on
Title and/or Abstract
216 Reports Retrieved for
Detailed Review
194 Excluded (Secondary
Analyses, Reviews,
and Commentaries)
22 Prospective Trials of
ICD Therapy
14 Excluded
7 Post-MI Trials
2 Nonrandomized Trials
4 No Medical Control
1 Sudden Unexplained
Death Syndrome∗ Trial
8 Trials Included in
Analytic Set
3 Secondary
Prevention
5 Primary Prevention
ICD indicates implantable cardioverter defibrillator; MI,
myocardial infarction; QUOROM, Quality of Reporting of Meta-analyses.19
*Sudden unexplained death syndrome is a syndrome
of primary ventricular fibrillation in healthy Southeast
Asian males with preserved left ventricular function, not
nonischemic cardiomyopathy.
and random-effects models. Betweenstudy heterogeneity was analyzed by
means of standard ␹2 tests, with Pⱕ.10
deemed statistically significant. Where
no significant statistical heterogeneity was
identified, the fixed-effect estimate was
used preferentially as the summary measure. Sensitivity analyses were performed to assess the contribution of each
study to the pooled estimate by excluding individual trials one at a time and
recalculating the pooled RR estimates for
the remaining studies. To assess the
impact of differential length of follow-up among the primary prevention
studies on the pooled estimate, the effects
of ICD therapy on all-cause mortality
were explored separately in trials with follow-up of less than 3 years and 3 or more
years. Publication bias was assessed
graphically using a funnel plot and mathematically using an adjusted rankcorrelation test, according to the method
of Begg and Mazumdar.20 All analyses
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2875
IMPLANTABLE DEFIBRILLATORS AND MORTALITY
were conducted using STATA version 8.2
(Stata Corp, College Station, Tex).
RESULTS
Search Results
As outlined in Figure 1, our search identified 8 prospective randomized controlled clinical trials of ICD vs medical
therapy enrolling at least some patients
with NICM. These included 3 trials of
ICD therapy for secondary prevention
(enrolling patients with previous resuscitated cardiac arrest or symptomatic
ventricular tachycardia) and 5 trials of
ICD therapy for primary prevention.
Qualitative Findings
Secondary Prevention Trials.The analyzed secondary prevention trials were
the Antiarrhythmics vs Implantable Defibrillators (AVID)1 trial, the Cardiac Arrest Study Hamburg (CASH),3 and the
Canadian Implantable Defibrillator
Study (CIDS).2 All trials included an active antiarrhythmic drug control group,
with most non-ICD patients receiving
amiodarone (AVID, CIDS). Patients in
the CASH study were initially randomized to ICD or 1 of 3 antiarrhythmic
drugs: amiodarone, metoprolol, or
propafenone. The propafenone arm was
terminated early due to evidence of increased mortality, and the final analysis pooled the amiodarone and metoprolol arms for comparison with ICD.3
None of the secondary prevention
trials exclusively enrolled patients with
NICM. Across all 3 trials enrolling a total
of 1963 patients, only 292 patients
(14.8%) were classified as having NICM.
The AVID and CIDS trials reported a nonsignificant reduction in all-cause mortality with ICD therapy in the subgroup
of patients with NICM,1,2 but independent outcomes for this subgroup were
not reported in CASH.
The baseline patient characteristics for
the secondary prevention trials are summarized in the TABLE. While the AVID
and CIDS trials enrolled patients with
similar characteristics in a comparable
trial design, the CASH trial was different: the mean left ventricular ejection
fraction in CASH was higher and, distinct from the other trials, more than 50%
of patients in CASH received epicardial
ICD systems rather than modern transvenous systems. Ultimately, the CASH
trial was excluded from the pooled analysis because of significant qualitative heterogeneity from the other trials, the small
number of patients with NICM enrolled, and the lack of reported estimates for ICD efficacy in the subgroup
of patients with NICM.
Primary Prevention Trials. The 5 primary prevention trials analyzed were
the Cardiomyopathy Trial (CAT),16 the
Amiodarone vs Implantable Cardioverter-Defibrillator Randomized Trial
(AMIOVIRT), 17 the Defibrillator in
Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Trial,15
the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT),14 and the Comparison of Medical Therapy, Pacing, and
Defibrillation in Heart Failure (COMPANION) Trial.21
There was substantial qualitative heterogeneity in trial design. The CAT,
AMIOVIRT, and DEFINITE trials exclusively enrolled patients with NICM,
while SCD-HeFT and COMPANION
enrolled patients with both ischemic
cardiomyopathy and NICM. CAT,
AMIOVIRT, and DEFINITE randomized patients to ICD or medical therapy
in a 2-arm design, but SCD-HeFT and
COMPANION were more complex.
