NASPE HISTORY SERIES
The Evolution of the Implantable Cardioverter
Defibrillator
DAVID S. CANNOM and ERIC N. PRYSTOWSKY*
From the Good Samaritan Hospital, Los Angeles, California and *The Care Group, LLC, Indianapolis, Indiana
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long battery life.3 This was at a time when pacemakers were large and bulky.
In addition to the clinical activity in the coronary care unit, heart station and private practice,
Mower and Mirowski worked in the hospital’s
clinical engineering and animal facilities and by
1969 had designed, constructed, and tested a prototype device in dogs.3 Mirowski always believed
that endocardial defibrillation was a viable concept, but it was years before such a lead system
could be designed and used in clinical practice.4,5
The first system design used a single transvenous
lead in the right ventricle (RV) and a patch on the
anterior chest wall with defibrillation achieved using 30 to 50 J,6 and indeed a variant of the superior
vena cava (SVC) coil to apical patch was chosen
for initial implantation. Later the lead design was
changed to include a completely transvenous system consisting of an RV apical electrode with a
second electrode in the SVC or right atrium (RA).4
The method of sensing ventricular fibrillation also
evolved. Initially an RV pressure transducer was
used to sense VF, and a drop in blood pressure
triggered the device.7 This sensing method, while
not unreliable, was considered by Mower and
Mirowski to be more radical than an electrocardiographic feature, and the probability density function, which distinguished VF from sinus rhythm
based on how much of the cardiac cycle is spent
on the isoelectric line, was selected as a means of
sensing VF.8,9
By the mid 1970s, the initial short-term studies outlined above were confirmed in a study of
25 animals with long-term implanted devices.10
An apical cup electrode was substituted for the
RV apical catheter because of frequent lead dislodgment. In chronically implanted dogs, defibrillation energy was achieved using 4–10 J with a
truncated exponential waveform. Over a 60 month
period there were 97 episodes of automatic resuscitation by the device with only four failures due
to lead malfunction.11 A movie of automatic defibrillation in animals shown by Dr. Mirowski at
scientific meetings in the 1970s igniting interest
in the device among clinicians.10
Subsequent studies in humans undergoing
coronary artery bypass grafting demonstrated that
intravascular defibrillation could be accomplished
with energies of 15 J or less, which confirmed the
earlier canine work.12 Over the period of a decade,
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Introduction
During the last 25 years, remarkable technical
and conceptual advances have occurred in clinical
electrophysiology. The scientific foundation that
underpins the everyday use of the implantable cardioverter defibrillator (ICD) involves more than the
mere invention of a defibrillating device. The ICD
was first demonstrated to be clinically useful in the
early 1980s. At the same time, clinical epidemiologists were beginning to identify specific high risk
groups of postmyocardial infarction patients who
might be candidates for the ICD. While a broad
series of observational studies in the 1980s quantified the impact of the ICD in comparison to other
available therapies for high risk patients, there followed in the 1990s a decade of well designed clinical trials of the ICD.
Contributions from many sources explain the
evolution of the ICD over the past 25 years. The
ICD and its important role in clinical electrophysiology have embellished the reputations of its inventors, dominated the day-to-day careers of many
electrophysiologists, and extended the lives of an
ever increasing number of patients.
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The Device
By the late 1960s, external cardiac defibrillation was acknowledged to be an effective means
of terminating several abnormal cardiac rhythms
including ventricular fibrillation (VF).1 The history of the ICD began at that time as well. Michel
Mirowski came to the Sinai Hospital in Baltimore in 1969 with the idea of developing an automatic implantable defibrillator. The concept that
he pioneered was “blind and immediate defibrillation treatment for cardiac arrest,”although the
implanted device was considered to have some
degree of “intelligence” built in.2 In a 1970 publication, Mirowski and his collaborator, Morton
Mower, described the key elements of such a device. Based on their experience in the coronary
care unit, it was clear that such a device must
quickly recognize and treat VF with a unit that is
small enough to implant in patients, yet still has
Address for reprints: David S. Cannom, M.D., Good Samaritan
Hospital, 1245 Wilshire Blvd., #703, Los Angeles, CA 90017.
Fax: 213-977-0225; e-mail: dcannom@lacard.com
Received December 16, 2003; accepted December 16, 2003.
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CANNOM, ET AL.
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rate that was low enough to detect a slower VT that
might not have been manifest, or that could occur
with the addition of an antiarrhythmic drug, but
not so low as to detect a supraventricular rate, either from sinus tachycardia or an SVT, e.g., atrial
fibrillation.
In September 1988, the Ventak P device
featured multiprogrammable integrated circuits
whose parameters could be changed by physicians. Rates could be programmed between 110
to 200 beats per minute and energies between 0.1
and 30 J.17 While the device itself was improved,
its clinical role was not well defined in the mid
1980s as Eli Lilly had little experience with or interest in medical technology.18
The character of the coinventors of the device also deserves comment. Michel Mirowski
was an extremely focused and charismatic individual who was convinced of the correctness
of the implantable defibrillator concept. Through
force of will, and despite many setbacks, he insisted the project be completed. However, without Morty Mower, whose brilliant problem-solving
skills made the device a reality, the ICD might have
been delayed for decades or not done at all. Without the availability of a reliable ICD, electrophysiologists would have limited tools with which to
treat survivors of or candidates for sudden death.
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the key elements of successful defibrillation of
clinical VF had extended from the inventors’ concept to the development of an implanted device
that provided reliable sensing and defibrillation
in a small volume unit. Despite these encouraging
published results, there were prominent dissenters
who stated that “the implanted defibrillator system represents an imperfect solution in search of
a plausible and practical application.”13 Mirowski
and Mower replied that rather than disqualify a
new approach, one should “await the test of clinical trials.”14
In 1980 the Institutional Review Board at
Johns Hopkins Hospital and the Food and Drug
Administration approved the clinical investigation of the automatic implantable defibrillator
(called the AID). The first implantation in a patient took place on February 4, 1980, at the Johns
Hopkins Hospital.15 To meet criteria for the first
pilot study, the patient had to have survived at
least two episodes of cardiac arrest not associated with an infarction and VF had to be documented at least once.16 The device used was nonprogrammable, committed, and had no telemetry
capabilities. It soon became apparent that many
sudden cardiac death (SCD) survivors also had
unstable ventricular tachycardia (VT) that degenerated into VF. Therefore, the second generation
defibrillator (called the AID-B) used an epicardial
bipolar right ventricular electrode for R wave synchronization and, in turn, VT detection.17 In retrospect, there seems little doubt that these and future refinements would never have occurred had
the first ICD defibrillation therapy in humans not
been reproducibly successful.
The AID-B weighed 293 grams and had a volume of 162 cc. Its circuits consisted of over 300 discrete components housed in a titanium outer can
that included capacitors, lithium batteries, and a
test-load resistor. An external monitoring device
called the AIDCHECK-B, tested battery strength
and determined the number of delivered pulses.
This complicated device required 200 man hours
to produce a single unit. In May, 1985, the manufacturer of the AID-B, Medrad/Intec Company,
was acquired by Cardiac Pacemakers, Incorporated
(CPI, St. Paul, MN, USA), a division of Eli Lilly.
This resulted in further refinement of the device,
called the Ventak C, which had hybrid electronic
modules utilizing integrated circuit technology instead of discrete components. However, its rate
sensing parameters were preset at assembly and
could not be changed.
