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Chapter 3 / Prevention of Sudden Cardiac Death

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Prevention of Sudden Cardiac Death


Joseph E. Marine, MD
CONTENTS
INTRODUCTION
CORONARY ARTERY DISEASE
DILATED CARDIOMYOPATHY
OTHER FORMS OF CARDIOMYOPATHY
FUTURE DIRECTIONS
REFERENCES

INTRODUCTION
Since the 1960s, important advances have been made in resuscitation of patients from
sudden cardiac death (SCD). Despite these advances, rates of survival to hospital discharge range from only 2 to 30% (generally 510%); rates of survival with intact neurological status are even lower (1). Approximately 400,000 out-of-hospital sudden deaths
occur in the United States each year (2). These grim statistics point to the importance of
prevention in approaching the problem of SCD from a public health standpoint.
It has been estimated that one-half to two-thirds of out-of-hospital sudden death is
caused by ventricular arrhythmias (VA) (ventricular tachycardia [VT] and ventricular
fibrillation [VF]) (3). Bradyarrhythmias, such as complete atrioventricular block and
asystole, are a less frequent cause of arrhythmic sudden death. A substantial minority of
cases of apparent SCD may be because of nonarrhythmic causes, such as massive pulmonary embolus, ruptured aortic aneurysm or dissection, or stroke (4). Because most research
into prevention of SCD has focused on VA, this subject will form the basis for this chapter.
Preventive strategies will be considered according to the etiology of cardiac disease.

CORONARY ARTERY DISEASE


Coronary artery disease (CAD) is the leading cause of death in Western countries and
the most common cardiac substrate for SCD. It is now recognized that CAD is a systemic
disease of the cardiovascular system that is often far advanced by the time it is clinically
manifest. The first signs of atheroma formation may begin in adolescence. As CAD
progresses, atheromas may encroach on the coronary artery lumen, causing flow-limiting
stenosis. At this stage, patients may develop ischemia in the absence of infarction, often
with exertion or stress. Ischemia in turn may lead to arrhythmias, particularly polymorphic VT and VF. Ischemic VA may also occur in the absence of significant atherosclerosis, usually associated with coronary artery spasm or congenital coronary anomalies.
From: Contemporary Cardiology: Cardiopulmonary Resuscitation
Edited by: J. P. Ornato and M. A. Peberdy Humana Press Inc., Totowa, NJ

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Coronary atherosclerotic plaques of any size may rupture, triggering platelet adhesion,
thrombus formation, and acute myocardial infarction (AMI). Serious VAs, especially
VFs, are common in this setting, and they account for a substantial proportion of deaths
from AMI, particularly in the prehospital setting. Later in the course of infarction, the
infarct zone undergoes cellular and tissue remodeling with the laying of collagen scar and
ventricular dilatation. This process creates the anatomic substrate for future VAs, particular sustained monomorphic VT.

Primary Prevention of CAD


Approximately 12.6 million people in the United States have CAD and about 1 million
suffer AMIs annually (2). Given the scope of the problem, effective primary prevention
of CAD could have a substantial impact on prevention of SCD. Particularly important is
changing modifiable risk factors, especially cigarette smoking, dyslipidemia, atherogenic diet, obesity, and physical inactivity (5). Optimal control of predisposing medical
conditions, such as systemic hypertension and diabetes mellitus, may also reduce the
incidence of coronary disease and related SCD. Hopefully, improved public education
regarding primary prevention of CAD will ultimately translate into reduction of SCD
rates as well as CAD incidence.
There is evidence that improvements in treatment of AMI are also reducing rates of
SCD. Both fibrinolytic therapy and primary percutaneous coronary intervention reduce
all-cause mortality as well as SCD. Moreover, by reducing infarct size, acute
revascularization in AMI likely reduces late risk of SCD by modifying the substrate for
arrhythmogenesis. Modification of the arrhythmic substrate may also account for some
of the mortality benefit of angiotensin-converting enzyme (ACE) inhibitors in treatment
of AMI. The Coronary Artery Surgery Study showed that coronary artery bypass grafting
(CABG) leads to improved survival in selected high-risk patients with CAD. Further
analysis of this trial has shown reduction in SCD in high-risk patients who underwent
surgery (6).

Medical Therapy for Prevention of SCD After Myocardial Infarction


Table 1 summarizes the outcomes of nine large trials of antiarrhythmic therapy after
AMI. Probably the most important aspect of medical treatment of AMI survivors for
prevention of SCD is `-blocker therapy. These agents block the `-1 adrenergic receptor
in the heart, blunting the pro-arrhythmic effects of the sympathetic nervous system and
circulating cathecholamines, and reducing myocardial oxygen consumption and ischemia.
In addition to reducing incidence of late coronary events, `-blockers have been shown in
several trials to reduce all-cause mortality as well as life-threatening VAs (710). The
antiarrhythmic action of `-blockers was also demonstrated in a recent small trial, which
showed that sympathetic blockade was superior to standard antiarrhythmic drugs for
treatment of recurrent VF in AMI (11).
Prospective observational studies published in the early 1980s established that frequent isolated ventricular premature contractions and nonsustained VT are markers of
increased mortality risk after MI, particularly in patients with left ventricular (LV) systolic dysfunction (12). Further studies showed that type I antiarrhythmic drugs effectively suppressed these VAs in this setting, leading to the organization of the Cardiac
Arrhythmia Suppression Trial (CAST). Publication of the results of this trial, which
showed a doubling of mortality rates in patients receiving flecainide, encainide, or

Chapter 3 / Prevention of Sudden Cardiac Death

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Table 1. Randomized Trials of Anti-Arrhythmic Medications After MI


Trial
BHAT (7)
ISIS-1 (8)
CAPRICORN (9)
CAST-I (13)
CAST-II (14)
SWORD (15)
DIAMOND (16)
EMIAT (19)
CAMIAT (20)