The SCD-HeFT trial randomized patients with congestive heart failure and
left ventricular ejection fraction of 35%
or less to therapy with ICD, amiodarone, or placebo; a total of 1676 patients were randomized to either ICD or
placebo, of whom 792 (47.3%) had
NICM. Since data were reported for the
efficacy of ICD relative to placebo in the
subgroup of patients with NICM (hazard ratio for all-cause death, 0.73; 95%
CI, 0.50-1.04),14 only this subset of patients was included in the analysis. The
COMPANION trial randomized patients with heart failure, ICM or NICM,
and QRS duration greater than 120 milliseconds in a 1:2:2 ratio to receive optimal pharmacologic therapy alone or in
combination with cardiac resynchronization therapy using either a pacemaker or pacemaker-defibrillator. Of the
2876 JAMA, December 15, 2004—Vol 292, No. 23 (Reprinted)
1520 patients randomized in the trial,
903 were allocated to either the medical therapy or defibrillator arms; of this
subset, 397 patients (44%) had NICM.
Cardiac resynchronization with a pacemaker-defibrillator reduced all-cause
mortality relative to pharmacologic
therapy alone in patients with NICM
(hazard ratio for all-cause death, 0.50;
95% CI, 0.29-0.88; P=.015),21 and this
estimate was used in the pooled analysis.
In total, our meta-analysis included
data on 1854 patients with NICM randomized to therapy with ICD or placebo in a primary prevention setting. The
baseline characteristics for the patients
enrolled in each trial are summarized in
the Table. The most notable difference
between the trials was the severity of illness of enrolled patients. AMIOVIRT,
DEFINITE, and SCD-HeFT enrolled a
comparable number of patients with
heart failure of at least 3 years’ duration
and New York Heart Association (NYHA)
class III or IV symptoms. In contrast, the
CAT trial enrolled patients with heart failure of short duration (⬍9 months) and
low control group mortality at 1 year
(3.7%), suggesting that some of these patients may have had transient ventricular dysfunction. The COMPANION trial
enrolled only NYHA class III/IV patients with prolonged QRS duration by
design and had a predictably higher control group mortality (19%) at 1 year.
Despite the noted heterogeneity in design between the primary prevention
trials, there was sufficient similarity between the populations and the hypotheses to merit inclusion of all 5 trials in
the quantitative meta-analysis. The most
dissimilar trials (CAT, COMPANION)
were sequentially eliminated in sensitivity analyses to assess their impact on
the pooled effect estimate.
All 8 of the trials included in the analysis were of comparable quality. Although all trials were randomized, the
method of allocation generation was not
described in detail for any of the studies. Allocation concealment and blinding were not possible in these trials given
that the intervention (ICD implantation) was surgical; however, all trials used
either an independent or blinded com-
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IMPLANTABLE DEFIBRILLATORS AND MORTALITY
mittee for adjudication of events. Careful accounting for dropouts and crossovers was provided in nearly all cases,
and all analyses were conducted by intention-to-treat. While wide variations in
crossover rates were noted in the trials,
it was anticipated that crossovers would
decrease the calculated benefit of ICD
therapy relative to medical therapy and
bias results to the null in an intentionto-treat analysis. Summary measures of
methodological quality for each trial are
outlined in the Table. Funding for the
majority of the trials was provided, at
least in part, by the company whose device was the subject of study.
Quantitative Findings
Secondary Prevention Trials. Of the
secondary prevention trials, only AVID
and CIDS reported estimates of ICD efficacy in the subgroup of patients with
NICM. Individually, while the point estimates in both trials favored ICD
therapy over therapy with antiarrhythmic drugs, the results were statistically nonsignificant. When data from
these 2 secondary prevention trials were
pooled using a fixed-effects model
(n = 256 patients with NICM), ICD
therapy was associated with a 31% reduction in all-cause mortality relative
to medical therapy that remained statistically nonsignificant (RR, 0.69; 95%
CI, 0.39-1.24; P=.22 [FIGURE 2]). There
was minimal trial heterogeneity and accordingly little difference in the pooled
result from random-effects modeling.