Since the sensing rate could not be changed,
it was imperative that the electrophysiologist consider not only the known VT rate but potential
future changes to the patient’s electrophysiologic
milieu. For example, one had to be sure to select a
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The Leads
The lead system used in the first human open
chest implantations in the 1980s was the spring
patch and apical cup. Soon the apical cup was replaced by an epicardial patch. After 20 cases in
the second year, a two patch system was used.2
During the l980s, research interest in bipolar cardiac defibrillation between two intracardiac coils
[one distal (RV) and one proximal (RA or SVC)]
continued.19 A series of design modifications resulted in the CPI Endotak lead. This was a single
lead with proximal and distal shocking coils; it
was first implanted transvenously in 1988 without
thoracotomy.20
More than any other feature, the development of stable, durable and biocompatible transvenous defibrillating leads has been responsible for
the rapid adoption of ICD technology. Transvenous leads transformed the implantation procedure from a 4 to 6 hour open chest procedure
with a 3% to 5% operative risk, to a far simpler procedure performed in the electrophysiology laboratory under conscious sedation. Recent
randomized trials point to the benefits of the ICD
in the very sickest patients (who have the lowest ejection fraction [EF]), but implantation procedures in such patients are possible because of the
transvenous lead. Also, as indications for the ICD
widen to include primary prevention in younger
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Evolution of ICD Systems
There has been a steady and remarkable evolution of device technology that has resulted in
greater patient safety and comfort. The first generation devices were designed only to recognize
VF and treat it with a high energy shock.21,22 The
second generation devices had bradycardia pacing capability and minimal programmability. The
bradycardia pacing feature was important as approximately 15% of patients with first generation
devices required separate pacemakers.23 ICDs in
such patients could undersense clinical VF if the
pacemaker spike was sensed by the ICD, inhibiting arrhythmia detection and an ICD shock.24 Second generation devices had limited telemetry and
simply noted the number of shocks delivered. The
third generation devices introduced in the early
1990s had much more flexibility. Besides bradycardia pacing, they introduced antitachycardia pacing and low energy shocking capabilities for treatment of VT, as well as defibrillation capability
and more extensive programmability and telemetry.22 Antitachycardia pacing can convert up to
90% of hemodynamically stable VT and is more
effective at slower cycle lengths, especially those
>350 ms.25,26
The concept of tiered therapy in a single device was introduced in the early 1990s in the socalled third generation devices. This concept described a progression of therapy for VT defined
by the rate of tachycardia and lack of success of
any prior therapy: tiered therapy devices were programmed to deliver bursts of antitachycardia pacing (ATP) followed by a low energy shock before
going on to a high energy shock.27 Although low
energy shocks can correct sustained VT, in most
cases the same VT can be terminated by ATP. If
ATP fails, shocks of ≤5 J also are typically unsuccessful to convert VT to sinus rhythm, but unlike
ATP are painful to the patient. Thus, we frequently
“skip” the tier of low energy shock, and program
ATP followed by a shock strength with high probability of terminating VT.
The initial defibrillation waveforms were
monophasic, truncated exponentially decaying
pulses with a tilt of 65%.28 This was a satisfactory waveform for thoracotomy implantations but
not for transvenous lead systems. The most important modification in the defibrillation waveform was the development of biphasic waveforms
that switch the output polarity from the capacitor
in mid-discharge.29 This innovation, introduced
in 1993, resulted in lowering the defibrillation
threshold (DFT) by 30% compared with monophasic shocks. DFTs were reduced to very low levels
(6.3 J ± 5.2 J in one study) using biphasic shocks.30
A parallel innovation has been the incorporation
of the infraclavicular pulse generator itself as the
active or “hot” can, which also reduces DFTs and
is now routinely used in all pectoral implants.31
An added benefit of the lower DFT with biphasic waveforms is the increased safety margin for
defibrillation, which has enabled the safe administration of antiarrhythmic drugs months or even
years after initial ICD implant. Careers were made
by studying the deleterious effects of drugs such
as amiodarone, which can increase the DFT in a
monophasic waveform ICD to the point that VF
cannot be terminated. Now, we rarely see a patient
who receives an antiarrhythmic drug to treat VT
yet has a high DFT. Of course, it is important to
retest these patients to evaluate the effect of drugs
on VT rate.
The early ICDs were only able to sense ventricular rate and could not distinguish ventricular tachycardia from sinus tachycardia or atrial arrhythmias, especially atrial fibrillation. This simplistic approach resulted in nearly 25% of delivered shocks being inappropriate and not caused
by ventricular arrhythmias.32 The ICD was often
“blamed” for any inappropriate shocks; in reality,
the programming physician was inappropriate in
selecting incorrectly the cut-off values. A series of
detection enhancements evaluating the onset and
stability of the arrhythmia have improved sensing
in the latest devices.32
The evolution of the technical features of the
ICD continues. The ICD generator will continue
to miniaturize and may become as small as 20–
25 cc. More complicated features are under study.
These include the use of various metabolic or electrophysiological sensors that might herald the development of a cardiac arrhythmia before it occurs
and use either pacing maneuvers, pharmacological
agents, or modulation of autonomic activity to prevent an ICD discharge.33,34 Recognition of a problem could lead to a pacing maneuver, drug infusion
(through a port in one of the intracardiac leads and
with a reservoir possibly in the generator), or both,
and hopefully would prevent or treat the problem.
All of this would be programmed by the physician, and the device could use artificial intelligence to “learn” and change parameters as needed.
Appropriate data would be sent wirelessly to the
physician as directed. These treatments would
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patients, it is critical that leads incorporate features of stability over time for pacing, sensing, and
defibrillation.
Another innovative idea that is currently under study is to create a leadless defibrillator. This
would use subcutaneous patches and a high energy
generator that would sense and defibrillate ventricular fibrillation. If feasible, such a unit would
eliminate transvenous lead malfunction and, perhaps, expand the acceptance of the ICD.
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Identification and Treatment of High Risk
Arrhythmia Patients in the 1980s
In the late 1970s and early 1980s electrophysiology was transformed from a descriptive extension of electrocardiography, focused on verifying
by intracardiac electrograms the interpretation of
surface electrocardiograms, to one that has a critical role in the management of high risk patients.
A number of research interests converged over a
short period of time in the early 1980s including
an interest in the mechanisms and clinical course
of patients who died suddenly, an understanding
of the ventricular arrhythmias which could be provoked in the closed environment of the electrophysiology laboratory, and the availability of pharmacological agents to treat these induced rhythms.
In the United States there are 350,000 to
450,000 out-of-hospital cardiac arrests per year.35
Data from the 1970s and early 1980s showed that
sudden death survivors who were untreated had
a one year subsequent sudden death mortality of
30%36,37 and a 5 year total mortality of 70%–
80%.37−40 Empiric drug treatment without serial
drug testing carried a one year recurrence rate
of 20%–30% and a 5 year mortality of 70%–
80%.36−40 Thus, it was clear that alternative treatment methods were necessary since empiric antiarrhythmic therapy was unsuccessful.
In the early 1980s, high risk populations such
as patients after myocardial infarction, those with
unstable angina, or heart failure were studied and
followed in an effort to quantify risk and establish the clinical variables that predict high risk.
The features that define high risk include measures
of left ventricular dysfunction, ambient ventricular arrhythmias, and abnormal autonomic nervous
system function.41 Over 20 years ago left ventricular ejection fraction (LVEF) was shown to be the
strongest predictor of death after myocardial infarction.41 Four large studies compared mortality
in patients with an EF less than and greater than
40%.42−45 In patients who have an EF <0.40, the
mortality rate at 2 years after infarction is 21.5%
compared with 7.6% in patients with an EF > 40%.
The risk of a low EF is hyperbolic, with the mortality rate sharply increasing as the EF falls: an EF
of <20% predicts a one year mortality of 50%.46
In the thrombolytic era, low EF postinfarction remains a powerful predictor of long-term mortality.47 These studies influenced patient selection
criteria for the ICD primary prevention trials of the
1990s.
Additional data from these studies emphasized the prognostic importance of ventricular ectopy.42−45 As premature ventricular contraction
(PVC) frequency increases to between 1 and 10
PVCs per hour, the mortality curve rises sharply
to rates approaching 20%.41,42,48 Complex ectopy,
pairs or runs of nonsustained VT, are predictors
of death independent of the number of PVCs.
