Annals of Internal Medicine
Implantable Cardioverter Defibrillators in Primary and Secondary
Prevention: A Systematic Review of Randomized, Controlled Trials
Justin A. Ezekowitz, MB, BCh; Paul W. Armstrong, MD, FRCPC; and Finlay A. McAlister, MD, MSc, FRCPC
Background: Sudden cardiac death is common in persons with
cardiovascular disease.
Purpose: To assess the efficacy of implantable cardioverter de-
fibrillators (ICDs) in persons at increased risk for sudden cardiac
death.
Data Sources: MEDLINE (1980 –2002), EMBASE (1980 –2002),
Cochrane Controlled Clinical Trial Registry (2002, Volume 3),
other databases, and conference proceedings. Primary study au-
thors and device manufacturers were contacted, and bibliogra-
phies of relevant papers were hand searched.
Study Selection: Randomized, controlled clinical trials evaluat-
ing ICDs versus usual care were selected.
Data Extraction: Two reviewers extracted data independently.
Data Synthesis: Eight trials were included in the final analysis
(4909 patients, 1154 deaths). Compared with usual care (most
commonly amiodarone therapy), ICDs significantly reduced sud-
den cardiac death (relative risk [RR], 0.43 [95% CI, 0.35 to 0.53])
and all-cause mortality (RR, 0.74 [CI, 0.67 to 0.82]). The included
S udden cardiac death accounts for approximately 50%
of all deaths from cardiovascular causes (1, 2). Some
patients are at higher risk for sudden cardiac death, partic-
ularly those with significant coronary artery disease (CAD)
and left ventricular systolic dysfunction. Until recently,
prevention of sudden cardiac death has focused on anti-
arrhythmic drugs, ␤-blockers, and improved management
of the underlying disease processes. Several published trials
in the past few years have evaluated implantable cardio-
verter defibrillators (ICDs) in patients with cardiovascular
disease. There seems to be little doubt that this interven-
tion should be routinely considered in some patients, such
as those with advanced ischemic cardiomyopathy who are
resuscitated after ventricular fibrillation arrest. However,
debate continues about the potential benefits of ICDs in
other patient groups (3– 6).
Approximately 85% to 90% of sudden cardiac deaths
are due to a first arrhythmic event; the remaining 10% to
15% are due to recurrent events (7). We defined primary
prevention as prevention of a first life-threatening arrhyth-
mic event (ventricular fibrillation, sustained ventricular
tachycardia, or cardiac arrest) (8). Primary prevention of
sudden cardiac death routinely focuses on patients at high
risk, including those with CAD and left ventricular sys-
tolic dysfunction, up to 60% of whom die of dysrhythmia
(9). Secondary prevention refers to the prevention of an ad-
ditional life-threatening arrhythmic event in survivors of
sudden cardiac death or patients with recurrent unstable
rhythms.
Article
trials were divided a priori into two categories: secondary preven-
tion (involving patients resuscitated after cardiac arrest or unstable
ventricular tachycardia or ventricular fibrillation [n ⴝ 1963]) and
primary prevention (involving patients at increased risk for sudden
cardiac death but without documented cardiac arrest, ventricular
fibrillation, or ventricular tachycardia [n ⴝ 2946]). Regardless of
baseline risk, ICDs were equally efficacious in preventing sudden
cardiac death in both types of trials (RR, 0.50 [CI, 0.38 to 0.66] for
secondary prevention vs. 0.37 [CI, 0.27 to 0.50] for primary pre-
vention). However, the magnitude of benefit in total mortality
varied within the primary prevention trials depending on baseline
risk for sudden cardiac death.
Conclusions: Implantable cardioverter defibrillators prevent sud-
den cardiac death regardless of baseline risk. However, their im-
pact on total mortality is sensitive to baseline risk for arrhythmic
death. Decisions about resource allocation for ICDs depend on
accurate stratification of patients according to risk.
Ann Intern Med. 2003;138:445-452. www.annals.org
For author affiliations, see end of text.
See editorial comment on pp 512-514.
A recent meta-analysis using individual-patient data
from three studies of secondary prevention suggested a sur-
vival benefit for ICD therapy compared with amiodarone
therapy but did not include any data on primary preven-
tion (10). Another recent systematic review involving 1610
patients included trials of primary and secondary preven-
tion published before January 2000 (11); however, two
primary prevention trials involving 1336 patients have
been published since then (12, 13). These trials, in turn,
focused exclusively on total mortality and did not calculate
summary effect estimates or explore reasons for heteroge-
neity in the total mortality data. Given the limitations of
the existing analyses, the potential impact of ICDs on pa-
tient survival, and the major socioeconomic implications of
this issue, we performed a systematic review of trials of
primary and secondary prevention with ICDs to examine
the effects of this therapy on rates of sudden cardiac death
and all-cause mortality.
METHODS
Search Strategy
We searched for randomized trials in MEDLINE
(1980 –24 September 2002), the Cochrane Controlled
Clinical Trial Registry (2002, Volume 3), EMBASE
(1980 –2002), Web of Science, National Library of Medi-
cine Gateway, Cardiosource, the Clinical Trials Registry,
Clinicaltrials.gov, the CRISP (Computer Retrieval of In-
formation on Scientific Projects) Database, the National
© 2003 American College of Physicians–American Society of Internal Medicine 445
Article Defibrillators and Sudden Cardiac Death

