Sudden Cardiac Death

9
8
Sudden Cardiac Death
Abdi Rasekh, Mehdi Razavi, and Ali Massumi
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Population Dynamics and Sudden Cardiac Death . . . .
Time Dependence of Risk Factors . . . . . . . . . . . . . . . . .
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Autonomic Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Toxins and Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Underlying Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Primary Electrophysiologic Abnormalities . . . . . . . . . .
Wolff-Parkinson-White Syndrome . . . . . . . . . . . . . . . . .
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Key Points
• Sudden cardiac death (SCD) is the unexpected natural
death from cardiac cause that occurs spontaneously or
within 1 hour from the onset of abrupt change in clinical
status in a person without a prior condition that would
have appeared to be fatal.
• This incidence of SCD ranges from 36 to 128 per 100,000
inhabitants per year in different studies.
• The epidemiology of SCD parallels that of coronary
artery disease (CAD).
• The annual incidence of SCD is three to four times higher
in men than in women.
• The most important predictor of SCD is a left ventricular
ejection fraction (LVEF) <30%.
• Coronary artery disease is the most common cause of
SCD in Western countries.
• The incidence of SCD associated with hypertrophic cardiomyopathy (HCM) is 2% to 4% per year, and it is higher
in younger than older patients with HCM.
• Arrhythmogenic right ventricular dysplasia is a rare but
important cause of SCD in young, otherwise healthy
people. It should be considered in patients with frequent
ventricular premature beats (VPBs) or ventricular tachycardia (VT), especially if the ventricular arrhythmias
have left bundle branch block (LBBB) morphology.
• Symptomatic valvular aortic stenosis is one of the most
common noncoronary causes of SCD.
• Approximately 10% of SCDs in the adult population
occur in patients with dilated cardiomyopathies.
• Patients with long QT syndrome, short QT syndrome, and
Brugada’s syndrome also have increased risk of SCD.
Brugada’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Short QT Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Idiopathic Ventricular Tachycardia . . . . . . . . . . . . . . . .
Catecholamine-Sensitive Polymorphic
Ventricular Tachycardia . . . . . . . . . . . . . . . . . . . . . .
Idiopathic Ventricular Fibrillation . . . . . . . . . . . . . . . . .
Sinus Node and Atrioventricular
Conduction Disturbances . . . . . . . . . . . . . . . . . . . . .
Pathophysiology of Sudden Cardiac Death . . . . . . . . . .
Evaluation and Risk Stratification . . . . . . . . . . . . . . . . .
Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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• Beta-blocker therapy may reduce the risk of SCD after
myocardial infarction (MI).
• Amiodarone has a reduced risk of SCD in several clinical
trials.
• The implantable cardioverter defibrillator reduces the
risk of SCD in patients with moderately severe left ventricular (LV) dysfunction and CAD.
Definition
Sudden cardiac death (SCD) is defi ned as an unexpected
natural death from cardiac cause that occurs spontaneously
or within 1 hour from the onset of abrupt change in clinical
status in a person without a prior condition that would have
appeared to be fatal.1,2
This definition incorporates the following facts: “natural,”
“unexpected,” and “within 1 hour of abrupt change.” The 1hour definition refers to the time between the onset of symptoms as a result of pathophysiologic changes and cardiac
arrest itself. Prodromal symptoms, defi ned as relatively
abrupt changes that begin during an arbitrarily defined
period up to 24 hours before the cardiac arrest, are often
nonspecific. Symptoms such as chest pain, palpitations, and
dyspnea can only be considered suggestive of certain causes.
The classification of death based on clinical circumstances
is difficult because as many as 40% of sudden deaths are
unwitnessed,3 and only monitoring of the patients at time of
sudden death provides a clear answer. The development of
life support system interventions has resulted in inconsistencies in the use of the term death, which is considered an
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Epidemiology
Annual incidence rate per 1000
Sudden cardiac death accounts for 300,000 to 350,000 deaths
annually in the United States,1,2,4–6 which corresponds to
about 50% of cardiac deaths in the United States and other
developed countries. The estimates of the incidence of
SCD in the U.S. varies largely based on the source of
information.
The reported incidence can vary from less than 200,000
per year based on emergency rescue data7 to more than
450,000 in a retrospective analysis of vital statistic mortality data.8 The incidence of SCD ranges from 36 to 128 per
100,000 inhabitants per year in different studies.9–11 However,
only victims of SCD resuscitated by emergency medical services personnel were included in these studies. The rates of
SCD in other industrialized countries are quite consistent
with those in the U.S. In developing countries, the rates of
SCD are considerably lower, paralleling the rates of ischemic heart disease. A review of age-adjusted risk of coronary heart disease death has shown a 15% to 19% decline
in death (Fig. 98.1).2,12,13 The age-adjusted risk curve demonstrates that cardiovascular death is occurring at older ages
but does not necessarily indicate that the prevalence of
heart disease or the absolute number of deaths has changed.
It seems that with development of earlier interventions and
coronary care units, there is a lower short-term mortality
rate and shifted age-adjusted risk.14 In an out-of-hospital ventricular fibrillation study,7 a major decline in the incidence
of out-of-hospital ventricular fibrillation (VF) was observed.
The authors concluded that these changes likely reflect
the national decline in coronary artery disease (CAD)
(Fig. 98.2). In this study, after age and sex adjustment to the
2000 U.S. population, the annual incidence of VF declined
by 56%.
All treated cardiac arrests
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
19791980
19891990
19992000
0
–20
–40
19791980
19891990
19992000
CHD
Stroke
Non-CVD
–60
–80
1950
1955
1960
1965
1970
1975
1980
1985
Year
FIGURE 98.1. Percent change in age-adjusted death rates since
1950. CHD, coronary heart disease; non-CVD, total mortality rate
minus cardiovascular disease.
Population Dynamics and Sudden
Cardiac Death
The epidemiologic data from the Framington Heart Study, a
26-year follow-up of 5209 men and women who were 30 to
59 years old and free of identified heart disease at baseline,
showed that SCD accounted for 46% of deaths due to CAD
among men and for 34% among women.15 The incidence of
SCD increased with age. However, the proportion of deaths
from CAD that were sudden and unexpected was greater in
the younger age groups. The 300,000 SCDs that occur annually in the United States can be expressed as a fraction among
an unselected adult population. The overall incidence, therefore, is 0.1% to 0.2% per year. When the high-risk subgroups
are identified and removed from this population base, the
calculated incidence for the remainder of the population decreases and the identification of individuals at risk becomes
more difficult (Figs. 98.3 and 98.4). Based on these estimates,
Ventricular fibrillation
FIGURE 98.2. The national decline in coronary artery disease
(CAD). Data are mean rates, with 95% confidence intervals (error
bars). Rates are adjusted to the Seattle, Washington, population in
2000. The fi rst recorded rhythms are represented for a 20-year span.
CAR098.indd 2040
20
Percent change
absolute and irreversible event. These interventions can
delay biological death beyond 1 hour or result in survival of
the patient, which is referred to as aborted sudden cardiac
death, a term that is in contradiction with the definition of
death as being irreversible.
98
Asystole
19791980
19891990
Pulseless electrical activity
19992000
19791980
19891990
19992000
Most of the reduced incidence was due to fewer cases with ventricular fibrillation as the fi rst identified cardiac rhythm. The proportion
of cases with ventricular fibrillation fell from 61% in 1980 to 41%
in 2000.
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2 0 41
su dden ca r di ac de at h
Incidence (%/yr)
Time dependence of risk of sudden death
Total events (n/yr)
General adult
population
Multiple-risk
subgroups
Any previous
coronary event
Follow-up free of major cardiovascular event
100
A
90
Interposition of new
cardiovascular event
EF <35% or
heart failure
Percent
80
SCD-HcFT
Cardiac-arrest,
VF/VT survivors
AVID-CIDS-CASH
High-risk post-MI
subgroups
MADIT-MUSTT
70
50
40
30
MADIT-2
0 1 2 5 10 20 30 0
100 200 300
( x 1000)
FIGURE 98.3. Relationship between population subsets, incidence
of sudden cardiac death, and total population burden for each group.
With increasing incidence, based on subgroup profi ling, there is a
decreasing proportion of the total sudden death burden. This relates
to the population impact of the outcomes of implantable cardiodefibrillator (ICD) trials.
any preventive measure must be applied to the 999 of 1000
individuals who would not have an event during the course
of a year to potentially influence the outcome in 1 of 1000.
The costs of such a low yield intervention are obviously prohibitive, and therefore, the identification of more specific
markers of high risk is needed. The present risk factors generally identify the risk of developing structural heart disease
rather than the proximate precipitator of the SCD event.
Time Dependence of Risk Factors
The risk of death after a major change in cardiovascular
status is not linear over time for most clinical circumstances.16,17 The highest secondary death rate happened
during the first 6 to 18 months after a major event such as
myocardial infarction (MI). The slope of survival curve
approaches that of a similar population that has remained
0
0
6
12
18
24
30
36
42
Event
0
6
12
18
24
Event
Months (Follow-up)
FIGURE 98.5. Time dependence of risk after cardiovascular events.
Survival curves for hypothetical patients with known cardiovascular disease free of major index event (curve A) and for patients surviving major cardiovascular events (curve C). Attrition is accelerated
during the initial 6 to 24 months after the event. Curve B shows the
dynamics of risk over time in low-risk patients with an interposed
major event that is normalized to a time point (e.g., 18 months). The
subsequent attrition is accelerated for 6 to 24 months.
free of an interposed major event at 18 to 24 months
(Fig. 98.5).1,16
Risk Factors
In a study by Gillum5 of persons between the ages of 35 and
74 years in 40 states, the epidemiology of SCD parallels that
of CAD. The annual incidence of SCD was 1.91 per 1000 for
white and nonwhite men, 0.57 per 1000 for white women, and
0.90 per 1000 for nonwhite women (Fig. 98.6). In patients with
ischemic heart disease, 60% of deaths in men and 50% in
women occurred out of hospital. In a more recent study of vital
100
50
≥30%
30
~20%
10–15%
20
10
5–10%
Arrhythmic
risk markers
Hemodynamic
risk markers
Acute MI;
unstable AP
First
clinical
event
~33%
Known
disease;
low power or
nonspecific
markers
0
FIGURE 98.4. Subgroups at risk for sudden cardiac death within
the category of ischemic heart disease. The population subset with
high-risk arrhythmia markers constitute <10% of the total sudden
death burden attributable to coronary artery disease. A somewhat
larger group is associated with hemodynamic risk markers and congestive heart failure. More than 50% of the total sudden death
burden is accounted for by those victims among whom sudden
cardiac death is the fi rst clinical event or those who have known
coronary heart disease but low power of risk. AP, action potential;
MI, myocardial infarction.
CAR098.indd 2041
Deaths per 100,000
Proportion of sudden deaths (%)
700
600
40
B
C
Follow-up after major cardiovascular event
60
White men
Nonwhite men
500
400
300
200
Nonwhite women
White women
100
0
600
35–44
45–54
55–64
65–74
White men
500
400
Nonwhite men
Nonwhite women
White women
300
200
100
0
35–44
45–54
55–64
65–74
Age ( years )
FIGURE 98.6. Mortality rates for ischemic heart disease occurring
out of hospital or in emergency departments (top) and occurring in
hospital (bottom) by age, gender, and race in 40 states during 1985.
11/29/2006 9:37:00 AM
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chapter
statistics mortality data in the United States, of more than
450,000 persons suffering SCD in 1998, 51.6% were women
and 82.8% were age ≥65 years. The mean age of SCD victims
was 70 years in men and 82.4 years in women. In 1998, coronary heart disease was listed as the underlying cause of 62.2%
of the death certificates. The cause of death for SCD varied
between ages 35 to 64 years and those age ≥65 years. Acute
ischemic heart disease, unspecified cardiovascular disease,
cardiomyopathy, and dysrhythmias were more common in
the younger group. Chronic ischemic heart disease and heart
failure, in contrast, were more frequent in the older group.
Although SCD rates declined between 1989 and 1998 in this
study, among men in all age groups and among women age 35
to 44 years they increased by about 21%. Overall, age-adjusted
SCD rates declined 8.3% during this 10-year period.
Influence of Age, Race, and Gender
Age
The incidence of SCD increases with age in men and women,
both white and nonwhite, as the prevalence of ischemic heart
disease increases with age. The peak incidences of SCD are
between birth and 6 months as a result of sudden infant
death syndrome, and between 45 and 75 years as a result of
CAD. However, the proportion of SCD caused by CAD
decreased with age from approximately 75% at ages 35 to 42
to approximately 50% at ages 75 to 84. In a retrospective
study of vital statistics mortality data,8 age-specific death
rates for SCD in 1998 increased with successive age groups
and were higher in men, although the gender differences
narrowed in older groups and disappeared for ages above 85
years of age.
Race
Data on racial differences in sudden death suggests that
blacks are more likely than whites to experience sudden death
in excess of the risk of death for ischemic heart disease.4,18,19
However, the data are conflicting and the interpretation of
data is complicated by several factors, as follows19:
1. A younger age distribution of the black population, so
crude rates give the impression of lower rates of CAD in
blacks, although age-specific rates are similar.
2. Frequent failure to report data for nonwhites separately from those for whites and to distinguish among minority groups, which have varying rates of ischemic heart disease
(e.g., blacks, Hispanics, Asians, American Indians, Pacific
Islanders, etc.). A large study in Chicago concluded that the
incidence of cardiac arrest was significantly higher for blacks
than for whites in every age group.20 The survival rate after
cardiac arrest was 2.6% in whites compared with 0.8% in
blacks. Blacks were significantly less likely to have witnessed cardiac arrest by standard-initiated cardiopulmonary
resuscitation or a favorably initial rhythm on admittance to
the hospital. When they were admitted, blacks were half as
likely to survive. The data from SCD in the U.S. from 1989
to 1998 revealed that the black population had higher death
rates for SCD than the white population. The Hispanic population had lower death rates for SCD than the non-Hispanic
population in the same study. In this study, whites had a
CAR098.indd 2042
98
greater proportion of cardiac death out-of-hospital than other
groups, whereas blacks had the highest proportion of cardiac
death occurring in the emergency room or as “dead on
arrival.”
Gender
The annual incidence of SCD is three to four times
higher in men than in women; approximately 75% of SCDs
occur in men. This difference can be explained by the difference in the incidence of CAD and the protection that women
have from atherosclerosis before menopause. After 20 years
of follow-up in the Framingham Heart Study, there was a
3.8-fold excess incidence of SCD in men compared with that
in women. The excess rate in men peaked at 6.75 : 1 in the
55- to 64-year age group and then fell to 2.17 : 1 in the 65- to
74-year age group.14 In an out-of-hospital ventricular fibrillation study from Seattle, the ratio of male-female incidence
rates decreased only from 4.0 to 3.5 in 20 years.
Physical Activity
Heavy exercise can trigger the onset of an acute MI, particularly in persons who are habitually sedentary. A prospective
case crossover study21 showed that the relative risk of sudden
death associated with an episode of vigorous exertion was
lower among those who exercised more frequently. Men who
rarely engaged in vigorous exercise (less than once a week)
had a relative risk of sudden death that was 74.1 in the period
during and 30 minutes after exertion. In comparison, men
who exercise at least five times per week had a relative risk
of 10.9, which was much lower. However, this risk was still
significantly higher than during periods of lighter exertion.
Despite the high relative risk, the absolute excess risk of
sudden death during any particular period of vigorous exertion was still extremely low and similar to that reported
in other populations. It has been suggested that vigorous
exercise increases platelet adhesiveness and aggregability,
whereas moderate physical activity may be beneficial by
decreasing platelet adhesiveness and aggregability.22 Furthermore, acute bouts of exercise accentuates the sympathetic
nervous system and decreases vagal activity, which can lead
to an acute increase in susceptibility to ventricular fibrillation.23 In contrast, regular vigorous exertion increases vasovagal tone, resulting in increased cardiac electrical stability
and protection against ventricular fibrillation.24 Cardiac
arrest occurs at a rate of 1 per 12,000 to 15,000 during rehabilitation programs, whereas during stress testing, cardiac
arrest occurs at a rate of 1 per 2000. This is at least six times
greater than the incidence of SCD for patients known to have
heart disease.2 Other data indicate that the impact of activity
on SCD may be small. In the Maastricht sudden death study,
67% of SCD victims were physically inactive at the time of
the event.
Psychological Factors
Psychological factors appear to influence the risk of SCD.
Psychological factors such as recent life change have been
associated with an increased risk of SCD.25 Rahe and associ-
11/29/2006 9:37:01 AM
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su dden ca r di ac de at h
140
Variables: age,systolic blood pressure
ECG abnormality: LVH, IV block,
nonspec. abn.
Serum cholesterol
Vital capacity
Cigarettes per day
Relative weight
Heart rate
120
Biennial rate per 10,000
ates25 reported a correlation between an increased life change
score in the preceding 6 months and the risk of coronary
events. This association was particularly notable for victims
of SCD. Study of SCDs among women showed an increased
risk for women who were not married, who had fewer or no
children, and who had a greater educational discrepancy with
their spouses than did age-related controlled subjects living
in the same environment.26 Other risk factors in this group
include prior psychiatric treatment, greater alcohol consumption, and cigarette smoking.26 In a large study of 2320 men
who survived MI, social isolation and high-level stress were
associated with an increased risk of SCD. Both of these factors
were directly associated with low educational levels.27
Type A personality has also been associated with an
increased incidence of CAD and with manifestations of
CAD, including SCD.28 However, the validity of these risk
factors remains somewhat controversial.28 In a study of SCD
at the time of an earthquake, it seems that risk clusters
around the time of stress. Furthermore, SCD occurred among
victims with preexisting risks. In this study, the stressors
simply advanced the time of an impending event.25
100
80
60
130.1
Men
Women
52.4 53.4
40
35.7
20
21.4
27.1
19.4
17.0
0
0.7 4.3 1.4 7.5 2.1
10.4
13.5
3.0
12.1
4.2
5.9
8.3
7
8
9
10
3
4
5
6
Decile of multivariate risk
FIGURE 98.7. Risk of sudden cardiac death by decile of multivariate risk: 28-year follow-up, Framingham Study. ECG, electrocardiographic; IV, interventricular; LVH, left ventricular hypertrophy;
Nonspec. abn., nonspecific abnormality.
1
2
Risk Factors for Coronary Artery Disease, Ischemic
Heart Disease, and Sudden Cardiac Death
The risk factors for SCD parallel those of CAD, which is the
most common cause of SCD in developing countries. Coronary heart disease is the single most common cause of SCD
in the United States and Western Europe. It accounts for
approximately 80% of the deaths.14 Sudden cardiac death is
the first clinical manifestation in more than 30% of patients
with CAD14 (see Fig. 98.4). The investigators of the AlbanyFramingham study considered age, smoking, hypertension,
hypercholesterolemia, and left ventricular hypertrophy in a
combined fashion to produce a multivariate model of the
probability of SCD. In their study of 4120 men, they showed
a 16-fold gradation in the incidence of sudden death from the
lowest to the highest deciles of the risk scores29 (Table 98.1).
TABLE 98.1. Incidence of sudden death according to decile of
multivariate risk: Framingham-Albany Combined Analysis
Sudden deaths (n)
Decile of
multivariate
incidence risk
1
2
3
4
5
6
7
8
9
10
Total
prior CHD?
Total
Yes
No
2-year of
SCD/1000
2
2
2
6
8
6
12
10
17
32
97
1
2
0
3
2
1
5
4
6
13
37
1
0
2
3
6
5
7
6
11
19
60
0.89
0.89
0.89
2.69
3.58
2.69
5.37
4.48
7.61
14.32
4.34
CHD, coronary heart disease; SCD, sudden cardiac death.