Primary Prevention Trials. Four of
the 5 individual primary prevention trials
demonstrated a statistically nonsignificant benefit of ICD over medical therapy
for all-cause mortality in NICM patients. Only the COMPANION trial,
which used a device with both cardiac
resynchronization and defibrillation capabilities, demonstrated a statistically significant all-cause mortality reduction
with ICD over optimal medical therapy.
Pooled analysis of the 5 primary prevention trials (representing 1854 patients with NICM) demonstrated a statistically significant 31% reduction in
all-cause mortality with ICD relative to
medical therapy in fixed-effect models
(RR, 0.69; 95% CI, 0.55-0.87; P=.002
[FIGURE 3]). As with the secondary prevention trials, there was minimal trial
heterogeneity of results. To assess the
impact of qualitative heterogeneity in
trial design and patient selection on the
pooled effect estimate, we performed
several sensitivity analyses. First, we excluded the COMPANION trial, which
enrolled a population with more advanced heart failure and used a device
Table. Baseline Patient Characteristics
Primary Prevention Trials
Secondary Prevention Trials
Characteristic
No. randomized
AVID1
1016
CASH3
288
CIDS2
659
CAT16
104 (100)
103 (100)
458 (100)
66 (26.4)
24 (14.4)
26 (4)
59 (11.5)
70 (72)
20 (21)
3.2 y
23 (9)
58
71 (326)
21 (96)
2.8 y
21 (14)
60
77 (1291)
30 (503)
24.5 mo
25 (5)
67
68 (611)
100 (903)
3.5 y
22
84.9 (389)
96.7 (443)
69 (1156)
96 (1609)
67 (608)
89 (810)
193 (19.0)
36 (12.5)
63 (9.6)
57 (34)
36
65 (10.5)
79 (808)
9.5 (96)
NR
32 (13)
58 (11)
80 (230)
18 (52)
NR
46 (18)
64 (9.6)
84.5 (557)
10.8 (71)
NR
34 (14)
52 (11)
80 (83)
34.6 (36)
3 mo
24 (7)
29.4 (293)
69.5 (690)
33.3 (96)
43.4 (125)
27.5 (181)
NR
3.8 (4)
96.2 (100)
Primary end point
Control 1-y mortality,
% (No./total)
ICD type, % (No.)
Transvenous
Epicardial
Internal validity
Follow-up, %
Crossovers, % (No.)
To ICD
To pharmacologic
Intent-to-treat
Events committee
COMPANION21
458
18.2 (12.2)
Design
SCD-HeFT14
103
Duration of follow-up,
mean (SD), mo
Medications at baseline,
% (No.)
␤-Blocker
ACE inhibitor/ARB
DEFINITE15
104
No. (%) with NICM
Demographics
Age, mean (SD), y
Male, % (No.)
NYHA class III/IV, % (No.)
Duration of CHF, mean
LVEF, mean (SD), %
AMIOVIRT17
51.5 (53)
85 (88)
(ICD vs placebo) (CRT-D vs medical) 903
1676
792 (47.3)
45.5
397 (44.0)
Range, 14.8-16.5
ICD vs
ICD vs
ICD vs
ICD vs
ICD vs
ICD vs
ICD vs
Pharmacologic vs CRT
antiarrhythmic
antiarrhythmic
amiodarone
pharmacologic
amiodarone
pharmacologic
amiodarone
vs CRT-D
(82%
(amiodarone/
vs placebo
amiodarone)
metoprolol/
propafenone)
Total mortality
Total mortality
Total mortality
Total mortality
Total mortality Total mortality
Total mortality Total mortality/all-cause
rehospitalization
18 (90/509)
15 (28/189)
10.3 (34/331)
3.7 (2/54)
10 (5/52)
6.2 (14/259)
7.2 (NR)
19 (59/308)
93 (472)
5 (25)
100
44 (44)
54 (55)
100
18.9 (96)*
25.7 (130)
Yes
Blinded
84 (277)
10 (33)
100
6.1 (6)
5.8 (11)
Yes
NR
100 (50)
0
100 (51)
0
100 (259)
0
100
100
100
NR
10 (23)
NR
NR
NR
15.7 (52)
NR
28.1 (92)
NR
Yes
Yes
Independent,
NR
not blinded
15.4 (8)
21.6 (11)
Yes
Blinded
Yes
Blinded
100 (NR)
0
Yes
NR
100 (595)
0
⬎95%
26 (80)†
NR
Yes
Blinded
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CHF, congestive heart failure; CRT, cardiac resynchronization therapy; CRT-D, CRT plus defibrillator; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; NICM, nonischemic cardiomyopathy; NR, not reported; NYHA, New York Heart Association.