prevention). The trial outcomes had to include sudden car-

Context diac death or all-cause mortality. Trials in patients with
Implantable cardioverter defibrillators (ICDs) clearly pre- inherited arrhythmic disorders were excluded. We also ex-
vent death from cardiac arrhythmias, but in which pa- cluded trials that did not report any of the outcomes of
tients? interest or had crossover rates of greater than 50% between
Contribution
study groups.
This meta-analysis summarizes findings from eight ran- Validity Assessment and Data Abstraction
domized trials that compared ICDs with usual care or anti- Intention-to-treat analyses were performed, and the
arrhythmic drugs. Implantable cardioverter defibrillators outcome definitions used by the original researchers were
reduced sudden death and total mortality in many pa- accepted. All discrepancies in trial eligibility or data collec-
tients, including patients with previous ventricular arrest or tion were resolved by consensus.
symptomatic sustained ventricular arrhythmias; patients Outcome Measures
with left ventricular dysfunction due to coronary artery We extracted data on all-cause mortality, sudden car-
disease who had asymptomatic nonsustained ventricular diac death, total cardiac mortality, and total noncardiac
tachycardia and sustained tachycardia that could be in- mortality. A priori, we decided to examine the effects of
duced electrophysiologically; and some patients with se-
ICD therapy in primary versus secondary prevention. Be-
vere left ventricular dysfunction (ejection fraction ⱕ 0.3)
cause we anticipated that the primary prevention trials
after myocardial infarction.
would encompass a broad spectrum of patients, we subdi-
vided them into those enrolling high-risk patients and
–The Editors
those enrolling moderate-risk patients. We defined high-
risk patients as those with an expected rate of sudden car-
Research Register, the Glaxo–Wellcome Clinical Trials diac death of at least 5% per year (that is, patients with
Register, the LILACS (Latin American and Caribbean ischemic cardiomyopathy, with or without ventricular ar-
Health Science Literature) Database, OCLC (Online rhythmia) (14).
Computer Library Center) ProceedingsFirst, and the Na- Statistical Analysis
tional Health Service Economic Evaluation Database. All We used Metaview 4.1 software (Update Software,
databases were last accessed on 24 September 2002. In Oxford, United Kingdom) to calculate summary relative
addition, bibliographies of relevant papers were hand risks (since the outcomes were relatively common) and
searched and experts, device manufacturers, and primary used the Cochran Q-test to assess for heterogeneity in each
authors were contacted for information on additional outcome of interest. We combined studies using the Der-
trials. Relevant conference proceedings were also searched. Simonian and Laird random-effects model as well as the
The search was not limited by language. We used the fol- Mantel–Haenszel–Peto fixed-effects model; when the re-
lowing textwords and Medical Subject Headings: ICD, sults from both models were identical and there was no
AICD, implantable defibrillators (exp), heart arrest (exp),
sudden cardiac death (exp), sudden death (exp), SCD, cardiac
arrest, coronary disease (exp), heart disease (exp), systolic dys- Figure 1. Selection of trials included in the meta-analysis.
function, ventricular dysfunction (exp), heart failure (exp),
ventric* arrhythmia, ventric* rhythm, ventric* fibrillation,
ventric* tachycardia, arrhythmia (exp), anti-arrhythmia agents
(exp), anti-arrhythmia drug*, anti-arrhythmia therap*, and
antiarrhythmi*.
Study Selection
Two of the study investigators independently reviewed
the titles and abstracts of all citations to identify any ran-
domized trials evaluating the efficacy of ICDs versus pla-
cebo or ICDs versus antiarrhythmic therapy. Both review-
ers used standardized data forms to review the full text of
potentially relevant articles. A funnel plot was used to eval-
uate publication bias.
We included any randomized, controlled trials involv-
ing patients at risk for sudden cardiac death or ventricular
arrhythmia (sustained ventricular tachycardia or ventricular
fibrillation) who had evidence of heart failure or CAD (pri-
mary prevention), as well as studies in survivors of sudden
cardiac death or unstable ventricular rhythm (secondary RCT ⫽ randomized, controlled trial.
446 18 March 2003 Annals of Internal Medicine Volume 138 • Number 6 www.annals.org
 Defibrillators and Sudden Cardiac Death Article
Table 1. Characteristics of Included Studies*