CAR098.indd 2043
A prior history of CAD is a powerful risk factor for SCD.
In a review of SCD in the Framingham study, the risk of SCD
was 3 to 12 times higher among those with clinical manifestation of CAD than among the general population of the
same age. In men, the risk was on average 6.7 times that of
persons without a CAD event. The risk of SCD was higher
in persons with an MI than in those who had angina pectoris.
However, even angina carried an almost fivefold increased
risk.30 In those without interim CAD, virtually all of the
major risk factors were related to the incidence of SCD. After
the onset of ischemic heart disease, none of the major modifiable risk factors were predictive of SCD in men. In women,
diabetes was the only significant predisposing factor, and
cigarette smoking had a sizable standardized logistic coefficient.30 In persons with established ischemic heart disease,
factors that reflect ischemic myocardial damage were the
chief predictors of sudden death. Electrocardiographic abnormalities indicating old MI, left ventricular hypertrophy,
intraventricular conduction, or repolarization abnormality
were significant predictors of SCD (Fig. 98.7). Ventricular
ectopy was a risk factor for SCD in men.30
In the Finnish cohort study, smoking appeared to be a
more important predictor of SCD than of non-SCDs, whereas
other coronary risk factors seemed to equally predict SCDs
and non-SCDs.31 Kuller and associates32 also found that
smoking probably is the most important risk for SCD. Continued cigarette smoking is an independent risk factor for
recurrent SCD in survivors of out-of-hospital cardiac
arrests.33,34 In patients with known ischemic heart disease,
left ventricular dysfunction is the most powerful predictor
of risk of subsequent SCD. The mortality rate due to SCD
increases when the left ventricular ejection fraction (LVEF)
is <50%; however, the rise in probability of SCD is particularly remarkable in the group with an LVEF of 30% to 39%
(a rise from 10% in the former to 30% in the latter group).35
An LVEF of 30% or less is the most powerful predictor of
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SCD. However, it has a low specificity. There also is a suggestion that an LVEF of <30% is a better predictor of early
death (6 months), whereas the presence of ventricular
arrhythmia was a better predictor of late death (more than 6
months). Several studies suggest that the presence of three
or more premature ventricular contractions (PVCs) is a powerful predictor of SCD.35,36 High-risk forms of ventricular
ectopy also include multifocal PVCs, bigeminy, short couplet
interval with the risk of R-on-T phenomenon, and three or
more consecutive ectopic beats.37 Hypertension is a wellestablished risk factor for CAD, but several epidemiologic
studies suggest that it plays a disproportionate role in increasing risk of SCD.34–36
The principal mechanism by which hypertension predisposes to SCD is via left ventricular hypertrophy (LVH). Other
factors that determine the presence of LVH include age,
obesity, stature, glucose intolerance,34,38–40 and genetic
factors. The greater prevalence of hypertension in blacks
compared to white men may explain the greater incidence
of SCD despite the lower prevalence of CAD.41 The presence
of electrocardiographic LVH as manifested by increased voltages and repolarization abnormalities was associated with a
5-year mortality of 33% in men and 21% in women.34,40 The
risk of SCD in the presence of electrocardiogram (ECG) fi ndings of LVH was comparable to that of CAD or heart failure.
There has been a downward trend in the prevalence of LVH
in the past four decades, which has coincided with improved
hypertension control. However, it seems that treated hypertensives still have a higher risk of SCD than those not treated
for hypertension, even after correction for achieved blood
pressure.38 Left ventricular hypertrophy identified by an
echocardiogram or ECG contributes independently to cardiovascular risk, and the presence of LVH by both criteria
confers a greater risk than having either alone.34 Other electrocardiographic findings also could be helpful in identifying
patients with an increased risk of SCD, including the presence of intraventricular conduction delays, QT prolongation,
and an increase in resting heart rate of survivors of out-ofhospital cardiac arrest.2 However, studies by Zabel and colleagues42 failed to support the usefulness of QT dispersion
in survivors of out-of-hospital cardiac arrest. In survivors of
cardiac arrest who have an LVEF of less than 30% in whom
the cause of arrest is obscure, the risk of SCD exceeds 30%
if they do not have inducible ventricular tachycardia (VT)
by programmed extra stimulation over a period of 1 to 3
years.2,43–45 In those who have inducible VT, the risk of recurrent arrest ranges from 15% to 50% over a 2- to 3-year period
despite therapy that suppresses inducible arrhythmia or with
amiodarone.43,45–47
Transient Risk Factors
Transient risk indicates a time limited and unpredictable
event or state that has a potential to initiate or allow the
initiation of an unstable electrophysiologic (EP) condition. It
increases the probability of transition from normal to benign
cardiac rhythm to VT or ventricular fibrillation (VF).1 Unfortunately, due to the transient nature of these risk factors,
they lack sufficient sensitivity, specificity, and predictive
values to be used for a specific preventive or therapeutic
intervention before an actual event.
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Transient Ischemia and Reperfusion Arrhythmias
Ischemia has a clear clinical correlation with potentially
fatal ventricular arrhythmias during the early phase of an
acute MI. However, approximately 80% of SCDs caused by
CAD are not associated with an acute MI. It is assumed that
transient acute ischemia is one of the major triggering factors
of SCD.48 A study in an experimental model demonstrated
that smaller decreases in blood flow are required to induce
VT or VF in the presence of MI compared to controlled subjects without prior infarct.49 Reperfusion can also induce
electrical instability50 via reentry or triggered activity
mechanisms.51
Systemic Factors
Reversible systemic abnormalities could contribute to the
life-threatening arrhythmias. Electrolyte imbalances such as
hypokalemia and hypomagnesemia, hypoxemia, and acidosis, may influence EP stability and cause VT/VF and SCD.
Recognition and correction of these factors are the only
required interventions. Hemodynamic dysfunction in
patients with an abnormal heart can result in cardiac arrest.
In an experimental model, volume loading of isolated perfused canine left ventricles shortened the refractory periods,1,52
and regional disparity in hearts with prior MI has been
demonstrated.1,52
Autonomic Variation
Alteration of heart rate variability has been suggested as a
marker for SCD among survivors of MI53 and survivors
of out-of-hospital cardiac arrest.54 A blunted baroreceptor
response to phenylephrine has also been suggested as a
marker for the risk of VT or SCD after MI.1,55 Clinically, the
induction of sustained VT by the use of isoproterenol among
survivors of sudden cardiac arrest and its prevention by the
use of beta-blockers suggest a role for autonomic influence
in the genesis of ventricular arrhythmias. Huikuri and associates56 studied the sinus node rate, as an estimate of cardiac
autonomic tone, immediately after the onset of VT. Sinus
node rate during ventricular atrial dissociation increased
progressively during the first 30 seconds of VT in patients
with stable VT, whereas in patients with unstable VT, the
sinus node rate increases more rapidly during the fi rst 5
seconds and then abruptly decreases.1,56 All of these observations support the role of an abnormal autonomic function as
a risk factor for VT/VF and SCD. These markers provide
information about autonomic balance. The risk is usually
increased when there are signs of reduced vagal activity to
the heart. The concept that an elevated heart rate increases
the risk has been validated in the Gruppo Italiano per lo
studio della Sopravvienza nell’ Infrato Miocardico (GISSI-2)
study.57 In 8,915 post-MI patients, heart rate at hospital discharge was an independent predictor of total mortality. In
this study, SCD represented almost 50% of all mortality.
The Autonomic Tone and Reflexes After Myocardial
Infarction (ATRAMI) study,58 which enrolled 1284 patients
with a recent (less than 28 days) MI provided prospective data
on the additional and independent prognostic value for
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cardiac mortality of heart rate variability and baroreflex sensitivity. The ATRAMI investigators demonstrated that after
MI, the analysis of autonomic markers has significant prognostic value independent of established clinical predictors
such as EF and ventricular arrhythmias. These investigators
demonstrated during 21 months of follow-up that depressed
heart rate variability and baroreceptor sensitivity carried a
significant multivariate risk of cardiac risk of mortality at
3.2 and 2.8, respectively. The combination of low heart variability and depressed baroreflex sensitivity further increased
the risk. In this study, 1-year mortality increased from 1%
when both markers were well preserved to 15% when both
were depressed. Furthermore, the association of LVEF of
<35% with low heart rate variability and even more with low
baroreflex sensitivity further increased the risk. However,
over the age of 65, the predictive power of baroreflex sensitivity declined much more markedly than heart rate variability.
For this reason, this specific prognostic value was higher
below age 65 for baroreflex sensitivity and above age 65 for
heart rate variability.
Toxins and Drugs
The risk of ejection fraction (EF) during anesthesia with
chloroform was the first recognized and published report of
a drug that caused a potentially fatal arrhythmia.1,59 Subsequently, the risk of arrhythmic death by torsades de pointes
(TdP) was reported during the treatment of chronic atrial
arrhythmias with quinidine. An emerging number of drugs
including antiarrhythmic drugs, antibiotics, antipsychotic
drugs, antihistamines, and prokinetic drugs have been recognized to present some antiarrhythmic potential by inducing an acquired long QT syndrome (LQTS)60 with or without
additional triggering conditions. The prolonged QT interval
can provoke TdP arrhythmias that either resolve spontaneously or deteriorate into ventricular fibrillation. The actual
incidence of drug-induced TdP is low and that of proven drugassociated syncope or SCD is even lower. Nevertheless, there
is an increasing number of medications that are not antiarrhythmic drugs but can be responsible for similar proarrhythmic responses.
Drug interaction during therapy by apparently innocuous
medications could be dangerous. Almost all drugs with
reported QT prolongation and TdP blocked the repolarizing
outward potassium current IKr encoded by HERG. The
HERG channel has been cloned and is sensitive to block by
a surprisingly large variety of agents including drugs used
for treating noncardiac conditions.34,61 Several other factors
besides underlying heart disease predispose for drug-induced
TdP. These factors include female gender, long QT interval
at baseline, bradycardia, hypokalemia, hypomagnesemia,
and old age. The drugs in question may act directly on ion
channels or interact pharmacodynamically or pharmokinetically with other drugs that also affect channels. It is well
recognized that class IA antiarrhythmic agents can cause
TdP. The Cardiac Arrhythmia Suppression Trial (CAST) also
showed an increased risk of death with class IC agents in an
ischemic context.62 Death in this population treated with
class IC agents may have resulted from an interaction among
a substrate of CAD, the transient risk factor for ischemia,
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and exacerbation of ischemia-induced slowing in the conduction by drugs with negative dromotropic actions, such as
encainide or flecainide.2,63 Most of these arrhythmias happen
within the first few days after the initiation of therapy.
However, in the CAST trial, SCD was observed even after
months of treatment.62 With the class III antiarrhythmic
amiodarone, the incidence of syncope and SCD was surprisingly low.64,65 In fact, amiodarone may be effective even in
patients with previous drug-induced TdP.66
D-sotalol has been associated with dose-dependent proarrhythmias and increased mortality in patients after MI.67
Torsades de pointes is also associated with dofetilide, which
is a new selective IKr blocker. Phosphodiesterase inhibitors
and other positive ionotropic agents can increase intracellular calcium loading, which also has been demonstrated to
exert proarrhythmic actions and increase the risk of SCD.2
The unselective calcium channel blockers bepridil and
prenylamine, formerly used as antianginal drugs, have
been associated with polymorphic ventricular arrhythmias
and TdP. Anecdotal reports exist about arrhythmias induced by other vasoactive agents including cocaine, the αadrenoreceptor blocker indoramin, sildenafil, vasopressin,
and vincamine.34
With the use of noncardiac drugs, current analysis of the
causal relationship becomes more difficult with multidrug
therapy and when the incidence of proarrhythmic events is
low. The nonsedating antihistamine terfenadine and astemizole are associated with acquired long QT syndrome (LQTS),
in particular, when the drugs were coadministered with an
antifungal that interferes both pharmacokinetically and
pharmacodynamically. Terfenadine and astemizole block
cardiac potassium channels and thus prolong repolarization.68,69 Terfenadine is metabolized to a cardio-inactive compound by a member of the cytochrome P-450 enzyme family,
CYP3A4 isoenzyme. The metabolism of terfenadine is
impaired by coadministration of ketoconazole, which is a
potent inhibitor of CYP3A4, and therefore, the plasma concentration of terfenadine may reach toxic levels. Furthermore, ketoconazole also blocks cardiac potassium channels
and directly adds to the action potential duration (APD)prolonging effect of terfenadine. These combined effects are
responsible for provocation of TdP. Similar interactions have
been observed after coadministration of terfenadine and
macrolide antibiotics70 and even grapefruit juice.71
Erythromycin has been associated with excessive lengthening of cardiac repolarization and TdP. Erythromycin
directly blocks IKr.72 The sulfamethoxazole moiety antibiotic combination of trimethoprim and sulfamethoxazole
may cause a QT prolongation and TdP.73,74 For fluoroquinolones a class effect of cardiac toxicity has been suggested.75
The actual reporting rate for malignant arrhythmia is low.
It is reported as one per million for ciprofloxacin. Pentamidine, which is used for the treatment of Pneumocystis carinii
pneumonia in patients with AIDS, could cause polymorphic
ventricular arrhythmia with and without additional precipitating factors.76
Torsades de pointes arrhythmias happen after a suicidal
overdose of amantadine.77 Many antipsychotic drugs including phenothiazines, tricyclic antidepressants, and serotonin
reuptake blockers have been associated with proarrhythmia
and SCD. A large survey of SCD in autopsies in Finland over
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a period of 3 years revealed that 49 cases of SCD were associated with the use of phenothiazines and all but three with
the use of thioridazine.78 Haloperidol is associated with
several cases of TdP arrhythmias.79 Several cases of SCD
were attributed to tricyclic antidepressants. Since many tricyclic antidepressants are metabolized by cytochrome P-450
enzymes, the plasma levels may rise unduly after the coadministration with enzyme inhibitors such as macrolide antibiotics, fungicides, or psychotropic fluoxetine and haloperidol.
Cisapride, which facilitates gastrointestinal motility and
was used for the treatment of dyspepsia and gastrointestinal
reflux disease, was reported to be associated with at least 341
cases of arrhythmias including 80 deaths. Following these
reports the drug was withdrawn from the U.S. market.80,81,82
Hypokalemia caused by potassium-wasting diuretics and
hypomagnesemia can cause QT prolongation and trigger
ventricular arrhythmia and SCD. However, it is sometimes
difficult to determine whether the arrhythmia was the result
of hypokalemia or whether the serum concentration of potassium was decreased as a result of catecholamine release after
cardiac arrest and the resuscitation effort.
Underlying Disease
Coronary Artery Disease and Acute
Myocardial Infarction
As discussed earlier, CAD is the most common cause of SCD
in Western countries. Approximately 80% of patients who
experience SCD have CAD. Death in this population may
occur in the acute ischemia phase or at a time remote from
a previous MI. In the Framingham Heart Study, more than
50% of coronary death was related to SCD.83 In survivors of
SCD, CAD with more than 75% cross-sectional stenosis is
found in 40% to 86% of patients, depending on the age and
gender of the population studied.2 Autopsy studies have
reported that a recent occlusive coronary thrombus was
found in 15% to 64% of victims of SCD caused by ischemic
heart disease. A study by Roberts and associates84 found
intraluminal thrombi in 29% of victims of SCD. However,
the thrombus was nonocclusive in more than 80% of this
group. In another study of 90 hearts, acute MI was present
in 21%, healed MI in 41%, and no MI was observed in 38%
of the hearts examined.85 Active coronary lesions (plaque
rupture or coronary thrombosis) were identified in 57% of
the entire group of sudden coronary death victims. These
data suggest that myocardial ischemia is a major cause of
SCD in patients with CAD. There is evidence of MI on the
basis of elevated cardiac enzymes in fewer than 50% of
patients with VF and fewer than 25% have Q-wave MI.2
Many factors can play a role in the process of SCD in patients
with CAD or with a history of previous MI. Three main
factors are ischemia, left ventricular dysfunction, and electrical instability.4
Observation during the ambulatory monitoring of victims
of SCD who had a history of previous MI showed that the
most common mode of death was either VF or VT deteriorating to VF. In the prethrombolytic era, the expected mortality
during the first 2 to 5 years following MI was a little greater
than 15%,86 with three quarters of all deaths being arrhyth-
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mic and about 70% of them being witnessed. Data from more
recent studies conducted in the postthrombolytic era have
shown that the incidence of cardiac and arrhythmic death
after MI have been substantially reduced, with figures of
about 5% and 2%, respectively, at 2.5 years’ follow-up.87,88
Mapping of ventricular activation during VT89 showed the
presence of fragmented, repetitive, low-voltage electrical
activity in the area of abnormal impulse formation covering
most of the interval between two successive tachycardia
beats. This was initially interpreted as an indication of
reentry circuit with a zone of slow conduction.90 However, it
was subsequently demonstrated that although the cells
incorporated in the circuit may have a normal intracellular
structure with normal electrical properties, they have lost
lateral intercellular connections that lead to a very long
maze-type circuit, which gives the impression of a marked
slowing of conduction velocity in the circuit.91,92 Sudden
death due to VF is most common in the 6-month period after
MI. It is independently predicted by LVEF,35,93 extent of CAD,
premature ventricular beats,94 evidence of ischemia during
post-MI exercise testing,95 late potentials,96 and decreased
heart rate viability.97 Approximately one third of SCD survivors were not inducible during EP testing despite aggressive
programmed stimulation.98,99 This may represent a population in whom ischemia is important as a trigger or to facilitate the induction of reentrant arrhythmias through
modulation of the underlying EP substrate.4
The incidence and importance of bradyarrhythmias as a
mechanism of SCD is difficult to assess. Severe bradycardia,
asystole, or electromechanical dissociation is generally considered to account for about 25% of SCD.100 In patients with
advanced heart failure who are scheduled for cardiac transplantation, this percentage may be as high as 62%.101 However,
these data supporting a bradyarrhythmic origin of SCD
derived primarily from small groups of patients undergoing
long-term ECG recordings at the time of death.
Hypertrophic Obstructive Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac
muscle disorder caused by mutations in genes that affect
sarcomeric proteins.101,102 It results in small-vessel disease,
myocyte and myofibrillar disorganization, and fibrosis with
or without myocardial hypertrophy.102 These features may
result in significant cardiac symptoms and are a potential
substrate for arrhythmias. The estimated prevalence of
HCM is approximately 1 in 500.34,102 The incidence of SCD
associated with HCM has been reported to be 2% to 4% per
year.103–105 Other studies reported an overall annual mortality
rate of 1%.106–108 The authors attributed previous reported
excess mortality rates to selection and referral bias.109 The
incidence of SCD is higher in younger patients than in elderly
patients with HCM. It is the most common cause of sudden
death in competitive athletes younger than 35 years of age110
(Fig. 98.8).
Since most sudden deaths occur in young asymptomatic
or mildly symptomatic individuals, a major focus in the
management of HCM is the identification of those patients
at increased risk for SCD. Despite intense investigation, the
identification of patients at high risk remains a challenge.
