Description
Make a presentation in Power Point of 15 slides of the research that I give you, including what the device is, the history of its development, what are the latest technologies and challenges facing it, what is the future outlook and benefit from it, and adding pictures regarding the device in general and simple words
introduction
Patients with heart failure (briefly and simply)
The first discovery of the device and how it developed
latest Technology
what is the problems?
Solution methods for problems
What is the future?
Conclusion
Every idea or piece of information should be properly cited using IEEE citation style; do not use artificial intelligence.
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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 82, NO. 4, 2023
ª 2023 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
THE PRESENT AND FUTURE
JACC HISTORICAL BREAKTHROUGHS IN PERSPECTIVE
Development of the Implantable
Cardioverter-Defibrillator
JACC Historical Breakthroughs in Perspective
Barry J. Maron, MD,a N.A. Mark Estes, MD,b Ethan J. Rowin, MD,a Martin S. Maron, MD,a
Matthew R. Reynolds, MD, MSCa
ABSTRACT
Implantable cardioverter-defibrillators (ICDs) represent transformational technology, arguably the most significant
advance in cardiovascular medicine in 50 years. The vision and determination of pioneers Mirowski and Mower was
fundamental to this monumental achievement, working with limited resources and confronted by skepticism/criticism
from medical establishment. The inventors were followed >35 years in which a multitude of innovative clinical scientists and engineers introduced technological advances leading to the sophisticated devices in practice today. A
pivotal patient experiment with automated termination of ventricular fibrillation (1980) led to U.S. Food and Drug
Administration approval. Transvenous lead systems converted ICDs from thoracotomy-based secondary prevention to
primary prevention of sudden death devices in countless patients worldwide. ICD acceptance was solidified by prospective randomized controlled trials showing reduced mortality superior to antiarrhythmic drugs. ICDs eventually
expanded from coronary disease to inherited arrhythmia conditions (eg, hypertrophic cardiomyopathy). The ICD
breakthrough story demonstrates how significant progress is possible in medicine against all odds, given fearless
imagination to pursue novel ideas that conflict with accepted wisdom. (J Am Coll Cardiol 2023;82:353–373) © 2023
The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
T
cardioverter-defibrillator
tachyarrhythmias and preventing sudden cardiac
(ICD) is a major breakthrough in cardiovascu-
he
implantable
death (SCD). Now 50 years later, it seems opportune
lar disease, responsible for saving thousands
to document the many events that led to the mature
of patients with a variety of conditions, including
ICD now in cardiovascular practice throughout the
most prominently ischemic (coronary) heart disease,
world (Central Illustration, Table 1).
dilated cardiomyopathy, and hypertrophic cardiomyopathy (HCM). Initial work on the ICD occurred in the
THE MIROWSKI STORY
early 1970s without fanfare in a very different era of
Listen to this manuscript’s
cardiovascular medicine, dependent on the inventors
The ICD was unequivocally the vision of Dr Michel
Michel Mirowski and Morton Mower (Figure 1).1-4 Ulti-
Mirowski, an unlikely and extraordinarily inspira-
mately, many scientists and clinicians are responsible
tional story as can be found within the annals of
for development of the ICD, reliable for automatically
modern cardiovascular medicine. Mirowski was born
sensing and terminating potentially lethal ventricular
in Warsaw Poland in 1924 and was a survivor of the
audio summary by
Editor-in-Chief
Dr Valentin Fuster on
www.jacc.org/journal/jacc.
From the aLahey Hospital and Medical Center, Burlington, Massachusetts, USA; and the bHeart and Vascular Institute, University
of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received February 22, 2023; revised manuscript received April 13, 2023, accepted April 28, 2023.