Year of publication
1981
1986
2001
1989, 1991
1992
1996
2000
1997
1997

Result
Improved survival with propranolol
Improved survival with atenolol
Improved survival with carvedilol
Increased mortality with flecainide or encainide
Increased mortality with moricizine
Increased mortality with D-sotalol
No effect of dofetilide on mortality
No effect of amiodarone on mortality
No effect of amiodarone on mortality

moricizine, led to a re-examination of the use of these agents in patients with CAD and
other forms of structural heart disease (13,14). There is now general agreement that type
I antiarrhythmic drugs, particularly type Ic agents, should be avoided in patients with
CAD because of the pro-arrhythmic effects demonstrated in CAST.
A similar increased risk of death was seen in a trial of the class III antiarrhythmic D-sotalol
in postinfarction patients (15). The Survival With Oral D-Sotalol trial recruited 3121 patients
with LV ejection fraction (EF) of 0.40 or less and prior MI. Patients were randomly
assigned to long-term treatment with D -sotalol (a pure type III anti-arrhythmic agent with
no `-blocking activity) or matching placebo. After a mean follow-up period of 150 days
and halfway into recruitment, the trial was stopped early because of a 65% increased
relative risk of mortality in the D -sotalol treatment arm (5 vs 3.1% in placebo group, p = 0.006).
The excess mortality was felt to be because of an increase in arrhythmic deaths.
In contrast, a large trial of dofetilide, another pure class III antiarrhythmic drug, found
no increase in mortality on survivors of MI (16). The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group randomized 1510 patients
with recent MI and LVEF of 0.35 or less to treatment with dofetilide (dose based on
creatinine clearance) or matching placebo. After a median follow-up of 456 days, mortality was nearly identical in the two groups (31 vs 32%, respectively, p = 0.61).
Amiodarone, a unique antiarrhythmic drug that exhibits actions of all four VaughnWilliams drug classes, was originally developed as an anti-anginal medication. On the
basis of its efficacy in the treatment of recurrent VA and its safety compared with other
antiarrhythmic drugs in survivors of cardiac arrest (CA), two large trials were organized
to test its efficacy in high-risk survivors of AMI (17,18). The European Myocardial
Infarction Amiodarone Trial (EMIAT) enrolled 1486 patients 5 or more days after MI
only on the basis of depressed LVEF of 0.40 or less (19). Patients were treated with
amiodarone (200 mg per day after loading) or placebo. After a median follow-up period
of 21 months, overall mortality was identical in the two groups (14% in each, p = 0.96).
The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) studied 1202 patients enrolled 642 days after AMI, who had frequent ventricular premature
contractions or nonsustained VT; LV systolic dysfunction was not required for entry into
the trial (20). Patients were treated with amiodarone (200 mg per day after loading) or
placebo and followed for a mean of 1.8 years. No significant difference in overall mortality was found (9.4% in the amiodarone group vs 11.4% in the placebo group, p = 0.129).

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Both EMIAT and CAMIAT did find a reduction in death ascribed to arrhythmia, but the
significance of this finding in the absence of overall mortality benefit has been questioned. A posthoc analysis of both trials suggested a possible synergistic benefit of
amiodarone and `-blockers, but this remains to be demonstrated prospectively.
In summary, proven medical therapy for primary prevention of sudden death in
patients with CAD is limited to `-blocker use. Type I antiarrhythmic drugs and D-sotalol
have been shown to be harmful in this population. Amiodarone and dofetilide had a
neutral effect on all-cause mortality and are relatively safe to use for treatment of symptomatic arrhythmias in patients with CAD.

Role of the Implantable Cardioverter Defibrillator in CAD


The implantable cardioverter defibrillator (ICD) has had a major impact on clinical
approach to prevention of SCD. Conceived by Morton Mower and Michel Mirowski and
introduced after a decade of preclinical development, the ICD was first used in humans
in the late 1970s (21). Implantation initially required thoracotomy to place epicardial
patches and rate-sensing electrodes. First generations of pulse generators were large
(>250 g) and required implantation in an abdominal pocket. Pacing function and programmability were extremely limited. Rapid evolution of the ICD ensued, leading to a
succession of improved lead systems and smaller generators with greater functionality (22).
Current ICD systems can be implanted transvenously via subclavian or cephalic vein
access, similar to pacemakers, using a single 810 French lead and a pectorally implanted
generator as small as 75 g. They are capable of all bradycardia-pacing functions, including, with addition of one or more leads, dual-chamber and biventricular pacing. They are
also capable of detecting arrhythmias in several different programmable rate zones and
delivering a different series of programmable therapies for each zone (Fig. 1). They have
capacity to store large amounts of information regarding each arrhythmia episode for
later analysis. Finally, they incorporate increasingly sophisticated algorithms for distinguishing supraventricular from VAs.
ICDs detect VAs from the tip electrode of the lead, usually implanted at the right
ventricular apex. When a ventricular rate is detected that exceeds the programmed
detection rate (usually 150200 beats per minute [bpm]) for the programmed number of
beats (usually 1020), the ICD begins charging the capacitors. This generally takes
between 1 and 5 seconds, after which the device confirms continuation of tachycardia
before delivering the programmed energy (anywhere from 140 J) between the metal
shell of the generator and one or more coils on the ICD lead (Fig. 2A). The ICD then
re-analyzes the ventricular rate to determine if therapy was successful. If the rate has not
fallen below the arrhythmia detection limit, the ICD proceeds to deliver the next therapy.
This process continues until the arrhythmia is terminated or all programmed therapies
(usually a maximum of six to eight) are exhausted.
In addition to delivering shock therapies, ICDs may be programmed to deliver sequences
of antitachycardia pacing (ATP), usually 812 beats, to terminate sustained monomorphic
(regular) VT (Fig. 2B). This therapy has the advantage of being delivered more rapidly
and being entirely painless. Potential disadvantages of ATP include possibility of accelerating the tachycardia to a more unstable type and delaying delivery of shock therapy
if ATP is unsuccessful. ATP is not useful for treating VF or polymorphic VT.
When first released for clinical use in the early 1980s, ICDs were targeted toward
patients who had survived multiple CAs with recurrent VAs that were refractory to
conventional anti-arrhythmic drug treatment. As the design of ICDs improved over the

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Fig. 1. Tiered therapy of VAs by the ICD. The figure shows stored single-channel telemetry strip
during an episode of ventricular tachyarrhythmia in a patient with an implantable cardioverter
defibrillator who was hospitalized. A ventricular premature beat initiates sustained monomorphic ventricular tachycardia (VT 1). Four cycles of antitachycardia pacing (ATP 1-4) fail to
terminate the arrhythmia. A low-energy cardioversion (CV 1) results in a different morphology
of monomorphic VT (VT 2). A second low-energy cardioversion (CV 2) results in polymorphic
VT (PVT). After the first high-energy defibrillation (DF 1), the rhythm degenerates into ventricular fibrillation (VF). A second high-energy defibrillation (DF 2), results in restoration of
sinus rhythm.

next decade, and the limitations of anti-arrhythmic drugs were exposed through randomized clinical trials, the ICD gained increasing favor for treatment of CA survivors. In this
setting, several clinical trials were organized to test the efficacy of the ICD in secondary
prevention (for patients who had survived a sustained life-threatening VA) and primary
prevention (for high-risk patients without history of sustained arrhythmia) of SCD
(Tables 2 and 3).
ICD FOR SECONDARY PREVENTION IN CAD
The first published trial comparing the ICD and conventional medical therapy for
secondary prevention of SCD was the Anti-arrhythmics Versus Implantable Defibrillator
(AVID) trial (23). This National Institutes of Health (NIH)-sponsored multicenter study
enrolled 1016 patients in 56 North American centers who were resuscitated from VF or
sustained VT between 1993 and 1997. The mean age of enrolled patients was 65 years
and the mean LVEF was 0.32. Eighty-one percent of patients had CAD and 67% had a
history of MI. Patients were randomly assigned to receive an ICD or to treatment with
anti-arrhythmic drug therapy, predominantly amiodarone (96% of assigned patients).
Over a mean follow-up period of 18 months, 122 of 509 patients (24%) in the antiarrhythmic drug therapy group died vs only 80 of 507 patients (16%) assigned to receive
an ICD. This difference corresponds to a 33% relative risk reduction and an 8% absolute
risk reduction in total mortality in favor of the ICD (p < 0.02). Of note, this treatment
effect was demonstrated despite a significant crossover to ICD therapy in the drug therapy
arm, reaching 25% at 3 years.