The strongest predictor of subsequent mortality is
nonsustained VT, but this only occurs in 10% of
the postinfarction population. Studies in patients
in the post-thrombolytic era confirm the risk of
greater than 10 PVCs per hour in the first 6 months
postinfarction. In the post-thrombolytic period,
the presence of nonsustained VT has dropped to
6%–8% of all patients.49
Early work from the University of Pennsylvania electrophysiology group in the late 1970s
demonstrated that the induction of monomorphic
VT was a reproducible and specific response to
catheter based programmed stimulation, which
supported reentry as the underlying mechanism.50
In the late 1970s and early 1980s, electrophysiologists in major centers routinely used programmed
stimulation in patients with the highest risk of recurrence (i.e., survivors of clinical VT or VF) to
stratify risk of recurrence. A large number of observational studies were performed to document the
clinical utility of pharmacological therapy guided
by programmed stimulation but, in fact, had variable results.51 In general the invasive approach in
the postevent population was reasonably successful at predicting lack of recurrence (typically 80%
to 100% effective) in an inducible patient, but a
drug regimen that prevented recurrence could be
found in only a minority of patients. Thus, most
patients were nonresponders and at ongoing clinical risk. If discharged on a regimen that was not
protective in the electrohysiology lab, the annual
mortality was at least 30% at 20 months.51 The
limitations of this approach were most marked in
the SCD survivors: up to 30% of survivors had no
inducible arrhythmias. This group of patients was
one of the first to consistently receive ICDs.
Two other studies in the late 1980s had a major effect on electrophysiologists’ thinking about
how to deal with the high risk patient. The Cardiac Arrhythmia Suppression trial (CAST) demonstrated a 2.5-fold increase in mortality in postmyocardial infarction (MI) patients treated with
encainide and flecainide despite suppression of
spontaneous ventricular ectopy.52 The continuation of the CAST trial with moricizine failed
to show any benefit despite arrhythmia suppression.53 A meta-analysis of 10 additional studies that assessed the risks and benefits of antiarrhythmic therapy in 4,122 post-MI patients suggested that these agents probably shorten post-MI
survival.54
Finally, the brief era of surgery for ventricular arrhythmias in the early 1980s was
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occur seamlessly and provide peace of mind for
the patient.33,34
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Early Results with the ICD (1980–1990)
The first patient to receive an ICD had a previous MI and recurrent episodes of drug resistant
VT requiring resuscitation. After the first three implantations, a paper describing the initial results
was published.60 In September 1982, the data from
the first 52 ICD implantations were published.61
Patients in this study had survived two cardiac
arrests despite antiarrhythmic drug therapy. During a mean follow-up of 14 months, 62 episodes
of symptomatic tachycardia were terminated in 17
patients. In this very sick group of patients, the
one year sudden death mortality was 8.5% and all
cause mortality 22.9% with the ICD.61 The clinical trial continued in two centers between 1980
and 1982 and then expanded to 40 centers until
the FDA approved the ICD device in 1985. At that
time approval was limited to patients with one
episode of cardiac arrest or patients with recurrent ventricular arrhythmias that were inducible
but not suppressed with conventional antiarrhythmic drugs.62 In January 1986, the Health Care
Finance Administration released its coverage issuance for Medicare that reimbursed for the ICD
only as a treatment of last resort.63 Also, arrhythmia inducibility was required initially, but was
later rescinded in 1991 by the Office of Health
Technology Assessment.64
In the late 1980s, a number of reports from
large ICD implanting centers consistently showed
a very low sudden death rate. The largest early
published experience was from the Stanford
group: 270 ICD recipients experienced a sudden death survival rate of 99% at one year and
96% at 5 years with the overall survival 92%
at one year and 74% at 5 years.65 Other studies, as well as the registry maintained by CPI and
the Billitch multicenter registry, reported similar survival figures.23,66−77 Comparisons between
different therapies was difficult, but it appeared
that patient survival with the ICD was better
than with competing therapies, including empiric
amiodarone, EP directed therapy, and arrhythmia surgery.50,78−80 Many prominent investigators
thought that the ICD should be considered best or
gold standard therapy rather than therapy of last
resort.
The late 1980s were a difficult time politically in the electrophysiology community as clinicians struggled to define the role of the ICD in
clinical practice. The advocates of the ICD were
under pressure to demonstrate the effectiveness
of the ICD. The ICD device and its lead system
were evolving quickly and a carefully designed
randomized trial would have been difficult to design and accomplish. There were also many, including the inventors of the ICD, who considered
such a randomized trial unethical in resuscitated
cardiac arrest patients. Intense criticism of this position emerged from a variety of sources.81,82 The
most compelling of these arguments was that any
new device needs its efficacy proven by a randomized trial. Other arguments against widespread use
of the ICD (and encouraging randomized trials) included the low ICD firing rate in some series, the
concept that the sickest patients would die from
their underlying cardiac disease anyway despite
effective shocks, and the speculation that the high
complication rate from an epicardial implantation
cancels out any benefit of the ICD.83 This was a
period of intense disagreement among prominent
electrophysiologists with pro and con “camps,”
each with their opinions but armed only with observational data to argue their point. Much of a
given investigator’s opinion seemed influenced by
his or her own medical center with its particular clinical skills and research interests. Finally,
as the ICD implantation rate began to grow exponentially in the late 1980s, the cost implications of
the therapy became a primary reason to undertake
randomized trials of the ICD.
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instructive in extending our understanding of the
mechanisms of ventricular arrhythmias but was
not widely applied clinically. Map-guided subendocardial resection was used in a few select centers in the 1980s, typically in patients with sustained VT and an aneurysm. The results of the
operation were successful in that typically 70%
to 98% of the patients were noninducible postoperatively. However, operative mortalities of 6%
to 15%–even in highly experienced centers with
highly skilled surgeons–were prohibitively high,
especially as the transvenous ICD with its low operative risk became more widely available.55−59
PACE, Vol. 27
Era of the Randomized Trials: Secondary
(Postevent) ICD Trials (1990–2003)
The early 1990s was a critical era in defining
the appropriate role of the ICD in the treatment of
the highest risk patients (Table I). Three trials—
the Antiarrhythmics Versus Implantable Defibrillators (AVID), the Canadian Implantable Defibrillator Study (CIDS), and the Cardiac Arrest Study
Hamburg (CASH)–were all conducted at roughly
the same time. Taken together, the results of these
trials support the use of ICD therapy for the secondary prevention of hemodynamically significant ventricular arrhythmias.
The AVID trial was National Heart, Lung, and
Blood Institute supported and randomized patient
groups thought by the AVID investigators to be at
highest risk, viz., (a) those who had survived a cardiac arrest not associated with an acute myocardial
infarction or transient cause, and (b) those with
documented sustained VT with syncope or near
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Table I.
Randomized Clinical Trials of the ICD
Patients
History of
Coronary
Mean
Mean
Resusciated
Artery
Ejection
Follow-up
Arrest (%) Disease (%) Fraction ± SD (mths)
45
100
48
82
0.32 ± 0.73
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0.45 ± 0.17
57
83
0.34 ± 0.14
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SECONDARY PREVENTION
AVID
1,016 pts resuscitated VF, Amiodarone,
sotalol
sustained VT with
syncope, VT with EF ≤
0.4 and Sx
CASH
288 pts resuscitated VF
Amiodarone,
metoprolol,
propafenone
Amiodarone
CIDS
659 pts resuscitated VF,
sustained VT with
syncope, sustained VT
with EF ≤ 0.35 and Sx,
syncope and VT
PRIMARY PREVENTION
Antiarrhythmic
MADIT
196 pts with MI 3 weeks
drugs primarily
before entry: EF ≤ 0.36;
amiodarone
NYHA class I, II, or III,
Sx nonsustained VT 3
to 30 beats, inducible
VT at EPS not
suppressed by IV
procainamide, 25 to 80
years of age
CABG Patch 900 pts with an EF ≤ 0.36 Usual care
and + signalaveraged
ECG; randomized in OR
after CABG; <80 years
of age
No
MUSTT
704 pts with EF ≤ 0.40
antiarrhythmics
and CAD, NYHA class I,
therapy
II, or III, nonsustained
VT > 3 beats, inducible
VT at EPS
Usual care
MADIT II
1,232 pts with MI ≥ 1
month; EF ≤ 0.3; NYHA
I, II, or III, >21 years of
age
Usual care
CAT
104 pts with EF ≤ 0.3,
NYHA class II, or III;
dilated cardiomyopathy
<9 months; CAD
excluded by
angiography; 18 to 70
years of age
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Study
Control
Therapy
0
100
0.26 ± 0.07
27
0
100
0.26 ± 0.06
32
0
100
0.30
39
0
100
0.23 ± 0.06
20
0
0
0.24 ± 0.07
66
Shown are the patient entry criteria used in the major published secondary and primary prevention ICD trials. Trial name abbreviations
are as used in the text. VF = ventricular fibrillation; VT = ventricular tachycardia; Sx = symptoms; EF = ejection fraction; NYHA = New
York Heart Association; IV = intravenous; MI = myocardial infarction; CAD = coronary artery disease; EPS = electrophysiological study;
Note that the mean ejection fraction in the primary prevention trials was lower than in the postevent trials (Modified from Ezekowitz).92
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Figure 1. The reduction in total mortality in the ICD
trials is shown. The relative risk (RR) is shown for the
published secondary and primary prevention trials with
the box size proportional to the sample size of the trial.