ISSN 0735-1097
https://doi.org/10.1016/j.jacc.2023.04.056
354
Maron et al
JACC VOL. 82, NO. 4, 2023
JULY 25, 2023:353–373
Development of the Implantable Defibrillator
ABBREVIATIONS
Holocaust (the only one in a family of 24). His
AND ACRONYMS
adolescence was greatly disturbed by World
ACC = American College of
Cardiology
War II after he left the Warsaw ghetto at 15
years of age to escape the Nazis. His father’s
final instructions on departure were “be a
AHA = American Heart
Association
physician, be a Jew.” He followed an intricate
ATP = antitachycardia pacing
itinerary, traveling through Soviet occupied
CAD = coronary artery disease
CPI = Cardiac Pacemakers Inc
CRT = cardiac
Poland and later eastward into Europe and
Russia working diverse jobs along the way (eg,
Army officer, shoe salesman, and medical
student [Lyon, France]), and always narrowly
resynchronization therapy
avoiding the Germans, eventually emigrating
ECG = electrocardiography
to Palestine (Israel) and arriving a full-fledged
EF = ejection fraction
Zionist by virtue of his war experiences,
EP = electrophysiologic
becoming a solo private practitioner in a small
FDA = U.S. Food and Drug
community hospital in Asaf Harofeh.
Administration
HIGHLIGHTS
We document the development and
enhancement over 50 years of ICDs
capable of automatically sensing and
reliably intervening to prevent
arrhythmic SCD.
Insights from the inventors and other
scientists and engineers leading to the
development of ICDs will likely be informative to future clinical investigators.
Thousands of patients with genetic or
acquired heart diseases worldwide
benefit from ICDs to prevent arrhythmic
sudden death and enhance survival.
Mirowski was inspired to action in medicine
HCM = hypertrophic
cardiomyopathy
as a resident in Sheba Tel-HaShomer Hospital
ICD = implantable
(Tel Aviv) when his mentor Henry Heller (chief
EARLY YEARS. From 1972 to 1980, Mirowski and
cardioverter-defibrillator
of internal medicine) inevitably died suddenly
Morton Mower worked systematically without insti-
LGE = late gadolinium
of intractable ventricular tachyarrhythmias at
tutional or outside financial support, performing ex-
enhancement
a time when effective antiarrhythmic agents
periments after clinical hours with conscious dogs in
LQTS = long QT syndrome
were unavailable and constant in-hospital
a small animal research and biomedical engineering
LV = left ventricular
external defibrillation was impractical.5 This
basement facility using off-the-shelf materials and
LVEF = left ventricular ejection
experience was a major motivating factor in
purchasing animals with personal funds. Remarkably,
fraction
ultimately
considered
it was possible for Mirowski and Mower to assemble a
MI = myocardial infarction
virtually impossible by many (“simple” only to
small research team at Sinai; early important con-
NIH = National Institutes of
the inventors), which met with enormous
tributors in the Sinai-Baltimore period were Stephen
Health
resistance, that is, a miniature permanently
Heilman and Alois Langer at MedRad; Albert Men-
RCT = randomized controlled
implanted battery-powered standby device
delhoff, William Staewen, and Bernard Tabatznik at
capable of delivering a defibrillation shock
Sinai Hospital; and Philip Reid, Levi Watkins, and
through an indwelling transvenous catheter to
Myron Weisfeldt at Johns Hopkins Hospital.
trial
SCD = sudden cardiac death
S-ICD = subcutaneous
triggering
an
idea
restore normal heart rhythm.
implantable cardioverter-
In the first few years working in relative isolation
Judging that support for a massive and
and anonymity with limited national professional and
novel ICD project would be impossible in
public visibility, Mirowski and Mower initiated a se-
Israel, but somehow assured that it could
ries of early experiments to optimize ICD design:
happen in America, in 1969 he relocated his
sensitivity of the detection algorithm and stored
family one last time, including wife and 3 daughters
memory capability to establish effectiveness, reli-
(who all eventually became physicians) to Baltimore,
ability, and safety of the system, eventually leading
Maryland. He became the part-time Coronary Care
to early commercialization. However, there were ob-
Unit Director of a new unit still under construction at
stacles that threatened the project even before it
Sinai Hospital, a small private practice nonacademic
could gain momentum.
defibrillator
VF = ventricular fibrillation
VT = ventricular tachycardia
suburban hospital.
