Download ICD in LV Dysfunction

Review
Annals of Internal Medicine
Systematic Review: Implantable Cardioverter Defibrillators for Adults
with Left Ventricular Systolic Dysfunction
Justin A. Ezekowitz, MB, BCh, MSc; Brian H. Rowe, MD, MSc; Donna M. Dryden, PhD; Nicola Hooton, MPH; Ben Vandermeer, MSc;
Carol Spooner, BScN, MSc; and Finlay A. McAlister, MD, MSc
Background: Patients with left ventricular (LV) systolic dysfunction
have an increased risk for ventricular arrhythmias.
Purpose: To summarize the evidence about benefits and harms of
implantable cardioverter defibrillators (ICDs) in adult patients with
LV systolic dysfunction.
Data Sources: A search of electronic databases (including MEDLINE, EMBASE, Cochrane Central, and U.S. Food and Drug Administration reports) from 1980 through April 2007, not limited by
language of publication, was supplemented by hand searches and
contact with study authors and device manufacturers.
Study Selection: Two reviewers independently selected studies on
the basis of prespecified criteria. They selected 12 randomized,
controlled trials (RCTs) (8516 patients) that reported on mortality
and 76 observational studies (96 951 patients) that examined safety
or effectiveness.
ICDs reduced all-cause mortality by 20% (95% CI, 10% to 29%)
in the RCTs and by 46% (CI, 32% to 57%) in the observational
studies. Death associated with implantation of ICDs occurred during
1.2% (CI, 0.9% to 1.5%) of procedures. The frequency of postimplantation complications per 100 patient-years included 1.4 (CI,
1.2 to 1.6) device malfunctions, 1.5 (CI, 1.3 to 1.8) lead problems,
and 0.6 (CI, 0.5 to 0.8) site infection. Rates of inappropriate discharges per 100 patient-years ranged from 19.1 (CI, 16.5 to 22.0)
in RCTs to 4.9 (CI, 4.5 to 5.3) in observational studies.
Limitations: Studies were of short duration and infrequently reported nonfatal outcomes. Few studies evaluated dual-chamber
ICDs. Lack of individual-patient data prevents identification of
subgroup-specific effects.
Data Extraction: Data were extracted in duplicate and independently by 2 reviewers.
Conclusions: Implantable cardioverter defibrillators are efficacious
in reducing mortality for adult patients with LV systolic dysfunction,
and this benefit extends to nontrial populations. Improved risk
stratification tools to identify patients who are most likely to benefit
from ICD are needed.
Data Synthesis: In adult patients with LV systolic dysfunction, 86%
of whom had New York Heart Association class II or III symptoms,
Ann Intern Med. 2007;147:251-262.
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L
effectiveness (that is, the risks and benefits of a therapy
when tested under usual clinical practice conditions) and
safety of ICDs when used in clinical practice.
eft ventricular (LV) systolic dysfunction carries a high
risk for sudden cardiac death (1). Implantable cardioverter defibrillators (ICDs) can potentially mitigate this
risk by delivering rapid life-saving therapy and have been
substantially refined since their initial development in the
late 1970s (2). Randomized, controlled trials (RCTs) have
tested the efficacy of ICDs in high-risk individuals. We
previously reported a systematic review of 8 RCTs (3
RCTs of secondary prevention in survivors of sudden cardiac death; 5 RCTs of primary prevention in patients without a history of ventricular arrhythmias) demonstrating a
26% reduction in all-cause mortality and a 57% reduction
in sudden cardiac death with ICDs (3). Since then, additional RCTs of primary prevention have been published,
and questions have arisen about the generalizability of the
RCT results for ICDs to clinical practice. In particular, it is
uncertain whether the benefits of ICDs seen in the trials
extend to nontrial populations and whether the risks associated with ICDs may be higher in clinical practice than
reported in trials.
Given the public policy implications, we extended our
previous systematic review of the efficacy (that is, the risks
and benefits of a therapy when tested under ideal circumstances) (4) of ICDs in patients with LV systolic dysfunction by updating it with recently published RCTs that
examined efficacy. In addition, we expanded the review to
include data from observational studies to determine the
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METHODS
A study protocol meeting Cochrane criteria, including
all of the elements described briefly in the following sections, was developed and followed by the study authors in
conjunction with the Agency for Healthcare Research and
Quality (AHRQ).
Search Strategy
We sought studies published between 1980 and 27
April 2007 by searching MEDLINE, Ovid MEDLINE InProcess & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of
Systematic Reviews, Database of Abstracts of Reviews of
See also:
Web-Only
Appendix Tables
CME quiz
Conversion of figures and tables into slides
Audio summary
© 2007 American College of Physicians 251
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
Figure 1. Flow diagram of study identification and selection.
implantation complications with ICDs in adult patients
with LV systolic dysfunction (left ventricular ejection fraction [LVEF] ⱕ0.35, regardless of whether the patients had
heart failure symptoms). To address efficacy questions, we
restricted the analyses to RCTs. To address effectiveness
questions, we expanded our inclusion criteria to include
observational studies with contemporaneous comparison
groups (such as cohort studies) and RCTs that did not
report efficacy outcomes. To address safety questions, we
included evidence from both RCTs and observational
studies (including those without contemporaneous control
groups, such as case series and registry data).
Data Extraction and Analysis
RCT ⫽ randomized, controlled trial.
Effects, Health Technology Assessment Database, EMBASE,
Science Citation Index Expanded (via Web of Science),
International Pharmaceutical Abstracts, PubMed, National
Library of Medicine Gateway, OCLC ProceedingsFirst and
PapersFirst, Computer Retrieval of Information on Scientific Projects, various trial registries (including the National
Research Register [United Kingdom], Australian Clinical
Trials Registry, ClinicalTrials.gov, and Current Controlled
Trials), and U.S. Food and Drug Administration reports.
In addition, we hand-searched abstracts from the annual
Heart Rhythm Society meetings and the reference lists of
review articles and included studies; we also contacted
authors of included studies for additional citations and
information. Unpublished studies and individual-patient
data were sought from device manufacturers, including
Medtronic (Minneapolis, Minnesota), Guidant Corp. (Indianapolis, Indiana), and St. Jude Medical (St. Paul, Minnesota). The search was not limited by language or publication status.
The search terms included MedtronicInSync, ELA medical, Guidant, St. Jude, implantable defibrillators, implantable cardioverter defibrillators, AICD, ICD, single chamber
ICD, dual chamber ICD, congestive heart failure, CHF,
chronic heart failure, and heart diseases. A full list of search
strategies (adapted for each database) and search results are
available at www.ahrq.gov/clinic/tp/defibtp.htm (5).
Study Selection
We selected original research studies that had at least
25 participants and reported mortality or peri- or post252 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
Study selection, quality assessment, and data extraction were completed by several investigators in duplicate
and independently, using the methods recommended by
the Quality of Reporting of Meta-analyses (QUOROM)
group (6). We assessed quality by using the methods of
Schulz and colleagues (7), the 5-item Jadad scale (8), and
the 27-point Downs and Black scale (9). Publication bias
was assessed visually by using funnel plots and quantitatively by using the rank correlation test (10), the graphical
test (11), and the trim-and-fill method (12). Randomeffects models were used to calculate pooled relative risks
(RRs) in Review Manager 4.2.5 (Cochrane Collaboration,
Copenhagen, Denmark). The length of study follow-up
versus all-cause mortality was plotted for each study, and
inverse variance–weighted least-squares regression was used
to create a best-fit line. Postimplantation complications
were expressed per 100 patient-years (calculated by multiplying the frequency of events in each study by the duration of follow-up, and standardizing to a denominator of
100) and are unadjusted rates. All results were reported
with 95% CIs and, where appropriate, SDs or SEs. Statistical heterogeneity was quantified by using the I2 statistic
(13). In addition to examining for differences in point
estimates across study designs and study quality, we explored device efficacy in different patient subgroups by using meta-regression. Covariates tested included presence of
cardiac resynchronization therapy, length of follow-up,
ischemic etiology, New York Heart Association (NYHA)
class, age, QRS interval, LVEF, and primary versus secondary prevention.