The multiplicity of mechanisms that can result in SCD and
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su dden ca r di ac de at h
Unexplained
Ruptured (3%) Coronary
aorta (7%)
HD (10%)
Coronary
anomalies
(14%)
Idiopathic
LVH
(18%)
Hypertrophic
CM (48%)
≤35 years
Hypertrophic
CM (5%) Valvular HD
(5%)
MVP (5%)
Unexplained
(5%)
Coronary
HD (80%)
>35 years
FIGURE 98.8. Causes of sudden death in competitive athletes. Estimated prevalences of disease responsible for death are compared in
young (≤35 yr) athletes. CM, cardiomyopathy; HD, heart disease;
LVH, left ventricular hypertrophy; MVP, mitral valve prolapse.
their interrelation represents different aspects of the same
phenomenon. The variables that seem to identify patients at
increased risk include a history of aborted SCD or sustained
VT, family history of sudden death, identification of a highrisk genotype, multiple repetitive nonsustained VT (NSVT)
on ambulatory Holter monitoring or during exercise testing,
recurrent syncope, and severe left ventricular hypertrophy of
more than 3 cm.102,110,111 Although it was initially thought
that the magnitude of the left ventricular outflow gradient
is a risk for sudden death, data have not shown an
association.112
During upright exercise testing, HCM patients commonly demonstrate an abnormal blood pressure response,
with either a fall or failure of blood pressure to rise. This
vascular response is useful in assessing SCD risk predominantly by virtue of a normal test result identifying the lowrisk young subsets. The absence of an abnormal blood
pressure response has a negative predictive value for sudden
death, which is 97% in the young population and can be
reassuring.102,113 This vascular response can be detected in
25% of HCM patients and thus its positive predictive accuracy for SCD is low at 15%.102,113 It is a more sensitive indicator of risk in patients younger than 40 years of age and is
associated with sudden death, although the relative risk is
low (1.8).114 Therefore, a positive result should be used in
conjunction with other risk factors.
An angiographic study of children with HCM suggested
that myocardial bridging was a significant risk factor for
SCD.115 However, these children were a highly select group
by virtue of having to undergo angiography and were examined retrospectively, which makes these findings difficult to
extrapolate to the general pediatric HCM population. The
significance of myocardial bridging and ischemia in initiating secondary arrhythmias remains unknown. However, the
available data do not provide sufficient justification for
routine angiography.
Other noninvasive electrophysiologic investigations have
been used to assess the risk stratification with little success.
Furthermore, there is no convincing evidence that EP testing
has an important role in identifying patients with hypertrophic cardiomyopathy who are at high risk for sudden death.111
Some studies have suggested that inducible VT/VF during
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programmed electrical stimulation in an EP lab in a patient
with HCM is associated with a higher risk of cardiac events.116
However, the response to programmed stimulation is highly
dependent on the protocol used. An aggressive protocol using
three or more premature stimuli can be expected to produce
sustained polymorphic VT in up to 40% of patients with low
predictive accuracy for SCD.117,118 Therefore, the hazard and
inconvenience of electrophysiologic studies cannot be justified in this population. Available data on genetic markers of
SCD in patients with high-risk HCM suggests that β-myosin
heavy chain mutations may account for 30% to 40% of cases
of familial HCM.119–121 The prognosis for patients with different myosin mutations varies considerably. Genotype-phenotype correlation studies have shown that mutations carry
prognostic significance. Nevertheless, the genotype-phenotype relation has to be clarified further to allow proband risk
prediction, as the existing data have been elicited from select
groups of patients and their families. β-myosin mutations are
heterogeneous in their associated levels of risk. The ARG403GLN, ARG453CYS, and ARG719TRP mutations in the
β-myosin heavy chain are associated with a high incidence
of SCD, while the VAL606MET mutation appears to carry a
better prognosis.
Troponin-T mutations can be exceptionally lethal and
appear to be more homogeneous in their high level of risk
than prognostic allelic heterogenicity, which characterizes
the other sarcomeric gene abnormalities. Troponin-T patients
tend to exhibit a mild degree of hypertrophy122 but with significant myocyte disarray, and therefore, may be at high risk
of SCD without conspicuous evidence of disease.101
Coronary Artery Abnormalities
A higher incidence of coronary anomalies has been consistently observed in young victims of sudden death than in
adults undergoing routine autopsy (4% to 15% in the former
group vs. 1% in the latter group).123 In patients with an anomalous origin of the left main coronary artery from the right
(anterior) sinus of Valsalva, with passage of the left main
coronary artery between the aorta and the pulmonary trunk,
there is an increased risk of SCD. About 75% of the patients
reported with this malformation died before age 20, usually
during or soon after vigorous exertion.124 The mirror image
coronary anomaly in which the right coronary artery originates from the left sinus of Valsalva has also been associated
with an increased risk for SCD, although the risk is not as
high as the former congenital anomaly.125 Other unusual
variants of coronary artery anomalies, including hypoplasia
of the right coronary and the left circumflex arteries,126 the
left or right coronary artery originating from the pulmonary
trunk, and coronary arterial intussusception that causes
coronary lumen occlusion,127 could be rarely associated with
SCD. Myocardial bridges have also been associated with
SCD during exercise in healthy individuals.128 It has been
suggested that dynamic mechanical obstruction may cause
myocardial ischemia. However, evidence that myocardial
bridges are responsible for sudden death remains controversial.129 Coronary dissection with or without aortic dissection
occurs in patients with Marfan’s syndrome.130 Among other
rare mechanical causes of SCD is a rupture of the sinus of
Valsalva aneurysm with involvement of the coronary arter-
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ies.131 Prolapse of myxomatous polyps from the aortic valve
into coronary arteries has also been reported as a rare cause
of SCD.132 Coronary spasm can cause ischemia and SCD.133
Coronary arteries as seen in polyarteritis nodosa can be
associated with SCD.134 Kawasaki’s disease can cause SCD
through involvement of the coronary arteries.135
Arrhythmogenic Right Ventricular Dysplasia
Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by ventricular arrhythmias and specific right ventricular cardiomyopathy that shows fatty infiltration on the
right ventricle.136 The term arrhythmogenic right ventricular
dysplasia was first proposed in 1977 by Fontaine and colleagues136 in a report of six patients with sustained VT who
were resistant to medical therapy and did not have overt
heart disease. In the three patients who underwent surgery,
the right ventricle was dilated and had paradoxical wall
motion. Arrhythmogenic right ventricular dysplasia should
be considered as a possible differential diagnosis in patients
with frequent premature ventricular beats or VT, particularly if the ventricular arrhythmias have a left bundle branch
block morphology.137 It is a rare but important cause of sudden
death in young, otherwise healthy populations and a subtle
cause of congestive heart failure.138
Typically ARVD occurs in young adults; there is predominance for males. In a review of a series of 52 patients,139
there was an 80% predominance of males. At least 80% of
the cases were diagnosed before the age of 40 years. The
disease seems to be common in northern Italy with prevalence of 1 out 1000. The disease is familial in at least 30%
of cases with an autosomal dominant inheritance and incomplete penetrance. An autosomal recessive variant of ARVD,
which is associated with wooly hair and palmoplantar keratoderma, has been reported from Naxos Island in Greece.140,141
The most common form of presentation includes ventricular
arrhythmias, ranging from symptomatic to asymptomatic
isolated ventricular extrasystoles to sustained poorly tolerated VT with left bundle branch morphology. Sudden unexpected death could be the first presentation of the disease.142
Ventricular fibrillation and SCD may be observed during
competitive sports and strenuous exercise,143 but they can
also occur at rest or even during sleep.144 The data suggest
that like other inherited cardiomyopathies, it is one of the
major causes of SCD in an age group <35 years, accounting
for up to 25% of deaths in young athletes.145–147
The ECG in sinus rhythm shows changes compatible
with right-sided abnormality. Repolarization abnormalities
in term of T-wave inversion in precordial leads beyond V1 and
particularly between V1 and V3, which are observed in 54%
of cases, are the first signs to attract medical attention.138
Extension of T-wave inversion in all precordial leads had a
positive correlation with left ventricular involvement.148 In
patients with suspected ARVD, a QRS duration of more than
110 ms in leads V1 to V3 has a sensitivity of 55% and a specificity of 100% for this condition.149 Another diagnostic
marker of the disease is the selective prolongation of the QRS
complex duration in lead V1 to V3 of more than 25 ms compared with the QRS duration in lead V6.150
In 25–33% of ARVD patients when evaluated by standard
ECG, a more specific change with the presence of a discrete
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98
wave just beyond the QRS complex at the beginning of ST
segment can be observed. This deflection has been named
the epsilon wave (Fig. 98.9). These waves represent potentials
of small amplitude, suggesting delayed ventricular activation
of some portion of the right ventricle. The hallmark feature
of ARVD, the epsilon wave, is considered a major diagnostic
criterion for ARVD according to the task force. This is a
highly specific but insensitive criterion for ARVD.
Other criteria that have been reported are a ratio of QRS
duration in lead V1 + V2 + V3/V4 + V5 + V6 ≥ 1.2. In a recent
publication, Nasir et al.151 reported a prolonged S-wave
upstroke in V1 to V3 as the most frequent ECG finding in
ARVD, which should be considered as a diagnostic ECG
marker. In this study, prolonged S-wave upstroke in V1 to V3
of more than or equal to 70 ms and QRS dispersion of more
than or equal to 40 ms were identified as the only significant
predictors of inducibility of VT at electrophysiologic study
(EPS). Among those without ARVD, the newly proposed criterion of prolonged S-wave upstroke in V1 to V3 ≥ 55 msec was
the most prevalent ECG feature and correlated with disease
severity and induction of VT on electrophysiologic study.
This feature also best distinguished ARVD from right ventricular outflow tract (RVOT) VT.151
During VT, the ECG shows a left bundle branch block
pattern, suggesting delayed activation of the left ventricle.
The QRS axis is normal or shifted to the right when the
tachycardia originates in the pulmonary infundibulum.
There may be extreme left axis deviation when the tachycardia rises from the diaphragmatic wall or near the apex of the
right ventricle.152 Patients with ARVD who have clinical VT
may have an abnormal signal averaged ECG.153 However, if
the disease is localized, the signal averaged ECG may be
normal. Echocardiogram shows localized abnormalities of
the right ventricle. They would be recognized only if systematically sought. These abnormalities include dilatation of the
right ventricle, presence of aneurysmal areas in the infundibulum during diastole, and dyskinetic areas in the inferobasal region.
Yoerger and associates154 recently determined quantitative criteria for defining abnormal RV size and function.
They concluded that diastolic dilatation of the RV outflow
tract in the parasternal long axis view of more than 30 mm
was the most common abnormality that occurs in patients
with ARVD. Furthermore, the use of RV dysfunction on
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE 98.9. An electrocardiogram (ECG) showing the presence
of the epsilon wave (arrow).
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echocardiography as the basis for diagnosing ARVD can be
defined as an RV fractional area change (FAC) <32% or the
presence of segmental RV wall motion abnormalities. The
authors also presented the strength of abnormal RV morphology in establishing the diagnosis. In this study, anterior RV
wall motion abnormalities were common in 70% of the
affected population; abnormally prominent trabeculations
were seen in the majority of this population (54%), and sacculations were seen in 17%. These fi ndings were not present
in normal, controlled individuals.
Magnetic resonance imaging (MRI) could be the most
effective noninvasive test to locate and localize increased
adipose tissue within the ventricular myocardium. The
diagnostic value of MRI was evaluated by Auffermann and
associates155 in 36 consecutive patients with biopsy proved
ARVD. They concluded that this method can replace angiography and possibly biopsy for the diagnosis of ARVD.
Magnetic resonance imaging in combination with signal
averaged ECG may help in the differential diagnosis of
ARVD as opposed to idiopathic RVOT VT.156 Tandri and
associates157 evaluated the role of myocardial delayed
enhancement (MDE) MRI for noninvasive detection of fibrosis in ARVD. This study suggests that fibrosis of the RV in
ARVD can be noninvasively visualized using MRI. The
presence of delayed enhancement in ARVD was associated
with inducibility during EP testing and may also be useful
in risk stratification. Abnormal RV enhancement in MRI
may help improve the specificity of MRI for ARVD diagnosis. Right ventriculography remains the reference imaging
method for diagnosis of ARVD. The broad spectrum of ventriculography patterns can be observed in ARVD. The diagnosis is based on segmental wall motion and morphologic
abnormalities.
The information that is available on risk assessment of
SCD in ARVD is limited. Predictive markers of SCD in
patients with ARVD have not yet been defined in a large
prospective study focusing on survival. Furthermore, the
risk profile of asymptomatic individuals who are identified
during pedigree evaluation has not been systematically
evaluated. The mechanism of SCD is most likely secondary
to ventricular tachyarrhythmias since both VT and VF have
been documented in patients with cardiac arrest.158–160 The
type of ventricular arrhythmia does not seem to be predictive of the occurrence of SCD.161 Atrioventricular conduction disturbances are rare in patients with ARVD.162 The
value of EPS to predict the propensity for ventricular
arrhythmias depends on the population studied and the protocol used. The rate of inducibility of sustained VT is
between 57% and 94% in patients with sustained monomorphic VT and 50% and 82% in patients with a localized
form or only right-side involvement.163,164 However, the rate
is low in patients with ventricular fibrillation or left ventricular involvement.
To recap, the proper diagnosis of patients with ARVD
remains an important problem as there is no gold standard
for making the diagnosis of ARVD. The diagnosis is based
on task force criteria (Table 98.2), which allows different
investigators to use a set of homogeneous findings. However,
these criteria are clearly imperfect as the true gold standard.
A positive diagnosis is made with the presence of two major,
one major, and two minor, or four minor criteria.
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TABLE 98.2. Criteria for diagnosis of right ventricular dysplasia
I. Global and/or regional dysfunction and structural alterations
Major
Severe dilatation and reduction of right ventricular ejection
fraction with no (or only mild) left ventricular
impairment
Localized right ventricular aneurysm (akinetic or dyskinetic
areas with diastolic bulging)
Severe segmental dilatation of the right ventricle
Minor
Mild global right ventricular or ejection fraction reduction
with normal left ventricle
Mild segmental dilatation of the right ventricle
Regional right ventricular hypokinesia
II. Tissue characterization of wall
Major
Fibrofatty replacement of myocardium on endomyocardial
biopsy
III. Repolarization abnormalities
Minor
Inverted T waves in right precordial leads (V2 and V3) in
people older than 12 years of age, in absence of right
bundle branch block
IV. Depolarization/conduction abnormalities
Major
Epsilon waves or localized prolongation (>110 ms) of the QRS
complex in right precordial leads (V1–V3)
Minor
Late potentials signal-averaged ECG
V. Arrhythmias
Minor
Left bundle branch block-type ventricular tachycardia
(sustained and nonsustained) by ECG, Holter, or exercise
testing
Frequent ventricular extrasystoles (>1000/24 h) (Holter)
VI. Family history
Major
Familial disease confi rmed at necropsy or surgery
Minor
Family history of premature sudden death (<35 years) due to
suspected right ventricular dysplasia
Familial history (clinical diagnosis based on present criteria)
Valvular Heart Disease
Aortic stenosis was one of the most common noncoronary
causes of SCD in the pre-valvular surgery era. However,
asymptomatic aortic stenosis is associated with a low risk of
SCD. Both ventricular arrhythmias and bradyarrhythmias
have been associated with SCD in this population. The
primary cause of ventricular arrhythmia in this population
is believed to be subendocardial ischemia due to left ventricular hypertrophy and high end-diastolic intracavitary
pressure. The arrhythmia may be due to atrioventricular
block caused by calcium penetration in the conduction
system or neurocardiogenic mechanism. Patients with aortic
valve replacement remain at some risk for SCD caused by
arrhythmias, prosthetic valve dysfunction, or coexistent
CAD.165 Sudden cardiac death has been reported to be the
second most common mode of death after valve replacement
surgery, with an incidence of 2% to 4% over a follow-up
period of 7 years, accounting for 21% of postoperative deaths.
The incidence peaked 3 weeks after surgery and then plateaued after 8 months.166
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It is not clear whether mitral valve prolapse can cause
SCD. Its prevalence is so high that its presence may be just
a coincidental finding in victims of SCD. Severe mitral
regurgitation, left ventricular dysfunction, and myxomatous
degeneration of the valve can be markers for the patients with
higher risk for complication such as endocarditis, cerebral
embolic events, and SCD.2 It has been shown that patients
who have valvular heart disease may develop bundle branch
reentrant tachycardia, particularly after valvular replacement.167,168 The arrhythmia usually occurs in the immediate
postoperative period and can result in either cardiac arrest
or syncope.168 Almost all VTs occurred within 4 weeks after
surgery (median of 10 days). Due to the proximity of the
His-Purkinje system, valvular surgery may result in HisPurkinje system conduction abnormalities that facilitate
bundle branch reentry.
Dilated Cardiomyopathy
Approximately 10% of SCDs in the adult population occur
in patients with dilated cardiomyopathy (DCM).169,170 Overall
survivor rates after clinical diagnosis have been reported to
be 70% at 1 year and 50% at 2 years.171,172 The annual mortality in DCM has been reported to range from 10% to 50%,
depending on the severity of disease, with up to 28% of death
being classified as sudden.2,172 More recent studies of the
DCM patients on optimal medical therapy have reported
considerably lower mortality rates of around 7% at 2 years.173
Mortality rates increased the higher the New York Heart
Association (NYHA) class, but the proportion of patients
dying suddenly rather than from progressive pump failure is
highest among those with less severe heart failure (NYHA
class II or III).174 Sudden cardiac death accounts for at least
30% of all deaths in DCM and may occur in patients with
advanced as well as mild disease, and in those who appear
clinically and echocardiographically to have recovered.
In DCM, malignant ventricular arrhythmias are not the
only cause of SCD. Reports vary on the extent to which other
mechanisms could be responsible for SCD. In advanced forms
of DCM, other causes such as bradyarrhythmias, systemic
embolization, pulmonary emboli, or pulseless electrical
activity may account for up to 50% of cardiac arrests.175,176
However, malignant ventricular arrhythmia is the most
common single cause of SCD in DCM. Predictors of overall
mortality include ejection fraction, end-diastolic dimension
or volumes, male gender, older age, hyponatremia, persistent
third heart sound, sinus tachycardia, elevated pulmonary/
capillary wedge pressure, systemic hypertension, and atrial
fibrillation.177
In a recent study of noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy, Grimm and
associates178 concluded that reduced LVEF and lack of betablocker use were important arrhythmia risk predictors in
idiopathic DCM, whereas signal averaged ECG, baroreflex
sensitivity, heart rate variability, and T-wave alternans do
not seem to be helpful for arrhythmia risk stratification. The
major shortcoming of ejection fraction and other variables
that reflect disease severity is the lack of specificity for
arrhythmic death.
Other investigators have focused on syncope and ventricular arrhythmia. In a study by Middlekauff and associ-
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ates,179 the probability of SCD was 45% among patients with
NYHA functional class III to IV who had unexplained
syncope in 1 year. This risk factor was specific for SCD and
did not predict the risk of dying from progressive heart
failure. Nonsustained VT correlates with disease severity
and is seen during ECG monitoring in approximately 20%
asymptomatic or mildly symptomatic patients and up to
70% of severely symptomatic patients.180,181 It has been
reported that NSVT was a sensitive (80%) but not specific
(31%) marker of SCD.180 A significant association between
the presence of couplets, NSVT, or PVCs of more than 1000
per day and SCD was reported in a study investigating 74
patients with dilated cardiomyopathy, NYHA class II to III
of whom 12 died suddenly.181 Inducibility of VT during programmed electrical stimulation predicts sudden death,182 but
failure to induce VT is not reassuring.183 In a meta-analysis
of six programmed electrical stimulation (PES) studies, which
included a total of 288 DCM patients, PES failed to identify
75% of patients who died suddenly.184
The role of microwave T-wave alternans for arrhythmia
risk stratification in DCM patients has to be determined.