Three years after the ICD initiative started, Dr
At that time, Mirowski was already 45 years of age
Bernard Lown, of Brigham and Women’s Hospital
and an unlikely candidate to change the course of
(later a Nobel Laureate), perhaps the most esteemed
cardiovascular medicine. He had virtually no national
cardiologist in the world at the time and inventor of
or international reputation and few relevant aca-
direct current external defibrillation, became highly
demic credentials (ie, 1-year pediatric cardiology
critical of the permanently implanted “standby defi-
fellowship and 2 years in Mexico City researching
brillator.” In an aggressive editorial published in
12-lead electrocardiography [ECG] theory, authoring a
Circulation, Lown and Axelrod 6 made a disparaging
few papers on vectorcardiography). Mirowski was
appraisal with a number of arguments that could
clearly outside the mainstream of academic medicine
ultimately have been destructive to the defibrillator
when he decided to invent the ICD.
project: “An imperfect solution in search of a
Maron et al
JACC VOL. 82, NO. 4, 2023
JULY 25, 2023:353–373
Development of the Implantable Defibrillator
plausible and practical application” because there is
F I G U R E 1 The Inventors of the ICD at Sinai Hospital (Baltimore, 1970)
“no evidence that a single bout of VF is likely to
recur.” There was also concern for possible “electrocution” and belief that ventricular fibrillation (VF)
survivors would be better served by coronary care
units and antiarrhythmic drugs, ultimately shown to
be inferior to ICD therapy. Others considered the ICD
to be a “time bomb in the chest.”
However, Arthur Moss, (University of Rochester),
himself a visionary, in a counterletter to Circulation
vehemently defended the ICD against prejudgment 7
and later would bring ICDs to randomized controlled
trials (RCT). The Lown and Axelrod editorial therefore
established an uneven controversy between the cardiology establishment and investigators working for
the very first years in relative isolation and anonymity with limited national professional and public
visibility.
At this time, other obstacles emerged. Medtronic,
Pioneers Michel Mirowski (right) and Morton Mower (left) began with a vision but with
as a potential suitor, rejected the ICD, considering it
little in terms of resources, support from their colleagues, or personal academic visibility.
impractical, with no interest in acquiring the Mir-
Their research association occurred largely by chance after Mirowski emigrated from Israel
owski patent (eventually issued to Eli Lilly). The Na-
to Baltimore.
tional
Institutes
of
Health
(NIH)
intramural
cardiology program in nearby Bethesda, Maryland,
rejected a proposal from Mirowski for collaboration.
Three highly selected patients (the first from cardi-
In retrospect, this was a low point for the ICD project.
ologist Roger Winkle of Stanford), 16, 43, and 57 years
Nevertheless, work at Sinai on the defibrillator
of age, met the particularly stringent U.S. Food and
persevered. In 1973, Mirowski and Mower showed for
Drug Administration (FDA) requirement of having
the first time that induced VF could be successfully
survived 2 prior cardiac arrests, reflecting hesitancy
terminated with a transvenous catheter (80% of pa-
of the agency toward ICD treatment; of the 3 patients,
tients) in the operating room during coronary artery
remarkably 2 had HCM and only 1 had prior myocar-
bypass grafting surgery and anoxic arrest.2 This was
dial infarction (MI).
their first Circulation paper,2 although Mirowski was
After thoracotomy, a 250-g defibrillator connected
hesitant to submit papers to establishment journals as
to
an unknown immigrant investigator fearing vigorous
induced VF was reliably terminated automatically
opposition in the review process (B.J. Maron, Lahey
(with a long detection interval of 30 seconds) a total
Hospital and Medical Center, personal communica-
of 7 times. It took another 5 years to further assemble
tion, May 1, 1973).
data, secure FDA approval, and release ICDs to market
A 1978 paper reported that prototype ICDs per-
epicardial
patch
electrodes
was
implanted;
(16 years after work began at Sinai).
formed reliably in 5 conscious dogs (also published in
The second pivotal advance came with imple-
Circulation),3 creating considerable visibility for the
mentation of the transvenous endocardial lead sys-
practicality of ICDs; however, it also generated attacks
tem; although initially envisioned by Mirowski, it
by animal rights activists (Figure 2). When real-time
nevertheless took many years to develop (1984-1993),
movie footage of the dogs shocked for induced VF
ultimately eliminating the requirement for thoracot-
was presented at a national cardiology meeting, it was
omy with epicardial patch electrodes and allowing for
met with not only excitement, but also skepticism.
subcutaneous
Remarkably, some critics accused Mirowski of training
generator. Only then did ICDs, initially considered a
the animals to behave due to classical Pavlovian con-
last resort, become a worldwide primary prevention
ditioning, when in fact simultaneously recorded ECGs
treatment.
confirmed that ICD shocks were responsible for ter-
occurred at the time of an emerging appreciation that
minating VF and the actions of the dogs.