*Crossover rates for AVID are reported at 2 years.
†For COMPANION, rate of withdrawal from medical therapy group is reported as crossover rate.
©2004 American Medical Association. All rights reserved.
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2877
IMPLANTABLE DEFIBRILLATORS AND MORTALITY
capable of both cardiac resynchronization and defibrillation; combining the
remaining 4 trials generated an attenuated but still statistically significant result favoring ICD therapy (fixedeffects RR, 0.74; 95% CI, 0.58-0.96;
P =.02). Second, we excluded the CAT
study, which enrolled patients with
heart failure of short duration and low
control group mortality. Without CAT
or COMPANION, there was still a statistically significant benefit for ICD
therapy in pooled analysis of the remaining 3 trials (fixed-effects RR, 0.73;
95% CI, 0.55-0.96; P = .03). In general, exclusion of any single trial from
the analysis did not substantively alter
the overall result of our analysis. Additionally, eliminating the primary prevention trials with long (ⱖ3 years) fol-
low-up did not substantially change the
pooled point estimate (fixed-effects RR,
0.63; 95% CI, 0.46-0.88; P =.006).
Combined Analysis
Analysis of the 7 primary and secondary prevention trials in combination
demonstrated a statistically significant 31% survival benefit for ICD over
medical therapy (RR, 0.69; 95% CI,
0.56-0.86; P= .002). Again, there was
minimal heterogeneity of results and the
finding of reduced death risk was insensitive to exclusion of any single trial.
Publication Bias
To assess publication bias we generated a funnel plot of the logarithm of
effect size vs the standard error for each
trial. There was no evidence of signifi-
Figure 2. All-Cause Mortality Among Patients With NICM Randomized to ICD vs Medical
Therapy in Secondary Prevention
Favors ICD
Years of
Enrollment
No. of
Patients
Risk Ratio (95% CI)
AVID1
1993-1997
193
0.6 (0.29-1.33)
CIDS 2
1990-1997
63
0.8 (0.33-2.00)
256
0.69 (0.39-1.24)
Study
Combined
Favors No ICD
χ21 for Heterogeneity = 0.198
P = .66
0.1
1.0
2.0
10
Risk Ratio (95% CI)
Number of patients with nonischemic cardiomyopathy (NICM) enrolled is reported. Size of the data marker
corresponds to the relative weight assigned in the pooled analysis using fixed-effects models. ICD indicates
implantable cardioverter defibrillator; CI, confidence interval.
Figure 3. All-Cause Mortality Among Patients With NICM Randomized to ICD or CRT-D vs
Medical Therapy in Primary Prevention
Study
Years of
No. of
Enrollment Patients
CAT16
1991-1997
104
0.83 (0.45-1.82)
AMIOVIRT17
1996-2000
103
0.87 (0.31-2.42)
DEFINITE15
1998-2002
458
0.65 (0.40-1.06)
SCD-HeFT14
1997-2001
792
0.73 (0.50-1.04)
COMPANION21 2000-2002
397
0.50 (0.29-0.88)
1854
0.69 (0.55-0.87)
Combined
Favors ICD
Risk Ratio
(95% CI)
Favors No ICD
χ24 for Heterogeneity = 1.969
P = .74
0.1
1.0
2.0
10
Risk Ratio (95% CI)
Number of patients with nonischemic cardiomyopathy (NICM) enrolled is reported. Size of the data marker
corresponds to the relative weight assigned in the pooled analysis using fixed-effects models. ICD indicates
implantable cardioverter defibrillator; CRT-D, cardiac resynchronization plus defibrillator; CI, confidence interval.
2878 JAMA, December 15, 2004—Vol 292, No. 23 (Reprinted)
cant publication bias (P=.81 by Begg
adjusted rank-correlation test).
COMMENT
The results of our analysis suggest that
ICD therapy may reduce all-cause mortality by 31% over medical therapy in
patients with NICM. The results from primary prevention are the most compelling, with data from 1854 patients with
NICM randomized in 5 different trials
demonstrating a 31% reduction in allcause mortality with ICD therapy relative to medical therapy. This result was
robust in sensitivity analyses, even
accounting for possible bias introduced
by the inclusion of COMPANION, which
randomized patients to a device capable
of both cardiac resynchronization and
defibrillation rather than ICD. No individual trial was able to demonstrate a statistically significant benefit to ICD
therapy, likely due to lower than anticipated control group mortality and systematic underpowering of these trials in
the design phase.