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Fig. 2. Treatment of different ventricular arrhythmias in the same patients with an implantable
cardioverter defibrillator (ICD). The figure shows stored internal electrograms and marker channels of two episodes of sustained monomorphic ventricular arrhythmia in a 38-year-old man with
cardiac sarcoidosis. The first event shown in A is an episode of ventricular fibrillation that was
successfully treated with a single 20-J internal defibrillation by the ICD, restoring the patient to
sinus rhythm. The second event shown in B is an episode of sustained monomorphic ventricular
tachycardia with a rate of 200 bpm successfully treated with a single sequence of 8 beats of antitachycardia pacing.

Strengths of the AVID trial include its relatively large size, NIH sponsorship, and its
use of total mortality as an unambiguous and unquestionably important primary endpoint. Because the trial included only a small proportion of patients without CAD, it is
difficult to draw conclusions about benefit of ICD in other subgroups. No placebo group
was used, raising the question of whether the some of the apparent benefit of the ICD was
because of a detrimental effect of amiodarone; other trials, however, have demonstrated
the safety of amiodarone in patients with structural heart disease. Finally, `-blocker use
was much greater in the ICD arm (about 40%) compared to the drug therapy arm (10
15%), probably because of the bradycardic effects of amiodarone; this discrepancy might
account for some of the apparent benefit of the ICD. Despite these criticisms, the AVID
trial has led to the ICD becoming the treatment of choice for survivors of CA without
contraindications to its use.
Two smaller trials of ICD therapy in secondary prevention of SCD have been reported
since the AVID trial was published. The first, the Canadian Implantable Defibrillator
Study (CIDS), enrolled 659 patients with an episode of unstable sustained VA in 24
centers in Canada, Australia, and the United States between 1990 and 1997 (24). Baseline
patient characteristics were similar to those of the AVID population, with a mean age of
63.5 years, mean LVEF of 0.34, and an 82% prevalence of CAD. After a mean follow-

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Table 2
ICD Trials for Primary and Secondary Prevention of SCD

Trial

Primary or
Year
secondary
of
prevention publication

AVID (23)
CIDS (24)
CASH (25)
MADIT (26)
MUSST (27)
CABG-Patch (28)
MADIT-II (29)

Secondary
Secondary
Secondary
Primary
Primary
Primary
Primary

1997
2000
2000
1996
1999
1997
2002

Number
of
patients

Mean
follow-up
(months)

Relative
risk
reduction

Absolute
risk
reduction

1016
659
288
196
704
900
1232

18
36
57
27
39
32
20

33%
28%
18%
59%
60%
8%
28%

8%
4.3%
8%
23%
31%
1.7%
5.6%

p-value
p < 0.02
p = 0.14
p = 0.08
p = 0.009
p < 0.001
p = NS
p = 0.016

Table 3
Nonischemic Cardiomyopathies Associated With Sudden CA
Dilated cardiomyopathies
Idiopathic
Postviral
Alcohol-related
Valvular heart disease
Postpartum
Familial
Chagas disease
Hypertrophic cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy
Cardiac sarcoidosis
Cardiac amyloidosis

up period of 3 years, 98 of 331 patients (29.6%) assigned to amiodarone had died vs 83


of 328 patients assigned to ICD therapy (25.3%). On an annualized basis, the absolute risk
reduction for death was 1.9% per year in favor of the ICD arm, with a relative risk
reduction of 19.7% (p = 0.142).
The Cardiac Arrest Study Hamburg (CASH) enrolled 288 CA survivors (84% with
VF) in eight centers in northern Germany between 1987 and 1996 and randomly assigned
them to ICD implantation, amiodarone therapy, or metoprolol treatment in a 1:1:1 fashion (25). The trial had originally included a propafenone treatment arm, which was
discontinued in 1992 because of the 61% higher all-cause mortality in that group. Over
a mean follow-up period of 57 months, the crude death rates were 36.4% in the ICD arm
and 44.4% in the two drug treatment arms, an absolute reduction of 8% and a relative risk
reduction of 18% (p = 0.081). The relative risk reduction was 42% at 1 year and 28% at
3 years. Secondary analysis showed that this nonsignificant reduction in total mortality
appeared to be due entirely to a significant reduction in sudden death (p = 0.005). As in
CIDS, there was a trend toward increased efficacy of the ICD in higher risk subgroups
with lower LVEF and higher New York Heart Association (NYHA) heart failure class.
Although neither CIDS nor CASH reached statistical significance, the degree of treatment effect was similar to that seen in AVID and these trials are generally viewed a
supportive for ICD treatment in secondary prevention of SCD.

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ICD FOR PRIMARY PREVENTION IN CAD