SCD and out-of-hospital cardiac arrest represented a
pectoral
Fortuitously,
placement
the
of
Sinai-ICD
the
pulse
initiative
On February 4, 1980, the pivotal clinical experi-
major public health problem, that defibrillation was
ment in man on which the future of the ICD likely
life-saving, and that antiarrhythmic drugs were
rested was conducted at Johns Hopkins Hospital.4
ineffective.
355
356
Maron et al
JACC VOL. 82, NO. 4, 2023
JULY 25, 2023:353–373
Development of the Implantable Defibrillator
C E NT R AL IL L U STR AT IO N Timeline of Highlights in Evolution of the Implantable Cardioverter-Defibrillator
Maron BJ, et al. J Am Coll Cardiol. 2023;82(4):353–373.
The data denote landmark events in the creation and maturation of the implantable cardioverter-defibrillator (ICD) from 1969 initiated by the vision of Drs Mirowski
and Mower and further advanced by Drs Bardy, Moss, Winkle, Zipes, and others. ATP ¼ antitachycardia pacing; AVID ¼ Antiarrhythmics Versus Implantable Defibrillators; FDA ¼ U.S. Food and Drug Administration; MADIT ¼ Multicenter Automatic Defibrillator Implantation Trial; MUSTT ¼ Multicenter Unsustained Tachycardia
Trial; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure.
Accelerated marketing and sales of ICDs occurred
before the transition to RCTs. Morton Mower, the
after the 1985 FDA approval with a growth rate
co-inventor, died in 2022, at 89 years of age, hav-
enhanced further by the RCTs beginning with AVID
ing witnessed the expansive clinical story of the
(Antiarrhythmics Versus Implantable Defibrillators)
device that he had a major role in building.
and MADIT (Multicenter Automatic Defibrillator Implantation Trial) (from 1996) and also with the penetration
of
ICD
data
into
societal
guidelines.
Acceptance and implementation was generally slower
in Europe compared with the United States (initially
by a factor of 4-5 times) and also differed among
European countries, with interest greatest in Italy,
Germany, and the Netherlands. The reasons for faster
growth in the United States were largely related to
greater numbers of electrophysiologists and centers,
differences in referral strategies, and certain cultural
and cost factors.8 Ultimately, the growth rate for ICDs
in Europe was driven by several cardiologists, but
namely John Camm, Seah Nisam, and Philippe
Coumel.
INDICATIONS FOR ICD IMPLANTATION
ICDs were initially conceived and approved as a
rescue therapy for survivors of unstable ventricular
arrhythmias. By 1983, a multicenter report of the
initial ICD experience showed the device to be clinically effective, with one-third of 52 patients experiencing successful therapy within about 1 year,
resulting in much lower 1-year mortality (23%)
than predicted without an ICD.9 While this convinced
many of the validity of the ICD concept, others argued
for RCTs to define the role of ICDs in clinical practice
more credibly.10
ICD CLINICAL TRIALS. From the early 1980s to mid-
Michel Mirowski died too soon, in 1990, at 65
1990s, a series of technical advances made ICDs
years of age, of multiple myeloma, 21 years after
smaller, more reliable, and markedly safer and easier
the defibrillator project began, but only 10 years
to implant (see Specific ICD Advances). What ensued
from the first implantations, and notably 6 years
was a decade of important prospective RCTs. Table 2
Maron et al
JACC VOL. 82, NO. 4, 2023
JULY 25, 2023:353–373
Development of the Implantable Defibrillator
T A B L E 1 Timeline of Key Events in Development of the ICD
Year
Event
1966
Mirowski mentor Dr Harry Heller dies of a sudden arrhythmic event, creating his vision of the ICD
1969
Mirowski/Mower begin collaboration at Sinai Hospital (Baltimore)
1971
Mirowski/Mower obtain patent for ICD
1972
Lown opposition editorial (Circulation)6
1972
Moss rebuttal to Lown (Circulation)7
1972-1977
Preclinical testing; optimize design; sensitivity detection algorithm; stored memory function; early efforts at commercializing the
system
1972