Study Patients Control Cross- Mean History Coronary Men Mean Mean
(Reference) Therapy over Age of Resus- Artery Ejection Follow-
Rate ± SD citated Disease Fraction up
Arrest ± SD

% y 4OOOOO % OOOOO3 mo
Secondary prevention
AVID (19) 1016 patients resuscitated after Amiodarone, sotalol 20 65 ⫾ 11 45 82 79 0.32 ⫾ 0.13 18
near-fatal VF; sustained VT with
syncope; sustained VT with EF
⬍0.4 and symptoms
CASH (23) 288 patients resuscitated after car- Amiodarone, metopro- 12 58 ⫾ 11 100 73 80 0.45 ⫾ 0.17 57
diac arrest secondary to docu- lol, propafenone
mented ventricular arrhythmia
CIDS (22) 659 patients resuscitated after out- Amiodarone 21 63 ⫾ 10 48 83 85 0.34 ⫾ 0.14 35
of-hospital cardiac arrest; docu-
mented VF; sustained VT with
syncope; sustained VT with EF
⬍0.35 and symptoms; syncope
and VT
Primary prevention
MADIT (24) 196 patients with MI ⱖ3 weeks be- Antiarrhythmic drugs 12 63 ⫾ 9 0 100 92 0.26 ⫾ 0.07 27
fore entry; EF ⬍0.36; NYHA class
I, II, or III; asymptomatic nonsus-
tained VT 3 to 30 beats; inducible
VT on EPS not suppressed by IV
procainamide; 25 to 80 years of
age
CABG Patch (20) 900 patients with EF ⬍0.36 and Usual care 5 64 ⫾ 9 0 100 84 0.27 ⫾ 0.06 32
abnormalities on signal-averaged
ECG; randomly assigned in OR
after CABG; ⬍80 years of age
MUSTT (21) 704 patients with EF ⱕ0.40 and No antiarrhythmic 3 66‡ 0 100 90 0.3‡ 39‡
coronary artery disease; NYHA therapy
class I, II, or III; nonsustained VT
⬎3 beats; inducible VT on EPS†
MADIT II (13) 1232 patients with MI ⱖ1 month Usual care 5 64 ⫾ 10 0 100 85 0.23 ⫾ 0.06 20
before entry; EF ⱕ0.3; NYHA class
I, II, or III; ⬎21 years of age
CAT (12) 104 patients with EF ⱕ0.3; NYHA Usual care 14 52 ⫾ 11 0 0 83 0.24 ⫾ 0.07 66
class II or III; dilated cardiomyopa-
thy ⱕ9 months; CAD excluded by
angiography; excluded if history of
symptomatic bradycardia, VT, or
VF; all underwent EPS; 18 to 70
years of age