Lines indicate 95% confidence intervals. The diamonds
indicate the pooled analysis for each stratum. For the
secondary prevention trials the ICD risk reduction was
24% and for the primary prevention trials overall the
risk reduction was 28% (which includes two trials—
CABG, Patch, and CAT—in which there was no ICD
benefit). Trial name abbreviations are as used in text.
Reproduced with permission from Ezekowitz.92
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syncope and an EF ≤ 40%. The randomization
scheme was very simple: patients were randomized to either the ICD or to amiodarone. Patients
needing revascularization (10%) could only be
randomized after the bypass procedure. The end
point of the trial was total mortality with secondary endpoints of quality of life and cost. The
pilot phase of the trial was initiated in June 1993
and enrollment was prompt. By March 1997, 1,000
patients had been enrolled and the study was terminated prematurely by the Data and Safety Monitoring Board (DSMB). At that time 1,016 patients
had been enrolled. At a mean follow-up period of
18.2 ± 12.2 months, the accrued death rates were
15.8% ± 3.2% in the ICD group and 24% ± 3.7%
in the drug group. Survival figures demonstrated
a decrease in mortality of 39% at 1 year, 27% at
2 years, and 31% at 3 years in the ICD arm of the
trial.84
The AVID patient population was virtually
identical to those patients treated by electrophysiologically guided therapy in the 1980s. The mean
EF was 31%–32%. Class III heart failure was
present in only 7% of the ICD group and 12% of
the drug group. Electrophysiological testing was
not required, although 572 of the patients did undergo electrophysiological study. Of the patients
studied, 384 (67%) had inducible arrhythmias, but
at 1 and 3 years there was no difference in survival between the inducible and the noninducible
groups.85
Subset analysis from the AVID study has provided additional insight into which patients benefit most from ICD therapy. Improved survival in the
AVID trial was noted with the ICD only in patients
with an EF of equal to or less than 35%, including patients with the lowest EFs. Patients with an
EF over 35% derived no survival benefit due in
large part to the overall better survival of the high
EF arms of the trial. The survival benefit of the
ICD was present in patients with both ischemic
and nonischemic cardiomyopathy, although the
latter group was only 25% of the population.86 Of
note, although the ICD and amiodarone had similar short-term survival statistics in patients with
LVEF ≥ 35%, a recent long-term follow up of a subset of these patients suggested a better survival in
ICD treated patients.87
The carefully kept AVID registry included patients from certain arrhythmia populations not included in the main trial because their risk was
thought low.88 The registry included patients with
asymptomatic VT, patients with VT/VF due to a
transient or correctible cause, and patients with
unexplained syncope and subsequent inducible
VT. These patient groups with an EF ≤35% had
two year death rates of 32% (asymptomatic VT),
29% (transient cause), and 17% (syncopal VT), re-
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spectively, similar to the low EF patients in the
main trial.88,89
The CIDS and CASH trials had similar design although the patient groups differed. CIDS
had a modest 20% reduction of mortality in the
ICD group compared with that of the amiodarone
group.90 The CASH trial had a more complicated
design and a long enrollment period, yet showed
a mortality reduction of 37% in the ICD arm compared to the antiarrhythmic drug arm.91 A recent
meta-analysis of the 1,963 patients included in
these three trials found that ICDs reduced the relative risk for sudden cardiac death by 50% and
provided a reduction in total mortality of 24%92
(Fig. 1). Based on these data, the 1998 ACC/AHA
guidelines for ICD implantation made the main
trial AVID patient groups a Class I indication
for ICD implantation.93 This recommendation increased access to ICD therapy for patients regardless of the insurer and diminished the need for
electrophysiological studies in selecting therapy.
Era of the Prophylactic ICD Trials
In 1970, Mirowski and Mower speculated that
the automatic defibrillator “might be implanted on
a permanent basis in selected patients with coronary heart disease identified as belonging to a high
risk population.”3 Although opposed to postarrest trials on ethical grounds, they embraced the
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CANNOM, ET AL.
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the conclusion of the study approximately 45%
of the inducible patients were discharged taking
a drug thought to be effective: the nonresponders
received an ICD. Because of the large number of patients in MUSTT, there were enough ICD patients
to compare the MUSTT results to the MADIT results. The risk of death over 5 years was substantially lower in patients discharged with an ICD
(24%) versus drug therapy (55%), which represents a 49% lower relative risk. The MUSTT patients who received an ICD after failing all drugs
had a survival rate comparable to the ICD arm of
MADIT.98
A subsequent analysis of the MADIT data
showed that all of the survival benefit of the ICD
was in patients who had an EF ≤ 26%.99 The
MADIT investigators incorporated this observation, plus a desire to simplify the screening process, into the design of MADIT II.100 This trial
was very simple in design; it randomized stable
postinfarction patients with an EF ≤ 30% to either an ICD or no ICD. There was no arrhythmia
requirement and no electrophysiological study. A
total of 1,232 patients were randomized to an ICD
or best medical therapy in a 3:2 ratio. The mean
EF in this trial was 23% compared to 25%–27%
in MADIT I. Nearly 70% were treated with ACE
inhibitors and β-blockers, a much higher proportion than in MADIT I. Nonetheless, in this well
treated patient group with advanced heart disease,
the ICD reduced mortality by 31% (19.8% mortality in the conventional arm versus 14.2% in ICD
arm). When studied independently in randomized
trials, the absolute contribution of the ICD to reduction in all cause mortality in this patient group
was larger than with other proven therapies such
as β-blockers, CABG, or ACE inhibitors.101
Therefore, in all three major primary prevention trials in postinfarction patients, MADIT,
MUSTT, and MADIT II, the use of the ICD reduced
mortality respectively by 54% (at 27 months), 55%
(at 39 months), and 31% (at 20 months) compared
with standard medical therapy. This reduction in
mortality is greater than the risk reduction noted
in the secondary prevention trials–AVID, CASH,
and CIDS–in which the mortality reduction was
31% (at 3years), 28% (at 3 years), and 20% (at 3
years), respectively. The MADIT II indication was
given a Class IIa indication in the 2002 revision
of the ACC/AHA ICD guidelines.102 Using the data
from the randomized clinical trials, a treatment algorithm can be constructed to help guide therapy
in any given patient (see Fig. 2).103
Not all patient groups studied in recently completed ICD trials have shown a benefit for the
ICD. The most surprising of these was the CABGPATCH trial, which randomized low EF patients
undergoing CABG surgery to either an ICD or no
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concept of randomized trials for patients at high
risk before cardiac arrest—namely, primary prevention. Nearly 20 years later a series of prophylactic ICD trials were designed by investigators such
as Bigger and Moss whose research interests were
associated more with risk stratification rather than
invasive electrophysiology. They used risk stratifiers from other studies of the 1980s including low
EF and nonsustained VT. These trials were conceived and initiated years before any secondary
prevention trial suggested a survival benefit for patients protected by an ICD. (Table I, Fig. 1)
The most interesting and controversial of
these trials was the Multicenter Automatic Defibrillator Implantation Trial (MADIT). The conceptual framework of this trial arose from the known
risk of nonsustained VT and a low EF in postinfarction patients. This risk model was verified by
a study showing that if such patients had inducible
VT and were not suppressed by an arrhythmic
drug in the electrophysiology laboratory, they had
a high risk of death.94 The MADIT trial enrolled patients with coronary disease, a low EF (≤ 35%) and
nonsustained VT who could be induced at electrophysiologic study but not suppressed by procainamide in the electrophysiology laboratory.95
Patients were randomized to either conventional
drug therapy, largely amiodarone, or to an ICD.