With the rapid evolution of the ICD and its clear effectiveness in treating VAs, it was
reasonable to presume that the ICD might be effective in primary prevention of SCD in
high-risk patients. Several trials were designed to test this hypothesis. The first to be
published was the Multicenter Automatic Defibrillator Implantation Trial (MADIT)
(26). This device industry-sponsored study enrolled 196 high-risk CAD patients in 32 US
and European centers from 1990 to 1996 and randomly assigned them to implantation of
ICD or to conventional therapy (determined by treating physician, with amiodarone in
74%). Eligible patients had a documented MI greater than 3 weeks prior to enrollment and
an episode of asymptomatic nonsustained VT of 3 to 30 beats with a rate of at least 120
bpm. Patients with NYHA class IV symptoms were excluded because of a known high
mortality from pump failure. Eligible patients then underwent invasive electro-physiologic study, with delivery of one, two, and three-paced ventricular premature beats at
increasingly close coupling intervals. If sustained VT or VF was induced, stimulation
was repeated after giving intravenous procainamide. If the arrhythmia remained inducible, then the patient became eligible for randomization. The mean age of randomized
patients was 64 years, the mean LVEF was 0.26, and 65% had NYHA class II or III
symptoms.
After a mean follow-up of 27 months, the trial was stopped early because of a marked
treatment effect in favor of the ICD. Over the follow-up period, 39 of 101 patients (39%)
in conventional treatment group died vs only 15 of 95 patients (16%) assigned to ICD,
an absolute risk reduction of 23% and a relative risk reduction of 59%. The relative hazard
for overall mortality was 0.46 in the ICD arm (p = 0.009).
Despite the results, MADIT initially met with skepticism owing to its small sample
size, ICD industry-sponsorship, and low use of `-blockers (58%) in the conventional
therapy arm. These criticisms were largely answered with the publication of the
Multicenter Unsustained Tachycardia Trial (MUSTT) 3 years later (27). This study
involved 704 patients with CAD enrolled at 85 centers in the United States and Canada
between 1990 and 1996, and was sponsored by the NIH, with additional grant support
from several drug and ICD manufacturers. Similar to MADIT, eligible patients had CAD
with depressed LVEF (0.40 or less), and a qualifying episode of nonsustained VT of three
or more beats at least 96 hours after a MI or revascularization procedure. Potential
patients underwent invasive electrophysiologic (EP) study and, if inducible for sustained
VA, were eligible for randomization to either electrophysiologically guided anti-arrhythmic therapy or to no anti-arrhythmic therapy. Patients in the therapy arm were then
randomly assigned to a Food and Drug Administration-approved class I or class III antiarrhythmic drug followed by repeat EP testing. If no effective anti-arrhythmic drug was
found, an ICD was implanted. ICD therapy was permitted, at investigator discretion, after
one to three failed drug trials. Out of 351 patients, 202 in this arm (58%) ultimately
received an ICD. `-Blocker and ACE inhibitor treatment was encouraged in all patients,
and 40% of all patients were receiving `-blockers at hospital discharge. The median age
of enrolled patients was 66 years and the median LVEF was 0.30.
After a median follow-up period of 39 months, the 2- and 5-year rates of overall
mortality were 28% and 48% in the group assigned to no anti-arrhythmic therapy and
22% and 42% in the EP-guided therapy arm (relative risk 0.80 at 5 years, p = 0.06).
Subsequent analysis of the data showed that this treatment effect was entirely attributable
to treatment with the ICD; the overall mortality rate at 5 years was 24% in patients

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receiving an ICD and 55% in those who did not (adjusted relative risk of overall mortality
0.40, p < 0.001). In fact, patients treated with anti-arrhythmic drugs without an ICD had
a trend toward higher mortality than the control arm of the study, possibly because of a
high use of type I anti-arrhythmic agents in the drug-therapy group (26% at initial hospital
discharge). Thus, although MUSTT had a complex design, which was not primarily
intended to test the efficacy of the ICD, its results supported the apparent benefit of the
ICD for primary prophylaxis demonstrated in MADIT and led to widespread use of the
ICD in high-risk coronary patients for this indication.
In contrast to MADIT and MUSST, the Coronary Artery Bypass Graft (CABG) Patch
trial used a different test (signal-averaged ECG) to identify high-risk CAD patients and
found no benefit to prophylactic epicardial ICD implantation in the population studied
(28). This NIH-sponsored study screened patients less than 80 years old with LVEF of
0.35 or less who were scheduled for CABG surgery at 37 centers in the United States and
Germany between 1990 and 1996. Patients were screened with signal-averaged electrocardiography (SAECG), a variation of the standard surface ECG used to analyze QRS
complexes for prolongation or the presence of late potentials, which reflect myocardial
scarring and substrate for VAs. A pilot study had shown that patients with abnormal
SAECG had a mortality rate in the 2 years after CABG surgery twice as high as patients
with normal SAECG, which is in line with previous studies of this technique. Neither
nonsustained VT nor invasive EP study was required for study entry.
After screening, 900 patients were assigned randomly to receive an epicardial ICD
system at the time of CABG surgery (446 patients) or to CABG surgery alone (454
patients). Baseline characteristics were similar to MADIT patients, with a mean age of
64 years, mean LVEF of 0.27, and 73% with NYHA class II or III heart failure symptoms.
Ninety-one percent of patients had two- (36%) or three- (55%) vessel CAD. After an
average follow-up of 32 months, the trial was terminated because of a lack of efficacy,
at which point 101 of 446 (22.6%) patients in the ICD arm had died vs 95 of 454 (20.9%)
patients in the control arm. No subgroups were identified that appeared to benefit from
the ICD.
There are several possible explanations for the difference in outcome between the
CABG-Patch Trial and other trials, which demonstrate efficacy of the ICD for primary
prophylaxis. These include relatively low mortality rate in the control arm, an independent anti-arrhythmic effect of complete revascularization, use of epicardial devices, and
potential harmful effect of prolonging operative time with ICD implant and testing.
The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) was
recently published and may significantly expand the population eligible for primary
prophylaxis of SCD with the ICD (29). This industry-sponsored trial randomized 1232
patients in 76 US and European centers with prior MI (1 month or more before entry) and
LVEF of 0.30 or less to receive a transvenous ICD or usual medical therapy. Patients were
not required to have any spontaneous or induced arrhythmias for entry. Enrolled patients
had a mean age of 64 years and a mean LVEF of 0.23. In contrast to MADIT, `-blocker
use was high (70% in each arm). After a mean follow-up of 20 months, 19.8% of patients
in the usual therapy group had died, and 14.2% of patients in the ICD arm (p = 0.016),
indicating a hazard ratio of 0.69 in favor of the ICD arm, and an absolute risk reduction
of 5.6%. There were no statistically significant interactions with baseline characteristics,
but patients with lower LVEFs and those with wider QRS duration showed trend toward
greater benefit from the ICD. An unexplained trend toward higher rates of hospitalization
for heart failure was also present in the ICD arm.

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ECONOMIC IMPACT OF ICD USE IN CAD