No interest expressed by Medtronic for supporting ICD project or patent
1972
Affiliation with MedRad; biomedical engineering and miniaturized electronic circuits
1973
NIH intramural (cardiology) program rejected Mirowski for collaboration with no interest
1973
First transvenous (low energy) defibrillation in setting of cardiac surgery (Mirowski/Mower; Circulation)2
1978-1981
ICD chronically implanted in dogs
1980
First permanent implants in 3 patients demonstrating automatic termination of induced VF, at Johns Hopkins Hospital (epicardial
patch lead system); (New England Journal of Medicine)4
1982
Low energy transvenous cardioversion of VT (Doug Zipes)
1982
First ICD implants in Europe; Seah Nisam (INTEC); Philippe Coumel (Paris); John Camm (St. George’s Hospital, London)
1984
First implant of permanent transvenous lead for low energy cardioversion (Zipes; Prystowsky; Saksena; Parsonnet)
1985
Formal FDA approval for ICD and market release
1986
Medicare reimbursement approval
1985-1990
Number of implants accelerates; mass production underway
1990-1993
Antitachycardia/bradycardia pacing; improved detection algorithm; biphasic waveform; stored memory function
1990
Mirowski dies (age 65 y)
1993
First transvenous endocardial pace/sense/defibrillation lead system introduced with FDA approval, allowing for primary
prevention
1994
Eli Lilly relinquished ICD division
1996
Era of prospective, multicenter, randomized trials begins (duration 10 y). ICD vs antiarrhythmic drugs (eg, amiodarone);
MADIT I (primary prevention without prior cardiac arrest in ischemic heart disease and proof of concept); Arthur Moss
1997
AVID trial (secondary prevention in survivors of cardiac arrest) (Zipes)
2000
ICD introduced to HCM and genetic heart diseases (New England Journal of Medicine)35 supported by Medtronic followed by
>20 year program; BJ Maron; MS Maron (Lahey Hospital and Medical Center)
2000
MUSTT trial (Alfred Buxton; Beth Israel-Deaconess, Boston)
2002
MADIT II (primary prevention and risk stratification); Arthur Moss
2002
First CRT-D devices with FDA approval
2005
SCD-HeFT, ischemic and nonischemic disease (Gust Bardy)
2005
“Guidant Affair”: Sudden death of young HCM patient with mechanically defective ICD triggers revelations of improper
communication between industry and practicing community/patients
2006
Boston Scientific acquires Guidant (and ICD)
2009
MADIT-CRT (Arthur Moss, Wojciech Zareba; Helmut Klein; James Daubert; Ilan Goldenberg)
2010
Subcutaneous ICD introduced (Gust Bardy)
2007-2011
Lead recalls: Sprint Fidelis; Riata
2021
ICDs in at least 60 countries; estimated 1.5 million devices in United States; countless lives saved and/or extended worldwide
AVID ¼ Antiarrhythmics Versus Implantable Defibrillators; FDA ¼ U.S. Food and Drug Administration; HCM ¼ hypertrophic cardiomyopathy; ICD ¼ implantable cardioverterdefibrillator; NIH ¼ national Institutes of Health; MADIT ¼ Multicenter Automatic Defibrillator Implantation Trial; MUSTT ¼ Multicenter Unsustained Tachycardia Trial; SCDHeFT ¼ Sudden Cardiac Death in Heart Failure; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
summarizes 11 RCTs involving almost 10,000 patients
S e c o n d a r y p r e v e n t i o n . Early epicardial ICDs were
recruited at a large number of centers in multiple
approved for use only in cardiac arrest survivors,
countries, published 1996 to 2005. Ultimately, these
without randomized evidence. While many clinicians
11 trials would provide lasting direction on 3 major
were already convinced of ICD efficacy, 11 procedural
issues: the safety and effectiveness of ICDs for sec-
risk
ondary and primary SCD prevention and survival
regarding the incremental value of ICDs compared
(reported as reduced total mortality, and also selec-
with antiarrhythmic drugs (particularly amiodarone)
tively as decreased arrhythmic death), the lack of
in survivors of cardiac arrest or unstable ventricular
effectiveness of conventional antiarrhythmic drugs,
tachycardia (VT).