Low mortality among medically
treated patients in the primary prevention setting also implies a relatively small
absolute mortality benefit to ICD therapy
in NICM. Assuming a mortality of approximately 7% per year (the averaged
control group mortality from CAT,
AMIOVIRT, DEFINITE, and SCD-HeFT,
affirmed in the recently published Marburg Cardiomyopathy Study10) and a
31% relative risk reduction, ICD therapy
could result in an absolute reduction of
approximately 2% per year in all-cause
mortality. At this rate, 25 patients with
NICM would need to be treated to prevent one death at 2 years. By comparison, in patients with ischemic cardiomyopathy, the number needed to treat
to achieve the same primary prevention
benefit is approximately 18.5
The data from randomized controlled
secondary prevention trials are less robust, primarily due to the small number
of enrolled patients with NICM. Though
underpowered (as reflected in the wide
CIs and lack of statistical significance),
the observed 31% reduction in mortality in the patients receiving ICD is consistent with a previous meta-analysis7
©2004 American Medical Association. All rights reserved.
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IMPLANTABLE DEFIBRILLATORS AND MORTALITY
of secondary prevention trials demonstrating a 28% reduction in mortality
with ICD therapy in unselected patients
(both ischemic and NICM). Furthermore, our conclusions are consistent
with the results of prior uncontrolled observational studies in secondary prevention suggesting that patients with NICM
and prior unexplained syncope or resuscitated cardiac arrest are at substantial
risk for sudden cardiac death.12,13,22-26
While few patients with NICM have been
randomized in the secondary prevention
setting, the unacceptable mortality associated with medical therapy in these
patients would likely make design of an
additional randomized controlled trial
ethically problematic.
Our analysis must be viewed in the
context of its limitations. First, we used
only data from randomized controlled
trials. Patients enrolled in randomized
trials may not be representative of patients
typically seen in clinical practice. However, because randomized trials balance
both known and unknown confounders across treatment groups, this is the
study design least vulnerable to bias.
Second, our results may be influenced
byapublicationbiasfavoringICDtherapy.
This risk was minimized through an exhaustive search of the available literature
and through the inclusion of an unpublished study (SCD-HeFT) in our analysis. Though the statistical tests did not indicatepublicationbias,thereisclearlylimited power to detect such bias, given the
small number of studies examined.
Third, our pooled analysis combines
theresultsfromclinicaltrialsthatenrolled
patients during a period of rapid evolution in the efficacy of medical therapy in
improving survival among patients with
NICM. It is this evolution that is in large
part likely responsible for the observed
reductionsincontrolgroupmortalityseen
in the more recent ICD primary prevention trials. Of the trials analyzed, only
COMPANION reported widespread use
of aldosterone-receptor antagonists
(⬇50%) in the medical therapy group.
In addition, rates of ␤-blocker use were
lowinbothCATandAMIOVIRT,andthis
may have led both trials to overestimate
the benefit of ICD therapy.
Despite these acknowledged limitations, we found that, based on a systematic review and meta-analysis, ICD
therapy is likely effective in both primary and secondary prevention of allcause mortality in the subgroup of patients with NICM, and ICD should be
considered for patients who meet the criteria for enrollment in the randomized
trials discussed above. It is important to
emphasize, however, that mortality reduction may not imply greater clinical
benefit among patients with advanced
heart failure. The decision regarding ICD
implantation must be influenced by careful consideration of patient preferences
and quality of life. Progressively worsening functional status may lead some
patients, in concert with their physicians, to engage advance directives that
elect against resuscitation, necessitating ICD deactivation. ICD implantation, while effective in reducing sudden
cardiac death, does not forestall the progression of heart failure.
Author Contributions: Dr Desai, as the principal investigator of this study, had complete access to the
data and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Study concept and design: Desai, Baughman.
Acquisition of data: Desai.
Analysis and interpretation of data: Desai, Fang, Maisel.
Drafting of the manuscript: Desai.
Critical revision of the manuscript for important intellectual content: Desai, Fang, Maisel, Baughman.
Statistical analysis: Desai.
Administrative, technical, or material support: Fang.
Study supervision: Fang, Baughman.
REFERENCES
1. The Antiarrhythmic versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular
arrhthmias. N Engl J Med. 1997;337:1576-1583.