The MADIT-II trial, for the first time, demonstrated efficacy of the ICD in reducing
all-cause mortality in a population defined solely by cardiac substrate (prior MI and
reduced LVEF) and not by presence of any arrhythmia. Other ongoing trials are testing
the ability of the ICD to reduce SCD mortality in other populations, including all patients
with heart failure and reduced EF from any cause, and in other lower risk populations with
CAD. The health care cost implications of such expansion of ICD indications are substantial. The MADIT-II authors estimated that up to 4 million patients in the United States
might qualify for ICD therapy under the new indication, with addition of up to 400,000
new patients annually (29). At a conservative estimate of $25,000 per ICD implant, it
would cost $100 billion to implant all current MADIT-II eligible patients in the United
States, and $10 billion to implant newly eligible cases each year. There would be additional costs associated with follow-up, generator replacements, and management of late
complications and device/lead malfunction.
Cost-effectiveness analysis of ICD therapy has been performed based on MADIT and
AVID data. Analysis of MADIT results, which had initial ICD implantation cost of
$18,000$27,000, showed a cost-effectiveness ratio of $27,000 per year of life saved,
based on a survival advantage of 0.8 years in the ICD group (30). Patients in the ICD arm
had higher initial costs, which were later balanced by higher medication costs in the
medically treated group after 4 years. Total net health care costs over follow-up were
about $98,000 in the ICD group and $76,000 in the control group; the difference was
largely because of a longer survival in the ICD group. Corresponding economic analysis
of the AVID study showed estimated 3-year medical costs of $87,000 in the ICD group
and $73,000 in the anti-arrhythmic drug group (31). As in MADIT, initial hospital costs
were higher in the ICD arm and medication costs were higher in the drug arm. Because
the mortality difference was smaller in AVID (about 0.21 years advantage for ICD), the
cost-effectiveness ratio was higherabout $67,000 per year of life saved. These costeffectiveness ratios, although high, are comparable to other accepted health care interventions.
Economic analysis of MADIT-II is currently in progress. Review of currently published data suggests that the cost-effectiveness ratio may be higher than in MADIT,
because of a smaller absolute survival advantage, higher costs for heart failure hospitalizations in the ICD group, and lower costs for anti-arrhythmic drugs in the control arm.
Regardless of the ratio, the absolute cost of expanding ICD indications will have to be
considered by health care payers. Some investigators have expressed hope that market
competition will reduce costs of ICD therapy and that expanding indications for the ICD
will spur manufacturers to design and market a lower cost model for primary prophylaxis
in lower risk patients (32).

DILATED CARDIOMYOPATHY
Although not as common as CAD, several other forms of cardiomyopathy (listed in
Table 2) are associated with an elevated risk of SCD. The most prevalent of these is
dilated cardiomyopathy (DCM). Numerous studies have shown that patients with DCM
have significantly elevated risk of all-cause mortality and SCD, and that degree of risk
correlates with heart failure class (33). Interestingly, although patients with the most
severe heart failure symptoms have the highest mortality rates, the proportion of deaths
classified as because of SCD is lower than in those with lower heart failure class; the

Chapter 3 / Prevention of Sudden Cardiac Death

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proportion of deaths because of pump failure rises accordingly. Other important risk
factors for arrhythmic mortality in DCM include degree of LV dilatation, impairment of
LV systolic function, and increased QRS duration, especially with left bundle branch
block. Frequency of nonsustained VT has also been shown to increase risk of mortality
in one study (34), but another failed to show this association (35). Syncope, regardless
of etiology, was shown in one study to increase risk of mortality nearly fourfold (36).
Although recognized as an insensitive marker, inducibility of sustained VAs at invasive
EP study also seems to confer elevated risk of death (37).

Medical Therapy of DCM


Several medications without anti-arrhythmic action have been shown to improve allcause mortality in DCM, and also may reduce SCD because of a modification of the
underlying arrhythmic substrate. These medications include ACE inhibitors, hydralazine-isosorbide, metoprolol, carvedilol, and spironolactone. Digoxin use, even though
improving heart failure symptoms and modestly reducing hospitalization, does not appear
to significantly affect survival (38). In contrast, several positive inotropic drugs, including
enoximone, amrinone, and high-dose vesnarinone, have been shown to increase mortality
in heart failure patients, possibly through ventricular proarrhythmic effects. Several studies of type I (sodium-channel blocking) anti-arrhythmic drugs have shown that these
agents are associated with excess mortality in patients with heart failure and structural
heart disease (13,14,39). Sodium-channel blocking drugs have both negative-inotropic
and proarrhythmic side effects in this population. On the basis of these trials, these drugs
should generally be avoided in patients with DCM.
AMIODARONE FOR DCM
There have been two large trials of amiodarone for primary prophylaxis of SCD in
heart failure patients. The GESICA trial was conducted in 26 hospitals in Argentina
between 1989 and 1993. Patients (N = 516, mean age 59 years) with stable chronic class
II, III, and IV congestive heart failure on appropriate medical treatment with LVEF of
0.35 or less (mean = 0.20) were randomized to receive amiodarone (300 mg/day chronically) or usual treatment (40). Forty percent of patients had prior MI and 10% had Chagas
disease. After a mean 13 months of follow-up, 87 of 260 patients (33.5%) treated with
amiodarone died vs 106 of 256 control patients (41.4%), a relative risk reduction of 28%
and an absolute risk reduction of 7.9% (p = 0.024). Subsequent substudies of GESICA
showed particular benefit in patients with baseline heart rate above 90 bpm.
The STAT-CHF trial was a US-based trial conducted in Veterans Affairs medical
centers enrolling 674 patients (99% men) with LVEF of 0.40 or less, class II, III, or IV
congestive heart failure symptoms, and 10 or more ventricular premature contractions
per hour on Holter monitor (41). Patients were randomized to amiodarone (300 mg per
day) or placebo and were followed for a mean of 4 years. In contrast to GESICA, this trial
showed no significant difference in outcome between the two groups, either in total
mortality or in sudden death.
The explanation for the discrepancy between the two trials has been attributed to the
difference in populations studied. GESICA included a higher proportion of patients with
nonischemic cardiomyopathy, including Chagas disease in 10%. In CHF-STAT, there
was also a trend toward improved survival with amiodarone in the smaller subgroup
without CAD. Additionally, mortality in the placebo group at 2 years was higher in
GESICA (50%) than in CHF-STAT (30%), suggesting that amiodarone may only benefit

32

Cardiopulmonary Resuscitation

those at very high risk. Alternatively, CHF-STAT included a much longer follow-up
period, and hence GESICA might have shown less benefit for amiodarone if patients had
been followed longer. No clear consensus exists for utility of amiodarone for primary
prevention of SCD in the heart failure population because of the conflicting results of
these two trials. Preliminary results of the Sudden Cardiac Death in Heart Rate Failure
Trial (SCD-HeFT; see below) also suggest that amiodarone does not prolong survival in
heart failure patients.
ICD FOR DCM
Patients with DCM who are resuscitated from sustained VT or VF warrant strong
consideration for ICD therapy based on AVID and the other secondary prevention
studies discussed above. ICDs are also appropriate for patients with symptoms consistent with VA (such as syncope) who have inducible VAs at EP study. Based on natural
history studies, unexplained syncope is considered by some to constitute an indication
for an ICD in patients with DCM. Other indications for ICD implantation in this group
need to be defined.
To date, there have been no completed large-scale randomized trials of the ICD for
primary prevention of SCD in patients with DCM. One small pilot trial conducted in
Germany randomized 104 patients with DCM and LV ejection of 0.30 or less to ICD or
usual therapy (42). After 5 years of follow-up, there was no significant difference in
mortality between the two groups. Lack of efficacy of the ICD was ascribed to lowerthan-expected mortality in this group. The Amiovert trial, recently reported in abstract
form, compared ICD therapy with amiodarone in 178 patients with nonischemic cardiomyopathy and nonsustained VT (43). This trial also appeared to be underpowered to
detect a treatment effect of the ICD, and was terminated prematurely having shown no
significant difference in outcome between the two groups.
The SCD-HeFT is a multicenter study that has enrolled approx 2500 patients with
DCM because of any cause with LVEF of 0.35 or less and class II or III heart failure
symptoms (44). Patients were randomly assigned to ICD implantation, amiodarone
therapy, or placebo in a 1:1:1 fashion. Follow-up was completed in 2003 and preliminary results were presented at the annual Scientific Sessions of the American College
of Cardiology in March 2004 (available at www.sicr.org). After a mean follow-up
period of 45 months, there was a statistically significant 23% relative reduction in allcause mortality in the patients assigned to ICD therapy. Patients with ischemic and nonischemic etiologies of heart failure appeared to benefit equally. There was no significant
mortality difference in patients assigned to amiodarone treatment. Assuming these
results are confirmed in the final published report, SCD-HeFT may result in significant
expansion in patients eligible for ICD therapy for primary prevention of SCD.