* AVID ⫽ Antiarrhythmic versus Implantable Defibrillator; CABG ⫽ coronary artery bypass grafting; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CAD ⫽
coronary artery disease; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; ECG ⫽ electrocar-
diogram; EF ⫽ ejection fraction; EPS ⫽ electrophysiologic study; IV ⫽ intravenous; MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; MADIT II ⫽
Multicenter Automatic Defibrillator Implantation Trial II; MI ⫽ myocardial infarction; MUSTT ⫽ Multicenter Unsustained Tachycardia Trial; NYHA ⫽ New York Heart
Association; OR ⫽ operating room; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
† Only the 161 patients randomly assigned to an implantable cardioverter defibrillator and the 353 patients randomly assigned to no antiarrhythmic therapy are included in
subsequent analyses; patients randomly assigned to electrophysiologically guided therapy were excluded.
‡ Median.

statistical heterogeneity, we reported only the fixed effects
(15). We also conducted sensitivity analyses to examine the
effect of year of publication, study quality, and allocation
concealment on the results (16, 17).
Role of the Funding Sources
The funding sources had no role in the collection,
analysis, or interpretation of the data or in the decision to
submit the paper for publication.
RESULTS
Of the 385 potentially relevant articles identified in
our search, 9 were parallel-group randomized trials. We
excluded 1 trial because patients in both study groups re-
www.annals.org
ceived ICD therapy (18). We then analyzed the data from
the 8 trials that fulfilled our inclusion criteria (12, 13,
19 –24) (Figure 1). There was no disagreement about any
of the articles selected for final inclusion in the meta-anal-
ysis. Funnel-plot analyses did not suggest any marked pub-
lication bias.
In the 8 trials we examined, 4909 patients were ran-
domly assigned to study groups. Three of the 8 trials were
trials of secondary prevention, and the remaining 5 (3 in-
volving high-risk patients and 2 involving moderate-risk
patients) were classified as trials of primary prevention
(Table 1). All but 1 study (12) enrolled patients with
ischemic heart disease. All trials reported all-cause mortal-
18 March 2003 Annals of Internal Medicine Volume 138 • Number 6 447
Article Defibrillators and Sudden Cardiac Death

Table 2. Therapies according to Treatment Assignment in the Trials*

Study Study ICD Aspirin ACE Digoxin Nonsotalol Sotalol Amiodarone Class I Anti-
(Reference) Group Inhibitor ␤-Blocker arrhythmic Agent

4OOOOOOOOOOOOOOOOOOOOOOOOOO n (%) OOOOOOOOOOOOOOOOOOOOOOOOOO3

AVID (19) ICD 497 (98)† 308 (61) 349 (69) 237 (47) 214 (42) 10 (1) 9 (2) 21 (4)
Control 51 (10) 301 (59) 347 (68) 207 (41) 84 (17) 14 (3) 488 (96) 6 (1)

CASH (23) ICD 99 (100)† 57 (58) 45 (45) 26 (26) 0 (0) 0 (0) 0 (0) 0 (0)
Control 11 (6) 81 (43) 79 (42) 38 (20) 96 (51) 0 (0) 91 (48) 0 (0)

CIDS (22) ICD 310 (95)† NA NA 97 (30) 110 (34) 65 (20) 0 (0) 18 (6)
Control 53 (16) NA NA 75 (23) 71 (21) 5 (2) 0 (0) 8 (2)

MADIT (24) ICD 90 (95) NA 57 (60) 55 (58) 25 (26) 1 (1) 2 (2) 11 (12)
Control 11 (11) NA 56 (55) 38 (38) 8 (8) 7 (7) 75 (74) 10 (10)