Role of the Funding Source
The funding source (AHRQ, U.S. Department of
Health and Human Services) had no role in the collection,
analysis, or interpretation of the data or in the decision to
submit the manuscript for publication.
RESULTS
Literature Search
From 4439 citations (Figure 1), we identified 12
RCTs (8516 patients) for the ICD efficacy review (14 –
26), 53 studies (26 840 patients from 5 nonefficacy RCTs
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
and 48 observational studies [25 retrospective and 23 prospective]) for the ICD effectiveness review (27–78), and 64
studies (86 809 patients from 11 efficacy RCTs, 10 RCTs
without efficacy outcomes, and 43 observational studies
[24 retrospective and 19 prospective]) for the ICD safety
review (14 –17, 19 –27, 29, 30, 34, 37– 40, 42– 45, 47, 48,
52, 54, 60, 61, 63– 66, 69, 70, 72–75, 78 –101). A full list
of search strategies, search results, detailed quality assessments for each included study, and tests for publication
bias are available at www.ahrq.gov/clinic/tp/defibtp.htm
(5). No publication bias was seen on the funnel plots.
RCTs with Efficacy Data
The 12 efficacy RCTs varied in quality (ranging from
1 to 3 on the Jadad scale) and duration (ranging from 15
to 66 months). All but 2 trials (16, 19) evaluated singlechamber ICDs (although no trials reported protocol adherence to single-chamber vs. dual-chamber ICDs). All patients in the RCTs had LV systolic dysfunction: Mean
LVEF ranged from 0.21 to 0.28 in the primary prevention
trials and from 0.32 to 0.46 in the secondary prevention
trials. Most patients also had symptoms of heart failure:
Review
50% had NYHA class II symptoms at baseline; 36%, class
III symptoms; and 3%, class IV symptoms. Eleven percent
of trial participants were in NYHA class I at baseline (Appendix Table 1, available at www.annals.org). The mean
age of RCT participants was 61 years (SD, 4), 74% were
male, and 59% had ischemic heart disease.
Use of ICDs reduced all-cause mortality in patients
with LV systolic dysfunction by 20% (95% CI, 10% to
29%; I2 ⫽ 44.4%) (Figure 2), largely because of a 54%
relative reduction (CI, 37% to 63%; I2 ⫽ 0%) in sudden
cardiac deaths. In patients with LV systolic dysfunction,
ICDs were equally beneficial in reducing all-cause mortality in both primary prevention trials (RR, 0.81 [CI, 0.69 to
0.95]; I2 ⫽ 53.1% across 9 RCTs) and secondary prevention trials (RR, 0.77 [CI, 0.65 to 0.91]; I2 ⫽ 13.2% across
3 RCTs) (P for this indirect comparison ⫽ 0.56).
A single trial included cardiac resynchronization therapy in both study groups for its comparison of ICDs versus
control (19). All-cause mortality (RR, 0.83 [CI, 0.66 to
1.05]) was similar to that reported from the remainder of
the studies, which did not contain cardiac resynchroniza-
Figure 2. Effect of implantable cardioverter defibrillator (ICDs) on all-cause mortality in randomized trials.
AMIOVIRT ⫽ Amiodarone vs. Implantable Defibrillator Randomized Trial; AVID ⫽ Antiarrhythmics Versus Defibrillators; CABG Patch ⫽ Coronary
Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator
Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; DEFINITE ⫽ Defibrillators in NonIschemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial; MADIT ⫽ Multicenter Automatic
Defibrillator Implantation Trial; RR ⫽ relative risk; SCD-HeFT ⫽ Sudden Cardiac Death in Heart Failure Trial.
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21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 253
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
Figure 3. Effect of implantable cardioverter defibrillators (ICDs) on all-cause mortality in observational studies with
contemporaneous control groups.
MUSTT ⫽ Multicenter Unsustained Tachycardia Trial; RR ⫽ relative risk.
tion therapy in either study group (RR, 0.79 [CI, 0.69 to
0.91]) (P for indirect comparison ⫽ 0.92).
Only 1 trial reported a statistically significant difference in the effect of ICDs across NYHA classes: The mortality benefits were greater in patients with NYHA class II
symptoms than in those with NYHA class III symptoms in
the Sudden Cardiac Death in Heart Failure Trial (P ⬍
0.001 for interaction term of NYHA class and mortality)
(22). In a series of univariate meta-regression sensitivity
analyses, none of the covariates we examined (duration of
follow-up, primary vs. secondary prevention, ischemic
cause, presence of cardiac resynchronization therapy,
NYHA class, mean age, mean LVEF, or mean QRS duration) contributed to the moderate statistical heterogeneity
observed in our meta-analysis of all-cause mortality. In addition, our estimate of treatment effect was not associated
with study quality.
Implantable cardioverter defibrillators did not seem to
be associated with an increase in symptoms of heart failure
or deteriorations in functional status or quality of life in
RCT participants; however, these outcomes were infrequently reported (see full AHRQ report for details [5]).
For example, hospitalizations for heart failure were reported in only 2 trials (pooled RR, 1.1 [CI, 0.76 to 1.59]).
Observational Studies and Trials with Effectiveness Data
The 47 cohort studies, 5 nonefficacy RCTs, and 1
case– control study varied in quality (ranging from 7 to 28
on the Downs and Black scale) and duration (median, 29
months [interquartile range, 19 to 37 months]). All studies
enrolled similar patient populations. Twenty of the 53
254 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
studies reported the type of ICD implanted: 18 studies
included patients receiving both single- and dual-chamber
ICDs, 1 study included those receiving dual-chamber
ICDs only, and 1 study included those receiving singlechamber ICDs only. Fifteen of these studies evaluated
ICDs for primary prevention, 4 reported ICD data for
secondary prevention, 30 reported on a mix of primary and
secondary prevention patients, and 4 studies were unclear.
All patients in these studies (Appendix Table 2, available at
www.annals.org) had LV systolic dysfunction (mean LVEF
ranged from 0.19 to 0.46), and most had symptoms of
heart failure (32% were in NYHA class II, 40% were in
class III, and 5% were in class IV). Demographic characteristics were similar to those of participants in the RCTs
of ICD efficacy: The mean age was 63 years (SD, 13), 82%
of patients were male, and 67% had underlying ischemic
heart disease.
The pooled effectiveness estimate from the controlled
observational studies suggested a greater benefit from ICDs
on all-cause mortality (RR, 0.54 [CI, 0.43 to 0.68]) than
had been seen in the RCTs (Figure 3), but with greater
heterogeneity between studies (I2 ⫽ 60.4%). The observational studies demonstrated a reduced frequency of noncardiac death in ICD recipients (RR, 0.74 [CI, 0.65 to
0.85] in 8 studies with 8759 patients; I2 ⫽ 0%). We evaluated the effect of quality (via meta-regression) on all-cause
mortality. Contrary to expectations, higher-quality studies
reported a greater benefit from ICDs, but this finding was
not significant (P ⫽ 0.09). As shown in Figure 4, mortality
over time was similar in ICD recipients enrolled in RCTs
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
and in observational studies (both prospective and retrospective).