OTHER FORMS OF CARDIOMYOPATHY


Several forms of cardiomyopathy expose individuals to elevated risk of SCD in the
absence of significant LV systolic dysfunction. These less common diseases include
hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, and cardiac amyloidosis.

Hypertrophic Cardiomyopathy
HCM is a group of diseases caused by inherited mutations in genes encoding protein
components of the cardiac sarcomere (45). To date, 11 different HCM-associated genes

Chapter 3 / Prevention of Sudden Cardiac Death

33

have been identified; others likely remain to be discovered. The disease results in myocyte disorganization, progressive myocardial wall thickening, and diastolic dysfunction.
Increased LV wall thickening develops during childhood and adolescence and is usually
present by young adulthood in affected individuals. Some forms may develop systolic
dysfunction late in the course of disease. The disease was first characterized in patients
that had disproportionate thickening of the interventricular septum with dynamic LV
outflow tract gradient (idiopathic hypertrophic subaortic stenosis [IHSS]). Further studies have demonstrated that neither septal hypertrophy nor outflow tract gradient is a
requirement for the disease, and numerous different patterns of LV wall thickening have
been identified.
SCD as a result of VAs is believed to be the most common cause of death in HCM, with
annual incidence ranging from 1% per year in all patients and up to 5% per year in highrisk subgroups. The highest risk is present in patients who have survived a CA or episode
of sustained VT. These patients generally warrant ICD therapy for secondary prophylaxis. Other proposed markers of risk include extreme LVH with wall thickness greater
than 30 mm, frequent runs of nonsustained VT on Holter monitoring, history of unexplained syncope, hypotensive response to exercise, and malignant family history. Preliminary data suggest that some genotypes, particular certain mutations in `-myosin
heavy chain and cardiac troponin T, confer increased risk of SCD. Genotyping, however,
is not widely available and not currently practical for risk stratification. Younger patients
appear to be at higher risk, although a cut-off age indicating low risk has not been defined.
Resulting from the relative rarity of the disease and the overall low mortality rate,
it has been difficult to define effective therapies for prevention of SCD in HCM.
Vigorous physical exertion and participation in competitive sports should be proscribed. `-Blockers have been used based on their efficacy in other cardiac substrates;
a retrospective study also suggests effectiveness (46). Amiodarone has been used to
treat nonsustained and sustained VAs, but the potential for extracardiac adverse effects
with lifelong treatment in relatively young patients is substantial (47). There are no
controlled trials of ICD use in patients with HCM. Criteria for secondary prevention
are applied generally as with other AVID-eligible patients. There are no prospectively
defined criteria for ICD implantation for primary prophylaxis in this disease.
A retrospective cohort study of 128 patients with HCM who had ICDs implanted for
perceived high risk of SCD was recently reported (48). This study found that, over a mean
follow-up period of 3 years, 19 of 43 patients (44%) implanted for secondary prophylaxis
had appropriate ICD discharges for VT or VF, and 10 of 85 patients (12%) implanted for
primary prophylaxis did as well. This percentage is lower than that seen in primary
prophylaxis trials in patients with CAD or DCM. Because the ICD cannot distinguish
between truly life-threatening arrhythmias and VT which would terminate spontaneously without treatment, it is difficult to draw conclusions regarding mortality reduction
in this study. Moreover, 18 of 128 patients (14%) had device-related complications in the
3-year follow-up period, including 12 ICD lead failures. Thirty-two patients (25%) had
inappropriate ICD discharges for sinus tachycardia, atrial fibrillation, or ICD lead failure;
25 of these patients did not receive an appropriate discharge from the device. These data
underscore the potential complications of ICD therapy, particularly applied to young
people with long life expectancy. Thus, while this study suggests that some HCM patients
may benefit from ICD therapy, definitive data to guide patient selection for primary
prophylaxis are not currently available.

34

Cardiopulmonary Resuscitation

Arrhythmogenic Right Ventricular Cardiomyopathy


Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare entity first
described in 1977, which appears to be more common in Italy (49). The pathologic
hallmark of the disease is progressive replacement of the free wall of RV with fibrofatty
tissue, often with discrete aneurysm formation. The interventricular septum and LV may
be involved later in the disease. Clinically, patients typically present with nonsustained
or sustained VT with a left bundle branch block pattern originating in the right ventricle
and may later develop heart failure symptoms. Resulting from the rarity of the disease and
its diverse clinical presentation and challenging diagnosis, the natural history of ARVC
and risk factors for SCD have not been well-defined. Sotalol was shown in one study to
be the most effective drug in suppressing inducibility of VT (50). AVID-eligible patients
with ARVC are generally treated with an ICD. Primary prevention with an ICD can be
considered for patients with unexplained syncope, a malignant family history, or
nonsustained VT with inducible VT at invasive EP study. Efficacy data for ICD therapy
in this disease are limited. One cohort study of 12 patients found that 8 (66%) had
appropriate ICD discharges in follow-up (51). Another study of nine patients implanted
for sustained VT also showed high rate of appropriate ICD therapies (52).

Cardiac Sarcoidosis and Amyloidosis


Cardiac sarcoidosis (CS) and amyloidosis are infiltrative heart diseases that may cause
conduction disturbances, including complete AV block, and VAs in the absence of LV
dysfunction. CS has a wide clinical spectrum and the natural history regarding risk of
SCD is not well-defined. Anti-arrhythmic drug and ICD therapy is generally prescribed
as with other forms of cardiomyopathy (53). Patients with cardiac amyloidosis and VAs
generally have a very poor prognosis in the absence of organ transplantation and/or highdose chemotherapy. One small cohort study of ICD use in this disease found a high
mortality rate and low ICD efficacy because of rapid progression of heart failure, pulseless
electrical activity, and failure of other organ systems (54).