Several studies evaluated its role for risk stratification of
SCD. Klingenheben et al.185 observed 13 arrhythmic events
in 107 patients with congestive heart failure of mixed pathogenesis, including 40 patients with nonischemic DCM. Of
the 13 patients with arrhythmic events during follow-up in
this study, 11 had positive T-wave alternans and two had
indeterminate T-wave alternans results, whereas a negative
T-wave alternans test predicted freedom of arrhythmic event
in all patients. Kitamura et al.186 investigated 104 patients
with DCM and observed major arrhythmic events in 12 of
83 patients (14%) during a mean follow-up of 21 months after
21 patients with an indeterminate T-wave alternans test had
been excluded from the analysis. As a result, Kitamura et al.
found that 11 of 12 arrhythmic events occurred in patients
with a positive T-wave alternans test with additional arrhythmia risk for patients with an onset heart rate of T-wave
alternans of ≤100 beats per minute (bpm). Finally, Hohnloser
et al.187 found a positive microvolt T-wave alternans analysis
to be the only significant arrhythmia risk predictor by multivariate analysis in 137 patients with DCM during mean
follow-up of 14 months. In contrast to these studies, the
study by Grimm et al.178 did not find a positive T-wave alternans to be associated with an increased arrhythmia risk in
this population, whereas a negative T-wave alternans test
showed a trend toward decreased arrhythmia risk by univariate analysis but not by multivariate analysis.
Primary Electrophysiologic Abnormalities
These are conditions in which an EP abnormality predisposes the patient to VT/VF in the absence of structural heart
disease. Electrocardiographic findings may provide a clue to
diagnosis.
Congenital Long QT Syndrome
The idiopathic long QT syndrome (LQTS) is a congenital
disease with frequent familial transmission, characterized
primarily by prolongation of the QT interval and by the
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occurrence of life-threatening tachyarrhythmias, particularly in association with emotional or physical stress. It is
caused by the prolongation of repolarization due to abnormal
inward movement of sodium or outward movement of potassium from cardiac myocytes, creating prolonged periods of
intracellular positivity.188 Such prolongation of repolarization
could cause the development of early afterdepolarizations,
which trigger TdP in patients with congenital or acquired
LQTS. The diagnosis of LQTS is reasonably certain when the
corrected QT (QTC) interval is unequivocally prolonged
(QTC ≥0.480 ms) in the absence of secondary causes or if
the QTC is borderline prolonged with either an abnormal
configuration of the T wave or a history of unexplained
syncope.189
Schwartz and colleagues190 developed LQTS diagnostic
criteria with a scoring system ranging from a minimum
value of 0 to maximum value of 9. The patient who has a
score of 4 or higher has a high probability of LQTS (Table
98.3). Congenital LQTS includes a group of genetic disorders
that affect cardiac ion channels. One form of LQTS that was
originally described in 1957 by Jervell and Lange-Nielsen191
was associated with deafness and was thought to be an
autosomal recessive disorder. A similar condition without
deafness but with autosomal dominant transmission was
subsequently reported in 1963 by Romano and colleagues192
and in 1964 by Ward.193 The discovery that distinct LQTS
variants were associated with genes coding for different ion
TABLE 98.3. Long QT syndrome diagnostic criteria
Pointsa
Criterion
b
ECG fi ndings
QTCc
≥480 ms
460–470 ms
450 ms (in males)
Torsades de pointesd
T-wave alternans
Notched T wave in three leads
Low heart rate for agee
Clinical history
Syncope
With stress
Without stress
Congenital deafness
Family historyf
Family members with defi nite LQTSg
Unexplained sudden cardiac death below age 30 years
among immediate family members
3
2
1
2
1
1
.5
2
1
.5
1
.5
ECG, electrocardiographic; LQTS, Long QT syndrome.
Scoring: ≤1 point, low probability of LQTS; 2–3 points, intermediate probability of LQTS; ≥4 points, high probability of LQTS.
a
2 0 51
channel subunit has had a major impact on the diagnosis and
analysis of LTQS patients. Over 300 different mutations
involving seven different genes (LQTS1 to LQTS7) have now
been reported.194 These mutations account for an estimated
50% to 60% clinically manifest long QT syndromes.195 The
specific mutant cardiac ion channel genes that encode abnormal channel proteins include the following:
LQT1
A mutant KCNQ1 (KvLQT1) gene on chromosome 11 encodes
an abnormal potassium channel protein (α subunit). The
KCNQ1 gene codes a pore forming α subunit and it coassembles with the protein coded by the KCNE1 (min K) gene
to form the slowly activating component of the delayed rectifier IKS potassium current. The IKS current plays a critical role
in repolarization as well as the necessary rate-dependent
shortening of the action potential.196 Patients with Jervell and
Lange-Nielsen syndrome, dominant for the long QT manifestation but recessive for associated deafness, were found to
have a homozygous mutation of KCNQ1 (KVLQT1). When
expressed with min K protein (β subunit) the α subunit
produces a negative effect in the slowly activating delayed
rectifying potassium current (IKS).189,197
LQT2
The KCNH2 (HERG) gene encodes the α subunit and the
KCNE2 (MiRP1), the β subunit of the rapid component of
delayed rectifier potassium current (IKr), which is the major
contributor to phase III rapid repolarization. A mutant HERG
gene on chromosome 7 encodes an abnormal potassium
channel protein that produces a dominant negative effect
in rapidly activating delayed rectifier potassium current
(IKr).188,198,199 It would represent 35% to 45% of genotype long
QT mutations.
LQT3
The SCN5A gene encodes the α subunit of the major cardiac
sodium channel,200 and various mutations of the SCN5A gene
on chromosome 3 can encode an abnormal sodium channel
protein, resulting in a continued leakage of sodium current
INa into the cell with prolongation of repolarization.189,200
LQT4
Ankiryn B2 gene encodes the Ankiryn B protein. So far, only
one family has been described with the mutation of the
Ankiryn B gene, causing LQT4 syndrome.201 The affected
patients present with a long QT interval associated with
severe sinus bradycardia and episodes of atrial fibrillation.
Ankiryn B is a structural protein, which most likely participates in the anchoring of several ion channels and proteins
to the cell membrane.
b
In the absence of medications or disorders known to affect these ECG
features.
c
QTC calculated by Bazzett’s formula, where QTC = QT/RR 2.
d
Mutually exclusive.
e
Resting heart rate below second percentile for the age.
f
The same family member cannot be counted in either of the following
criteria.
* Defi nite LQTS is defi ned by LQTS score ≥4.
g
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LQT5
The KCNE1 gene mutation accounts for 2% to 5% of genotyped long QT mutations, causing the LQT5 syndrome and
in homozygous or compound heterozygous (two differently
mutant alleles of the same gene) for the Jervell and LangeNielsen type II syndrome.202,203
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LQT6
The KCNE2 gene can have loss of function-type mutations,
which may cause the rare LQT6 syndrome.204
LQT7
The KCNJ2 (Kir2.1) gene codes for the inward rectifier potassium current (IK1), which contributes to phase-3 repolarization and to maintenance of the resting membrane potential.198
A mutation of KCNJ2 gene resulting in loss of function
would cause the Anderson syndrome (LQT7),205 which is a
rare disorder characterized by potassium sensitive periodic
paralysis, dysmorphic features, and a variable degree of QT
interval prolongation, often with giant U waves. The penetrance is incomplete, similar to the other long QT syndromes,
and the specificity of the gene varies.196 Although sudden
death is rare, bidirectional or polymorphic tachycardia has
been documented.206
The prevalence of LQTS is estimated to be between 1 in
3000 to 5000 individuals, with onset of symptoms typically
occurring during the first two decades of life. Long QT syndrome has a wide spectrum of presentation ranging from
marked prolongation of the QT interval and recurrent
syncope to subclinical forms with borderline QT prolongation and no arrhythmias.207 Syncope is the most common
clinical manifestation in LQTS, and its first occurrence is
commonly between ages 5 and 15. Males become symptomatic earlier than females.208 The age of occurrence of the first
syncope has prognostic implications. If the first syncope
occurs before the age of 5, it would predict a severe form of
disease, and syncope occurring in the first year of life is
associated with extremely poor prognosis.34 A history of
cardiac arrest increases by 13 times the probability of cardiac
arrest or SCD at follow-up. It would provide a rationale for
the use of ICD in secondary prevention of SCD.209
Conclusive data on the predicted accuracy of a family
history of SCD is not yet available. Risk stratification based
on an individual genetic defect is still being defined, but a
few firm points have already been established. The incidence
of a cardiac event is higher in LQT1 and LQT2, whereas the
lethality of cardiac events is higher in LQT3 than in LQT1
and LQT2 patients.34,188 Most LQTS patients are not inducible during programmed electrical stimulation, and therefore, PES should not be used for risk stratification.210
An international, prospective longitudinal study of
patients with congenital LQTS was initiated in 1979.211 The
Chromosome 3
Chromosome 7
98
registry shows that the mean age at enrollment was
21 ± 15 years. The mean age at the first cardiac event was
14 ± 12 years, 85% had a family member with QTC of
more than 0.44 second, and 69% were women. The frequency of syncope was 5% per year and the cardiac mortality was 0.9% per year. Syncope occurred in association
with intense emotion, vigorous physical activity, or arousal
by auditory stimuli. In this study, the risk of syncope or
sudden death was related to the length of the QTC, a
history of prior cardiac events, and an elevated heart rate.167
Although the genetic analysis of LQTS patients reveal that
the syndrome is characterized by significant genetic heterogeneity, different mutations in different genes can result
in a similar phenotypic presentation. The LQTS1 syndrome
is characterized by long T-wave duration (Fig. 98.10). LQTS2
patients usually have small and/or notched T waves, while
in LQTS3 patients the onset of T wave is prolonged
(Fig. 98.10).212
Acquired Long QT Syndrome
Acquired long QT syndrome describes a pathologic QT
interval prolongation, generally to 550 to 600 ms, upon
exposure to an environmental stressor and reversion back
to normal following withdrawal of the stressor.213 When QT
intervals are markedly prolonged, the polymorphic ventricular tachycardia and TdP become a real risk. These episodes
of ventricular tachyarrhythmia can be self-limited or can
degenerate to fatal arrhythmias such as ventricular fibrillation. The drugs that produce acquired long QT syndrome
almost inevitably target specific potassium current in the
rapid component of the delayed rectifier potassium channel
(IKr). QT interval prolongation, with the exception of that
induced by quinidine, is increased at high plasma concentrations. Therefore, genetic variants that impair elimination
of an IKr blocking agent may increase the risk of TdP. The
genetic analysis has also identified polymorphisms in long
QT syndrome and channel genes, some of which may be
overpresented in patients with drug-induced or other
arrhythmias.
Antiarrhythmic drugs have long been recognized as a
possible cause of ventricular tachyarrhythmias, TdP, and
SCD. Class IA agents such as quinidine can cause TdP by
prolongation of QT interval. The reported incidence of TdP
from quinidine ranges from 0.5% to 8.8%. Quinidine at low
plasma concentrations blocked potassium channels, whereas
Chromosome 11
II
aVF
V5
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FIGURE 98.10. Electrocardiogram recordings from leads II, aVF, and V5 in
three patients from families with long
QT syndrome linked to genetic markers
on chromosomes 3, 7, and 11. None of
the patients were receiving β-adrenergic
blocking medication at the time the
ECGs were obtained.
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at higher plasma concentrations it also blocked sodium channels. Therefore, QT prolongation and TdP can be observed
even at subtherapeutic doses. Sotalol, a class III drug that
blocks potassium channels and therefore lengthens repolarization, can be responsible for QT prolongation and TdP.
Prolonged QT is dose related with increasing incidence at
higher doses. Ibutilide is another class III drug that prolongs
repolarization by activating the slow inward sodium current
during the plateau phase. Polymorphic VT has been reported
after the infusion of ibutilide. Almost all of these episodes
occurred within a few hours after ibutilide infusion. Dofetilide is also a class III drug that targets the rapid component
of the delayed potassium rectifier (IKr) and can cause significant QT prolongation, which may result in TdP. We earlier
discussed in detail the role of a number of nonarrhythmic
drugs in the genesis of ventricular arrhythmias caused by
QT prolongation. Table 98.4 summarizes the causes of
acquired LQTS.
TABLE 98.4. Causes of acquired long QT syndrome
Antiarrhythmic agents
Class IA. Quinidine, procainamide, disopyramide,
N-acetylprocainamide
Class III. Sotalol, bretylium, ibutilide, amiodarone (low risk for
torsades de pointes)
Class IV. Bepridil, mibepridil
Antihistamines
Astemizole, terfenadine
Antimicrobials
Erythromycin, clarithromycin, azithromycin
Trimethoprim-sulfamethoxazole
Ketoconazole, cotrimoxazole
Pentamidine
Chloroquine
Serotonin antagonists
Ketanserin, zindeline
Lipid lowering agents
Probucol
Gastrointestinal agents
Cisapride, liquid protein diets
Psychotropic agents
Tricyclic and tetracyclic antidepressants
Phenothiazines
Haloperidol
Risperidone
Other drugs
Chloral hydrate amantadine
Anthracycline
Diuretics (reduced K+, Mg 2+)
Vasopressin (severe bradycardia)
Organophosphorus
Insecticides
Electrolyte abnormalities
Hypokalemia
Hyponatremia
Hypocalcemia
Bradyarrhythmias
Anorexia nervosa and altered nutritional states
Cerebrovascular diseases
Intracranial and subarachnoid hemorrhage
Intracranial trauma
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Wolff-Parkinson-White Syndrome
Sudden death in the Wolff-Parkinson-White (WPW) syndrome is rare. The estimated prevalence of WPW varies from
0.1% to 0.3% of the population.214,215 Sudden cardiac death in
the majority of patients with WPW occurs during atrial
fibrillation. In these patients, antegrade conduction via the
accessory pathway is very rapid. This rapid ventricular
response causes hemodynamic dysfunction and disorganization of the ventricular rhythm, which leads to VF and SCD.
The estimated incidence of SCD in WPW has been suggested
to be from 0% to 0.4%.216,217 The most pessimistic estimate
would be no more than one per 100 patient-years.218 A review
of retrospective data from patients resuscitated from VF and
found to have WPW pattern, showed that the most important
risk factor was a rapid ventricular response over the accessory pathway during atrial fibrillation. The shortest R-R
interval following atrial fibrillation was <250 ms.219,220
Although this criterion identifies virtually 100% of patients
at risk for developing VF, its specificity is low. Other risk
factors include the presence of multiple accessory pathways,221 the presence of symptoms (particularly a history of
both reciprocating tachycardia and atrial fibrillation), and
the use of digitalis and intravenous verapamil. Patients with
Ebstein’s anomaly are probably also at a greater risk of developing VF.222 Syncope has shown no predictive value for SCD
in one study.223 However, SCD may be the first manifestation
of the disease.224 During EPS, approximately 20% of asymptomatic patients would manifest a rapid ventricular rate
during induced atrial fibrillation.225 But the specificity and
positive predictive value of this invasive prognostic indicator
may be too low for routine use in asymptomatic patients
with WPW.225 Therefore, the use of EPS for risk stratification
should be reserved for select patients with a family history
of SCD or individuals whose lifestyle or occupational activities require that risk is assessed.
Brugada’s Syndrome
In 1992, Brugada and Brugada226 described eight patients with
a history of aborted SCD who had a distinct electrocardiographic pattern of right bundle branch block with ST segment
elevation in the right precordial leads (V1 to V3) and a normal
QT interval without any demonstrable structural heart
disease. There is a male predominance (an 8 : 1 to 10 : 1 ratio
of males to females).227,228 Although age at presentation varies
from 2 to 77 years, there was a peak around the fourth
decade.228 The risk of recurrent syncope or SCD was high.
During a mean follow-up of 34 ± 32 months, an arrhythmic
event occurred in 34% of previously symptomatic patients
and 27% of patients without any prior event.
Brugada syndrome is an inherited cardiac arrhythmia
disorder caused by mutation in the cardiac sodium channel
gene SCN5A.229 Carriers of the disease may develop a variety
of cardiac arrhythmias including ventricular tachycardia
and ventricular fibrillation. The symptom reaches endemic
characteristics in some areas, such as Southeast Asia, where
it has been reported to be the most common cause of natural
death in men of less than 50 years of age.230 The diagnosis
of the syndrome is based on a combination of ECG features
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5/2/99
type 1
13/2/99
type 2
type 3
V1
V2
V3
V4
V5
V6
1 mV
500 ms
FIGURE 98.11. Precordial leads of a resuscitated patient with
Brugada syndrome. Note the dynamic ECG changes in the course
of a couple of days. All three patterns are shown. Arrows denote the
J wave. Calibrations are given.
(Fig. 98.11) and symptoms of syncope or aborted SCD caused
by rapid polymorphic VT. Three different ECG patterns have
been reported in individuals with proven Brugada syndrome.231 The type I ECG (Fig. 98.11) is the classic characteristic ECG of Brugada syndrome. The patients in this group
have cove-type ST segment elevation in leads V1 to V3. The
two other patterns—types II and III (Fig. 98.12)—concern the
saddleback-type ECG, which are suspicious but not characteristic of Brugada syndrome. Type II and III patterns are
frequently seen in individuals with true Brugada syndrome
at the time of near normalization of the ECG. The prevalence
of saddleback or cove-type ST elevation ranges from 0.5% to
0.6%.232,233 These studies on a large-scale population revealed
that the saddleback-type ST elevation was much more frequent in the general population,232,233 while the cove-type ST
elevation in the European studies was a very infrequent
finding among asymptomatic individuals.234,235 Furthermore,
the Japanese registry data and the European experience with
symptomatic patients revealed that the majority of symptomatic patients had cove-type ST elevation.236 These data
suggest that cove-type ST elevation carries a higher risk of
arrhythmic events. Unfortunately, the characteristic covetype ECG has a dynamic nature during long-term follow-up
in up to 50% of the patients. The ECG normalizes transiently
or in some cases becomes the saddleback type.237
The administration of the class I antiarrhythmic drugs
(sodium channel blockers) ajmaline, procainamide, or flecainide unmasks the characteristic cove-type pattern in
patients with normal ECG or baseline saddleback type.237
The natural history of the disease depends on the presence
of symptoms.236 In a study by Brugada and associates,238 62%
of patients who were identified following aborted SCD had
recurrent documented VF or SCD during 54 months’ followup. In this study, the calculated yearly recurrence rate of
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98
ventricular fibrillation was 13.7% in the aborted SCD group
and 8.8% in the group of patients presenting with syncope.
Controversy persists regarding risk stratification of
patients with an asymptomatic Brugada electrocardiogram
and the best treatment approach in this population. Two
recent published papers by Brugada and associates239,240 of 547
patients with spontaneous or drug-induced cove ST elevation
without previous sudden death, showed that 8% of this population suffered sudden death or documented ventricular
fibrillation during the 24-month follow-up. Multivariate
analysis showed that inducibility of sustained ventricular
arrhythmia during programmed ventricular stimulation
with (p < .0001) and a history of syncope (p < .01) were the
main predictors of arrhythmic events during follow-up. The
authors concluded that the individuals with a spontaneously
abnormal ECG should undergo programmed ventricular
stimulation for appropriate risk stratification. If inducible,
then the implantation of an implantable cardiodefibrillator
(ICD) is recommended. However, in noninducible patients,
the data from the study showed a low event rate during
follow-up, not justifying an aggressive approach.
Furthermore, in asymptomatic members of a family with
Brugada syndrome with a normal ECG, a pharmacologic test
should be done to identify carriers of the disease. Those
individuals with the characteristic ECG (spontaneously or
after drug challenge) should undergo programmed ventricular stimulation. However, another study by Priori and Napolitano241 concluded that in their experience, the rate of events
Type 1
Type 2
Type 3
FIGURE 98.12. Electrocardiogram traces that may suggest the presence of Brugada syndrome: type 1 (>2 mm ST elevation with “covetype morphology”); type 2 (ST elevation >2 mm and “saddleback”
morphology), and type 3 (ST elevation 2 mm and “saddleback
morphology”).
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after diagnosis among asymptomatic patients is significantly
lower than that reported by Brugada and Brugada. In their
study, asymptomatic patients had an accumulative probability of 14% experiencing a cardiac arrest by age of 40, which
corresponds to an incidence of cardiac arrest of 0.35% per
year. The reasons underlying the markedly different occurrence of cardiac arrest in the two populations is not clear.