CABG Patch (20) ICD 434 (97)† 370 (83) 245 (55) 308 (69) 80 (18) 5 (1) 18 (4) 76 (17)
Control 18 (4) 386 (85) 245 (54) 295 (65) 109 (24) 5 (1) 14 (3) 295 (65)

MUSTT (21) ICD 161 (100) 103 (64) 116 (72) 84 (52) 47 (29) NA NA NA
Control 11 (3) 222 (63) 272 (77) 187 (53) 180 (51) NA NA NA

MADIT II (13) ICD 710 (96) NA 505 (68) 534 (72) 519 (70) NA 96 (13) 22 (3)
Control 22 (4) NA 353 (72) 279 (57) 343 (70) NA 49 (10) 10 (2)

CAT (12) ICD 46 (92) NA 47 (94) 43 (86) 2 (4) NA NA NA

Control 3 (6) NA 53 (98) 41 (76) 2 (4) NA NA NA

* ACE ⫽ angiotensin-converting enzyme inhibitor; AVID ⫽ Antiarrhythmic versus Implantable Defibrillator; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial;
CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; ICD ⫽ implantable cardioverter defibrillator;
MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; MADIT II ⫽ Multicenter Automatic Defibrillator Implantation Trial II; MUSTT ⫽ Multicenter
Unsustained Tachycardia Trial; NA ⫽ not available.
† Received a transthoracic or epicardial lead ICD (AVID, 7%; CASH, 56%; CIDS, 10%; CABG Patch, 100%).

ity, and all but 1 (21) used all-cause mortality as the pri-
mary outcome. The control groups and crossover rates are
described in Table 1, and concomitant medication use is
described in Table 2.
The included trials were randomized and controlled.
Because of the nature of the intervention, none of the trials
were blinded. Randomization and allocation concealment
were adequate in all trials. All-cause mortality and sudden
cardiac death were reported in all trials, but other end
points were not consistently reported. For several trials, we
needed to review secondary publications or contact the
authors to determine causes of death.
The summary relative risk (RR) for sudden cardiac
death was 0.43 (95% CI, 0.35 to 0.53) for all 8 trials. This
confirms that ICDs are highly efficacious in preventing
sudden cardiac death, both as primary prevention (RR,
0.37 [CI, 0.27 to 0.50]) and secondary prevention (RR,
0.50 [CI, 0.38 to 0.66]) (Figure 2). No appreciable heter-
ogeneity was seen among trials, although no sudden car-
diac deaths occurred in either study group in 1 trial (12)
because the investigators had recruited lower-risk patients.
There was no appreciable difference between types of
ICD (transthoracic vs. transvenous) in the summary ef-
fect estimates for prevention of sudden cardiac death
(19, 20).
Four trials reported a statistically significant survival
benefit in ICD-treated patients (Figure 3). The summary
relative risk of 0.74 (CI, 0.67 to 0.82) for all-cause mor-
tality in all 8 trials demonstrates a beneficial effect of ICD
448 18 March 2003 Annals of Internal Medicine Volume 138 • Number 6
therapy. Effect estimates were similar in trials of primary
and secondary prevention (RR, 0.72 [CI, 0.63 to 0.84] vs.
0.76 [CI, 0.65 to 0.89]) (Figure 3). Random-effects mod-
els yielded similar summary relative risks for overall mor-
tality, all-cause mortality in primary prevention, and all-
cause mortality in secondary prevention (0.72 [CI, 0.58 to
0.90], 0.69 [CI, 0.46 to 1.03], and 0.77 [CI, 0.65 to 0.91],
respectively).
Substantial heterogeneity in total mortality was ob-
served between primary prevention trials enrolling high-
risk patients and those enrolling moderate-risk patients
(P ⬍ 0.001). Indeed, the latter trials failed to demonstrate
any survival benefit with ICD therapy. This is not surpris-
ing, however, when the differences between patients en-
rolled in the 3 high-risk trials and the 2 moderate-risk trials
are considered. In the 3 trials demonstrating a substantial
survival benefit with ICDs, virtually all of the patients had
known CAD and left ventricular dysfunction (Table 2); in
2 of these 3 trials, the patients also had inducible ventric-
ular arrhythmias on electrophysiologic testing (21, 24).
However, while both of the moderate-risk trials enrolled
patients with left ventricular systolic dysfunction, 1 in-
cluded only patients with nonischemic dilated cardiomy-
opathy but no inducible ventricular arrhythmia and the
other enrolled patients after successful coronary artery sur-
gery; in the latter group, the issue of myocardial ischemia
was presumably resolved (20).
Five trials (12, 13, 20, 22, 24) reported total cardiac
mortality, with a summary point estimate of 0.81 (CI, 0.69
www.annals.org
 Defibrillators and Sudden Cardiac Death Article