Observational Studies and Trials with Harms Data
In 53 studies (Appendix Table 2, available at www
.annals.org) enrolling patients with LV systolic dysfunction
only (median LVEF, 0.31), rate of success of ICD implantation was 99% (CI, 98.8% to 99.3%) and peri-implantation deaths occurred in 1.2% (CI, 0.9% to 1.5%) of procedures. These studies varied in quality (ranging from 18
to 27 on the Downs and Black scale) and duration (median, 28 months [interquartile range, 19 to 48 months])
but enrolled similar patient populations. In 24 studies, patients received either a dual- or a single-chamber ICD; in 4
studies, patients received dual-chamber ICDs only; and in
10 studies, patients received single-chamber ICDs only.
The remaining studies did not report the type of device.
The frequency of postimplantation complications (per 100
patient-years) included 1.4 (CI, 1.2 to 1.6) device malfunctions, 1.5 (CI, 1.3 to 1.8) lead problems, and 0.6 (CI, 0.5
to 0.8) implant site infection. The rate of inappropriate
discharges per 100 patient-years was 19.1 (CI, 16.5 to
22.0) in the RCTs and 4.9 (CI, 4.5 to 5.3) in the observational studies (Table 1).
We also examined peri-implantation deaths and success rates in 12 studies (68 848 patients) that enrolled all
patients undergoing ICD implantation (that is, not just
those patients with LV systolic dysfunction: 1 study of
primary prevention, 3 studies of secondary prevention, 7
studies of both, and 1 study unclear) (90 –101). The proportions were similar to those reported in the studies restricted to patients with LV systolic dysfunction: The implantation success rate was 98.6% (CI, 98.3% to 98.9%),
and peri-implantation deaths occurred during 1.3% (CI,
1.2% to 1.4%) of procedures.
DISCUSSION
This systematic review examined the efficacy, effectiveness, and safety of ICDs in adult patients with LV dysfunction. The results confirm that ICDs reduce the relative risk
for death by 20% for adults who have an LVEF of 0.35 or
less and predominantly NYHA class II and III symptoms.
This effect exists regardless of whether a patient has a history of hemodynamically apparent ventricular arrhythmias
or an ischemic cause. Our review goes beyond previous
reviews of this topic in demonstrating that 1) the survival
benefits of ICDs extend beyond the RCT setting and 2)
the implantation success rate and safety of ICDs are similar
in clinical practice and RCTs. The fact that the controlled
observational studies demonstrated a reduced frequency of
noncardiac death in ICD recipients suggests that clinicians
select healthier patients for ICD insertion, and this probably accounts for the larger apparent benefit from ICDs on
all-cause mortality in observational studies than in RCTs.
However, our data on patient and device-related complication rates highlight the perhaps underappreciated risks
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Review
of ICDs, particularly in light of 3 findings. First, three
quarters to two thirds of ICD recipients in the observational studies received no therapeutic ICD discharges, and
only 5% to 12% of trial participants received an appropriate shock per year (102). Second, the frequency of inappropriate shocks was surprisingly high, and at least 1 study
has demonstrated that inappropriate shocks are associated
with an increase in risk for death (hazard ratio, 1.97 [CI,
1.29 to 3.01] in the Sudden Cardiac Death in Heart Failure Trial) (103). Third, although the studies we reviewed
infrequently report quality-of-life outcomes, some studies
have shown that quality of life declines in many ICD recipients (104), especially those who experience frequent ICD
firings (105, 106). Not unexpectedly, patient anxiety and psychological distress scores increase substantially after an ICD
shock (107) or after publicity about device recalls (108).
Thus, whereas the Multicenter Automatic Defibrillator Implantation Trial II and Sudden Cardiac Death in
Heart Failure Trial eligibility criteria are commonly cited
as a way to identify patients who might benefit from an
ICD, the development and validation of risk stratification
tools (such as microvolt T-wave alternans [109] or elevated
natriuretic peptide levels [110]) to identify patients who
are most likely to benefit from an ICD are vitally important (111, 112). This is particularly true because less than
one quarter of patients with cardiac arrest have an LVEF
less than 0.30 before the event (113). Although our metaregressions did not reveal any patient subgroups who were
statistically more or less likely to benefit from an ICD, we
should emphasize that these analyses were post hoc and
underpowered because of the small number of RCTs. A
Figure 4. Scatter plot of all-cause mortality versus length
of follow-up for recipients of implantable cardioverter
defibrillators who were enrolled in different types of
studies.
Circle ⫽ prospective cohort study; square ⫽ randomized, controlled
trial; triangle ⫽ retrospective cohort study. Size of plotting character is
proportional to the square root of the sample size of study.
21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 255
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
Table 1. Peri- and Postimplantation Risks of Implantation of Cardioverter Defibrillators*
Outcome
Peri-implantation complications
Death
Implantation success rate
Mechanical complication
Postimplantation complications
Mechanical malfunction
Device malfunction
Lead problems
Infections
Inappropriate shocks
Type of Study
Studies, n
Raw Data†
Pooled Risk Estimates
(95% CI)‡
RCT (LVSD)
RCT (non-LVSD)
Observational (LVSD)
Observational (non-LVSD)
Total
RCT (LVSD)
RCT (non-LVSD)
Observational (LVSD)
Observational (non-LVSD)
Total
RCT
Observational studies
Total
8
4
20
6
38
10
4
14
3
31
5
13
18
35/2014
0/725
24/2888
454/34 231
513/39 858
3657/3716
766/777
2473/2473
4107/4163
11 003/11 129
88/1740
88/1559
176/3299
1.7 (1.2–2.4)
0.0 (0.0–0.4)
0.8 (0.5–1.2)
1.3 (1.2–1.5)
1.3 (1.2–1.4)
98.4 (98.0–98.8)
98.6 (97.5–99.3)
100.0 (99.9–100.0)
98.7 (98.3–99.0)
98.9 (98.7–99.1)
5.1 (4.1–6.2)
5.6 (4.6–6.9)
5.3 (4.6–6.2)
RCT
Observational
Total
RCT
Observational
Total
RCT
Observational
Total
RCT
Observational
Total
RCT
Observational
Total
3
6
9
5
5
10
6
10
16
8
9
17
2
27
29
11/1477
33/5478
44/6955
91/6429
57/4436
148/10 865
38/2303
123/6354
161/10 527
58/1232
18/7037
76/12 436
155/810
556/11 448
711/12 258
0.7 (0.4–1.3)
0.6 (0.4–0.8)
0.6 (0.5–0.8)
1.4 (1.1–1.7)
1.3 (1.0–1.7)
1.4 (1.2–1.6)
0.9 (0.6–1.2)
1.9 (1.6–2.3)
1.5 (1.3–1.8)
1.1 (0.8–1.4)
0.3 (0.2–0.4)
0.6 (0.5–0.8)
19.1 (16.5–22.0)
4.9 (4.5–5.3)
5.8 (5.4–6.2)
* LVSD ⫽ studies restricted to patients with left ventricular systolic dysfunction; non-LVSD ⫽ studies of all persons receiving an implantable cardioverter defibrillator;
RCT ⫽ randomized, controlled trial.
† Data for peri-implantation complications are expressed as the number per attempted procedure. Data for postimplantation complications are expressed as the number of
patients/patient-years.
‡ Risk estimates for peri-implantation complications are expressed as percentages. Risk estimates for postimplantation complications are expressed per 100 patient-years.
meta-analysis of individual-patient data would be necessary
to more thoroughly examine this issue. Indeed, the establishment of the ICD Registry by the American College of
Cardiology National Cardiovascular Data Registry (ACCNCDR) in conjunction with the Heart Rhythm Society is
an important initiative that will permit the collection of
comprehensive data on ICD implantations and long-term
outcomes. These efforts should help to identify whether
particular patient subgroups derive more or less benefit and
whether specific devices or particular programming variables are associated with improved outcomes (114).