and the value and limitations of risk stratification for
selecting ICD recipients (Figure 3).
was
not trivial and
uncertainty remained
With only the available epicardial systems, secondary prevention RCTs were initiated in Germany in
357
358
Maron et al
JACC VOL. 82, NO. 4, 2023
JULY 25, 2023:353–373
Development of the Implantable Defibrillator
F I G U R E 2 An Early Animal Experiment With Chronically Implanted ICDs
In this experiment, the inventors were able to demonstrate (A, B) defibrillation of a dog, (C) loss of consciousness in ventricular fibrillation
when (D) shocked by the implantable defibrillator and (E, F) recovering. This animal model was used as key evidence supporting the
feasibility of implantable cardioverter-defibrillator (ICD) performance with chronic device implantation and part of the reason the ICD could
move forward to Food and Drug Administration approval. Reproduced with permission from Kastor.5
1987 (CASH [Cardiac Arrest Study Hamburg]) 12 and
ethical dilemma arose for clinical investigators in
Canada in 1990 (CIDS [Canadian Implantable Defi-
secondary
13
prevention
trials, 12
some
of
whom
Enrollment proved difficult. CIDS
(including Mirowski and Mower) were opposed to
took over 6 years to enroll 659 patients, while CASH
randomization in the first place. 11,14 Nonetheless, the
recruited only 288 patients over 9 years. Both trials
central question of whether ICDs could reduce all-
were published in 2000 after findings from AVID were
cause mortality, in addition to SCD, remained unan-
released. Both CASH and CIDS showed a trend toward
swered,
improved survival with ICDs that fell short of statis-
continued research and clinical trials. 10
brillator Study]).
tical significance, albeit underpowered.
As
CASH
and
CIDS
enrolled
patients,
providing
a
compelling
argument
for
AVID ultimately settled these issues, cementing
safer
the role of ICDs for secondary prevention. 15 With NIH
nonthoracotomy systems appropriate for primary
funding,
prevention became available. With this, a potential
Douglas Zipes, and support from master clinicians
leadership
from
principal
investigator
Maron et al
JACC VOL. 82, NO. 4, 2023
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359
Development of the Implantable Defibrillator
T A B L E 2 Major Prospective Randomized Trials of ICD Therapy, 1996 to 2005
NYHA
Male
EF
Functional
(%) Cutoff (%) Class
Year
N
Mean
Age (y)
AVID15
1997
1,016
65
80
None
CIDS13
2000
328
64
85
CASH12
2000
349
58
MADIT19
1996
196
CABG-Patch16
1997
MUSTT20
Study
Risk Stratifier
Comparator
Follow-Up
Duration
All
N/A
Amiodarone or sotalol
3y
ICD Y total mortality by 31%
(P < 0.02)
None
All
N/A
Amiodarone
3y
ICD Y total mortality by 19.7%
(P ¼ 0.14)
80
None
All
N/A
Amiodarone, metoprolol, or
propafenone
$2 y
ICD Y total mortality by 28.3%
at 3 y
HR: 0.76 (P ¼ 0.08)
63
94
#35
I-III
NSVTþEPS
MedRx (74% amiodarone)
27 mo
ICD Y mortality
HR: 0.46 (P ¼ 0.009)
900
63
84
#35
All
SAECG
CABGþMedRx
32 $16 mo
No survival difference
HR: 1.07 (P ¼ 064)
Result
Secondary
prevention
trials
Primary
prevention
trials
1999
702
66
90
#40
All
NSVTþEPS
MedRx (vs “EP-guided” Rx)
39 mo
(median)
ICD Y mortality with
“EP-guided”
23
MADIT II
2002
1,232
64
84
#30
II-III
PVCs
MedRx (no AAD)
20 mo
ICD Y mortality
HR: 0.69 (P ¼ 0.016)
DEFINITE30
2004
458
58
70
#35
I-III
PVCs or NSVT
MedRx
29 mo
Mortality
HR: 0.65 (P ¼ 0.08)
DINAMIT17
2004
674
62
76
#35
I-III
Y HRV
MedRx
30 mo
Mortality
HR: 1.08 (P ¼ 0.66)
COMPANION26 2004
1,520
67
67
#35
III/IV
16 mo
Both CRT-P and CRT-D Y
mortality vs MedRx
SCD-HeFT25
2,521
60
77
#35
II/III
45 mo
(median)
ICD vs placebo
HR: 0.77 (P ¼ 0.007)
Amiodarone vs placebo
HR: 1.06 (P ¼ 0.53)
2005
QRS duration >120 ms; CRT-D vs CRT-P vs MedRx
HF admission
No others
ICD vs amiodarone vs
placebo
A downward arrow (Y) indicates a decrease.