to 0.96) for relative risk. Noncardiac mortality did not
differ between patients receiving ICDs and those receiving
medical therapy alone in the 3 trials that reported this
outcome (RR, 0.91 [CI, 0.60 to 1.38]) (13, 22, 24). Peri-
operative infection rates after ICD implantation ranged
from 0.7% to 12.3% in these 8 trials, and rates of lead
fracture or device malfunction ranged from 1.8% to 14%.
Rates of serious bleeding ranged from 1% to 6%, and
pneumothorax occurred in less than 1% of patients. Not
unexpectedly, the complication rates were higher for trans-
thoracic ICD. The more recent trials, which used newer
ICD models, reported lower complication rates.
The risk difference for total mortality was 0.08 (CI,
0.02 to 0.13) for all included trials, yielding a number
needed to treat for benefit of 13 (CI, 8 to 50). However,
this summary estimate is inadequate because its calculation
varies depending on baseline risk. For example, for primary
prevention, 18 patients with severe ischemic cardiomyop-
athy (left ventricular ejection fraction ⱕ 0.3) would need
to receive ICDs to prevent one death over the next 2 years
(13). However, if ICDs were implanted only in patients
with similar left ventricular dysfunction and inducible ven-
tricular arrhythmias, the number needed to treat for bene-
fit would be 4 (21, 24).
DISCUSSION
Implantable cardioverter defibrillators reduce the rela-
tive risk for sudden cardiac death by approximately 50%,
regardless of baseline risk. However, the effect of ICD ther-
apy on all-cause mortality varies according to baseline risk.
We would expect that the impact of any intervention on a
combined end point (such as total mortality) would vary if
the intervention affects only one component of that end
point (such as arrhythmic death). The effect of an inter-
vention on a combined end point will be greater in high-
risk persons (in whom a greater proportion of all deaths
will be due to arrhythmia) and less dramatic in moderate-
risk persons (in whom other causes of death will predom-
inate) (25). As expected, while ICDs reduced all-cause
mortality by approximately one third in survivors of car-
diac arrest and in high-risk patients who had not yet had
an arrest (for example, patients with CAD and severe left
ventricular systolic dysfunction), the trials we examined
did not show a significant impact on total mortality rates
in patients at lower risk for sudden cardiac death (for ex-
ample, patients with left ventricular systolic dysfunction
but no CAD or inducible ventricular arrhythmias).
Since it has been proven that ICDs are efficacious in
reducing sudden cardiac deaths, the challenge is to accu-
rately stratify patients by baseline risk to identify those most
likely to benefit from ICD therapy. Our data support the
policy of considering ICD therapy for secondary prevention
(for example, in survivors of cardiac arrest) or for primary
prevention in high-risk patients (26). However, additional
research is required before we can more accurately estimate
the risk for sudden cardiac death in particular patients.

Figure 2. Sudden cardiac death for included trials.

Relative risk (RR) is shown with box size proportional to sample size; lines indicate 95% CIs. For each stratum, the diamond represents the pooled
analysis. AVID ⫽ Antiarrhythmic versus Implantable Defibrillator; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest
Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; ICD ⫽ implantable cardioverter defibrillator;
MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; MADIT II ⫽ Multicenter Automatic Defibrillator Implantation Trial II; MUSTT ⫽
Multicenter Unsustained Tachycardia Trial.
www.annals.org 18 March 2003 Annals of Internal Medicine Volume 138 • Number 6 449
Article Defibrillators and Sudden Cardiac Death

Figure 3. All-cause mortality for included trials.