Brugada and associates postulated that the difference could
be due to inclusion of individuals with a saddleback-type
ECG in some other studies. The two groups agree that
patients resuscitated from cardiac arrest and patients with a
spontaneous ECG pattern and a history of syncope should
receive an ICD. However, Priori and associates concluded in
their study that asymptomatic individuals and patients with
a diagnostic pattern that can be observed only after pharmacologic challenge are at low risk of cardiac events, and therefore, management of patients with Brugada syndrome should
not be based on programmed electrical stimulation.
Pathogenesis of electrocardiographic changes seems to be
secondary to the heterogeneity of repolarization across the
wall of the right ventricular outflow tract, which contributes
to the electrocardiographic pattern and the genesis of arrhythmias in Brugada syndrome. In contrast to endocardial cells,
action potentials of epicardial cells display a pronounced
phase I, referred to as spike and dome morphology. The transient outward current Ito, which is present in epicardial cells
and virtually absent in endocardial cells, underlines the difference between the action potential configurations.242 The
loss of the action potential dome occurs in epicardial cells,
but nonendocardial cells may cause transmural heterogeneity and ST segment elevation as a result of transmural current
flow from the endocardium to the epicardium.243 Cardioselective and Ito-specific blockers are not available. The only
agent on the U.S. market with significant Ito-blocking properties is quinidine. It is for this reason that it was suggested
that this agent may be of therapeutic value in Brugada syndrome.244 Studies have shown quinidine to be effective in
restoring the epicardial action potential dome and therefore
normalizing the ST segment and preventing phase II reentry
and polymorphic VT in experimental models of Brugada syndrome.245 Clinical evidence of the effectiveness of quinidine
in normalizing ST segment elevation in patients with Brugada
syndrome has been reported. However, relatively high doses
of quinidine are recommended (1200 to 1500 mg per day).246
Short QT Syndrome
The short QT syndrome constitutes a new clinical entity
that is associated with a high incidence of SCD, syncope, or
atrial fibrillation even in young patients and newborns.247
The characteristic ECG fi nding is the persistently short QT
interval (QTC < 320 ms or below 80% of the normal QT
interval) (Fig. 98.13). The mean age of patients with a short
QT syndrome was 40 ± 24. The age of sudden death victims
varied between 3 months and 70 years.248 The risk for an
arrhythmic event is high in patients with a short QT syndrome, comprising syncope or SCD due to ventricular
tachyarrhythmias. Furthermore, episodes of atrial fibrillation were documented in patients with a short QT syndrome
even in adolescents.249 In fact, the first patients with a short
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I
V1
II
V2
III
V3
aVR
V4
aVL
V5
aVF
V6
FIGURE 98.13. Twelve-lead surface ECG of a 16-year-old patient
with congenital short QT syndrome (QT interval 248 ms, QTc
252 ms, paper speed 25 mm/s).
QT syndrome were discovered because of symptomatic
episodes of atrial fibrillation. In patients with a short QT
syndrome, the lack of adaptation of the QT interval during
exercise with increasing heart rate is present.250 Furthermore, a paradoxical behavior of the QT interval with shortening during low heart rate has been observed in two
symptomatic patients. Eleven patients have undergone invasive electrophysiologic analysis. During programmed atrial
and ventricular stimulation, the atrial and ventricular effective refractory periods were extremely short. Additionally, in
a very high percentage of patients, ventricular tachyarrhythmia, predominantly ventricular fibrillation/ventricular
flutter, was inducible. The role of inducibility of ventricular
tachycardia in short QT syndrome cannot be determined at
the present because of the limited number of patients.247
Recently, mutations of two genes have been identified in
the four studied families, suggesting genetic heterogeneity.251,252 Initially, in two families missense mutations of the
KCNH2 (HERG) gene responsible for gain of function of the
IKr channel have been described.252 The mutation causes a
loss of the normal rectification of the current plateau voltages, which results in a significant increase in IKr during the
action potential plateau and leads to an abbreviation of the
action potential and refractoriness. The other mutation was
identified in a patient with slightly different phenotype presentation.251 A previously asymptomatic 70-year-old patient
presented with ventricular fibrillation in the setting of the
short QT interval. In this patient, a Novo KCNQ1 (KvLQT1)
gene mutation resulting in gain of function of the IKS channel
has been identified.251 Interestingly, another gain of channel
function-type mutation of the same KCNQ1 gene has been
associated with familial atrial fibrillation without QT shortening. The gain of function mutation effect IKS resulted in
abbreviation of the action potential duration and shortening
of the QT interval. The possible substrate for the development of ventricular tachyarrhythmias may be a significant
transmural dispersion of the repolarization due to heterogeneous abbreviation of the action potential duration.247
The ICD is the therapy of choice in patients with syncope
and a positive family history of SCD. However, ICD therapy
in patients with a short QT syndrome has an increased risk
for inappropriate shock due to possible T-wave oversensing.
The impact of sotalol, ibutilide, flecainide, and quinidine on
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QT prolongation has been evaluated, but only quinidine
effectively suppressed the gain of function in IKr with prolongation of the QT interval. In patients with a mutation in
HERG, it rendered ventricular tachycardias/ventricular
fibrillation noninducible, and stored the QT interval/heart
rate relationship toward the normal range.247 It may serve as
a joint therapy along with ICD.
Idiopathic Ventricular Tachycardia
Idiopathic VTs with monomorphic morphology, which occur
in patients with structurally normal hearts, include the
paroxysmal, repetitive form that may originate from the
following:
• Right ventricular outflow tract: It entails left bundle
branch block morphology and an inferior axis, and
terminates with vagal maneuvers such as adenosine
infusion.253
• Left posterior septum: Also called fascicular tachycardia
because it is often preceded by a fascicular potential. It
has right bundle branch block morphology with left axis
deviation. Calcium channel blockers usually suppress
this arrhythmia. Sudden cardiac death is extremely rare
in patients with idiopathic VT.
Catecholamine-Sensitive Polymorphic
Ventricular Tachycardia
These VTs are associated with less favorable outcome than
idiopathic monomorphic VTs. In 1994, Leenhardt and colleagues254 reported this variant. In this series, VTs were typically triggered by emotion or physical activity and could be
reproduced by exercise or infusion of isoproterenol. Catecholaminergic polymorphic ventricular tachycardia (CPVT)
is characterized by physical or emotional stress that induced
bidirectional or polymorphic ventricular tachycardia,
syncope, and sudden death in the setting of a structurally
normal heart. The syndrome was originally described in
children with a mean age at the onset of symptoms of 7.8 ±
4 years.254 The family history of syncope or sudden death was
noted in 30% of patients. During a 7-year follow-up period,
there were five deaths of the initial 21 patients, and four of
the five deaths were sudden.
A typical sequence of events was noted during exercise.
Although baseline rhythm was normal, sinus tachycardia
would lead to junctional tachycardia during exercise. Isolated monomorphic premature ventricular beats gradually
increased in frequency and became polymorphic, followed
by bursts of monomorphic and bidirectional salvos. If activity persisted, polymorphic VT and VF eventually occurred.
The arrhythmia can be reproduced by exercise stress test
above a certain rate of sinus tachycardia in 80% of the
affected individuals.255 The mortality without treatment is
high.255 Beta-blockers are usually effective, but in many
patients ICD implantation may also be required.255 Mutations of two different genes are responsible for approximately
50% of the cases of catecholaminergic polymorphic ventricular tachycardia.256
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The hRyR2 mutation causes about 50% of the genotype
clinical cases of the CPVT.255 These mutations show autosomal dominant inheritance. The hRyR2 gene of the cardiac
ryanodine receptor plays an important role in the calcium
homeostasis of cardiac cells. During the plateau phase of
action potential, the calcium enters the cells through the
voltage gated L-type calcium channels and serves as a trigger
for the sarcoplasmic reticulum calcium release channel.
Some mutations of the cardiac ryanodine gene, in the presence of sympathic activation, seem to result in a gain of
function of the ryanodine release channel, leading to calcium
leak. These data strongly support the concept of genetically
determined intracellular calcium overload, possibly due to
leakage of calcium from the sarcoplasmic reticulum. The
natural history of CPVT is still poorly defined because the
large studies are not available. The disease is associated with
a high risk of SCD at a young age, but the risk stratification
parameters are missing. Inducibility at PES is not considered
as an accurate predictor of outcome. A history of syncope, a
previous occurrence of SCD, and rapid and sustained runs of
ventricular tachycardia in Holter recording or during exercise stress tests are regarded as predictors of risk of major
arrhythmic events. Treatment is based on beta-blocker
therapy. However, the relevance of a relatively high mortality
in patients treated with beta-blockers (10.5%) may indicate
the need for an ICD, at least in those patients with early
onset of symptoms and a positive family history of SCD.
Idiopathic Ventricular Fibrillation
Idiopathic ventricular fibrillation is more common than previously recognized. An estimated 1% to 5% of SCDs are due
to idiopathic VF without apparent evidence of structural
heart disease.257,258 The mean age is the mid-30s to early 40s,
and the ratio of men to women is approximately 2 : 1. Preliminary data suggest that these patients have a 30% recurrence rate of VF, syncope, and cardiac arrest. This means that
70% of the patients remain free of symptoms during followup. Therefore, it is extremely important to risk stratify the
patients and identify those at high risk. Unfortunately, at
present, no predictor of poor outcome has been identified.
Among the patients enrolled in the European registry,
UCARE, only 50% were inducible by PES. Both positive and
negative predicted values or PES were low.259 According to
UCARE investigators, prevention of recurrence with antiarrhythmic agents and beta-blockers failed.259 Therefore, the
survivors of idiopathic ventricular fibrillation should be
regarded as candidates for an ICD.
Sinus Node and Atrioventricular
Conduction Disturbances
Bradyarrhythmias account for approximately 20% of documented SCDs.260 Sinus node dysfunction can be associated
with dizziness, presyncope, syncope, and probably SCD.
Sinus node dysfunction may cause SCD in patients with left
ventricular dysfunction. The pathologic mechanism that
leads to death is usually a prolonged pause with no escape
rhythm or ventricular arrhythmia due to pause-dependent
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repolarization abnormalities. Unfortunately, very few parameters are available for the evaluation of risk of SCD in patients
with sinus node dysfunction. A permanent pacemaker in
patients with sinus node dysfunction relieves symptoms and
improves quality of life. However, the effect of pacing on
survival is not known. Primary fibrosis (Lenegre’s disease)261
or secondary mechanical injury (Lev’s disease)262 of the HisPurkinje system can be the cause of intraventricular conduction abnormalities and symptomatic atrioventricular block.
However, these entities are less commonly associated with
SCD.
The significance of bundle branch block as an independent marker for SCD is also controversial. The bundle branch
block has been implicated as a contributing factor in SCD,
largely due to its frequent presence in high-risk patients. In
patients with a normal heart, bundle branch block does not
appear to reflect an adverse outcome. In patients with myocardial infarction, receiving thrombolytic therapy, bundle
branch block identifies a subset at high risk.263 Sudden cardiac
death may be the initial manifestation of congenital complete heart block in previously asymptomatic patients, even
without structural heart disease. The mechanism of SCD is
attributed to either pauses without an escape pacemaker or
pause-mediated ventricular tachyarrhythmias.264
In patients with congenital complete heart block, a low
heart rate (<50 bpm), the presence of a prolonged QT interval,
and the existence of structural heart disease constitute risk
factors for SCD and therefore, are indications for pacemaker
implantation. The occurrence of polymorphic ventricular
tachyarrhythmia and SCD following atrioventricular (AV)
node radiofrequency ablation has been observed in 2% to 3%
of patients following this procedure. The mechanism of SCD
is still unclear. It may be due to bradycardia-dependent prolongation of repolarization and refractoriness, mainly in the
first 24 hours after the procedure, particularly in patients
whose duration of the repolarization is already prolonged.
Recommendations for dealing with this problem include
pacing at relatively higher rates and ECG monitoring during
the first 24 hours after the procedure.265
Pathophysiology of Sudden Cardiac Death
While the final common pathway for SCD is malignant ventricular arrhythmia, the cascade of events that lead to such
an end point is variable and depends on the underlying structural, electrical, or environmental abnormalities. The most
relevant of these are discussed in the following subsections.
Stable Coronary Artery Disease
This is the most common cause of SCD, even in patient
populations that did not have a premorbid diagnosis of
CAD.266,267 A healed MI has been found in up to 70% of
patients with SCD.268 While there is a strong association
between CAD and SCD,269 the causative role for acute ischemia is somewhat less clear. The results of pathologic studies
of victims of SCD have been mixed,270–272 with some studies
showing as few as 20% of victims have acute coronary
thromboses, while other studies have shown an incidence
upward of 95%.
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The role of acute ischemia in the genesis of SCD in
patients with CAD remains debated.273–277 There is no preponderance of evidence to suggest a clinical progression of
ischemic symptoms prior to SCD,276 and it has been uncommon for monitored patients to show ischemic changes prior
to ventricular fibrillation.277,278
Ischemia leads to a cascade of events that include calcium
overload, decrease in pH, and inhibition of the sodium-potassium pump, all of which may then lead to triggered activity
in the form of delayed afterdepolarizations (DAD),279,280
which are associated with any state of calcium overload and
as such, can provide the trigger for the onset of VF.281
It has been clearly shown that transient ischemia in the
setting of a previous myocardial scar is extremely arrhythmogenic and could account in part for the low incidence of
acute coronary occlusion in some studies.282 Alternatively,
spontaneous thrombolysis may explain the lower incidence
of acute thrombosis.283
Hypertrophic Cardiomyopathy
This is the most common cause of SCD in young athletes.284
The incidence of death is 2% to 3% per year.285 Most of the
patients have had no symptoms prior to death. Although
there is a correlation between the degree of hypertrophy and
the incidence of SCD,286 the actual mechanism leading to
SCD has not been clearly established. There has been no
clear association between diminished left ventricular (LV)
filling, LV noncompliance, or outflow tract gradients and
SCD.287,288 It has been shown that patients with SCD and
HCM have a higher incidence of myofibrillar disarray than
patients with HCM who die of heart failure.289 It is thought
that such disarray increases anisotropic conduction and acts
as the substrate for microreentrant circuits and VF.290
Note that in this patient population atrial arrhythmias
may be the inciting factor that leads to ischemia and subsequently to malignant VF and death.
Dilated Cardiomyopathy
Patients with congestive heart failure (CHF) have up to a
ninefold increase in the risk of SCD compared to the general
population.291 Prolongation of the APD is a uniform finding
in failing hearts.292 This is in part due to the downregulation
in potassium channels, which leads to APD prolongation by
delaying repolarization phase of the action potential (AP).293,294
Furthermore this change in APD is nonuniform throughout
the myocardium.295 The role of APD prolongation in the
onset of VF has not been clearly defi ned, but it is thought
that the extent to which dispersion of repolarization accompanies such changes is a determining factor.296
It is also thought that changes in calcium homeostasis
play a role in SCD.296 The calcium channels show a slower
rate of decay,297 and the calcium transient’s amplitude is
decreased.298 However, these changes are also nonuniform,299
thus raising the possibility that further perturbations in AP
dynamics are created.300
Slowed conduction and poor electrical coupling have
been consistently shown in patients with CHF.301 These
factors facilitate reentry and increase the likelihood of SCD.
Conduction velocity is associated with sodium channel
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current, and the levels of these currents have been found to
be attenuated in heart failure.302,303 Fibrosis leads to the
same findings and is associated with a decreased safety
factor for propogation.304 If conduction fails (blocks), one of
the criteria for initiation of reentry has been satisfied. This
then also predisposes the heart to reentrant ventricular
arrhythmias.
Finally, neurohumoral factors may play a role in the onset
of ventricular arrhythmias.286 Activation of the rennin-angiotensin-aldosterone system (RAAS) is well documented in
these patients, and the blockade of these systems has been
shown to decrease overall mortality and SCD.305,306 The
failing heart has heterogeneities of sympathetic innervation
that are thought to be arrhythmogenic.307,308
Dysrhythmias During Sudden Cardiac Death
Ventricular fibrillation (VF) is the most common cause of
SCD. It is the first rhythm documented in approximately
75% of patients with cardiac arrest.309 However, it is most
likely that the actual dysrhythmia originates as ventricular
tachycardia that subsequently degenerates into VF. A study
of 157 patients with ambulatory Holter monitors during
cardiac arrest found this to be the case in 62% of patients.310
Ventricular fibrillation without antecedent VT occurred in
only 8% of cases.
Bradycardia as the initiating rhythm of SCD is not
thought to be as common as ventricular arrhythmias,311
although this appears to be more frequently the presenting
dysrhythmia in patients with more advanced heart
failure.312
Sudden Cardiac Death in the Setting of Recent
Ischemia or Infarction
After coronary occlusion, there are two peaks in the acute
incidence of ventricular arrhythmias.313 The first occurs
before 10 minutes and the second at 15 to 20 minutes postocclusion. These are typically polymorphic VT, presumably
due to the acute ischemia–induced derangements in membrane depolarization, repolarization, and refractoriness.
Subsequently, VF can occur within the first 4 days after
infarction. These are usually initiated by PVCs, the mechanism of which is thought to be abnormal automaticity.314 It
is in the chronic stages after the myocardium has healed and
scar tissue has evolved that the macroreentrant circuits
leading to monomorphic VT evolve.315
Evaluation and Risk Stratification
Although during the past 25 years multiple diagnostic tests
have been used to evaluate different cardiac and noncardiac
factors that play a role in the occurrence of SCD, the relatively low positive predictive accuracy of these tests affect
their usefulness.316 Our understanding of these risk factors
is incomplete. When screening a patient for the presence of
risk factors for SCD, one should first evaluate the underlying
cardiac pathology as well as the presence of possible comorbid noncardiac conditions. The first step would be a complete history and physical examination, which can provide
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clues regarding the risk of SCD. Because CAD is the most
common underlying factor in SCD, particular attention
should be directed toward a history of chest discomfort or
recent exertional intolerance. Because left ventricular dysfunction is a major risk factor for SCD, potential symptoms
of CHF should be carefully evaluated. A prior history of
cardiac arrest is the most significant risk factor for recurrent
cardiac arrest.317 In patients with structural heart disease,
particular attention should be paid to the history of an unexplained syncope that puts this population at higher risk for
SCD.316 In the setting of unexplained syncope in patients
with structural heart disease or in patients who survive
SCD, the interrogation of those who witnessed the event can
provide crucial information. Documentation of all rhythm
strips recorded during the event is also paramount. Any
current use of cardiac or noncardiac drugs, whether prescribed or over-the-counter medications, must be carefully
determined because of the possibility of QT prolongation.
Interrogation of the patient should include any family history
of hypertrophic cardiomyopathy, Marfan’s syndrome, and
sudden or unexplained death. A careful physical examination also provides further insight into the presence of underlying structural heart disease and all other comorbid
conditions. Various noninvasive methods are used to evaluate the underlying cardiac pathology and help the risk stratification process.
Electrocardiography
An ECG is helpful in the diagnosis of underlying CAD and
MI. Furthermore, it provides other helpful markers such as
QT interval (prolonged QT interval in acquired and congenital LQTS, short QT interval in short QT syndrome), delta
wave (a clue to WPW syndrome), epsilon wave (in ARVD),
and right bundle branch block and ST segment elevation in
V1 to V13 (in Brugada syndrome). An ECG is also a specific
but insensitive tool with which to evaluate left ventricular
hypertrophy.