Regardless, the current evidence base does provide
some guidance in the selection of candidates for a primary
prevention ICD. For example, because ICDs were not associated with mortality benefits when implanted at the
time of bypass surgery (15), within 40 days of a myocardial
infarction (21), or within 6 months of coronary revascularization (hazard ratio, 1.19; P ⫽ 0.76) (115), the recommendation in the American College of Cardiology/American Heart Association/European Society of Cardiology
2006 guidelines (116) to delay ICD implantation after
acute coronary events or coronary revascularization is ap256 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
propriate. Reports that ICD recipients with a baseline QRS
interval of 120 ms or greater are at increased risk for subsequent heart failure (117) highlight a subgroup of ICDeligible patients (those with NYHA III symptoms,
LVEF ⱕ0.35, and QRS interval ⱖ120 ms) who should be
considered for a combined cardiac resynchronization therapy–ICD device per the recommendations of the American
Heart Association, American College of Cardiology, and
Heart Rhythm Society (116).
Our analysis is limited by a paucity of data on dualchamber ICDs. While 1 study reported a 47% improvement in the odds of detecting supraventricular tachycardia
and averting potentially inappropriate ICD therapy (81)
with a dual-chamber ICD, 3 observational studies (118 –
120) and 1 small RCT (87) failed to show benefit with
dual-chamber ICDs over single-chamber ICDs. Indeed,
the largest RCT to date has suggested that dual-chamber
ICDs may exacerbate heart failure in patients without an
indication for dual-chamber pacing (121). In addition, a
post hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial II demonstrated a higher risk for
death or heart failure hospitalization among patients who
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Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
received a dual-chamber ICD than among those who received a single-chamber ICD (122). Because the choice of
single- versus dual-chamber ICDs was not randomized,
this subgroup comparison may be biased. For example,
patients who received dual-chamber devices were older,
had more advanced heart failure symptoms, and had more
comorbid conditions; thus, after multivariable adjustment,
the excess risks with dual-chamber ICDs were not statistically significant (hazard ratio for death, 1.27 [CI, 0.76 to
2.12]; hazard ratio for heart failure hospitalization, 1.27
[CI, 0.87 to 1.86]). An unpublished RCT (the Dual
Chamber and Atrial Tachyarrhythmias Adverse Events
Study) (123), which used different device settings with a
longer atrioventricular delay, reported fewer inappropriate
shocks with dual-chamber ICDs than with standard singlelead ICDs. Thus, dual-chamber ICDs must be tested
against single-chamber ICDs in an appropriately powered
RCT before definitive conclusions can be drawn about
which device to use. In the meantime, although the most
recent guidelines for ICDs and the prevention of sudden
cardiac death are silent on the indications for dual-chamber
devices (116), we believe it prudent to restrict the use of
dual-chamber ICDs to patients who require an ICD and
have conventional indications for dual-chamber pacing
(such as chronotropic incompetence, the sick sinus syndrome, or atrioventricular conduction abnormalities) (124).
While we report on patient and device-related complication rates in this review, it should be recognized that it is
difficult to estimate the true incidence of ICD device failure. The observed failure rates are probably underestimated
because of the tendency to attribute patient deaths to the
underlying disease process rather than unrecognized device
malfunction. Indeed, an analysis of U.S. Food and Drug
Review
Administration Enforcement Reports over the past decade
demonstrated marked increases in device recall rates over
time (as devices have become smaller and more complicated). Currently, ICD recall rates are as high as 16.4 per
100 person-years—54% for hardware malfunctions (electrical or circuitry malfunctions, battery or capacitor malfunctions, problems with hermetic seals, defective crystals,
and defective headers) and 41% for firmware malfunctions
(integral device computer programming) (125).
The cost-effectiveness of ICDs in patients with LV
dysfunction has been analyzed several times. Results have
varied (126 –129); however, no study has accounted for
ICD advisories and replacements, which increased total
health care costs by as much as $90 million per year (125).
Since variability in model estimates is due in part to uncertainty about complication rates, our data should
strengthen the assumptions upon which these analyses are
based. Accounting for these new data and observations
should be a priority for all future analyses of ICD cost.
Our systematic review has a few limitations that deserve consideration, some of which were identified in previous reviews (130). The conclusions of a systematic review
are limited by available data; we sought to minimize this by
an extensive search that included gray literature and U.S.
Food and Drug Administration reports. We could not obtain individual-patient data to explore the subgroups that
get more or less benefit from an ICD; however, we performed meta-regression by using aggregate trial-level data,
which did not reveal variation across the variables we
tested. Because of incomplete reporting of outcomes in the
selected studies, certain device-related issues cannot be explored, such as benefits and safety of dual-chamber versus
single-chamber devices, even within an RCT. In the obser-
Table 2. Summary of Evidence for Implantable Cardioverter Defibrillators in Patients with Left Ventricular Systolic Dysfunction*
Symptom Status
Quality of Evidence
Magnitude of Effect (95% CI)†
Conclusion
History of ventricular fibrillation or tachycardia
NYHA class II or III
High (many RCTs with homogeneous results)
High (many RCTs with homogeneous results)
Definite benefit
Definite benefit
NYHA class I
Low (post hoc metaregression using
aggregate trial data from 12 RCTs)
Primary prevention in NYHA class IV
Moderate (within-RCT comparison, but not
primary aim of RCT; in addition, study
used post hoc metaregression with
aggregate trial data from 12 RCTs)
Reduced mortality: 0.77 (0.65–0.91)
Reduced mortality: 0.81 (0.69–0.95)
No significant effect on hospitalizations
for heart failure: 1.10 (0.76–1.59)
No significant association in
meta-regression between proportion
of patients with class I symptoms
and reduction in mortality
(P ⫽ 0.13)
Mortality hazard ratio, 1.27 (0.68–2.37),
in CRT-ICD group vs. CRT-alone
group among patients with class IV
symptoms in COMPANION, but no
significant association in metaregression between proportion of
patients with class IV symptoms and
reduction in mortality
(P ⫽ 0.62)
Inconclusive
Inconclusive
* Other considerations may outweigh the trial evidence in some situations (e.g., the patient who wishes to have a do-not-resuscitate order), and there are no data on the effects
of ICDs in patients with advanced age or severe comorbid conditions (such as end-stage renal disease). Patients with indications for an ICD and indications for a conventional
pacemaker (chronotropic incompetence, the sick sinus syndrome, or atrioventricular conduction abnormalities) should be considered for a dual-chamber ICD rather than a
single-chamber ICD. COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy;
ICD ⫽ implantable cardioverter defibrillator; NYHA ⫽ New York Heart Association; RCT ⫽ randomized, controlled trial.
† Unless otherwise indicated, values are relative risks.
www.annals.org
21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 257
Review
Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction
vational studies, we report unadjusted outcomes, and this
may introduce bias if there were baseline imbalances between study groups. However, adjustment for study-level
variables, such as the incidence of diabetes, may also introduce bias if these variables are not consistently reported
and if the spectrum of disease is not clear. Alternatively,
using within-study adjusted numbers will lead to bias between studies. Finally, there is a paucity of long-term data
(that is, beyond the first 28 months after implantation) in
the literature. The importance of long-term data are highlighted by a recent report of 990 patients from a single
center followed for up to 10 years, which reported rates of
ICD lead failure as high as 20% at 10 years (131).