During the course of the trial, there were 39 deaths
in the conventional arm and only 15 deaths in the
ICD arm. At 4 years, only 51% of the conventional
group patients were alive. Also, 60% of the MADIT patients received a shock at 2 years confirming
the protective effect of the ICD.95
The degree of risk reduction, 54% at 2 years,
was anticipated in the design of the study; however, controversy about the design of the study
quickly arose.96 There was no registry of screened
patients as in AVID; a high percentage of patients
discontinued their amiodarone, and there was disproportionate use of β-blockers in the ICD arm.
The electrophysiology community did not adopt
this study in everyday practice because of concerns regarding the data as well as cost implications. The general consensus was that more data
were needed to support the MADIT findings. Despite these concerns, the ACC/AHA guidelines in
1998 gave the MADIT indication Class I status.93
The MADIT results received unexpected
support when the results of the Multicenter
Unsustained Tachycardia Trial (MUSTT) were
published.97 This trial assessed the role of electrophysiological testing in choosing appropriate
therapy in a population similar to MADIT. Patients
with coronary disease and an EF ≤ 40% with nonsustained VT who could be induced at electrophysiological study were randomized to electrophysiologically guided therapy or to placebo. At
426
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PACE, Vol. 27
NASPE HISTORY SERIES
Challenges and Future Directions
Data from the clinical trials showed that device therapy is expensive due in large part to the
high cost of the ICD itself. A recent analysis suggested that in the AVID trial the incremental costeffectiveness of the ICD compared with drug therapy was $66,677 per year of life saved in post VF
patients.111,112 In MADIT, which had a more substantial risk reduction due to the ICD, the cost was
$25,000 per life year saved.113
The number of patients eligible for ICD implantation is large and growing. Some 300,000 new
patients with LV dysfunction and coronary disease
present in the United States each year.114 The number of ICDs implanted is growing at about 20% per
year. Analysts expect that in 2003 nearly 130,000
new ICDs will be implanted world wide.115 There
is marked variability among countries in ICD implantation rates. In the United States there are
185 ICDs implanted/million population; in Western Europe 31 ICDs are implanted per million population and in Japan, 8 per million.116
It is clear that the recent evolution and acceptance of cardiac resynchronization therapy (CRT)
in patients with NYHA Class III and IV heart failure will further accelerate the growth rate of the
ICD. The recently completed COMPANION trial
showed that CRT therapy implanted with an ICD,
reduced mortality by 40% in a low EF population
(≤35%) with heart failure and a QRS ≥120 ms,
while CRT alone reduced mortality by only 20%
compared with the control population. 117 Thus,
based on both the MADIT II and COMPANION
data, most patients who qualify for a CRT device
will likely receive it with an ICD.118
The DAVID trial evaluated the effect of ICD
bradycardia programming on a composite endpoint of heart failure hospitalization and mortality. Patients had pacemakers programmed to either
no pacing or to DDD pacing. Of the pacing group,
59% received continuous RV pacing and incurred
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Figure 2. The results of the primary and secondary ICD
trials simplify the treatment of high risk patients with
ventricular arrhythmias. This treatment algorithm summarizes an approach to each patient subgroup based
on trial data. The recommendations are all either Class
I or Class IIA indications based on the most recent
ACC/AHA guidelines.102 These recommendations indicate at least one reasonable option for each patient subgroup and are not a substitute for sound clinical judgment. Future trial data may modify these recommendations. AA = antiarrhythmic; CAD = coronary artery
disease; CM = cardiomyopathy (dilated); EPS = electrophysiologic study; Amio = amiodarone; EF = ejection fraction; PVCs = premature ventricular complexes;
Rx = therapy; Sxs = symptoms; VT-NS = nonsustained
ventricular tachycardia; VT-S = sustained ventricular tachycardia; RFCA = radiofrequency catheter ablation; ICD = implantable cardioverter defibrillator. Numbers reflect trial data supporting each recommendation: (1) AVID/CASH/CIDS; (2) MADIT I/MUSTT; and (3)
MADIT II.
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may have a lower mortality rate than expected
compared to ischemic patients, perhaps due to an
additional survival benefit of ACE inhibitors and
β-blockers. There are other patient groups at significant risk of SCD that have not been subjected
to randomized trials. These are patients groups often treated as ACC/AHA Class IIb indications for
an ICD including those with Brugada syndrome,
the long QT syndrome, or hypertrophic cardiomyopathy. If such patients have had cardiac arrest,
then an ICD is generally implanted. However, often these patients are asymptomatic yet come from
a family with history of sudden death or have had
prior syncope but no documented arrhythmia. Preliminary data suggested that the use of the ICD in
such populations is warranted.109,110
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ICD.104 The defibrillator did not benefit mortality
in the ICD arm of this trial. Mortality was 18%
at 2 years and only 13% if one excludes operative
mortality. Patients with a two year mortality of under 20% have little chance of benefitting from ICD
therapy.105
A major unanswered question is the usefulness of the ICD as primary prevention for SCD in
patients with nonischemic dilated cardiomyopathy. Recent data from two major trials have shown
no benefit from the ICD compared to best medical
therapy or amiodarone.106,107 However, the results
of the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial presented at the 2003 Scientific Sessions of the American Heart Association, clearly showed a survival
trend favoring the ICD. Other ongoing trials involving dilated cardiomyopathy patients hopefully will clarify this issue.108 This patient group
PACE, Vol. 27
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References
2.
3.
.p
4.
w
5.
w
8.
w
6.
7.
Zoll PM, Linethal AJ, Gibson W, et al. Termination of ventricular
fibrillation in man by externally applied electric shock. N Engl J
Med 1956; 254:727.
Morton Mower, personal communication.
Mirowski M, Mower MM, Staewen WS, et al. Standby automatic defibrillator: An approach to prevention of sudden coronary
death. Arch Intern Med 1970; 126:158–161.
Mirowski M, Mower MM, Denniston RH, et al. Prevention of sudden coronary death through automatic detection and treatment of
ventricular fibrillation (VF) using a single intravascular catheter
c system.(abstract) Circulation 1971; 43:II–124.
Mirowski M, Mower MM, Staewen WS, et al. Ventricular defibrillation through a single intravascular catheter electrode system.(abstract) Clin Res 1971; 19:328.
Troup PJ. Implantable Cardioverters and Defibrillators. In RA
O’Rourke, MH Crawford (eds.): Current Problems in Cardiology Year Book Medical Publishers, Inc, Chicago, Illinois, 1989,
pp. 682.
Mirowski M, Mower MM. Transvenous automatic defibrillator as
an approach to prevention of sudden death from ventricular fibrillation. Heat and Lung 1973; 2:567–569.
Langer A, Heilman MS, Mower MM, et al. A novel ventricular fibrillation detector for implantable defibrillator. Circulation 1975;
52:II–205..
Mirowski M, Mower MM, Staewen WS, et al. The development
of the transvenous automatic defibrillator. Arch Intern Med 1979;
129:773–779.
Mirowski M, Mower MM, Langer A, et al. A chronically implanted
system for automatic defibrillation in active conscious dogs: Experimental model for treatment of sudden death from ventricular
fibrillation. Circulation 1978; 58:90–94.
Mower MM, Hauser RG. Historical Development of the
AICD. In NAM Estes III, AS Manolis, PJ Wang, (eds.): Implantable Cardioverter-Defibrillators: A Comprehensive Textbook., Marcel Dekker, Inc., New York, New York, 1994.
pp. 174.
Mirowski M, Mower MM, Gott VL, et al. Feasibility and effectiveness of low-energy catheter defibrillation in man. Circulation
1973; 47:79–85.
co
m
Acknowledgments: The authors acknowledge the helpful
suggestions of Drs. Arthur Moss and Morton Mower and the
preparation and editorial assistance of Janice Zemlicka.
ac
1.