Echocardiography
Echocardiography provides information regarding LVEF,
which is one of the most powerful predictors of recurrent
cardiac arrest.318 Left ventricular ejection fraction is an independent predictor of death. An EF of <0.40 indicates an
increased risk of death by at least three- to fourfold.319
However, when the LVEF is severely depressed (<15–20%),
the prevailing mode of cardiac death is not sudden, or when
sudden, it is often related to bradyarrhythmias or electromechanical dissociation rather than ventricular tachyarrhythmias. The meta-analysis of pooled data from the European
Myocardial Infarction Amiodarone Trial (EMIAT), the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT),
Survival with Oral d-Sotalol (SWORD), Trandolapril Cardiac
Evaluation (TRACE), and the Danish Investigations of
Arrhythmia and Mortality on Dofetilide study group
(DIAMOND) assessed the risk of death in patients who survived at least 45 days after MI.320 The prognostic value of EF
was adjusted for treatment and other demographic factors
associated with survival. The meta-analysis confirmed that
LVEF significantly predicted 2-year, all-cause, arrhythmic
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and cardiac mortality. A 10% absolute increase in EF reduced
the mortality at 2 years with a hazard ratio of 0.61. The EF
is usually combined with other risk factors. While it is
unclear which combination of noninvasive variables provides the strongest risk prediction in the current thrombolytic era, it seems logical to combine the variables that reflect
different factors linked to SCD, for example, the substrate
(EF), the trigger (ventricular premature beats, nonsustained
ventricular tachycardia), or the modulator (autonomic
dysfunction).
The ATRAMI investigators, as discussed earlier, demonstrated that a combination of low values of autonomic
markers and reduced EF identified a group of post-MI patients
at highest risk for sudden death. The results from another
study321 confirmed prethrombolytic era findings322 that echocardiographic left ventricular end-systolic and end-diastolic
volumes were strong predictors of mortality at 6 months
after acute MI. Echocardiography can also be used to evaluate segmental wall motion abnormalities associated with
CAD, significant valvular dysfunction, evidence of hypertrophic cardiomyopathy, pericardial disease, intracardiac
tumors, and congenital heart disease. The presence of LV
dysfunction precludes the use of certain antiarrhythmic
agents that can produce a negative inotropic effect or a proarrhythmic event.
Ambulatory Electrocardiographic Monitoring
The role of Holter monitoring in the evaluation of patients
with arrhythmias has been the subject of multiple studies,
particularly in most MI patients. Several studies confirmed
the prognostic significance of frequent premature ventricular complexes and NSVT in post-MI patients.332,333 However,
the specificity of a spontaneous ventricular ectopy is
limited.334 Mortality rates are not influenced by the frequency, duration, or rate of NSVT.332,333 However, all of the
above-mentioned studies were performed in the prethrombolytic era. In the thrombolytic era, the risk associated with
the presence of NSVT has become uncertain. The GISSI-II
study investigators reported that the prevalence of NSVT was
only 6.8% and its presence was not predictive of SCD at 6
months post-MI.335 In another study, there was a low prevalence (9%) of NSVT shortly after acute MI. At multivariate
analysis, unlike heart rate variability, EF, or status of the
infarct artery, NSVT was not an independent predictor of
SCD.
Recent data from primary prevention of SCD by prophylactic ICD implantation has demonstrated that the combination of NSVT with other variables, including reduced EF and
electrophysiologic testing after acute MI, was effective in
identifying post-MI patients at high risk of arrhythmic
death.
Exercise Stress Testing
Exercise stress testing is a recognized prognostic test in survivors of acute MI. Several studies have shown that the presence of ST segment changes, the occurrence of exercise-induced
angina, inappropriate blood pressure response, and exerciseinduced ventricular arrhythmia in post-MI patients during
submaximal predischarge stress testing are predictors of
recurrent ischemic events, the need for revascularization,
and overall cardiac mortality rates. Several authors found
that these findings are predictive of ventricular arrhythmia
and sudden death.322–325 However, other investigators have
not found exercise test results to specifically predict the risk
of SCD.326–328 Exercise testing is also useful in the identification of patients with exercise-induced or exercise-aggravated
ventricular tachycardia.329–331 Stress testing is most commonly used as a noninvasive test to evaluate the presence of
CAD in patients with chest pain. The sensitivity and the
specificity of stress test improve when combined with nuclear
methods.
Radionuclide Imaging
Radionuclide angiography is another noninvasive method
that can be used to quantitatively assess the left ventricular
function. It can also provide information regarding regional
left ventricular performance and myocardial viability.
Magnetic Resonance Imaging
Magnetic resonance imaging can provide information regarding myocardial viability, left ventricular function, and left
ventricular end-diastolic and end-systolic volumes. Furthermore, as discussed earlier, MRI can be a useful tool for evaluation of patients with suspicion of ARVD.
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Signal Averaged Electrocardiography
Low amplitude, fragment, and delayed electrical activity can
be recorded from areas bordering the infarction in an experimental model of MI. The signal-averaged ECG (SAECG)
records this delayed fractionated activity from the body
surface. A number of studies have evaluated the prognostic
significance of this signal SAECG alone or in combination
with Holter monitoring or LVEF in the post-MI population.336–339 In these studies, the sensitivity during a follow-up
period of 6 to 24 months in patients who experienced sustained VT or SCD was between 50% and 90%. Its primary
benefit was its excellent negative predictive value, which has
been reported to be about 95%. However, the positive predictive value of SAECG (the risk of arrhythmia in a patient with
positive results) has been lower, averaging 20% in these
studies.
Kuchar and colleagues339 risk-stratified patients after an
acute MI by using SAECG, Holter monitoring, and radionuclide ventriculography. The patients were followed for a
median of 14 months for an arrhythmic event that was
defined as sudden death or sustained VT. The results of each
of these three tests were independently predictive of arrhythmic events. An LVEF of <40% was the most powerful predictive of an arrhythmic event. The addition of a positive SAECG
to the LVEF further increased the probability of predicting
an event (from 4% for LVEF of <40% alone to 34% with LVEF
<40% plus a positive SAECG). A SAECG is more predictive
of arrhythmic events in inferior infarction and is less useful
in anterior infarctions. This difference is probably due to the
fact that the periinfarct tissue in anterior infarction is activated relatively early in the sequence of ventricular activation. This makes it more difficult to detect late potentials.
A meta-analysis of all available prospective studies, during
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the prethrombolytic era on the use of SAECG after MI
showed that the SAECG predicted a sixfold increase in risk
of arrhythmic events independent of left ventricular function, and an eightfold increase in risk of arrhythmic events
independent of Holter results.340 Thrombolysis reduced the
frequency of SAECG abnormalities by 37%,341 and therefore
the predictive value of late potentials was significantly
diminished.342 The most recent studies supported the concept
that SAECG is an independent predictor of arrhythmic
events after MI.342,343
Heart Rate Viability
Heart rate viability is a measure of beat-to-beat variation of
sinus-initiated RR intervals. It has been evaluated as an indicator of decreased parasympathetic tone, which is associated
with poor prognosis in post-MI patients. Schneider and Costiloe 344 evaluated the relationship between sinus arrhythmia
and prognosis after MI and concluded that sinus arrhythmia
decreases in normal patients with age, that sinus arrhythmia
is less evident after MI, and that patients with the least evidence of sinus arrhythmia had the worst prognosis during
follow-up.
Kleiger and colleagues demonstrated the relation between
increased mortality rates and decreased heart rate viability
in a study of 808 post-MI patients. They showed that heart
rate viability has a significant relation with other prognostic
indicators, relating directly to LVEF and exercise capacity.
However, the heart rate viability correlated to a much lower
degree with ventricular ectopy, suggesting that these two
factors acted independently. Farrell and associates345 observed
that the sensitivity of heart rate variability in the prediction
of arrhythmic events (sudden death and sustained VT) was
higher than that of other risk factors, including exercise
testing, LVEF, ventricular ectopy, and SAECG. In the analysis of a combination of risk factors, the combination of
decreased heart rate variability and the presence of late
potentials in SAECG was more predictive of arrhythmic
events than other combinations. The decrease in heart rate
variability suggests a relative decrease in parasympathetic
tone.346 Another possible explanation is that increased vagal
tone protects against VF in the presence of ischemia.
As we discussed earlier, the ATRAMI (Autonomic Tone
and Reflexes After Myocardial Infarction) investigators58
studied heart rate variability and baroreceptor sensitivity on
1284 patients in the first month post-MI. They concluded
that these variables were significant predictors of cardiac
mortality. They demonstrated that during 21 months of
follow-up, depressed heart rate variability and baroreceptor
sensitivity carried a significant multivariate risk of cardiac
mortality of 3.2 and 2.8, respectively. The combination of
low heart rate variability and depressed baroreceptor sensitivity further increased the risk. One-year mortality increased
from 1% when both markers were well preserved to 15%
when both were depressed. Furthermore, the investigators
demonstrated that the predictive power of baroreceptor sensitivity declined much more markedly than heart rate variability over the age of 65. The ATRAMI investigators have
demonstrated that after MI, the analysis of the autonomic
markers has significant prognostic value independent of
established clinical predictors, such as EF and ventricular
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arrhythmias. Furthermore, the combination of low values of
autonomic markers and reduced ejection fraction identifies
a group of post-MI patients at high risk for SCD.
Cardiac Catheterization
Cardiac catheterization should be performed in almost all
survivors of SCD to establish the presence, extent, and severity of CAD. It can also exclude congenital coronary vessel
anomalies in younger SCD survivors. Cardiac catheterization can confirm the results of noninvasive studies for evaluation of left ventricular function, wall motion abnormalities,
and valvular disease.
Electrophysiologic Testing
Wellens and colleagues347 demonstrated that programmed
stimulation could safely and reproducibly initiate VT in the
majority of patients who experienced sustained VT. Subsequent studies confi rmed this observation. From 60% to 90%
of patients who survive sudden death unassociated with
acute MI are inducible during EP study. 347–351 Sustained
monomorphic VT can be induced during EP study in 50% to
60% of cardiac arrest survivors, and polymorphic VT or VF
can be induced in an additional 10% to 20%.352–354 However,
in the thrombolytic era, EP testing for risk stratification of
patients has progressively lost favor. Nearly half of all
reported trials found inducibility of sustained VT during
programmed stimulation to be unhelpful in predicting later
mortality or arrhythmic events.355 Many post-MI patients
with SCD have negative predischarge electrophysiologic
tests, resulting in a low negative predictive accuracy.356 Furthermore, when used alone, EF is superior to EP testing in
predicting arrhythmic events after acute MI.357 Therefore, a
two-step strategy using EF of ≤40% and ventricular arrhythmias on Holter monitoring and then electrophysiologic
testing significantly improved the positive predictive accuracy of risk stratification process but only to a moderate level
of 18.2%.358 Furthermore, the evidence from primary prevention trials [Multicenter Automatic Defibrillator Implantation Trial (MADIT) and Multicenter UnSustained Tachycardia
Trial (MUSTT)] have confirmed that a two-step risk stratification procedure using reduced EF and nonsustained VT
followed by electrophysiologic testing was helpful in selecting a high-risk subgroup of patients who benefited from prophylactic ICD implantation for the primary prevention of
SCD. However, the precise value of VT inducibility is
uncertain.
Microvolt T-Wave Alternans
Microvolt T-wave alternans (TWA) is beat-to-beat variability
in the T wave.359 Its precise mechanism remains unclear, but
proposed mechanisms include beat-to-beat changes in the
intracellular levels of Ca2+. The beat-to-beat variability in
intracellular Ca2+ leads to modulation of repolarization currents, which may contribute to TWA.360 It has been clearly
demonstrated that metabolic disturbances during ischemia
leads to microvolt TWA.361 T-wave alternans is thought to
contribute to induction of malignant arrhythmias by leading
to dispersion of refractoriness.362 This in turn can lead to
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functional block and induction of reentrant arrhythmias.
Using the spectral method and sophisticated signal-processing techniques, microvolt TWA is analyzed during standard
stress exercise protocols, treadmill stress echocardiography,
pharmacologic stress testing, or atrial pacing in the electrophysiology lab.363 A positive test is the presence of significant
sustained alternans measured in any three orthogonal leads
or two adjacent precordial leads. It should be present for at
least 1 minute with an onset at a heart rate greater than
110 bpm.363 Microvolt TWA testing is a reliable marker for
late post-MI risk stratification, but there is some controversy
about its accuracy in patients with recent infarction.364–368 In
patients with idiopathic dilated cardiomyopathy, it has
shown promise as a clinically important risk stratifier, but
larger clinical studies are needed to better define its role.363
There are only limited data for microvolt TWA testing in
patients with hypertrophic cardiomyopathy or the inherited
arrhythmic disorders.
Prevention
The majority of patients who suffer an SCD have no symptoms and are not identified as being at high risk before the
event.262 Therefore, in addition to the secondary prevention
of SCD (prevention of recurrent cardiac arrest), primary prevention is a major therapeutic goal. As discussed earlier,
patients with the highest risk factor profile constitute a
small percentage of the total number of people at risk for
SCD. Furthermore, when the high-risk subgroups are identified and removed from this population base, the calculated
incidence for the remainder of the population decreases and
the identification of individuals at high risk becomes more
difficult. During the past decade, multiple trials have been
conducted regarding the primary prevention of SCD in
patients with heart disease who are at high risk and the secondary prevention of SCD in patients who have been successfully resuscitated. Here, we summarize pertinent data
from the extensive literature that is available, but it is beyond
the scope of this chapter to review the extensive data from
numerous trials.
Primary Prevention
Pharmacologic Studies
BETA-BLOCKER T HERAPY
Available data from several prospective double-blind studies
revealed that beta-blockers reduce the overall mortality and
SCD rates after acute MI. In the beta-blocker heart attack
trial (BHAT),369 propranolol (180 to 240 mg per day) decreased
the total mortality rate over an average follow-up period of
25 months by 26.5% (from 9.8% in the placebo group to 7.2%
in the propranolol group). The benefit was remarkable in
high-risk patients. Propranolol reduced the risk of death in
this group by 43% (p < .001).370 Propranolol decreased the
incidence of SCD by 47% in patients who had previous heart
failure versus 13% in the patients who did not, with a 35%
reduction in adjusted mortality rate.
In the Norwegian multicenter study on timolol after an
acute myocardial infarction, 371 timolol reduced the total
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mortality by 38%. Sudden cardiac death was decreased by
45% from 13.9% in the placebo group to 7.7% in the timolol
group (P = .0001). The beneficial results persisted for up to
72 months.372
In the Acebutolol Postinfarction Trial (Acebutolol et
Prevention Secondaire de L’Infarctus, APSI),373 acebutolol
reduced the mortality rates by 48% and cardiovascular death
by 58% compared with placebo. The benefit was maintained
after several years of follow-up.374 In the Goteborg trial,375
metoprolol (intravenous infusion followed by 200 mg a day
p.o.) reduced mortality rates by 36% from 8.9 to 5.7%.
In the Metoprolol in Acute Myocardial Infarction (MIAMI
study),376 the metoprolol group had statistically insignificant
13% reduction in mortality rate. However, retrospective
analysis showed that the treatment was beneficial in highrisk patients and reduced mortality rate from 8.5 to 6% (p =
.03). Metoprolol was also used in the Thrombolysis in Myocardial Infarction (TIMI-IIB study)377 as an adjunct to intravenous tissue plasminogen activator. The patients were
randomly assigned to receive immediate intravenous metoprolol followed by oral therapy or to defer therapy with metoprolol starting on day 6 after the MI. There was a lower rate
of recurrent ischemia and nonfatal MI in the group that
received immediate therapy.
In a meta-analysis of 26 trials by Yusuf and associates,378
therapy with beta-blockers resulted in a 23% reduction in
mortality rates. The mechanism of beneficial effects of betablockers is unclear. The survival benefits appear to be mediated by a reduction in arrhythmic-related death and recurrent
MI. Beta-blockers reduce the threshold for VF, most likely
through the antisympathetic effect. Beta-blockers also reduce
hyperkalemia by blocking the catecholamine-induced influx
of potassium into cells.379 Patients with depressed left ventricular function and a history of CHF show the greatest
survival benefit. Beta-blockers may improve survival in
patients with CHF by reducing myocardial oxygen demand,
improving diagnostic relaxation, reducing sympatheticmediated vasoconstriction and tachycardia, or reducing
catecholamine-induced myocardial damage or by their antiarrhythmic effect.379
The Metoprolol in Dilated Cardiomyopathy (MDC) trial
decreased the risk of sudden death or need of heart transplantation by 35%. It also caused significant improvement in
cardiac function and exercise capacity.380 Bisoprolol was
noted to be beneficial in the Cardiac Insufficiency Bisoprolol
(CIBIS) study.381 Although there was no overall benefit in
survival, there was a 57% reduction in mortality rate in
patients with previous MI. In the CIBIS-II study,382 bisoprolol
showed a significant mortality benefit. In this multicenter,
double-blinded, randomized, placebo-controlled trial, all
controlled patients were in NYHA functional classes III to
IV with an LVEF of <0.35. The all-cause mortality rate was
significantly lower with bisoprolol (11.8% vs. 17.3% in the
placebo group, p < .0001). Furthermore, the incidence of SCD
decreased by 44% among patients receiving bisoprolol (3.6%
vs. 6.3% in placebo group, p = .0011).
In the mortality effect of metoprolol in patients with
heart failure (MERIT-HF trial),174,383 treatment with metoprolol CR/XL was associated with a 34% decrease in all-cause
mortality rates, a 38% decrease in cardiovascular mortality
rates, a 41% decrease in SCD, and a 49% decrease in death
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due to progressive heart failure. Carvedilol, a nonselective
β-receptor agonist with some α1-receptor antagonist activity,
improved survival rates in patients with CHF in a U.S. multicenter study.384 There was a 65% reduction in mortality
rates. The result of this trial was supported by another trial
from Australia/New Zealand,385 which showed a 26%
decrease in death or hospital admission in patients with
ischemic cardiomyopathy.
In a more recent study, the CAPRICORN investigators386
in a multicenter, randomized, placebo-controlled trial, evaluated 1959 patients with a proven acute MI and LVEF of ≤40%.
The patients were randomly assigned to carvedilol or a
placebo. Carvedilol reduced the frequency of all-cause mortality in the study. The authors reported a 23% relative
reduction in mortality. The reduction in all-cause mortality
was additional to the effects of angiotensin-converting
enzyme (ACE) inhibitors and reperfusion therapy, which
were prescribed in 98% and 46% of patients, respectively.
The Carvedilol or Metroprolol Trial (COMET) investigators,387 in a multicenter double-blind and randomized parallel
group trial, assigned 1511 patients with chronic heart failure
to treatment with carvedilol and 1518 patients to metoprolol.
The patients were required to have NYHA class II to IV,
previous admission for a cardiovascular reason, an ejection
fraction <0.35, and to have been treated optimally with
diuretics and ACE inhibitors unless not tolerated. The allcause mortality was 34% for carvedilol and 40% for metoprolol (hazard ratio of 0.83, p = .122). The authors concluded
that carvedilol extends survival compared with metoprolol
in patients optimally treated with diuretics and ACE inhibitors. The absolute reduction in mortality over 5 years was
5.7%. The COMET trial brings up the issue of the need for
a better understanding of specific mechanisms of action of
selective and nonselective beta-blockers in heart failure
patients.
A NGIOTENSIN-CONVERTING ENZYME INHIBITORS AND
A NGIOTENSIN-II R ECEPTOR A NTAGONIST
The beneficial effect of ACE inhibitors appears to be a class
effect that is mediated by a reduction in ventricular size,
reinfarction, the appearance of CHF, and a new ischemic
event. There has been a 6% to 22% reduction in mortality
rate in several studies. Despite the beneficial effect on total
mortality rate, the precise role of these agents in reducing
SCD is still not clear. In the Veterans Administration Cooperative II study (V-HeFT-II),388 there was a 28% reduction in
mortality rate in the enalapril group from reduced incidence
of SCD compared with the hydralazine-isosorbide group. In
the Trandolapril Cardiac Evaluation (TRACE) study,389 trandolapril reduced the mortality rates by 22% and SCD rates
by 24% (p = .03) in post-MI patients with evidence of left
ventricular dysfunction. However, other studies did not show
any significant reduction in the SCD rate.