Long QT Syndrome
The long QT syndrome (LQTS) is the most common of the cardiac ion channel diseases that cause SCD. The acquired form is most commonly caused by medications,
which prolong cardiac repolarization. For a complete updated list of medications associated with LQTS, the reader is referred to www.torsades.org. Other causes of acquired
LQTS include hypokalemia and hypomagnesemia; severe bradycardia, such as during
complete AV block; and neurological insults, such as subarachnoid hemorrhage and
stroke. The congenital form of the disease is associated with mutations in one of at least
six identified gene loci (LQT 16) (55). LQT1, LQT2, LQT5, and LQT6 are all caused
by mutations in different genes encoding for components of cardiac potassium channels,
but LQT3 is caused by mutations in the cardiac sodium channel. All result in prolonged
repolarization of the cardiac action potential with resulting prolongation of the QT interval and predisposition to torsades de pointes, which may in turn degenerate into VF.
Recognition of the ECG pattern in patients presenting with symptoms is an important component of sudden death prevention in this disorder (56). The ECG in LQTS is
highly variable in degree of QT prolongation and morphology of the T wave, which
may make recognition difficult. Detection of LQTS is an important reason for careful
review of the ECG in any patient presenting with palpitations or syncope. Occasion-

Chapter 3 / Prevention of Sudden Cardiac Death

35

ally, the syndrome presents as a seizure disorder in young children. Once an affected
individual has been identified, family members should be screened for the disease.
The most important medical component of treatment for congenital LQTS is `-blocker
therapy. This medication has been shown to reduce incidence of syncope and sudden
death in congenital LQTS patients (57). Other treatments that have been shown to reduce
symptoms include left cardiac sympathectomy and permanent atrial pacing. Preliminary
data suggest that sodium channel blockade may be beneficial in the LQT3 subtype.
Criteria for ICD implantation are controversial, and the decision is difficult in young
patients with long life expectancy. Patients resuscitated from CA and those with recurrent
syncope because of torsade de pointes despite `-blockade are the most obvious candidates. Patients with syncope of undetermined etiology and patients with malignant family
history are often considered as well.

Brugada Syndrome
The Brugada syndrome is a recently described inherited disease consisting of an
abnormal ECG pattern (incomplete right bundle branch block with coved ST segment
elevation in leads V1V3) and idiopathic VF (58). In some cases, the ECG pattern is
elicited only after sodium-channel blockade. Patients usually present after resuscitation
from CA or, less commonly, with recurrent syncope. ICD implantation is currently the
only effective therapy for symptomatic individuals. Evaluation and treatment of asymptomatic patients and affected family members is controversial. One report suggests that
VT or VF inducibility at EP study has prognostic value (59). Although another report
reached the opposite conclusion (60).

Commotio Cordis
Commotio cordis has received attention as a cause of SCD in children and young
adults during sporting activities, particularly baseball and hockey (61). The mechanism is believed to be VF induced by a blow to the precordium during the vulnerable
period of the cardiac cycle (just prior to the peak of the T-wave). Most affected individuals have structurally normal hearts. Although very rare, events have a high mortality rate and wider impact on affected families and communities. Preventive efforts
have focused on use of softer baseballs and improved chest protection equipment.

FUTURE DIRECTIONS
Recent efforts to reduce the public health burden of SCD have focused on expansion
of indications for ICD therapy. These trials have clearly shown efficacy of the ICD in the
high-risk groups in which it has been studied. It has been noted that the majority of victims
of SCD do not have risk factors that would currently make them eligible for an ICD (62).
Although further reduction in implant-related complications may make the ICD effective
in lower risk patients, the cost-effectiveness ratios associated with this approach would
be prohibitively high without a reduction in ICD costs. Additionally, the long-term
economic, psychological, and health effects of chronic ICD therapy in low-risk populations are not yet well-understood, and it is unclear to what degree low-risk populations
would accept ICD therapy.
The disappointing history of anti-arrhythmic drug trials for prevention of SCD make
these agents unattractive for primary prophylaxis of SCD in lower risk groups. To be
useful for this purpose, an agent should have low cost and side-effect profile and negli-

36

Cardiopulmonary Resuscitation

gible proarrhythmic risk. Preliminary studies of t-3 polyunsaturated fatty acids (fish
oils) have shown marked protective effect against VF in animal models of ischemia and
infarction, possibly because of stabilizing effects on the membrane of the cardiomyocyte
(63). Further trials in humans will be required to demonstrate clinical efficacy.
In order to better target preventive therapies, others have worked on identifying novel
markers of high risk of SCD. A recent report has observed that patients with congestive
heart failure and depressed LVEF who had elevated brain natriuretic peptide levels (>130
pg/mL) had more than 10-fold higher risk of sudden death than those with lower values
(64). Other noninvasive electrocardiographic markers of risk include microvolt T-wave
alternans, heart rate variability, and heart rate turbulence. Whether any of these markers
can predict benefit of ICD or other preventive strategies remains to be proven (65).

REFERENCES
1. Eisenberg MS, Horwood BT, Cummins RO, Reynolds-Haertle R, Hearne TR. Cardiac arrest and resuscitation: a tale of 29 cities. Ann Emerg Med 1990; 19:17986.
2. Centers for Disease Control and Prevention (CDC). State-Specific Mortality From Sudden Cardiac
DeathUnited States, 1999. MMWR 2002; 51(6);1236.
3. Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation 1998; 98:23342351.
4. Pratt CM, Greenway PS, Schoenfeld MH, Hibben ML, Reiffel JA. Exploration of the precision of
classifying sudden cardiac death. Circulation 1996; 93:519524.
5. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular
Disease and Stroke: 2002 Update. Circulation 2002; 106:388.
6. Holmes DR, Davis KB, Mock MB, et al. The effect of medical and surgical therapy on subsequent sudden
cardiac death in patients with coronary artery disease: a report from the Coronary Artery Surgery Study.
Circulation 1986; 73:12541263.
7. Goldstein S. Propranolol therapy in patients with acute myocardial infarction: the Beta-Blocker Heart
Attack Trial. Circulation 1983; 67:I53I57.
8. ISIS-1 (First International Study of Infarct Survival) Investigators. Randomised trial of intravenous
atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986; 2:5766.
9. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in
patients with left ventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001; 357:
13851390.
10. Norris RM, Brown MA, Clarke ED, et al. Prevention of ventricular fibrillation during acute myocardial
infarction by intravenous propranolol. Lancet 1981; 2:883886.
11. Nademanee K, Taylor R, Bailey WE, Rieders DE, Kosar EM. Treating electrical storm: sympathetic
blockade versus advanced cardiac life support-guided therapy. Circulation 2000; 102:742747
12. Bigger JT, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM. The relationships among ventricular
arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984; 69:250258.
13. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide,
flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781788.
14. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent
moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227233.
15. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular
dysfunction after recent and remote myocardial infarction. Lancet 1996; 348:712.
16. Kober L, Bloch-Thomsen PE, Moller M, et al. Effect of dofetilide in patients with recent myocardial
infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356:20522058.
17. Herre JM, Sauve MJ, Malone P, et al. Long-term results of amiodarone therapy in patients with recurrent
sustained ventricular tachycardia or ventricular fibrillation. J Am Coll Cardiol 1989; 13:442449.
18. The CASCADE Investigators. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest
(the CASCADE study). Am J Cardiol 1993; 72:280287.
19. Julian DG, Cam AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in
patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997;
349: 667674.