A remaining clinical challenge is to assure
that patients who meet criteria for an ICD actually
receive them.122 The uncompleted research challenge for the prevention of sudden death is to identify and protect a larger number of patients at risk
in the general population but who do not have any
of the well studied risk factors of the 1980s.123
The ICD is now regarded as everyday therapy
for large groups of patients in hospitals of every
size around the world. It will be the core therapy
for groups of patients identified by new techniques
as being at risk for sudden death and a component of any implantable device to treat heart failure. The evolution and acceptance of the ICD over
two decades is comparable to that of the other
building blocks of clinical cardiology including
pacing, interventional cardiology, and echocardiography. This therapy is unique, however, in that
its inventors—Mirowski and Mower—envisioned
its importance 10 years before the first device was
implanted and 30 years before clinical trials established its efficacy.
er
ic
d.
a 39% increase in the one year risk of hospitalization or death.119 This shows that RV pacing itself
worsens outcome and may explain in part the increase in heart failure in MADIT II. This observation will likely mean that any long-term ICD patient with substantial LV dysfunction who relies
on RV pacing will be considered for CRT in addition to ICD whether or not heart failure is present.
A 15-year era, between 1988 and 2003, of randomized clinical trials of the ICD in high risk
patient groups is concluding. A few more select
patient populations will be studied in randomized trials in the future, such as patients with
dilated cardiomyopathy and syncope. Yet there
are no other major patient populations at high
risk who are unstudied using current stratification
techniques. We need to develop better noninvasive tools–perhaps including genetic and neurohumoral markers–to identify the patient populations
with low EF who may benefit from ICD, but to date
this promise is unrealized.120,121 The prophylactic
ICD trials have all shown that mortality risk is associated with a low EF (≤40%) in coronary artery
disease patients and that other risk stratifiers including nonsustained VT, the signal average ECG,
and electrophysiological study add little.
9.
10.
11.
12.
428
13.
Lown B, Axelrod P. Implanted standby defibrillators. Circulation
1972; 46:637–639.
14. Mirowski M, Mower MM, Mendeloff AI. Implanted standby defibrillators. Letters to the Editor. Circulation 1973; 47:1135–1136.
15. Mirowski M, Reid PR, Mower MM, et al. Termination of malignant
ventricular arrhythmias with an implanted automatic defibrillator
in human beings. N Engl J Med 1980; 303:322–324.
16. Winkle RA, Thomas A. The Automatic Implantable Cardioverter
Defibrillator: The U.S. experience. In P. Brugada, HJJ Wellens,
(eds.): Cardiac Arrhythmias: Where to Go From Here?, Futura Publishing Company, Inc., Mount Kisco, New York, 1987, pp. 663–
680.
17. Staewen WS, Mower MM. History of the ICD. In MW Kroll,
MH Lehmann, (eds.): Implantable Cardioverter Defibrillator Therapy, Kluwer Academic Publishers, Norwell, Massachusetts, 1996,
pp. 26.
18. Mower MM, Hauser RG. Developmental history, early use and
implementation of the automatic implantable cardioverter defibrillator. Prog in Cardiovasc Dis 1993; 36:89–96.
19. Mirowski M, Mower MM, Gott VL, et al. Feasibility and effectiveness of low-energy catheter defibrillation in man. Circulation
1973; 47:79–85.
20. Moser S, Troup P, Saksena S, et al. Nonthoractomy implantable
defibrillator system.(abstract) PACE 1988; 11:887.
21. Mirowski M, Reid PD, Mower MM, et al. Termination of malignant
ventricular arrhythmias with implanted defibrillator in human
beings. N Engl J Med 1980; 303:322–324.
22. Furman S, Kim S. The present status of implantable cardioverter
defibrillator therapy. J Cardiovas Electrophysiol 1992; 3:602–
625.
23. Kelly PA, Cannom DS, Garan H, et al. The automatic implantable
cardioverter-defibrillator: Efficacy, complications and survival in
patients with malignant ventricular arrhythmias. J Am Coll Cardiol 1998; 11:1278–1286.
24. Calkins H, Brinker J, Veltri EP, et al. Clinical interactions
between pacemakers and automatic implantable cardioverterdefibrillators. J Am Coll Cardiol 1990; 16:666–673.
25. Saksena S, Chandran P, Shah Y, et al. Comparative efficacy of
transvenous cardioversion and pacing in patients with sustained
March 2004
PACE, Vol. 27
NASPE HISTORY SERIES
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
w
44.
w
45.
46.
47.
48.
49.
51.
52.
53.
54.
55.
56.
57.
co
m
30.
50.
dial infarction in the fibrinolytic era: GISSI-2 results. Circulation
1993; 87:312–322.
Josephson ME, Horowitz LN, Farshidi A, et al. Recurrent sustained ventricular tachycardia. Mechanisms. Circulation 1978;
57:431–440.
Troup PJ. Programmed stimulation-guided therapy compared
with implantable cardioverter defibrillator device therapy in the
treatment of ventricular tachyarrhythmias. PACE 1991; 14:267–
272.
The Cardiac Arrhythmia Suppression Trial (CAST) Investigators.
Preliminary report: Effect of encainide and flecainide on mortality
in a randomized trial of arrhythmia suppression after myocardial
infarction. N Engl J Med 1989; 321:406–412.
The Cardiac Arrhythmia Suppression Trial II Investigators. Effect
of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227–233.
Hine LK, Laird NM, Hewitt P, et al. Meta-analysis of empirical long-term antiarrhythmic therapy after myocardial infarction.
JAMA 1989; 262:3037–3040.
Harken AH, Josephson ME, Horowitz LN. Surgical endocardial resuscitation for the treatment of malignant ventricular tachycardia.
Ann Surg 1979; 190:456–460.
Miller JM, Kienzle MG, Harken AH, et al. Subendocardial resection for ventricular tachycardia: Predictors of surgical success.
Circulation 1984; 70:624–631.
Josephson ME, Harken AH, Horowitz LN. Endocardial excision—
A new surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979: 60:1430–1439.
Horowtiz LN, Harken AH, Kastor JA, et al. Ventricular resection
guided by epicardial and endocardial mapping for treatment of
recurrent ventricular tachycardia. N Engl J Med 1980; 302:589–
593.
Cox JL. Patient selection criteria and results of surgery for
refractory ischemic ventricular tachycardia. Circulation 1989;
79(Suppl. I):162–177.
Mirowski M, Reid PR, Mower MM, et al. Termination of malignant
ventricular arrhythmias with an implanted automatic defibrillator
in human beings. N Engl J Med 1980; 303:322–324.
Mirowski M, Reid PR, Winkle RA, et al. Mortality in patients with
implanted automatic defibrillators. Ann Intern Med 1983; 98:585–
588.
U.S. Food and Drug Administration, 50 Fed Reg. 47276, 1985.
Healthcare Finance Administration. Section 35-85. Implantation
of automatic defibrillator, January, 1986, and interim payment procedures for defibrillator implants, March, 1986.
Handelsman H. Office of health technology assessment report no.
10. Implantation of the automatic cardioverter-defibrillator: Noninduciblity of ventricular tachyarrhythmia as a patient selection
criterion. DHHS, PHS, Agency for Health Care Policy and Research Center for Research Dissemination and Liasison, Rockville,
MD, 1991.
Winkle RA, Mead RH, Ruder MA, et al. Long-term outcome with
the automatic implantable cardioverter-defibrillator. J Am Coll
Cardiol 1989; 13:1353–1361.
Nisam S, Mower M, Moser S. ICD clinical update: First decade,
initial 10,000 patients. PACE 1991; 14:255–262.
Borbola J, Denes P, Ezri MD, et al. The automatic implantable
cardioverter-defibrillator: Clinical experience, complications and
follow-up in 25 patients. Arch Intern Med 1988; 148:70–
76.
Manolis AS, Tan-DeGuzman W, Lee MA, et al. Clinical experience in seventy-seven patients with the automatic implantable
cardioverter defibrillator. Am Heart J 1989; 118:445–450.
Veltri EP, Mower MM, Mirowski M, et al. Follow-up of patients
with ventricular tachyarrhythmia treated with the automatic implantable cardioverter defibrillator: Programmed electrical stimulation results do not predict clinical outcome. J Electrophysiol
1989; 3:467–476.