In conclusion, ICDs are efficacious and effective in
adults with LV systolic dysfunction. Our systematic review
identifies the areas of certainty and uncertainty in the literature about which patients should be considered for an
ICD (Table 2). In addition, our findings highlight 3 research priorities. First, the importance of the prospective
ACC-NCDR registry for providing “real world” estimates
of benefits and risks with these devices cannot be underestimated. For example, recent studies (81) demonstrate
that ICDs are being implanted by less experienced providers working in hospitals with lower implantation volumes
than in the RCTs of ICDs included in this systematic
review, and their effectiveness should be assessed. This
would also permit policymakers to track changes in complication rates as device implanters, the tools for implantation, and the sophistication of the devices change over
time, and to track effectiveness and complication rates with
single-chamber versus dual-chamber ICDs. Second, although more complex ICDs (dual-chamber ICDs, or those
capable of antitachycardia pacing) are gaining popularity,
evidence comparing such devices with single-lead ICDs,
especially in patients without conventional indications for
dual-chamber pacing, is limited. Finally, and most important, our meta-analysis reports average treatment effects;
the development of risk stratification tools to identify who
should (and should not) get an ICD is clearly a research
priority. In the words of one editorialist, “it is the entry
criterion and not the group actually studied that has driven
practice guidelines” (132), and most patients currently implanted with an ICD never receive a therapeutic discharge
but are exposed to the risks of ICDs outlined in our report.
Thus, we call for the investigators of RCTs on ICDs to
collate their individual-patient data to collaboratively explore subgroup effects and define which patients are most
likely to benefit from this therapy.
From the University of Alberta Evidence-based Practice Center, Edmonton, Alberta, Canada.
Disclaimer: The authors of this report are responsible for its content.
Statements in the report should not be construed as endorsement by the
AHRQ or the U.S. Department of Health and Human Services.
Acknowledgments: The authors thank the members of the technical
258 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
expert panel for this AHRQ report: Dr. Gillian Sanders (Duke University, Durham, North Carolina), Dr. Mark Hlatky (Stanford University,
Stanford, California), Dr. Richard Page (University of Washington
School of Medicine, Seattle, Washington), Dr. William Abraham (Ohio
State University, Columbus, Ohio), and Mary Nix (AHRQ, Rockville,
Maryland), who provided direction for the scope and content of the
review. They also thank the librarians (Carol Friesen and Tamara Durec)
and the external reviewers who submitted written comments on earlier
drafts of this report: Dr. David Atkins (AHRQ), Dr. Eric Fain (St. Jude
Medical, St. Paul, Minnesota), Dr. Martin Fromer (Centre Hospitalier
Universtaire Vaudois, Lausanne, Switzerland), Dr. Gordon Moe (University of Toronto, Toronto, Ontario, Canada), Dr. Robert Rea (Mayo
Clinic College of Medicine, Rochester, Minnesota), Dr. John Spertus
(University of Missouri–Kansas, Kansas City, Missouri), Bob Thompson
(Medtronic, Minneapolis, Minnesota), and Dr. Clyde Yancy (Baylor
Heart and Vascular Institute, Dallas, Texas).
Grant Support: This manuscript is based on an evidence report pro-
duced by the University of Alberta Evidence-based Practice Center under
contract 290-02-0023 from the AHRQ, U.S. Department of Health and
Human Services. Dr. Ezekowitz is supported by the Canadian Institutes
of Health Research Randomized Controlled Trials Program. Dr. Rowe is
supported by the 21st Century Canada Research Chairs program
through the Government of Canada. Dr. McAlister is a Population
Health Scholar supported by the Alberta Heritage Foundation for Medical Research, is a New Investigator of the Canadian Institutes of Health
Research, and holds the Merck Frosst/Aventis Chair in Patient Health
Management at the University of Alberta, Edmonton. Drs. Ezekowitz,
Rowe, and McAlister are also supported by the Faculty of Medicine and
Dentistry, University of Alberta, Edmonton, and the Capital Health
Authority, Edmonton.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Finlay A. McAlister, MD, MSc, Univer-
sity of Alberta Hospital, 2E3.24 WMC, 8440 112th Street, Edmonton,
Alberta T6G 2R7, Canada; e-mail, [email protected].
Current author addresses are available at www.annals.org.
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262 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
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Current Author Addresses: Dr. Ezekowitz: 2C2 Cardiology WMC,
University of Alberta Hospital, 8440 112th Street, Edmonton, Alberta
T6G 2B7, Canada.
Dr. Rowe: Department of Emergency Medicine, University of Alberta
Hospital, 1G1.42, 8440 112th Street, Edmonton, Alberta T6G 2B7,
Canada.
Dr. Dryden, Ms. Hooton, Mr. Vandermeer, and Ms. Spooner: University of Alberta Evidence Based Practice Center, Aberhart Centre, 11402
University Avenue, Edmonton, Alberta, T6G 2J3, Canada.
Dr. McAlister: University of Alberta Hospital, 2E3.24 WMC, 8440
112th Street, Edmonton, Alberta T6G 2R7, Canada.
Appendix Table 1. Description of Randomized Trials Included in the Review*