Chapter 3 / Prevention of Sudden Cardiac Death

37

20. Cairns JA, Connolly SJ, Roberts R, et al. Randomised trial of outcome after myocardial infarction in
patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet 1997; 349:
675682.
21. 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; 303:322324.
22. Peters RW, Gold MR. Implantable cardiac defibrillators. Medical Clinics of North America 2001; 85:
343367.
23. The AVID Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators
in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997; 337:15761583.
24. 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;
101:12971302.
25. Kuck K-H, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy
with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study
Hamburg (CASH). Circulation 2000; 102:748754.
26. Moss AJ, Hall J, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with
coronary disease at high risk for ventricular arrhythmias. N Engl J Med 1996; 335:19331940.
27. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G, 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; 341:18821890.
28. Bigger JT, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. Prophylactic use
of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronaryartery bypass graft surgery. N Engl J Med 1997; 337:15691575.
29. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 345:877883.
30. Mushlin AI, Hall WJ, Zwanziger J, et al. The cost-effectiveness of automatic implantable cardiac
defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial. Circulation
1998; 97:21292135.
31. 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 Defibrillators (AVID) economic analysis substudy. Circulation
2002; 105:204957.
32. Exner DV, Klein GJ, Prystowsky EN. Primary prevention of sudden death with implantable defibrillator
therapy in patients with cardiac disease. Circulation 2001; 104:15641570.
33. Dec GW, Fuster V. Medical progress: idiopathic dilated cardiomyopathy. N Engl J Med 1994; 331:
15641575.
34. Doval HC, Nul DR, Grancelli HO, et al. Nonsustained ventricular tachycardia in severe heart failure:
independent marker of increased mortality due to sudden death. Circulation 1996; 94:31983203.
35. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart
failure do not specifically predict an increased risk of sudden death. Circulation 2000; 101:4046.
36. Middlekauff HR, Stevenson WG, Stevenson LW, Saxon LA. Syncope in advanced heart failure: high
risk of sudden death regardless of origin of syncope. J Am Coll Cardiol 1993; 21:110116.
37. Gossinger HD, Jung M, Wagner L, et al. Prognostic role of inducible ventricular tachycardia in patients
with dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia. Int J Cardiol
1990; 29:215220.
38. The Digitalis Investigation Group. The Effect of Digoxin on Mortality and Morbidity in Patients with
Heart Failure. N Engl J Med 1997; 336:525533.
39. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy
for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials.
Circulation 1990; 82:11061116.
40. Doval HC, Nul DR, Grancelli HO, et al. Randomised trial of low-dose amiodarone in severe congestive
heart failure. Lancet 1994; 344:493498.
41. Singh BN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and
asymptomatic ventricular arrhythmia (CHF-STAT). N Engl J Med 1995; 333:7782.
42. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated
cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002; 105:14531458.
43. Strickberger AS. Amiodarone vs implantable defibrillator in patients with nonischemic cardiomyopathy
and asymptomatic nonsustained ventricular tachycardia. Circulation.2000; 102:2794

38

Cardiopulmonary Resuscitation

44. Klein H, Auricchio A, Reek S, Geller C. New primary prevention trials of sudden cardiac death in
patients with left ventricular dysfunction: SCD-HEFT and MADIT-II. Am J Cardiol 1999; 83:
91D97D.
45. Maron BJ. Hypertrophic cardiomyopathy: A systematic review. JAMA 2002; 287:13081320.
46. Ostman-Smith I, Wettrell G, Riesenfeld T. A cohort study of childhood hypertrophic cardiomyopathy:
improved survival following high-dose beta-adrenoceptor antagonist treatment. J Am Coll Cardiol
1999; 34:18131822.
47. McKenna WJ, Oakley CM, Krikler DM, et al. Improved survival with amiodarone in patients with
hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985; 53:412416.
48. Maron BJ, Shen W-K, 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; 342:365373.
49. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll
Cardiol 2001; 38:17731781.
50. Wichter T, Borggrefe M, Haverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic drugs in
patients with arrhythmogenic right ventricular disease: results in patients with inducible and non-inducible ventricular tachycardia. Circulation 1992; 86:2937.
51. Link MS, Wang PJ, Haugh CJ, et al. Arrhythmogenic right ventricular dysplasia: Clinical results with
implantable cardioverter-defibrillators. J Interventional Cardiac Electrophysiol 1997; 1:4148.
52. Tavernier R, Gevaert S, De Sutter J, et al. Long term results of cardioverter-defibrillator implantation
in patients with right ventricular dysplasia and malignant ventricular tachyarrhythmias. Heart 2001;
85:5356.
53. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline update for implantation
of cardiac pacemakers and antiarrhythmia devices: summary article. Circulation 2002; 106:21452161.
54. Falk RH, Monahan K, Smith T. Failure of implantable defibrillator to prevent sudden death in cardiac
amyloidosis. Circulation 2002; 102:II396.
55. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll
Cardiol 2000; 36:112.
56. Brugada P, Geelen P. Some electrocardiographic patterns predicting sudden cardiac death that every
doctor should recognize. Acta Cardiologica 1997; 52:473484.
57. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital
long-QT syndrome. Circulation 2000; 101:616623.
58. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: clinical,
electrophysiologic and genetic aspects. J Am Coll Cardiol 1999; 33:515.
59. Brugada P, Geelen P, Brugada R, Mont L, Brugada J. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol 2001; 12:10041007.
60. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk
stratification and management. Circulation 2002; 105:13421347.
61. Maron BJ, Gohman TE, Kyle SB, Estes NA, Link MS. Clinical profile and spectrum of commotio cordis.
JAMA 2002; 287:11421146.
62. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001;
345:14731482.
63. Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation 1999; 99:24522457.
64. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients
with chronic heart failure. Circulation 2002; 105: 23922397.
65. Myerburg RJ. Scientific gaps in the prediction and prevention of sudden cardiac death. J Cardiovasc
Electrophysiol 2002; 13:709723.

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