Thomas AC, Moser SA, Smutka ML, Wilson PA. Implantable defibrillator: Eight years clinical experience. PACE 1988; 11:2053–
2058.
Fogoros RN, Fiedler SB, Elson JJ. The automatic implantable
cardioverter-defibrillator in drug-refractory ventricular tachyarrhythmias. Ann Intern Med 1987; 107:635–641.
Lehmann MH, Steinman RT, Schuger CD, et al. The automatic
implantable cardioverter defibrillator as antiarrhythmic treatment modality of choice for survivors of cardiac arrest unrelated to acute myocardial infarction. Am J Cardiol 1988; 62:803–
805.
er
ic
d.
29.
ac
28.
.p
27.
w
26.
ventricular tachycardia: A prospective, randomized, crossover
study. Circulation 1985; 72:153–160.
Naccarelli GV, Zipes DP, Rahilly GT, et al. Influence of tachycardia cycle length and antiarrhythmic drugs on pacing termination and acceleration of ventricular tachycardia. Am Heart J 1983;
105:1–5.
Bardy GH, Troutman C, Poole JE, et al. Clinical experience with
a tiered-therapy, multiprogrammable antiarrhythmia device. Circulation 1992; 85:1689–1698.
Troup PJ. Implantable cardioverters and defibrillators. In RA
O’Rourke, MH Crawford, (eds.): Current Problems in Cardiology,
Year Book Medical Publishers, Inc, Chicago, 1989, pp. 732.
Winkle RA, Mead RH, Ruder MA, et al. Improved low energy
defibrillation efficacy in man with the use of a biphasic truncated
exponential waveform. Am Heart J 1989; 117:122–127.
Bardy GH, Ivey TD, Allen MD, et al. A prospective randomized
evaluation of biphasic versus monophasic waveform pulses on
defibrillation efficacy in humans. J Am Coll Cardiol 1989; 14:728–
733.
Bardy GH, Johnson G, Poole JE, et al. A simplified, single-lead
unipolar transvenous cardioversion-defibrillation system. Circulation 1993; 88:543–547.
Nisam S. Technology update: The modern implantable cardioverter defibrillator. Annals of Noninvasive Electrocardiology
1997; 2:69–78.
Morris MM, KenKnight BH, Warren JA, et al. A preview of implantable cardioverted defibrillator systems in the next millennium: An integrative cardiac rhythm management approach. Am
J Card 1999; 83:48D–54D.
Prystowsky EN. Future expectations of implantable cardioverter
defibrillator therapy. PACE 1995; 18:609–615.
Zheng ZJ, Croft JB, Giles WH, et al. Sudden cardiac death in the
United States, 1989 to 1998. Circulation 2001; 104:2158–2163.
Baum RS, Alvarez H III, Cobb LA. Survival after resuscitation
from out-of-hospital ventricular fibrillation. Circulation 1974;
50:1231–1235.
Myerburg RJ, Kessler KM, Estes D, et al. Long-term survival after
prehospital cardiac arrest: Analysis of outcome during an 8 year
study. Circulation 1984; 70:538–546.
Yusef S, Teo KK. Approaches to prevention of sudden death: The
need for fundamental reevaluation. J Cardiovasc Electrophysiol
1991; 2(Suppl.):S233–S239.
Liberthson RR, Nagel EL, Hirschman JC, et al. Prehospital ventricular defibrillation. Prognosis and follow-up course. N Engl J Med
1974; 291:317–321.
Cobb LA, Werner JA, Trobaugh GB. Sudden cardiac death. I.
A decade’s experience with out-of-hospital resuscitations,. Mod
Concepts Cardiovasc Dis 1980; 49:31–36.
Multicenter Post-Infarction Research Group. Risk stratification after myocardial infarction. N Engl J Med 1983; 309:331–336.
Bigger JT Jr, Fleiss JL, Kleiger R, et al., and the Multicenter PostInfarction Research Group. The relationships among ventricular
arrhythmias, left ventricular dysfunction and mortality in the
2 years after myocardial infarction. Circulation 1984; 69:250–
258.
Mukharji J, Rude RE, Poole JE, et al., the MILIS Study Group.
Risk factors for sudden death after acute myocardial infarction:
Two-year follow up. Am J Cardiol 1984; 54:31–36.
Coromilas J, Bigger JT Jr, Kleiger RE, et al., and the MDPIT Research Group. Relations among left ventricular dysfunction, ventricular arrhythmias, and mortality after myocardial infarction.
Circulation 1989; 80(Suppl. II):48.
Nicod P, Gilpin E, Eitrich H, et al. Prognostic significance of complex ventricular arrhythmia for cardiac death during the first year
after myocardial infarction. J Electrophysiol 1987; 1:93–102.
Bigger JT Jr. Risk stratification after myocardial infarction.
Zeitschr Kardiol 1985; 74(Suppl. 6):147–157.
Yap YG, Duong T, Bland M, et al. Left ventricular ejection fraction in the thrombolytic era remains a powerful predictor of longterm but not short-term all cause cardiac and arrhythmic mortality
after myocardial infarction—A secondary meta-analysis of 2828
patients. J Am Coll Cardiol 2001; 37(Suppl. A):445A.
Bigger JT Jr, Weld PM, Coromilas J, et al. Prevalence and Significance of Arrhythmias in 24-hour ECG Recordings Made Within
One Month of Acute Myocardial Infarction.. In H Kulbertus, HJJ
Wellens, (eds.): The First Year After a Myocardial Infarction, Martinus Nijhoff, Boston, Massachusetts, 1983, pp.161–175.
Maggioni AP, Zuanetti G, Franzosi MG, et al. Prevalence and prognostic significance of ventricular arrhythmias after acute myocar-
PACE, Vol. 27
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
March 2004
429
CANNOM, ET AL.
74.
75.
76.
77.
78.
79.
81.
82.
83.
84.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
ac
85.
86.
.p
87.
w
88.
w
w
89.
90.
95.
Moss AJ, Hall WJ, Cannom DS, et al., for the Multicenter Automatic Defibrillator Implantation Trial investigators. Improved
survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmias. N Engl J
Med 1996; 335:1933–1940.
Friedman PL, Stevenson WG. Unsustained ventricular
tachycardia—To treat or not to treat. N Engl J Med 1996;
335:1984–1985.
Buxton AE, Lee KL, Fisher JD, et al., for the Multicenter Unsustained Tachycardia Trial Investigators. A randomized study of the
prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999; 341:1882–1890.
Prystowsky EN, Nisam S. Prophylactic implantable cardioverter
defibrillator trials: MUSTT, MADIT, and beyond. Am J Cardiol
2000; 86:1214–1215.
Moss AJ, Fadl Y, Zareba W, Cannom DS, for the Multicenter Automatic Defibrillator Implantation Trial Investigators. Survival benefit with an implanted defibrillator in relation to mortality risk
in chronic coronary heart disease. Am J Cardiol 2001; 88:516–
520.
Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a
defibrillator in patients with myocardial infarction and reduced
ejection fraction. Multicenter Automatic Defibrillator Implantation Trial II investigators. N Engl J Med 2002; 346:877–883.
Moss AJ. MADIT II and its implications. European Heart Journal
2003; 24:16–18.
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002
Guideline update for implantation of cardiac pacemakers and antiarrhythmic devices—summary article: A report of the American
College of Cardiology/American Heart Association Task force on
Practice Guidelines (ACC/AHA/NASPE Committee to Update the
1998 Pacemaker Guidelines). J Am Coll Cardiol 2002; 40:1702–
1719.
Cannom DS, Prystowsky E. Management of ventricular
arrhythmias–detection, drugs, and devices. JAMA 1999; 281:172–
179.
Bigger JT Jr, Whang W, Rottman JN, et al. Mechanisms of death
in the CABG Patch trial: A randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death
after coronary artery bypass graft surgery. Circulation 1999; 99:
1416.
Nisam S, Farre J. Is prophylaxis the best use of the ICD? (Editorial)
Eur Heart J 2002; 23:700–705.
Bansch D, Antz M, Boczor S, et al., for the CAT investigators.