In the Survival and Ventricular Enlargement (SAVE)
trial,390 although captopril reduced total mortality rates by
19% in survivors of MI with asymptomatic left ventricular
dysfunction (LVEF ≤40%), there was no statistical difference
in the SCD rate. In the Studies on Left Ventricular Dysfunction (SOLVD) prevention trial,391 captopril did not reduce
significantly total mortality and SCD rates in asymptomatic
(NYHA functional class I to II) patients with an LVEF of 0.35
CAR098.indd 2062
98
or less. In a more recent study, the Heart Outcomes Prevention Evaluation (HOPE) study392 concluded that treatment
with ramipril reduced the rates of death from cardiovascular
causes (6.1% as compared to 8.1% in the placebo group with
p < .001), death from any cause (10.4% vs. 12.12%, p = .005),
and cardiac arrest (p = 0.03). The authors concluded that
ramipril, an ACE inhibitor, is beneficial in a broad range of
patients without evidence of left ventricular systolic dysfunction or heart failure who are at high risk for cardiovascular events.
The angiotensin-II receptor antagonists that block the
receptor without increasing bradykinin levels have the
potential to be as effective as or even more effective than
ACE inhibitors in the treatment of patients with heart failure
and possibly reducing the risk of SCD. Because angiotensin
II can be produced through alternate pathways, this class of
drugs may have an advantage over ACE inhibitors. In the
Evaluation of Losartan in the Elderly (ELITE) trial,393 which
was a prospective, randomized, double-blind clinical trial
comparing the safety and efficacy of losartan and captopril
in patients with documented LVEF of <40%, the mortality
rate was 46% lower in the losartan group than in the captopril group. To further study the results of this trial, the
ELITE-II trial evaluated the effects of losartan and captopril
on mortality and morbidity in a larger number of patients
with heart failure.394 ELITE-II was a double-blind, randomized, controlled trial of 3152 patients of age 60 years or older
with NYHA class II to IV heart failure and an ejection fraction of 40% or less, who were randomly assigned to losartan
or captopril. The primary and secondary end points were
all-cause mortality and sudden death or resuscitated arrest.
There were no significant differences in all-cause mortality
or sudden death or resuscitated arrests between the two
treatment groups. In contrast to ELITE-I, the results of
ELITE-II suggested that losartan was not superior to captopril in improving survival in elderly patients with heart
failure, but was significantly better tolerated. It was suggested that ACE inhibitors should be the initial treatment of
heart failure, although angiotensin-II receptor antagonists
may be useful to block the renin-angiotensin system when
ACE inhibitors are not tolerated.
The Optimal Trial in Myocardial Infarction with
Angiotensin-II Antagonist Losartan (OPTIMAAL)395 was a
multicenter, randomized trial to test the hypothesis that the
angiotensin-II antagonist losartan, would be superior or not
inferior to the ACE inhibitor captopril, in decreasing allcause mortality in high-risk patients after acute MI. There
was a nonsignificant difference in total mortality in favor of
captopril; however, losartan was significantly better tolerated than captopril with fewer patients discontinuing the
study medication. Therefore, ACE inhibitors were recommended as a first choice of therapy in patients after complicated acute MI. There is evidence to suggest that some
benefits of ACE inhibitors are derived from elevated levels of
bradykinin.396 Therefore, the combination of an ACE inhibitor and angiotensin-II receptor antagonist may have additive
actions.
Several studies evaluated this hypothesis. The Valsartan
in Acute Myocardial Infarction Trial (VALIANT)397 compared the effects of valsartan, captopril, and the combination
of valsartan and captopril in a population of high-risk patients
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A LDOSTERONE A NTAGONISTS
Spironolactone (the RALES study)403 achieved a significant
30% reduction in overall mortality and a 35% reduction in
hospitalization in 1663 patients with NYHA class III to IV
heart failure. In this study, all patients were on ACE inhibitors but only 10% were on beta-blockers. Investigators in
the EPHESUS trial,404 using eplerenone in patients with
recent MI and LVEF <40%, showed a significantly lower
all-cause mortality (14.4% vs. 16.7%). In this study, 75% of
patients were on beta-blockers and 87% were on ACE inhibitors. In the CHARM trial, 17% of patients were on spironolactone, and a subset analysis in this group did not fi nd
significant improvement of the primary end point by the
addition of candesartan. It has been postulated that because
a considerable proportion of the beneficial effect of both
aldosterone antagonist and the angiotensin-II receptor
antagonist are the result of blockade of the local reninangiotensin system in the cardiac muscle and the vasculature and because they use the same pathway, the effects on
reducing end points by a combination of the two may not
be additive.405
CAR098.indd 2063
A NTIARRHYTHMIC DRUG T HERAPY
Class I Antiarrhythmic Drugs. Frequent and complex
ventricular activities in survivors of MI have been demonstrated to be a risk marker for subsequent SCD. The objective
of the Cardiac Arrhythmia Suppression Trial (CAST) I and
II,406,407 was to test the hypothesis that the suppression of
ventricular ectopy after an MI would reduce the incidence of
SCD. In the CAST-I study,406 patients who had asymptomatic
PVCs after MI suppressed by encainide or flecainide were
randomly assigned to receive long-term drug therapy or
placebo. After an average of 9.7 months, the total mortality
was 7.7% in the class IC group versus 3% in the placebo
group (relative risk 2.5, p = .0001). Arrhythmic death was
more common in the class IC group (4.5% versus 1.2% in the
placebo group). The relative risk of death of resuscitative
cardiac arrest was 2.38 (Fig. 98.14). Further analysis showed
that the adverse event rate was highest in patients with the
lowest LVEF. The presence of an LVEF of more than 0.30 was
associated with improved survival rates.
In a subgroup analysis, patients who were treated with
beta-blockers in addition to class IC antiarrhythmic agents
had lower mortality rates than the group of patients who
were treated with class IC agents alone. This observation
suggests a protective effect of beta-blockers.407 The results of
the CAST trial disproved the hypothesis that suppression of
ventricular arrhythmia improves mortality rates. Furthermore, meta-analysis of other class I agent trials showed a
significantly higher mortality rate for antiarrhythmic agenttreated patients compared with placebo-treated patients.408
A third drug, moricizine, was subsequently studied in the
CAST-II trial.409 The overall mortality rate was similar for
patients treated with moricizine and those treated with
placebo. However, there was a significantly higher mortality
rate among patients treated with moricizine during the
initial 2 weeks of therapy (2.3% vs. 0.3%). The cause of this
proarrhythmic response is unknown. The unexpectedly low
placebo mortality rate suggests that a low-risk population
was chosen for the trial, which exposed the patients to all
the risks of active therapy without much hope of benefit.
Class III Antiarrhythmic Drugs. Amiodarone is a
unique antiarrhythmic drug with class I, II, III, and IV effects.
The effect of amiodarone in the prevention of SCD was
Patients without event (%)
with clinical or radiologic evidence of heart failure, evidence
of left ventricular systolic dysfunction, or both after an acute
MI. The primary end point on this study was death from any
cause. The results of this study showed that there were no
additional benefits of using combination therapy in CHF
after acute MI as compared with ACE inhibitor alone or
angiotensin receptor antagonist. Furthermore, the two agents
were equivalent in terms of overall mortality and in terms
of rate of composite end points of fatal and nonfatal cardiovascular events. Adverse events were less common with
monotherapy than with combination therapy. These results
were challenged in a much larger trial, the Candasartan in
Heart Failure Assessment of Reduction in Mortality and
Morbidity (CHARM),398 which was a randomized doubleblind, placebo-controlled, clinical trial comparing Candasartan with placebo in patients with symptomatic heart failure.
The primary outcome of this study was all-cause mortality.
The patients eligible for CHARM study were enrolled in
three different subgroups according to LVEF: higher than
40% (CHARM-preserved),399 40% or lower and being treated
with an ACE inhibitor (CHARM-added),400 or 40% or lower
and not being treated with an ACE inhibitor because of previous intolerance (CHARM-alternative).401 Review of the data
from the CHARM-added portion of the trial showed that the
number of deaths from any cause in the Candasartan group
was 377 (30%) compared with 412 (32%) in the placebo group.
These data demonstrated a trend toward decreased mortality
with combination therapy.
However, the Valsartan Heart Failure Trial (Val-HeFT),402
which was a randomized placebo-controlled, double-blind,
parallel group trial in patients with NYHA class II to IV,
showed that the overall mortality was similar in the two
groups. The patients were divided into four subgroups on the
basis of the use or nonuse of ACE inhibitor and beta-blocker
therapy at baseline. In the three groups receiving neither
drug or either ACE inhibitor or beta-blockers alone, there was
a significantly favorable effect of Valsartan on the rate of the
combined end point and a favorable point estimate of the
odds ratio for death.
100
95
p = .001
Placebo (n = 743)
90
Encainide or
flecainide (n = 755)
85
80
0
91
182
273
364
455
Days after randomization
FIGURE 98.14. Actuarial probabilities of freedom from death or
cardiac arrest from arrhythmias in 1498 patients receiving encainide,
flecainide, or corresponding placebo.
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extensively studied in post-MI patients. In the Basel AntiArrhythmic Study of Infarct Survival (BASIS),410 there was
61% reduction in mortality rate with amiodarone. Amiodarone also decreased VF or SCD compared with the controlled
group (p = .024). The beneficial effect of amiodarone persisted
several years after drug discontinuation. The Polish Amiodarone Trial (PAT)411 showed a reduction in cardiac death rates
from 10.7% in the placebo group to 6.9% in the amiodarone
arm of study.
The goal of the European Myocardial Infarction Amiodarone Trial (EMIAT)412 was to assess the efficacy of amiodarone in reducing mortality rates in patients with depressed
left ventricular function after an MI. This study enrolled
1486 patients with an LVEF ≤0.40 within 5 to 21 days of
MI. The median follow-up was 21 months. Patients were
randomly assigned to treatment with amiodarone or placebo.
The primary end point was all-cause mortality, and secondary end points were cardiac death, arrhythmic death, and
the combination of arrhythmic death and resuscitated
cardiac arrest. Amiodarone reduced arrhythmic death by
35% (p = .05) and arrhythmic death and resuscitated cardiac
arrest by 32% (p = .05). However, amiodarone did not show
any beneficial or detrimental effect on all-cause mortality
rates.
The Canadian Amiodarone Myocardial Infarction Trial
(CAMIAT)413 evaluated the hypothesis that amiodarone
could reduce arrhythmic death among post-MI patients (6 to
45 days after MI) who had frequent PVCs (≥10 PVCs per hour)
or any run of VT on baseline Holter recording. The primary
end point was arrhythmic death or resuscitated VF. Secondary end points were arrhythmic death, cardiac death, and
all-cause mortality. In the efficacy analysis, resuscitated VF
or arrhythmic death occurred in 6% of patients in the placebo
group and 3.3% of patients in the amiodarone group. Amiodarone reduced the relative risk by 48.5%. Intention-to-treat
analysis showed 38.2% risk reduction in the amiodarone
group compared to the placebo group (6.9% in the placebo
group to 4.5% in the amiodarone group, p = .029). The absolute risk reduction was greatest among patients with CHF or
a history of MI. Although amiodarone reduced all-cause mortality by 18%, the difference was not statistically different.
In EMIAT and CAMIAT, there was a significant reduction
in arrhythmic death among patients. However, these two
trials did not show any benefit in the total mortality rates,
and CAMIAT was not powered to predict the overall survival
benefit.
Sim and associates414 showed a 21% reduction in overall
mortality rates in a meta-analysis of eight post-MI trials in
patients who received amiodarone. Two other studies investigated the effects of amiodarone in patients with CHF. The
Grupo de Studio de la Sobrevida en la Insuficiencia Cardiaca
en Argentina (GESICA) trial415 studied the effect of amiodarone in patients with severe CHF who did not have any
symptomatic ventricular arrhythmias. In this multicenter
prospective study, 516 patients with LVEF of <0.35 were randomized to receive optimal medical therapy with or without
amiodarone; 39% of patients had a prior history of MI; the
remainder of the patients had nonischemic dilated cardiomyopathy or Chagas’ disease. The mortality rate was 33.5% in
the amiodarone-treated group and 41.4% in the controlled
group. The primary end point was total mortality, and there
CAR098.indd 2064
98
was a 28% risk reduction (p = .024), which was observed after
90 to 120 days of therapy and persisted to the end of the study.
The reduction in mortality rates reflected improved rates of
SCD and death due to worsening of heart failure. However,
these trends were not statistically significant. Further subsequent analysis showed that 2-year SCD rate increased from
8.7% in patients without NSVT to 23.7% in patients with
NSVT (p < .001). Therefore, the presence of NSVT was an
independent risk marker for SCD.416
However, these results were not reproducible in the Survival Trial of Antiarrhythmic Therapy in Congestive Heart
Failure (CHF-STAT),417 which examined the use of amiodarone in patients with CHF with an LVEF of <0.40 and asymptomatic ventricular arrhythmias (>10 PVCs per hour). This
was a multicenter, double-blind, placebo-controlled study
that was performed to determine whether amiodarone could
reduce overall mortality rates. A total of 674 patients were
randomly assigned to treatment with either amiodarone or a
placebo. There was no significant difference in the rates of
overall mortality or sudden death between the two groups,
despite the improved left ventricular function and suppressed
ventricular arrhythmia in the amiodarone-treated group.
However, amiodarone tended to improve survival rates in the
nonischemic heart disease group (p = .07). The difference in
the results between the GESICA study and the CHF-STAT
trial can be attributed to the much higher percentage of
patients with nonischemic cardiomyopathy in the GESICA
study.418
Sotalol is another class III antiarrhythmic medication
with beta-blocking properties that was studied in post-MI
patients in a double-blind, randomized trial. Julian and associates419 studied 1465 patients 5 to 14 days after MI. The
patients were randomized to receive 320 mg per day of dlsotalol or placebo. The dl-sotalol group had an 18% improvement in survival rates. However, the total mortality rate was
not significantly different at 1 year (4.8% for the placebo
group vs. 7.3% for dl-sotalol). Reinfarction rates were 41%
lower (p < .05 in the dl-sotalol treated group). d-Sotalol was
developed as a pure type III antiarrhythmic medication
without beta-blocking properties, as an alternative to
dl-sotalol.
The Survival with Oral d-Sotalol (SWORD) trial420
studied the effect of d-sotalol, racemic isomer of dl-sotalol
in survivors of acute MI to evaluate reduction in all-cause
mortality rates. There were 3121 patients who were randomized to receive d-sotalol or placebo. Entry criteria included
history of MI 6 to 42 days before entry and an LVEF of
<0.40. In addition, patients who had an MI more than 42
days earlier could be enrolled if they had symptomatic
NYHA functional class II to III CHF. The study was permanently terminated due to excess death rates in the dsotalol arm (5% vs. 3.1% in the placebo arm). The majority
of excess death appeared to be secondary to enhanced
arrhythmic death (p = .008). Dofetilide is a newer class III
antiarrhythmic agent that was evaluated in the Danish
Investigations of Arrhythmia and Mortality on Dofetilide
(DIAMOND) trial.421 In this study, 1518 patients with symptomatic CHF and severe left ventricular dysfunction were
randomly assigned to receive either dofetilide or placebo in
a double-blind study. Treatment was initiated in the hospital and included 3 days of cardiac monitoring and dose
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adjustment. The primary end point was death from any
cause. Investigators concluded that dofetilide had no effect
on mortality.
Implantable Cardioverter Defibrillator Trials
for Primary Prevention
The efficacy of defibrillators in the termination of ventricular arrhythmias is well established.422,423 Several primary
prevention trials have focused on the role of prophylactic
ICDs in patients at high risk of SCD (Table 98.5).
MULTICENTER AUTOMATIC DEFIBRILLATOR
IMPLANTATION T RIAL
The presence of NSVT in patients with depressed ventricular
function, CAD, and inducible nonsuppressible VT on EP
study is a predictor of poor prognosis with a 2-year mortality
rate of 30%. The Multicenter Automatic Defibrillator Implantation Trial (MADIT)424 was designed to evaluate the possible
benefit of prophylactic ICD implantation in 196 patients
from 32 centers in the United States and Europe who were
enrolled in the trial. The enrollment criteria included a
history of Q-wave MI (more than 3 weeks before entrance in
the study), LVEF of 0.35 or less, documented NSVT, inducible
sustained VT not suppressed by antiarrhythmic drug on EP
study, and NYHA functional class I to III. The average LVEF
among MADIT patients was 26%, and half of the patients
had evidence of CHF. There were 101 patients in the drug
therapy arm, including 80 receiving amiodarone and 95
receiving ICD therapy.
The trial was terminated early by the safety monitoring
committee due to the significant improvement in survival
rates in the ICD group. There were 39 deaths (38.6%) in the
antiarrhythmic group compared with 15 (12%) in the ICD
group (hazard ratio 0.46, 95% confidence interval 0.26–0.82,
p = .009). Death from cardiac causes was reduced by 57% in
the ICD group (Fig. 98.15). Subanalysis from the MADIT
database revealed a 2-year mortality rate of 8% in MADIT
noninducible patients, 20% in MADIT inducible and suppressible patients, and 25% in inducible nonsuppressible
patients who refused randomization into the study.425 The
investigators concluded that in a high-risk population with
LV dysfunction and CAD, ICD therapy improved survival
rates. Critics of the MADIT study raised several issues
regarding the study. A large number of patients in the antiarrhythmic arm were not taking any antiarrhythmic drugs at
the time of death (about 23%), and approximately 30% of the
patients who initially received amiodarone therapy discontinued it. On the other hand, 25% of patients assigned to the
ICD group were taking amiodarone by the end of the study.
TABLE 98.5. Prospective Multicenter Intracardiac Defibrillator Primary Prevention Trials
Study
424
MADIT
CABG Patch426
MUSTT428
MADIT II431
SCD Heft432
DEFINITE433
Patient inclusion criteria
End point(s)
Treatment arms
Key results
Q-wave MI ≥3 wk
Asymptomatic NSVT
LVEF ≤0.35
Inducible, nonsuppressible
VT on EPS with
procainamide
NYHA classes I–III
Scheduled for elective
CABG surgery
LVEF <0.36
Abnormal SAECG
CAD
EF ≤0.40
NSVT
Inducible VT or VF
CAD, MI
MI >1 month
Revascularization >3
months
EF ≤0.30
Ischemic or nonischemic
DCMP
NYHA class II–III
EF ≤0.35
Overall mortality
Costs and costeffectiveness
ICD (n = 95)
Conventional therapy
(n = 101)
ICD reduced overall mortality
by 54%
ICDs cost $16,900 per life-year
saved
Overall mortality
ICD (n = 446)
Standard treatment
(n = 454)
Sudden arrhythmic
death or
spontaneous
sustained VT
Overall mortality
EP-guided therapy
vs
No antiarrhythmic
therapy
ICD (n = 742)
Conventional therapy
(n = 490)
Survival was not improved by
prophylactic implantation of
ICD at the time of elective
CABG
EP-guided therapy is useful in
reducing sudden arrhythmic
death or VT
Benefit mainly arising from ICD
ICD reduced overall mortality
by 31%
Overall mortality
Arrhythmic mortality
Costs
Quality of life
ICD (n = 829)
Amiodarone (n = 845)
Placebo (n = 847)
Nonischemic DCMP
EF ≤0.35
NSVT or 10 PVCs/hr
on Holter
Overall mortality
Arrhythmic mortality
Conventional Therapy
vs
ICD + Conventional
Therapy
ICD reduced overall mortality
by 23%
Amiodarone conferred no benefit
Similar result in non-ischemic
population of the study
No significant difference in allcause mortality with a trend
toward ICD for improved
survival
ICD reduced the incidence of
sudden arrhythmic death
CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DCMP, dilated cardiomyopathy; DEFINITE, Defibrillators
in Nonischemic Cardiomyopathy Treatment Evaluation; EP, electrophysiologic; EPS, electrophysiologic study; ICD, implantable cardioverter-defibrillator; LVEF,
left ventricular ejection fraction; MADIT, Multicenter Automatic Defibrillator Implantation Trial; MI, myocardial infarction; MUSTT, Multicenter Unsustained Tachycardia Trial; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; SAECG, signal-averaged electrocardiogram; SCD
Heft, Sudden Cardiac Death in Heart Failure Trial; VF, ventricular fibrillation; VT, ventricular tachycardia.