AAD ¼ antiarrhythmic drug; CABG ¼ coronary artery bypass grafting; CABG-Patch ¼ Coronary Artery Bypass Graft Patch; CASH ¼ Cardiac Arrest Study Hamburg; CIDS ¼ Canadian Implantable Defibrillator
Study; COMPANION ¼ Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure; CRT ¼ cardiac resynchronization therapy; CRT-D ¼ cardiac resynchronization therapy with defibrillator; CRT-P ¼ cardiac resynchronization therapy with pacemaker; DEFINITE ¼ Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation; DINAMIT ¼ Defibrillator in Acute Myocardial Infarction;
EF ¼ ejection fraction; EP ¼ electrophysiologic; EPS ¼ electrophysiology study; HF ¼ heart failure; HRV ¼ heart rate variability; MedRx ¼ medical treatment; N/A ¼ not available; NSVT ¼ nonsustained
ventricular tachycardia; PVC ¼ premature ventricular contraction; Rx ¼ treatment; SAECG ¼ signal-averaged electrocardiogram; other abbreviations as in Table 1.
and early supporters such as David Cannom, AVID
history of cardiac arrest or unstable VT. Five were
enrolled 1,016 patients between 1993 and 1997. The
positive by conventional statistical standards, in
study ended when interim analysis met a predefined
aggregate proving benefit for prophylactic ICDs in a
statistical stopping rule, with ICDs reducing total
widening patient population.
mortality by 31%. A meta-analysis of CASH and CIDS
The only negative trials in patients with ischemic
combined with AVID subsequently reported consis-
heart disease were CABG-Patch (Coronary Artery
tent treatment effects from ICDs across the 3 second-
Bypass Graft Patch) and DINAMIT (Defibrillator in
ary prevention trials. 16
Acute Myocardial Infarction). CABG-Patch random-
These observations represented a major threshold
ized patients with reduced left ventricular ejection
for the ICD in changing clinical practice (Figure 3).
fraction (LVEF) and severe coronary artery disease
Any lingering uncertainty regarding the relevant
(CAD) to placement of epicardial ICDs vs medical
role of ICDs for secondary prevention, to terminate
therapy at coronary artery bypass. 16 The negative
life-threatening arrhythmias and enhance survival
result was attributed to a protective effect from cor-
with superiority vs antiarrhythmic drugs (as well
onary revascularization. DINAMIT randomized pa-
as VT ablation), would no longer be seriously
tients with recent (6-40 days) MI 17 with its findings
entertained.