Relative risk (RR) is shown with box size proportional to sample size; lines indicate 95% CIs. For each stratum, the diamond represents the pooled
analysis. AVID ⫽ Antiarrhythmic versus Implantable Defibrillator; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest
Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; ICD ⫽ implantable cardioverter defibrillator;
MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; MADIT II ⫽ Multicenter Automatic Defibrillator Implantation Trial II;
MUSTT ⫽ Multicenter Unsustained Tachycardia Trial.

A collaborative individual-patient meta-analysis of the
three available trials of secondary prevention established
that ICDs were most beneficial in patients who were resus-
citated after cardiac arrest and had ejection fractions less
than or equal to 0.35 (10). A preliminary subanalysis of the
data from the Multicenter Automatic Defibrillator Implan-
tation Trial (MADIT) II found that ICDs had the greatest
benefit in patients with a QRS duration greater than 0.12
seconds (27). The Amiodarone versus Implantable Defi-
brillator in Patients with Nonischemic Cardiomyopathy
and Asymptomatic Nonsustained Ventricular Tachycardia
(AMIOVIRT) Trial, a trial of primary prevention, in-
volved 103 patients with nonischemic cardiomyopathy,
ejection fraction less than 0.35, and nonsustained ventric-
ular tachycardia. Two sudden cardiac deaths occurred in
the amiodarone group, and one occurred in the ICD
group. However, preliminary results from this trial did not
reveal any significant difference between therapy with ICD
or with amiodarone (28). These results are similar to the
negative results of the Cardiomyopathy Trial (12) and con-
firm our findings that the benefits of ICDs on total mor-
tality are sensitive to baseline risk for sudden cardiac death.

Appendix Table. Included Trials and Their Completion Dates

Acronym Trial Name Completion Date

AVID Antiarrhythmic versus Implantable Defibrillator May 1997
CABG Patch Coronary Artery Bypass Graft Patch Trial April 1997
CASH Cardiac Arrest Study Hamburg March 1998
CAT Cardiomyopathy Trial June 1997
CIDS Canadian Implantable Defibrillator Study January 1997
MADIT Multicenter Automatic Defibrillator Implantation Trial March 1996
MADIT II Multicenter Automatic Defibrillator Implantation Trial II November 2001
MUSTT Multicenter Unsustained Tachycardia Trial October 1998
AMIOVIRT Amiodarone versus Implantable Defibrillator in Patients with Nonischemic November 2000*
Cardiomyopathy and Asymptomatic Nonsustained Ventricular Tachycardia
BEST-ICD ␤-Blocker Strategy plus Implantable Cardioverter Defibrillator Trial 2003
DEFINITE Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation December 2002
DINAMIT Defibrillators in Acute Myocardial Infarction Trial September 2003
MAVERIC Midlands Trial of Empirical Amiodarone versus Electrophysiology-guided January 1999*
Interventions and Implantable Cardioverter-Defibrillators
SCD-HeFT Sudden Cardiac Death in Heart Failure Trial October 2003

* Principal investigators contacted; manuscripts not yet in press as of 23 September 2002.

450 18 March 2003 Annals of Internal Medicine Volume 138 • Number 6 www.annals.org