Author, Trial Name, Year
(Reference)
Primary prevention
Moss et al., MADIT, 1996 (14)
Design,
Duration
Patients
Randomly
Assigned,
n
Men, n
(%)
Mean Age (SD), y
95
101
446
87 (92)
93 (92)
386 (86.5)
62 (9)
64 (9)
64 (9)
27 (7)
25 (7)
27 (6)
34
29
100
Mean LVEF (SD)
Ischemic
Heart
Disease,
%
NYHA Class, %
II
III
II or III ⫽ 63
II or III ⫽ 67
II or III ⫽ 71
IV
Bigger, CABG Patch,
1997 (15)
RCT, 32 mo
ICD
OPT
CABG ⫹ ICD
Moss et al., MADIT II,
2002 (16)
RCT, 20 mo
CABG
ICD
454
742
373 (82.2)
623 (84)
63 (9)
64 (10)
27 (6)
23 (5)
100
100
35
25
Bänsch et al., CAT, 2002 (17)
RCT, 66 mo
Strickberger et al., AMIOVIRT,
2003 (18)
RCT, 2 y
OPT
All
ICD
OPT
All
490
104
50
54
103
417 (85)
83 (79.8)
43 (86)
40 (74)
72 (69.9)
65 (10)
52 (11)
52 (12)
52 (10)
59 (11)
23 (6)
24 (7)
24 (6)
25 (8)
22 (9)
100
0
0
0
0
34
65.3
66.7
64.1
64
23
34.6
33.3
35.8
19.4
RCT, 15 mo
ICD
Amiodarone
CRT ⫹ OPT
51
52
617
34 (67)
38 (74)
413 (67)
58 (11)
60 (12)
Median, 67
22 (10)
23 (8)
Median, 20
64
63
Excluded
16
24
87
595
399 (67)
Median, 66
Median, 22
55
Excluded
86
14
RCT, 29 mo
CRT ⫹ ICD
⫹ OPT
OPT only
All
308
458
213 (69)
326 (71.2)
Median, 68
58 (range, 20–84)
Median, 22
21.4 (range, 7–35)
59
0
Excluded
57.4
82
21
18
0
ICD
OPT
229
229
166 (72.5)
160 (69.9)
58 (range, 20–84)
58 (range, 22–79)
0
0
54.2
60.7
20.5
21.4
0
0
ICD
332
252 (75.9)
61.5 (10.9)
20.9 (range, 7–35)
21.8 (range,
10–35)
28 (5)
100
NR
NR
0
OPT
ICD
342
829
262 (76.6)
639 (76)
28 (5)
Median, 25
100
52
NR
71
NR
29
0
0
Amiodarone
845
639 (77)
Median, 25
50
70
30
0
Placebo
847
655 (77)
62.1 (10.6)
Median, 60 (IQR,
52–69)
Median, 60 (IQR,
52–68)
Median, 59.7
(IQR, 51–68)
Median, 25
53
68
32
0
ICD
Antiarrhythmic
ICD
505
509
328
395 (78)
412 (81)
280 (85.4)
65 (11)
65 (10)
63.3 (9.2)
32 (13)
31 (13)
NR
81
81
82.2
I or II ⫽ 48
I or II ⫽ 48
I or II ⫽ 37.8
Amiodarone
331
277 (83.7)
63.8 (9.9)
NR
82.9
I or II ⫽ 39.9
ICD
Metoprolol
Amiodarone
99
97
92
78 (79)
152 (80)
58 (11)
57.5 (10)
46 (19)
46 (17)
73
73.5
59
56
7
0
12
0
III or IV ⫽
11.0
III or IV ⫽
10.6
18
0
16
0
Bristow et al., COMPANION,
2004 (19)
Kadish et al., DEFINITE,
2004 (20)
RCT, 27 mo
Study Group
Hohnloser et al., DINAMIT,
2004 (21)
RCT, 30 mo
Bardy et al., SCD-HeFT,
2005 (22)
RCT, 46 mo
(median)
Secondary prevention
AVID, 1997 (23)
RCT, 18 mo
Connolly et al., CIDS,
2000 (24)
RCT, 35 mo
Kuck et al., CASH, 2000 (25)
RCT, 57 mo
0
0
54
0
0
NR
II or III ⫽ 74
NR
5
4
0
0
0
0
0
0
13
* AMIOVIRT ⫽ Amiodarone vs. Implantable Defibrillator Randomized Trial; AVID ⫽ Antiarrhythmics Versus Defibrillators; CABG ⫽ coronary artery bypass graft;
CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable
Defibrillator Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy;
DEFINITE ⫽ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial; ICD ⫽ implantable
cardioverter defibrillator; IQR ⫽ interquartile range; LVEF ⫽ left ventricular ejection fraction; MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; NR ⫽
not reported; NYHA ⫽ New York Heart Association; OPT ⫽ optimal pharmacologic therapy; RCT ⫽ randomized, controlled trial; SCD-HeFT ⫽ Sudden Cardiac Death
in Heart Failure Trial.
W-48 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
www.annals.org
Appendix Table 2. Baseline Characteristics of Patients in Studies Included in the Review*
Duration, mo
Author, Trial Name, Year (Reference)
Design
Alter et al., 2005 (26)
AVID, 1997 (23)
Prospective cohort
RCT
46
18
Backenköhler et al., 2005 (27)
Prospective cohort
48
Bänsch et al., CAT, 2002 (17)
RCT
66
Bardy et al., SCD-HeFT, 2005 (22)
RCT
46
Bigger, CABG Patch, 1997 (15)
RCT
32
Blangy et al., 2003 (28)
Bode-Schnurbus et al., 2003 (29)
Bokhari et al., CIDS, 2004 (30)
Retrospective cohort
Prospective cohort
Prospective cohort
Bristow et al., COMPANION, 2004 (19)
RCT
15
Bruch et al., 2006 (31)
Brunckhorst, 2004 (32)
Buxton et al., MUSTT, 1999 (33)
Prospective cohort
Prospective cohort
RCT
12
12
39
Capoferri et al., 2004 (34)
Prospective cohort
20
Carlsson et al., 2003 (79)
Chan and Hayward, 2005 (35)
RCT
Prospective cohort
NR
60
Chan et al., 2006 (36)
Connolly et al., CIDS, 2000 (24)
Prospective cohort
RCT
27
35
Cuesta et al., 2003 (37)
Dorian et al., ASTRID, 2004 (38)
Dorian et al., SHIELD, 2004 (80)
Dubner et al., 2005 (39)
Duray et al., 2005 (40)
Elhendy et al., 2005 (41)
Ellenbogen et al., 2003 (42)
Ermis et al., 2003 (43)
Prospective cohort
RCT
RCT
Retrospective cohort
Retrospective cohort
Prospective cohort
Prospective cohort
Retrospective cohort
30
12
12
27
26
34
69
15
Ermis et al., 2004 (77)
Evonich et al., 2004 (44)
Friedman et al., 2006 (81)
Prospective cohort
Retrospective cohort
RCT
57
72
6
Gaita et al., 2000 (45)
Gatzoulis et al., 2005 (46)
Prospective cohort
Prospective cohort
12
33
Greenberg et al., 2002 (47)
Grimm et al., 2002 (48)
Grimm et al., 2006 (82)
Ho et al., 2005 (49)
Hohnloser et al., DINAMIT, 2004 (21)
Retrospective cohort
Prospective cohort
Retrospective cohort
Retrospective cohort
RCT
31
35
38
53
30
Hreybe et al., 2006 (83)
Kadish et al., DEFINITE, 2004 (20)
Prospective cohort
RCT
48
29
Koplan et al., 2006 (50)
Kuck et al., CASH, 2000 (25)
Retrospective cohort
RCT
40
57
Lampert et al., 2004 (51)
Leosdottir et al., 2006 (52)
Lickfett et al., 2004 (84)
Moss et al., MADIT, 1996 (14)
Retrospective cohort
Retrospective cohort
Retrospective cohort
RCT
30
120
47
27
Moss et al., MADIT II, 2002 (16)
RCT
25
24
132
20
Study Group
Sample Size, n
Men, n (%)
Mean Age (SD), y
Ischemic Heart Disease, %