later replicated in a similar RCT, IRIS (Immediate Risk
P r i m a r y p r e v e n t i o n . Table 2 and Figure 3 include
Stratification Improves Survival).18
8 RCTs assessing the capability of ICDs to reduce total
The primary prevention ICD era began in earnest
mortality (and arrhythmic risk) for at-risk patients
with the completion of Arthur Moss’ 1996 Cardiac
with systolic dysfunction but without a preceding
Pacemakers Inc (CPI)/Guidant-funded MADIT19 and
Maron et al
360
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JULY 25, 2023:353–373
Development of the Implantable Defibrillator
F I G U R E 3 Prospective Randomized Clinical ICD Trials for Primary or Secondary Prevention of Sudden Death
B
Proportion Surviving
1.0
1.0
Defibrillator group
Probability of Survival
A
0.8
Antiarrhythmic-drug group
0.6
0.4
0.2
AVID
0.0
0.8
Defibrillator
0.6
Conventional
therapy
0.4
0.2
MADIT I
0.0
0
1
2
3
0
1
2
Years After Randomization
Patients at risk 1,016
644
333
104
4
89.3
81.6
75.4
Antiarrhythmic-drug group 82.3
74.7
64.1
Defibrillator
C
95
80
53
31
17
3
Conventional 101
therapy
67
48
29
17
0
D
HR
(97.5% CI)
0.4
Defibrillator
Mortality Rate
Probability of Survival
1.0
0.9
0.8
Conventional
0.7
0.6
5
No. of patients
Percent surviving
Defibrillator group
3
Year
1.06 (0.86-1.30)
0.53
ICD therapy vs placebo
0.77 (0.62-0.96)
0.007
Placebo
(244 deaths; 5-y event
rate, 0.361)
Amiodarone
(240 deaths; 5-y event rate, 0.340)
0.3
P Value
Amiodarone vs placebo
ICD therapy
(182 deaths; 5-y event
rate, 0.289)
0.2
0.1
MADIT II
SCD-HeFT
0.0
0.0
0
1
2
3
4
0
12
Year
24
36
48
60
Months of Follow-Up
No. at risk
No. at risk
Defibrillator
742
503 (0.91) 274 (0.84) 110 (0.78)
9
Amiodarone
845
772
715
484
280
97
Conventional
490
329 (0.90) 170 (0.78)
3
Placebo
847
797
724
505
304
89
ICD therapy
829
778
733
501
304
103
65 (0.69)
Patients enrolled were primarily those with ischemic (coronary) heart disease, systolic dysfunction, and prior myocardial infarction, although SCD-HeFT (Sudden Cardiac
Death in Heart Failure) included patients with nonischemic cardiomyopathy. These data were subsequently incorporated into societal guidelines and state-of-the-art
reviews and consequently translated into clinical practice. (A) AVID (Antiarrhythmics Versus Implantable Defibrillators); (B) MADIT (Multicenter Automatic Defibrillator
Implantation Trial) I; (C) MADIT II; (D) SCD-HeFT. ICD ¼ implantable cardioverter-defibrillator.
was subsequently reinforced by the results of Al
antiarrhythmic drugs were continued if inducibility
Buxton’s
(Multicenter
was suppressed, with ICDs reserved only for drug
Unsustained Tachycardia Trial). 20 MADIT and MUSTT
failures. Both trials demonstrated very large re-
both enrolled patients with prior MI, reduced LVEF
ductions in all-cause mortality in their experimental
(#35% and #40%, respectively), nonsustained VT,
arms. In MUSTT, the benefit of EP-guided therapy
1999
NIH-funded
MUSTT
and inducible VT at electrophysiologic (EP) study,
was entirely confined to the group treated with
providing important information about risk stratifi-
ICDs. 20
cation methods. MADIT randomized patients not
Taken together, MADIT and MUSTT confirmed the
suppressible with procainamide to ICD or standard
high SCD risk of the post-MI population and the great
medical therapy, usually (74%) amiodarone. MUSTT
potential of ICDs to improve total mortality relative to
randomized inducible patients to standard medical
antiarrhythmic drugs, which appeared wholly inef-
treatment,
or
“EP-guided
therapy,”
whereby
fective. Therefore, by the late 1990s a role for primary
Maron et al
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JULY 25, 2023:353–373
Development of the Implantable Defibrillator
prevention ICDs was emerging, but only for patients
heart failure, reduced EF, and atrioventricular con-
meeting MADIT or MUSTT criteria. Subsequent trials
duction abnormalities (left bundle branch block).
simplified patient selection by eliminating EP testing
Given the extensive overlap in the eligibility criteria
supported by analyses of MUSTT patients who expe-
for CRT and primary prevention ICDs, most CRT im-
rienced a 24% rate of cardiac arrest or arrhythmic
plants, at least in the United States, would become
death at 5 years (31% in those with an LVEF 2,000 consecutive HCM
much the data initially assembled in Minneapolis and
patients in a “real-world” clinical setting (Figure 4).
Boston (B.J.M., M.S.M., and colleagues).35-51 The ICD
Patients selected for ICDs with $1 major AHA/ACC
stands as the only available treatment option capable
markers (associated with physician judgment and
of reliably preventing SD in HCM, as pharmacologic
shared decision making) experienced appropriate
strategies have been abandoned as ineffective.
therapy with 95% sensitivity for predicting SCD
As in all the inherite