Primary prevention of sudden cardiac death in idiopathic dilated
cardiomyopathy: The Cardiomyopathy Trial (CAT). Circulation
2002; 105:1453–1458.
Strickberger SA, Hummel JD, Bartlett TG, et al., for the AMIOVIRT
investigators 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.
Bardy GH, Lee KL, Mark DB, and the SCD-HEFT pilot investigators. The sudden cardiac death in heart failure trial: Pilot study.
PACE 1997; 20:1148.
Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable
cardioverter-defibrillators for the prevention of sudden death in
patients with hypertrophic cardiomyopathy. N Engl J Med 2000;
342:365–373.
Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter
defibrillator in high-risk long QT syndrome patients. J Cardiovasc
Electrophysiol 2003; 14:337–341.
Larsen G, Hallstrom A, McAnulty J, et al. Cost effectiveness
of the implantable cardioverter defibrillator versus antiarrhythmic drugs in survivors of serious ventricular tachyarrhythmias:
Results of the Antiarrhythmics Versus Implantable Defibrillator
(AVID) economic analysis substudy. Circulation 2002; 105:2049–
2057.
Larsen GC, Manolis AS, Sonnenberg FA, et al. Cost-effectiveness
of the implantable cardioverter defibrillator: Effect of improved
battery life and comparison with amiodarone therapy. J Am Coll
Cardiol 1992; 19:1323–1334.
Mushlin AI, Hall WJ, Swanziger J, et al. The cost-effectiveness of
automatic implantable cardiac defibrillators: Results from MADIT
Multicenter Automatic Defibrillator Implantation Trial. Circulation 1998; 97:2129–2135.
American Heart Association. 1999 Heart and stroke statistical update. American Heart Association, Dallas, Texas 1998.
er
ic
d.
80.
Fogoros RN, Elson JJ, Bonnet CA. Survival of patients who have
received appropriate shocks from their implantable defibrillators.
PACE 1991; 14:1842–1845.
Tchou PJ, Kadri N, Anderson J, et al. Automatic implantable
cardioverter defibrillators and survival of patients with left ventricular dysfunction and malignant ventricular arrhythmias. Ann
Intern Med 1988; 109:529–534.
Fogoros RN, Elson JJ, Bonnet CA, et al. Efficacy of the automatic
implantable cardioverter defibrillator in prolonging survival in
patients with severe underlying cardiac disease. J Am Coll Cardiol
1990; 16:381–386.
Myerburg RJ, Luceri RM, Thurer R, et al. Time to first shock and
clinical outcome in patients receiving an automatic implantable
cardioverter defibrillator. J Am Coll Cardiol 1989; 14:508–514.
Newman D, Sauve MJ, Herre J, et al. Survival after implantation of the cardioverter defibrillator. Am J Cardiol 1992; 69:899–
903.
Lehmann MH, Steinman RT, Schuger CD, et al. The automatic implantable cardioverter defibrillator as antiarrhythmic treatment
modality of choice for survivors of cardiac arrest unrelated to
acute myocardial infarction. Am J Cardiol 1988; 62:803–805.
Akhtar M, Garan H, Lehmann MH, et al. Sudden cardiac
death: Management of high-risk patients. Ann Intern Med 1991;
114:499–512.
Powell AC, Fuchs T, Finkelstein M, et al. Influence of implantable
cardioverter-defibrillators on the long-term prognosis of survivors
of out-of-hospital cardiac arrest. Circulation 1993; 88:1083–1092.
Furman S. AICD benefit. PACE 1989; 12:399–400.
Connolly SJ, Yusuf S. Evaluation of the implantable cardioverter
defibrillator in survivors of cardiac arrest: The need for randomized trials. Am J Cardiol 1992; 69:959–962.
Kim SG, Fisher JD, Furman S, et al. Benefits of implantable defibrillators are overestimated by sudden death rates and better
represented by the total arrhythmic death rate. J Am Coll Cardiol
1991; 17:1587–1592.
The Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic drug therapy with
implantable defibrillators in patients resuscitated from near-fatal
ventricular arrhythmias. N Engl J Med 1997; 337:1576–1583.
Brodsky MA, Mitchell LB, Halperin BD, et al. Prognostic value
of baseline electrophysiology studies in patients with sustaine
ventricular tachycardia: The Antiarrhythmics Versus Implantable
Defibrillators (AVID) Trial. Am Heart J 2002; 144:478–484.
Ehlert FA, Cannom DS, Renfroe, EG, et al., and the AVID Investigators. Comparison of dilated cardiomyopathy and coronary artery
disease in patients with life-threatening ventricular arrhythmias:
Differences in presentation and outcome in the AVID registry. Am
Heart J 2001; 142:816–822.
Bokhari FA, Newman D, Korley V, et al. Implantable cardioverter
defibrillator vs amiodarone: Eleven years follow up of the Canadian Implantable Defibrillator Study (CIDS). Circulation 2002;
106(19):II–497.
Anderson JL, Hallstrom AP, Epstein AE, et al. Design and results of
the Antiarrhythmics vs implantable defibrillators (AVID) registry.
Circulation 1999; 99:1692–1699.
Wyse DG, Friedman PL, Brodsky MA, et al., for the AVID Investigators. Life-threatening ventricular arrhythmias due to transient
or correctable causes: High risk for death in follow-up. J Am Coll
Cardiol 2001; 38:1718–1724.
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.
Kuck KH, Cappato R, Siebels J, et al. 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.
Ezekowitz JA, Armstrong PW, McAlister FA. Implantable cardioverter defibrillators in primary and secondary prevention: A
systematic review of randomized, controlled trials. Ann Intern
Med 2003; 138:445–452.
Gregoratos G, Cheitlin MD, Conill A, et al. ACC/AHA guidelines
for implantation of cardiac pacemakers and antiarrhythmic devices: A report of the ACC/AHA Task Force on practice guidelines.
J Am Coll Cardiol 1998; 31:1175–1209.
Wilber DJ, Olshansky B, Moran JF, et al. Electrophysiological testing and nonsustained ventricular tachycardia: Use and limitations
in patients with coronary artery disease and impaired ventricular
function. Circulation 1990; 82:350–358.
co
m
73.
91.
92.
93.
94.
430
106.
107.
108.
109.
110.
111.
112.
113.
114.
March 2004
PACE, Vol. 27
NASPE HISTORY SERIES
119.
The DAVID Trial Investigators. Dual chamber pacing or ventricular backup pacing in patients with an implantable defibrillator.
JAMA 2002; 288:3115–3123.
120. Buxton A. The clinical use of implantable cardioverter defibrillators: Where are we now? Where should we go? (editorial) Ann
Intern Med 2003; 138:512–514.
121. Josephson ME, Callans DJ, Buxton AE. The role of the implantable
cardioverter defibrillator for prevention of sudden cardiac death.
Ann Intern Med 2000; 133:901–910.
122. Ruskin JN, Camm AJ, Zipes DP, et al. Implantable cardioverter
defibrillator utilization based on discharge diagnoses from Medicare and managed care patients. J Cardiovasc Electrophysiol 2002;
13:38–43.
123. Myerburg RJ. Scientific gaps in the predication and prevention of
sudden cardiac death. J Cardiovas Electrophysiol 2002; 13:709–
723.
co
m
Reicin GM, Wittes J. Morgan Stanley Equity Research North
American, Hospital Supplies and Medical Technology. Industry Overview—An Investors’ Guide to ICDs, October 8,
2002.
116. Seidl K, Senges J. Geographic differences in implantable cardioverter defibrillator usage. J Cardiovasc Electrophysiol 2002;
13:S100–S105.
117. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac resynchronization therapy (CRT) reduces hospitalizations, and CRT + an
implantable defibrillator (CRT-D) reduces mortality in chronic
heart failure: Preliminary results of the COMPANION trial. Available at: http://www.uchsc.edu/cvi/clb.pdf. Accessed August 13,
2003.
118. Saxon LA, Ellenbogen KA. Resynchronization therapy for
the treatment of heart failure. Circulation 2003; 108:1044–
1048.
w
w
w
.p
ac
er
ic
d.
115.
PACE, Vol. 27
March 2004
431