ICD
ICD
Antiarrhythmic
All participants
Secondary prevention
Primary prevention
All participants
ICD
Control
ICD
Amiodarone
CABG ⫹ ICD
CABG
Participants with LVEF ⱕ0.35
All participants
ICD
Amiodarone
CRT ⫹ OPT
CRT ⫹ ICD ⫹ OPT
OPT only
All participants
All participants
EP–Antiarrhythmics
No antiarrhythmics
Secondary prevention
Primary prevention
All participants
All participants
ICD
Control
ICD
ICD
Amiodarone
All participants
All participants
Placebo group
All participants
All participants
ICD
ICD
All participants
ICD
No ICD
All participants
All participants
ICD (dual-chamber)
ICD (ventricular only)
All participants
All participants
Primary prevention
Secondary prevention
All participants
All participants
All participants
ICD
ICD
Control
All participants
All participants
ICD
Control
All participants
ICD
Antiarrhythmics
All participants
All participants
All participants
ICD
Control
ICD
Conventional treatment
440
1885
357 (81.1)
395 (78)
412 (81)
196 (80)
157 (78)
39 (91)
83 (79.8)
43 (86)
40 (74.1)
639 (77)
639 (76)
386 (86.5)
373 (82.2)
124 (86.1)
132 (80)
50 (83)
50 (83)
413 (67)
399 (67)
213 (69)
67 (80)
97 (93.3)
316 (90)
318 (90)
NR
NR
NR
86 (90)
NR
NR
339 (86)
280 (85.4)
277 (83.7)
115 (95.8)
124 (83.2)
199 (93)
578 (75)
309 (82)
63 (70)
58 (78.4)
231 (74.5)
40 (67.8)
191 (76.1)
96 (76.1)
122 (79.7)
163 (81)
156 (78)
88 (92)
142 (84)
18 (100)
124 (82.1)
630 (86)
82 (81)
83 (89)
288 (80)
252 (75.9)
262 (76.6)
181 (79)
326 (71.2)
166 (72.5)
160 (69.9)
285 (82)
78 (79)
152 (80)
340 (85)
44 (71)
87 (83)
87 (92)
93 (92)
623 (84)
417 (85)
58 (14)
65 (11)
65 (10)
62.8 (0.8)
63 (11)
62 (10)
52 (11)
52 (12)
52 (10)
Median, 60.1 (IQR, 51.9–69.2)
Median, 60.4 (IQR, 61.7–68.3)
64 (9)
63 (9)
60.5 (11.9)
61.8 (9.7)
64 (9.2)
64 (8.7)
Median, 67
Median, 66
Median, 68
60 (12)
67 (10)
Median, 67 (IQR, 60–72)
Median, 66 (IQR, 58–72)
55 (13)
49 (15)
53 (13.9)
61 (10.3)
66.2
68.6
66 (9.9)
63.3 (9.2)
63.8 (9.9)
63.3 (9)
60 (13)
62 (12)
60 (13)
63.6 (10)
65 (13)
62 (16)
49.3 (11.9)
51.1 (9.9)
48.9 (12.3)
69 (11.5)
65.6 (12.6)
64.3 (11.3)
65.1 (11.3)
66 (8)
59.9 (12.5)
57 (18)
61 (12)
62.6 (12.4)
51 (14)
56 (13)
62 (13)
61.5 (10.9)
62.1 (10.6)
63 (14)
58.3 (range, 20.3–83.9)
58.4 (range, 20.3–83.9)
58.1 (range, 21.8–78.7)
70 (8)
58 (11)
57.5 (10)
67.4 (SE ⫾1.3)
58 (14)
NR
62 (9)
64 (9)
64 (10)
65 (10)
48
81
81
75.1
73.8
81
0
0
0
52
50
100
100
72.9
72.7
80
80
54
55
59
74
100
96
93
70
67
69
67.7
100
100
100
82.2
82.9
66.7
71.1
NR
39.7
84
48.9
65
45.2
44.1
45.4
56
64.4
81
81
NR
60
78
58
79
NR
34.4
68
100
100
75
0
0
0
80.6
73
74
100
62
65
34
29
100
100
245
104
2521
1055
283
603
120
1520
98
104
2202
100
96
6996
395
659
120
149
214
770
375
90
74
310
158
153
400
96
169
732
101
93
360
674
230
458
348
293
650
62
105
196
1232
NYHA Class, %
Mean LVEF (SD)
II
III
IV
49
I or II ⫽ 48
I or II ⫽ 48
NR
NR
NR
65.3
66.7
64.1
57.4
54.2
II or III ⫽ 71
II or III ⫽ 74
NR
0
I or II ⫽ 95
I or II ⫽ 95
Excluded
Excluded
Excluded
2.7 (0.5)
NR
39
38
NR
NR
NR
NR
NR
NR
NR
I or II ⫽ 37.8
I or II ⫽ 39.9
NR
51.7
43
I or II ⫽ 81
43.5
NR
NR
15.8
13.6
16.3
NR
34
NR
NR
II, III, or IV ⫽ 100
NR
NR
NR
NR
61
38
NR
95
98
NR
57
54
61
NR
59
59
NR
NR
NR
II or III ⫽ 63
II or III ⫽ 67
35
34
37.3
7
12
NR
NR
NR
34.6
33.3
35.8
21.0
21.5
0
0
NR
100
III or IV ⫽
III or IV ⫽
87
86
82
29 (10)
NR
24
25
NR
NR
NR
NR
NR
NR
NR
III or IV ⫽
III or IV ⫽
III or IV ⫽
9.5
9
III or IV ⫽
III or IV ⫽
NR
NR
58.4
61
57.8
III or IV ⫽
44
NR
NR
22 (6)
NR
NR
NR
NR
35
58
NR
40
49
III or IV ⫽
21
21
21
NR
18
18
NR
NR
NR
0
0
25
23
2
0
0
NR
NR
NR
0
0
0
Excluded
Excluded
27 (6)
27 (6)
NR
0
33.9 (12.5)
32.1 (11.1)
13
14
18
NR
NR
0
0
NR
NR
NR
NR
NR
NR
NR
34.3 (14.5)
33.3 (14.1)
33.7 (10.9)
0
Excluded
37.7 (14.3)
32.8 (11.4)
NR
NR
18.7
25.4
17.1
NR
0
NR
NR
NR
NR
NR
NR
NR
0
4
NR
Excluded
Excluded
17
Excluded
Excluded
Excluded
NR
0
0
NR
NR
NR
NR
NR
5
4
5
5
11
10.6
22.5
19
23.5
87
45
34 (15)
32 (13)
31 (13)
35.6 (15.4)
36 (16)
34 (12)
24 (7)
24 (6)
25 (8)
Median, 24.0 (IQR, 19.0–30.0)
Median, 25.0 (IQR, 20.0–30.0)
NR
NR
27 (5)
32.5 (13.6)
NR
NR
Median, 20
Median, 22
Median, 22
NR
35 (15)
Median, 30 (IQR, 20–35)
Median, 29 (IQR, 22–35)
35 (13)
36 (13)
35.3 (12.9)
34.1 (13.2)
NR
NR
26.2 (6.0)
NR
NR
NR
35 (15)
34 (14)
NR
NR
33.7 (11.9)
34 (11)
NR
18.7 (6.8)
20.8 (9.8)
22 (8.7)
25.4 (9.01)
32 (13)
32 (13)
NR
34.2 (14)
28 (10)
35 (14)
29.2 (11.2)
25 (8)
NR
33 (17)
28 (5)
28 (5)
26 (13)
21.4 (range, 7–35)
20.9 (range, 7–35)
21.8 (range, 10–35)
30 (11)
46 (19)
46 (17)
31.6 (SE, ⫾1.7)
40% ⱕ0.40
31 (7)
27 (7)
25 (7)
23 (5)
23 (6)
Continued on following page
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21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 W-49
Appendix Table 2—Continued
Author, Trial Name, Year (Reference)
Design
Duration, mo
Study Group
Nazarian et al., 2005 (53)
Niehaus et al., 2003 (85)
Noseworthy et al., 2004 (54)
Pappone et al., 2003 (55)
Parkash et al., 2006 (56)
Pires et al., 2002 (57)
Pires et al., 2006 (58)
Raitt et al., 2005 (59)
Raviele et al., BEST⫹ICD, 2005 (60)
Rienstra et al., 2007 (61)
Robin et al., 2006 (62)
Russo et al., 2003 (63)
Saba et al., 2003 (64)
Retrospective cohort
Retrospective cohort
Retrospective cohort
Prospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort
RCT
RCT
Prospective cohort
Retrospective cohort
Prospective cohort
Retrospective cohort
36
12
84
28
38
24
22
120
24
31
132
16
48
Saeed et al., LESS, 2003 (86)
Sánchez et al., 2005 (65)
Prospective cohort
Case–control
8
NR
Sánchez et al., 2006 (66)