The Sudden Cardiac Death in Heart Failure Trial (SCD-
HeFT), in which 2500 patients with ischemic or nonisch-
emic cardiomyopathy and an ejection fraction less than
0.35 have been randomly assigned to amiodarone or ICD
and are being followed for 2.5 years, will further refine the
evidence base for primary prevention. Results are expected
in 2004.
As a first step, a meta-analysis using individual-patient
data and incorporating the results from the 8 trials exam-
ined in our study and 6 ongoing trials with mortality end
points (Appendix Table) would be invaluable in refining
the definition of risk and the potential impact of ICDs in
particular patient subgroups. Such a meta-analysis would
also permit exploration of potential interactions between
ICDs and cardiac medications, such as ␤-blockers.
Other issues that remain to be addressed by ongoing
studies include the cost-effectiveness of ICD therapy and
its impact on quality of life. The latter may be important in
determining whether an ICD should be used because some
patients may have poorer quality of life after defibrillator
implantation, particularly if they receive frequent shocks.
Much work is needed to clearly define which patients are at
risk for worsened quality of life (29 –31). A recent analysis
suggested that the incremental cost-effectiveness ratio for
ICD placement compared with drug therapy was $66 677
per year of life saved in patients resuscitated after cardiac
arrest (32, 33). As expected, given the variability in base-
line risks among patient subgroups, incremental cost-effec-
tiveness ratios are estimated to range from $17 700 to
$138 800 per year of life saved (34 –39). The wide vari-
ability in cost-effectiveness ratios again emphasizes the im-
portance of accurate risk stratification tools to assist in de-
termining who should receive ICD therapy.
Our conclusions are limited by the paucity of trials in
this area, particularly for some groups of patients (such as
those with nonischemic cardiomyopathy). However, we
used the rigorous methods of the Cochrane Collaboration
to maximize the validity of our results. Given the nature of
the trial reports we examined, we were unable to examine
the relationship between specific baseline characteristics
and the efficacy of ICDs; such analysis can be performed
only in a meta-analysis using individual-patient data or a
very large trial. Finally, in any systematic review, there is
always concern about the potential for publication bias.
However, we conducted an exhaustive search, including
contact with primary study authors, device manufacturers,
and experts in the field, to ensure that we had identified all
relevant randomized trials, including trials with negative
results.
Implantable cardioverter defibrillators are clearly more
beneficial than drug therapy for secondary prevention of
sudden cardiac death and for primary prevention in certain
high-risk groups. However, further research is needed to
develop accurate risk stratification tools, to determine the
economic impact of ICD therapy in different subgroups of
patients, and to evaluate quality-of-life issues.
www.annals.org
Defibrillators and Sudden Cardiac Death Article
From the University of Alberta, Edmonton, Alberta, Canada.
Acknowledgments: The authors thank Dr. Terry Klassen, Dr. Brian
Rowe, and Ms. Ellen Crumley for their assistance.
Grant Support: By a CIHR Strategic Training Fellowship in TORCH
(Tomorrow’s Research Cardiovascular Health Professionals) (Dr. Ezeko-
witz) and by the Alberta Heritage Foundation for Medical Research (Dr.
McAlister).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Finlay A. McAlister, MD, MSc, FRCPC,
2E3.24 Walter Mackenzie Centre, 8440 112th Street, Edmonton, Al-
berta T6G 2B7, Canada; e-mail, finlay.mcalister@ualberta.ca.
Current author addresses and author contributions are available at www
.annals.org.
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www.annals.org
Current Author Addresses: Drs. Ezekowitz and Armstrong: 2-51 Med-
ical Sciences Building, University of Alberta, Edmonton, Alberta T6G
2H7, Canada.
Dr. McAlister: 2E3.24 Walter Mackenzie Centre, 8440 112th Street,
Edmonton, Alberta T6G 2B7, Canada.
Author Contributions: Conception and design: J.A. Ezekowitz, F.
McAlister.
Analysis and interpretation of the data: J.A. Ezekowitz, P.W. Armstrong,
F. McAlister.
Drafting of the article: J.A. Ezekowitz, P.W. Armstrong, F. McAlister.
www.annals.org
Critical revision of the article for important intellectual content: J.A.
Ezekowitz, P.W. Armstrong, F. McAlister.
Final approval of the article: J.A. Ezekowitz, P.W. Armstrong, F. McAli-
ster.
Provision of study materials or patients: J.A. Ezekowitz.
Statistical expertise: J.A. Ezekowitz, F. McAlister.
Obtaining of funding: P.W. Armstrong.
Administrative, technical, or logistic support: J.A. Ezekowitz, P.W. Arm-
strong.
Collection and assembly of data: J.A. Ezekowitz, F. McAlister.
Annals of Internal Medicine Volume • Number E-453