2. Connolly SJ, Gent M, Roberts RS, et al. Canadian
Implantable Defibrillator Study (CIDS): a randomized
trial of the implantable cardioverter defibrillator against
amiodarone. Circulation. 2000;101:1297-1302.
3. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with
implantable defibrillators in patients resuscitated from
cardiac arrest: the Cardiac Arrest Study Hamburg
(CASH). Circulation. 2000;102:748-754.
4. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implantable defibrillator in patients with
coronary disease at high risk for ventricular arrhythmia.
N Engl J Med. 1996;335:1933-1940.
5. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J
Med. 2002;346:877-883.
6. Buxton AE, Lee KL, Fisher JD, et al. A randomized study
of the prevention of sudden death in patients with coronary artery disease. N Engl J Med. 1999;341:1882-1890.
7. Connolly SJ, Hallstrom AP, Cappato R, et al. Metaanalysis of the implantable cardioverter defibrillator sec-
©2004 American Medical Association. All rights reserved.
ondary prevention trials: AVID, CASH, and CIDS. Eur
Heart J. 2000;21:2071-2078.
8. Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiologic substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation. 2003;108:
704-710.
9. Grimm W, Hoffmann J, Menz V, et al. Programmed ventricular stimulation for arrhythmia risk
prediction in patients with idiopathic dilated cardiomyopathy and nonsustained ventricular tachycardia.
J Am Coll Cardiol. 1998;32:739-745.
10. Grimm W, Christ M, Bach J. Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study.
Circulation. 2003;108:2883-2891.
11. Tamburro P, Wilber D. Sudden death in idiopathic dilated cardiomyopathy. Am Heart J. 1992;124:
1035-1045.
12. Fonarow GC, Feliciano Z, Boyle NG, et al. Improved survival in patients with nonischemic advanced heart failure and syncope treated with an implantable cardioverter-defibrillator. Am J Cardiol. 2000;
85:981-985.
13. Russo AM, Verdino R, Schorr C, et al. Occurrence of implantable defibrillator events in patients with
syncope and nonischemic dilated cardiomyopathy Am
J Cardiol. 2001;88:1444-1446.
14. Bardy G. SCD-HeFT: the Sudden Cardiac Death in
Heart Failure Trial. Presented as a late-breaking clinical
trial at the American College of Cardiology Scientific Sessions, March 8, 2004. Available at: http://www.sicr.org
/scdheft_results_acc_lbcc.pdf. Accessed May 15, 2004.
15. Kadish A, Dyer A, Daubert J, et al. Prophylactic
defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:
2151-2158.
16. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated
cardiomyopathy. Circulation. 2002;105:1453-1458.
17. Strickberger SA, Hummel JD, Bartlett TG, et al.
Amiodarone versus implantable cardioverterdefibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia (AMIOVIRT). J Am
Coll Cardiol. 2003;41:1707-1712.
18. Haynes RB, Wilczynski N, McKibbon KA, et al. Developing optimal search strategies for conducting clinically sound studies in MEDLINE. J Am Med Inform
Assoc. 1994;1:447-458.
19. Moher D, Cook DJ, Eastwood S, et al. Improving
the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Lancet.
1999;354:1896-1900.
20. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias.
Biometrics. 1994;50:1088-1099.
21. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
N Engl J Med. 2004;350:2140-2150.
22. Knight BP, Goyal R, Pelosi F, et al. Outcome of
patients with nonischemic dilated cardiomyopathy and
unexplained syncope treated with an implantable
defibrillator. J Am Coll Cardiol. 1999;33:1964-1970.
23. Steinberg JS, Beckman K, Greene HL, et al. Followup of patients with unexplained syncope and inducible ventricular tachyarrhythmias. J Cardiovasc
Electrophysiol. 2001;12:996-1001.
24. Rankovic V, Karha J, Passman R, et al. Predictors
of appropriate implantable cardioverter-defibrillator
therapy in patients with dilated cardiomyopathy. Am
J Cardiol. 2002;89:1072-1076.
25. Grimm W, Hoffman J, Muller H-H, et al. Implantable defibrillator event rates in patients with idiopathic
dilated cardiomyopathy, nonsustained ventricular tachycardia on Holter, and a left ventricular ejection fraction
below 30%. J Am Coll Cardiol. 2002;39:780-787.
26. Levine JH, Waller T, Hoch D, et al. Implantable cardioverter defibrillator: use in patients with no symptoms and at high risk. Am Heart J. 1996;131:59-65.
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