Schaer et al., 2006 (67)
Sears et al., 2004 (68)
Soundarraj et al., 2006 (69)
Retrospective cohort
Prospective cohort
Prospective cohort
Retrospective cohort
22
18
14
2
Takahashi et al., 2002 (70)
Tandri et al., 2006 (71)
Telfer et al., 2002 (72)
Theuns et al., 2004 (87)
Retrospective cohort
Retrospective cohort
Retrospective cohort
RCT
12
276
26
12
Theuns et al., 2005 (88)
Theuns et al., 2005 (73)
Tiroke et al., 2003 (89)
Trappe, 2002 (74)
Prospective cohort
Prospective cohort
Retrospective cohort
Prospective cohort
60
48
60
28
All participants
All participants
All participants
All participants
All participants
ICD
All participants
ICD (placebo group)
All participants
All participants
All participants
All participants
ICD
Control
All participants
ICD
Conventional therapy
All participants
All participants
All participants
All
ICD (single-chamber)
ICD (dual-chamber)
All participants
All participants
ICD
ICD (single-chamber)
ICD (dual-chamber)
All participants
All participants
All participants
All participants
All participants
Wase et al., 2004 (75)
Wilkoff et al., EMPIRIC, 2006 (78)
Zecchin et al., 2004 (78)
Retrospective cohort
RCT
Retrospective cohort
48
12
24
ICD
All participants
All participants
Non-LVSD (for peri-implantation safety
only)
Al-Khatib et al., 2005 (90)
Bänsch et al., 2004 (91)
Boriani et al., 2003 (92)
Brockes et al., 2002 (93)
Gradaus et al., 2003 (94)
Hlatky et al., 2002 (95)
Nademanee et al., DEBUT, 2003 (96)
Reynolds et al., 2006 (97)
Rosenqvist et al., 1998 (98)
Schläpfer et al., 2002 (99)
Vollmann et al., 2003 (100)
Wiegand et al., 2004 (101)
Retrospective cohort
RCT
RCT
Retrospective cohort
Retrospective cohort
Retrospective cohort
RCT
Retrospective cohort
Prospective cohort
Prospective cohort
RCT
Retrospective cohort
33
12
6
72
34
84
36
12
4
63
12
144
ICD
ICD
ICD
ICD
ICD
ICD
ICD
ICD
ICD
ICD
ICD
ICD
Sample Size, n
94
25
637
135
469
2030
861
100
143
290
585
51
35
Men, n (%)
Mean Age (SD), y
Ischemic Heart Disease, %
55 (11)
60.8 (12)
74.9 (4.4)
64 (11)
65 (15)
64.4 (12.4)
65.4 (12.7)
62 (13)
66.5 (9.6)
59.9 (12.5)
63 (15)
70 (9) (range, 41–98)
51 (12)
51 (12)
64 (12)
60 (16)
61 (13)
66.7 (9.3)
56.4 (12.7)
65 (13)
67 (11)
68 (11)
66 (11)
64
62 (11)
59 (13)
57 (17)
61 (10)
59 (14)
60 (13)
59 (11)
62 (range, 51–72)
57 (11)
45
72
80
43
62
78
57
71
100
72
60
100
20
73
63
47
59
100
0
69
81
83
75
61
72
NR
72
84
78
71
72
77
NR
NYHA Class, %
II
III
IV
20
NR
I or II ⫽ 90.1
0
ⱕ II ⫽ 81
55
NR
14
NR
I or II ⫽ 88
NR
NR
Excluded
Excluded
42
NR
NR
NR
NR
NR
NR
35
NR
NR
III or
III or
III or
NR
50
NR
11
NR
NR
III or
III or
23
NR
NR
NR
NR
NR
NR
33
NR
NR
28 (6)
31
NR
NR
8
Excluded
⬍1
NR
NR
17
26
0
Excluded
Excluded
NR
NR
NR
NR
NR
III or IV ⫽ 23
NR
NR
NR
NR
NR
III or IV ⫽ 28
38
II or III ⫽ 29
III ⫽ 22
NR
III or IV ⫽ 14.5
NR
NR
NR
NR
NR
NR
NR
NR
0
2
0
25 (10)
35 (14)
34.1 (12.1)
NR
35 (16)
33.7 (13.8)
24.1 (10.4)
34 (15)
31.1 (4.1)
29 (7.8)
33 (15)
29 (9)
21.9 (6.8)
22.1 (9.7)
33.6 (14.8)
27 (7)
27 (6)
26.6 (7.7)
25 (8.8)
30.5 (16.4)
26.2 (8.9)
26.4 (9.1)
25.6 (8.3)
33 (15)
33 (11)
22 (7)
29 (11)
31 (10)
30 (10.5)
31 (14)
35 (15)
NR
NR
NR
0
NR
29 (12.5)
32.0 (12.7)
26.5 (7.6)
NR
16.6
NR
NR
20.9
NR
0
NR
23.1
NR
16.6
NR
NR
0
NR
NR
1.1
NR
0
NR
0.9
NR
0
NR
NR
37.5 (13.5)
46 (16)
36 (12)
70.6% ⬎0.30
NR
66.1 (10.3)
NR
39 (17)
NR
37.5 (13.5)
46 (16)
127
326
149
410
69 (73)
20 (80)
169 (80)
102 (76)
356 (76)
1654 (81.5)
641 (77)
86 (86)
98 (71)
231 (80)
462 (79)
41 (92)
29 (82.9)
114 (71.7)
38 (79)
15 (79)
26 (81)
93 (89)
50 (86)
73 (83)
297 (77)
226 (77)
71 (78)
144 (81)
1050 (76)
26 (96)
24 (83)
23 (74)
47 (78)
216 (83)
105 (83)
136 (91.3)
368 (89.8)
256
900
54
66 (71)
731 (81.2)
43 (79.6)
66.5 (12.2)
65 (12.6)
52.5 (17.2)
NR
69.4
0
NR
38
NR
NR
NR
NR
NR
I or II ⫽ 72
42
I or II ⫽ 12
II ⫽ 37
NR
I or II ⫽ 47
I or II ⫽ 76
9854
102
89
130
3344
22 565
47
30 984
778
41
542
372
7724 (78.4)
NR
69 (77.5)
115 (88.5)
2682 (80.2)
18 255 (80.9)
45 (95.7)
24 401 (78.8)
635 (81.6)
7724 (78.4)
NR
69 (77.5)
NR
NR
64.1 (12.5)
61 (11)
61.1 (12.1)
71.5
40.9 (11)
NR
58 (13)
NR
NR
64.1 (12.5)
NR
82.4
60
100
64.6
6
NR
NR
58
NR
82.4
60
NR
58.8
60
NR
54.3
NR
0
NR
53.3
NR
58.8
60
229
102
123
58
88
386
295
91
178
1382
379
60
Mean LVEF (SD)
IV ⫽ 100
IV ⫽ 19
IV ⫽ 19
IV ⫽ 100
IV ⫽ 100
* ASTRID ⫽ Atrial Sensing Trial to prevent Inappropriate Detections; AVID ⫽ Antiarrhythmics Vs. Defibrillators; BEST⫹ICD ⫽ BEta-blocker STrategy plus ICD trial; CABG ⫽ coronary artery bypass grafting; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator
Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy; DEBUT ⫽ Defibrillator versus ␤-blockers for unexplained death in Thailand; DEFINITE ⫽ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial;
EMPIRIC ⫽ Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators; EP ⫽ electrophysiology; ICD ⫽ implanted cardioverter defibrillator; IQR ⫽ interquartile range; LESS ⫽ Low-Energy Safety Study; LVEF ⫽ left ventricular ejection fraction; LVSD ⫽ left ventricular systolic dysfunction; MADIT ⫽ Multicenter Automatic Defibrillator Implantation
Trial; MUSTT ⫽ Multicenter Unsustained Tachycardia Trial; NR ⫽ not reported; NYHA ⫽ New York Heart Association; OPT ⫽ optimal pharmacologic therapy; RCT ⫽ randomized, controlled trial; SCD-HeFT ⫽ Sudden Cardiac Death in Heart Failure Trial; SHIELD ⫽ Shock Inhibition Evaluation With Azimilide.
W-50 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4
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