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Probability of survival
1.0
0.8
Defibrillator
0.6
Conventional
therapy
0.4
0.2
0.0
0
1
2
3
4
5
Year
No. of patients
Defibrillator
95
80
53
31
17
3
Conventional 101
67
48
29
17
0
therapy
FIGURE 98.15. Kaplan-Meier analysis of probability of death
according to assigned treatment. The difference in mortality rates
between two treatment groups was significant (p = −.009).
Beta-blockers, which are known to improve survival in postMI patients, were administered more frequently in the ICD
group. Thus, critics have argued that MADIT demonstrates
that an ICD in combination with an antiarrhythmic agent
was better than no antiarrhythmic agent at all. The MADIT
investigators believe that the reduction in overall mortality
rate could have been attributed to the more frequent use of
beta-blockers in the ICD arm and cite the Beta-Blocker Heart
Attack Trial (BHAT),369 which reported just a 2.5% difference
in mortality rates between the placebo arm and the Propranolol arm over an average follow-up period of 25 months.
Despite these concerns, the MADIT trial was the first randomized study that suggested that the prophylactic use of an
ICD not only can save lives in a selected group of patients
with LV dysfunction, but also might save more lives than
amiodarone therapy.
CORONARY A RTERY BYPASS GRAFT PATCH T RIAL
In the Coronary Artery Bypass Graft (CABG) Patch Trial,426,427
the prophylactic use of ICDs was evaluated in a high-risk
population with established CAD, depressed LV function,
and an abnormal signal averaged ECG. The trial was based
on evidence that the 2-year mortality rate of patients who
undergo bypass graft surgery with a baseline LVEF of <0.36
is 27.5%,427 and approximately 40% of these patients died
suddenly. Pilot data also suggested that the positive signal
averaged ECG increased the mortality risk. The prestudy
hypothesis was that an ICD would reduce the 3-year total
mortality rate by 26%.
A total of 900 patients younger than 80 years with an
LVEF <0.36 and a positive signal averaged ECG were randomized to undergo elective coronary artery bypass graft surgery
alone (n = 454), or to undergo prophylactic implantation of
an ICD during elective coronary artery bypass graft surgery
(n = 446). The primary end point was overall mortality.
During an average follow-up period of 32 ± 16 months, there
were 101 deaths in the ICD group (71 from cardiac causes)
and 95 deaths in the controlled group (72 from cardiac causes)
by intention to treat analysis.426 The hazard ratio overall
mortality rate was 1.07 (95% confidence interval, 0.81 to
1.42, p = .64). The CABG Patch Trial demonstrated no benefit
from the prophylactic ICD implantation in patients with
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98
depressed LVEF and ischemia who underwent revascularization. Nonsustained VT (NSVT) was present in only 30% of
the CABG Patch Trial patients (based on average of 16 hours
of Holter monitoring) but was present in 100% of MADIT
trial patients. Signal averaged ECG was abnormal in 100%
CABG Patch Trial patients compared with 60% of the
MADIT trial patients. All of the patients in the CABG Patch
Trial had been revascularized compared with only two thirds
of the MADIT patients. Only 90 patients (10% of enrolled
patients) in the CABG Patch Trial had an EPS during enrollment, but inducibility estimated to be about 22% using
mathematical models. Considering these facts, the different
results of MADIT and the CABG Patch Trial could be
explained in two ways: (1) A positive signal averaged ECG
seems to be a poor risk stratifier in these subsets of patients.
As demonstrated in the MADIT trial, inducible sustained
VT during EP study may be a better risk stratifier for subsequent arrhythmic events. (2) This study provides additional
evidence that revascularization may have reduced a number
of arrhythmic deaths by preventing the ischemic trigger and
led to subsequent preservation and even improvement of
LVEF.
T HE MULTICENTER UNSUSTAINED TACHYCARDIA T RIAL
The
Multicenter
UnSustained
Tachycardia
Trial
(MUSTT)428–430 is not a direct study of the efficacy of ICD, but
the inclusion of device therapy in one arm of the trial offers
an opportunity to evaluate the usefulness of ICD therapy. The
hypothesis was that EP study-guided antiarrhythmic or ICD
therapy, or both, would reduce the risk of arrhythmic death
or cardiac arrest in patients with NSVT and left ventricular
dysfunction. The inclusion criteria for this study were LVEF
of 0.40 or less, a history of MI preceding entrance to the study
for at least 1 week, and NSVT. A total of 704 patients were
randomly assigned to EP-guided therapy with different antiarrhythmic medications or an ICD if the patient had persistent inducible VT, or no antiarrhythmic therapy. All of these
patients had inducible sustained VT, VF, or both on programmed electrical stimulation. The primary end point of
the trial was arrhythmic death or cardiac arrest. The secondary end point was total or cardiovascular death. There was
no difference between the two groups in average age, gender,
LVEF, history of prior MI, prior CABG, and use of beta-blockers or ACE inhibitors. The mean duration of follow-up was
39 months. The incidence of arrhythmic death or cardiac
arrest at 2 years was 18% in patients randomized to no antiarrhythmic therapy and 12% in the EP-guided therapy group.
At 5 years the incidence of the primary end point was 32%
in the former group and 25% in the EP-guided group. A total
of 46% of patients in the EP-guided therapy group underwent
defibrillator implantation after failing EP-guided drug testing.
Primary end point events in the EP-guided group patients
who received an ICD were reduced by more than 50% compared with the patients who did not receive an ICD in this
group,428 whereas EP-guided pharmacologic therapy alone did
not seem to convey survival benefit. The investigators concluded that in high-risk patients with CAD, depressed LV
function, and inducible sustained VT, EP-guided therapy is
useful in reducing the risk of arrhythmic death and cardiac
arrest. The benefit seems to arise from the use of ICDs. These
findings were consistent with MADIT trial results.
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MULTICENTER AUTOMATIC IMPLANTATION DEFIBRILLATOR
T RIAL II (MADIT-II) 431
This randomized trial was designed to evaluate the effect of
an implantable defibrillator on survival of patients with
reduced left ventricular function after MI. The study enrolled
1232 patients with a prior MI and an LVEF of 0.30 or less.
The patients were randomly assigned in a 3 : 2 ratio to receive
an ICD (742 patients) or conventional medical therapy (490
patients). Invasive electrophysiologic testing for risk stratification was not required. Death from any cause was the end
point. Patients of either sex who were more than 21 years of
age were eligible for the study if they had cardiomyopathy as
a result of previous MI. The MI had to be at least 1 month
old, with no percutaneous or surgical revascularization
within 3 months of enrollment. The MI was diagnosed using
the following criteria: the finding of an abnormal Q wave on
ECG, elevated cardiac enzyme levels on laboratory testing
during hospitalization for suspected MI, or a fi xed defect on
thallium scanning or localized akinesis on ventriculography
with evidence of obstructive coronary disease and angiography. The patients were eligible for the study if they had an
ejection fraction of 0.30 or less within 3 months before entry,
as assessed by angiography, radionuclide scanning, or echocardiography. Patients with NYHA class IV symptoms were
excluded from the study. All patients received optimal
medical therapy. The study was terminated prematurely
under the recommendation of the Data Safety Monitoring
Board after data analysis demonstrated that prespecified efficacy boundary had been reached. The overall incidence of
the primary end point of the trial (all-cause mortality) was
19.8% in the controlled group and 14.2% in the ICD group
(hazard ratio of 0.69, p = .016) (Fig. 98.16). Subgroup analysis
showed that the survival advantage was conferred across all
subgroups with hazard ratios similar across these groups (Fig.
98.17). Thus, regardless of age, gender, ejection fraction, QRS
duration, creatinine level, and the presence of diabetes or
hypertension, patients demonstrated significant benefit from
ICD implantation. Also of significance, the survival curves
Variable
Age
<60 yr
60–69 yr
≥70 yr
No.of patients
Sex
Male
Female
370
426
436
1040
192
LVEF
≤0.25
>0.25
831
401
NYHA class
I
≥ II
461
771
QRS interval
<0.12 sec
0.12–0.15 sec
>0.15 sec
618
351
262
All patients
Hazard ratio
1232
0.2 0.4
0.6 0.8
1.0 1.2
1.4 1.6
Conventional
Defibrillator
therapy better
better
FIGURE 98.17. Hazard ratios and 95% confidence intervals for
death from any cause in the defibrillator group as compared with
the group assigned to receive conventional medical therapy, according to selected clinical characteristics. The hazard ratios in the
various subgroups were similar, with no statistically significant
interactions. The dotted vertical line represents the results for the
entire study (nominal hazard ratio, 0.66, without adjustment for the
stopping rule). The horizontal lines indicate nominal 95 percent
confidence intervals. LVEF, left ventricular ejection fraction; NYHA,
New York Heart Association.
4
began to diverge at 9 months of follow-up and continued to
extend for the duration of the study. The incidence of lead
problems was 1.8%, and nonfatal infections were observed in
0.7% of patients. The incidence of new or worsened heart
failure was slightly higher in the defibrillator group than in
the conventional therapy group.
This primary prevention trial in ischemic cardiomyopathy patients based on ejection fraction of 0.30 or less demonstrated a 31% reduction in the risk of death. Electrophysiologic
testing or inducible ventricular arrhythmias were not eligibility criteria. In contrast with the earlier MADIT trial, in
which the survivor rate improved within the first few months
after the implantation of the device, in the MADIT-II study,
survival benefit began approximately 9 months after the
device was implanted. The authors attribute the difference
to a somewhat lower mortality rate in the conventional
therapy group in the current study, the absence of risk stratification for arrhythmia as an entry criterion, the use of lower
cutoff value for ejection fraction as a criterion for eligibility,
and the use of more vigorous medical treatment.
No. at risk
Defibrillator 742
503 (0.91)
274 (0.84) 110 (0.78)
9
Conventional 490
329 (0.90)
170 (0.78)
65 (0.69)
3
FIGURE 98.16. Kaplan-Meier estimates of the probability of survival in the group assigned to receive an implantable defibrillator
and the group assigned to receive conventional medical therapy. The
difference in survival between the two groups was significant
(nominal p = .007, by the log-rank test).
SUDDEN CARDIAC DEATH IN HEART FAILURE T RIAL
(SCD-HE FT) 432
This randomized trial tested the hypothesis that ICD or
amiodarone could improve survival in patients with heart
failure. A total of 2521 patients with NYHA class II or III
CHF and an LVEF of 35% or less were randomly assigned
to conventional medical therapy for CHF plus placebo
Probability of survival
1.0
0.9
Defibrillator
0.8
Conventional
0.7
0.6
0.0
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1
2
Year
3
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2068
chapter
98
(847 patients), conventional therapy plus amiodarone (845
patients), or conventional therapy plus a conservatively programmed, shock only, single-lead ICD (829 patients). Placebo
and amiodarone were administered in a double-fold blind
fashion. The primary end point was death from any cause.
The patients had to be at least 18 years of age, and had NYHA
class II or III chronic, stable, CHF due to ischemic or nonischemic causes, and LVEF of no more than 35%. Ischemic CHF
was defined as left ventricular systolic dysfunction associated with at least 75% narrowing of at least one of the three
major coronary arteries or a documented history of an MI.
Nonischemic CHF was defi ned as left ventricular systolic
dysfunction without marked stenosis. All patients were
required, if such treatment was clinically reasonable, to
receive treatment with a beta-blocker and an ACE inhibitor,
as well as aldosterone inhibitor, aspirin, and statin, when
appropriate. There was no requirement for documented ventricular arrhythmias or electrophysiology study performance.
Patients with NYHA class I or IV symptoms, prior cardiac
arrest, sustained ventricular arrhythmias, permanent pacemakers, or valvular or hypertrophic cardiomyopathy were
excluded. The ICD was set to detect only ventricular fibrillation with shock only therapy.
This was the largest primary prevention device trial to
date, with a total of 2521 randomized patients. The results
showed that after a 5-year follow-up, ICD use was associated
with a decrease in the incidence of death by 23% (hazard
ratio 0.77, p = .007), compared to the placebo group. Amiodarone conferred no benefit. It is important to note that this
study was not prematurely terminated by the data safety
monitoring board. The mortality rate for placebo patients
was 7.2% per year over 5 years, significantly lower than
MADIT-II patients (see above). This may be due to the slightly
higher ejection fraction cutoff for enrollment. Also, there
was excellent use of ACE inhibitors and beta-blockers in this
study. Subgroup analysis found that the hazard ratio was 1.08
in those patients with an ejection fraction greater than 0.30
and was 1.61 in patients with NYHA class III symptoms.
Thus, these findings point to possible decreased efficacy in
patients with higher ejection fractions and worse heart
failure. While the former finding is expected, it may be that
the latter demonstrates that patients with more advanced
heart failure may ultimately succumb to pump failure from
which ICDs confer no protection. The SCD-HeFT was the
first trial to conclusively show ICDs offer a benefit for those
patients with nonischemic, nonhypertrophic cardiomyopathies. Nearly half the patients (792 out of 1676 patients randomized to receive ICDs) had nonischemic cardiomyopathy.
The hazard ratio for these patients was very comparable to
that for patients with ischemic cardiomyopathy (0.73 vs. 0.79)
(Fig. 98.18). As in the MADIT-II trial, the benefit of ICD use
occurred across many subgroups (Fig. 98.19).
FIGURE 98.18. (A) Kaplan-Meier estimates of death from any cause.
CI, confidence interval. (B) Kaplan-Meier estimates of death from
any cause for the the prespecified subgroups of ischemic congestive
heart failure (CHF) (top) and nonischemic CHF (bottom).
DEFIBRILLATORS IN NONISCHEMIC CARDIOMYOPATHY
T REATMENT EVALUATION (DEFINITE) 433
The DEFINITE trial tested the hypothesis that an ICD would
reduce the risk of death in patients with nonischemic cardiomyopathy and moderate to severe left ventricular dysfunction. Patients with an ejection fraction less than 0.36
and ambient arrhythmias were included. Ambient arrhythmias were defined by an episode of NSVT on monitoring for
an average of at least 10 premature ventricular complexes per
hour on 24-hour Holter monitoring. Absence of ischemic
component to cardiomyopathy was confirmed by coronary
angiography or nuclear perfusion scanning. Exclusion criteria included NYHA class IV; ACE inhibitor use and betablocker use were strongly encouraged. The primary end point
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su dden ca r di ac de at h
Amiodarone vs. placebo Subgroup
ICD therapy vs. placebo
No. Hazard ratio (97.5% CI)
1.17(0.72–1.90)
398
1.04(0.83–1.30)
1294
1119
1.00(0.76–1.32)
573
1.13(0.83–1.52)
1.06(0.84–1.34)
1292
1.08(0.71–1.62)
573
No.
382
1294
1407
285
999
692
FIGURE 98.19. Hazard ratios for the
comparison of amiodarone and implantable cardioverter-defibrillator (ICD)
therapy with placebo in various subgroups of interest.
517
547
545
1162
530
515
1178
Probability of survival
Death from any cause
1.0
0.9
0.8
ICD
0.7
Standard therapy
0
1
2
A
3
4
Survival (yr)
5
Probability of survival
Sudden death from arrhythmia
1.0
6
ICD
0.9
Standard therapy
0.8
0.7
p = .006
0.0
0
1
2
229
210
131
3
4
Survival (yr)
5
6
No. at risk
B
Standard-therapy
Group
ICD group
67
32
229
218
140
77
41
FIGURE 98.20. Kaplan-Meier estimates of death from any cause (A)
and sudden death from arrhythmia (B) among patients who received
standard therapy and those who received an implantable cardioverter-defibrillator (ICD). In the ICD group, as compared with the
standard-therapy group, the hazard ratio for death from any cause
was 0.65 (95% confidence interval, 0.40 to 1.06) and the hazard ratio
for sudden death from arrhythmia was 0.20 (95% confidence interval, 0.06 to 0.71).
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1.10(0.85–1.42)
0.98(0.69–1.38)
1.20(0.87–1.65)
1.00(0.77–1.30)
1098
578
1283
393
0.68(0.50–0.93)
0.86(0.62–1.18)
0.78(0.61–1.00)
0.75(0.48–1.17)
1390
285
QRS < 120 msec 977
QRS ≥ 120 msec 699
6-Min walk test
526
< 950 ft
536
950–1275 ft
526
> 1275 ft
1157
Beta-blocker
No beta-blocker 519
0.73(0.57–0.92)
1.08(0.57–2.07)
White race
Nonwhite race
LVEF ≤ 30%
LVEF > 30%
Diabetes
No diabetes
524
1152
0.84(0.62–1.14)
0.67(0.49–0.93)
1.14(0.81–1.60)
0.57(0.38–0.88)
0.45(0.27–0.76)
0.68(0.51–0.91)
0.92(0.65–1.30)
0.95(0.68–1.33)
0.67(0.50–0.90)
ICD Placebo
better better
was all-cause mortality. There was no significant difference
in the two groups in all-cause mortality (p = .08), although a
trend was noted (6.2% in standard therapy vs. 2.6% in the
ICD group). There was a significant decrease in the incidence
of sudden arrhythmic death in the ICD group (p = .006) (Fig.
98.20). Thus, this study showed that while ICDs decreased
0.0
1.61(1.17–2.23)
0.82(0.56–1.20)
0.72(0.46–1.12)
Hazard ratio (97.5% CI)
0.96(0.58–1.61)
0.73(0.57–0.93)
0.25 0.5 1.0 2.0 4.0
0.25 0.5 1.0 2.0 4.0
Amiodarone Placebo
better
better
p = .08
1.04(0.84–1.29)
1.24(0.66–2.31)
1.06(0.80–1.41)
1.05(0.78–1.41)
Female sex
Male sex
Age < 65 yr
Age ≥ 65 yr
the incidence of arrhythmic death, they do not affect overall
survival in nonischemic cardiomyopathy patients. There was
a strong trend in favor of ICD use but it did not reach statistical significance. The authors suggest that the study was not
powered sufficiently because the estimated incidence of
arrhythmic death contributing to overall mortality was less
than expected (one third seen in the trial vs. one half expected
at the trial design). The authors concluded that the ICD use
cannot be routinely recommended in this population but
that a case-by-case approach would be most prudent.
CARDIOMYOPATHY T RIAL (CAT) 434
This trial evaluated patients with idiopathic dilated cardiomyopathy and impaired left ventricular function. Patients
with recent onset of dilated cardiomyopathy (≤9 months) and
ejection fraction ≤30% were randomly assigned to the
implantation of an ICD or control. The primary end point of
the trial was all-cause mortality at 1 year of follow-up. The
trial was terminated after the inclusion of 104 patients
because the all-cause mortality rate at 1 year did not reach
the expected 30% in the control group. Cumulative survival
was not significantly different between the two groups (93%
and 80% in the control group vs. 92% and 86% in the ICD
group after 2 years and 4 years, respectively). The lack of any
survival benefit of ICD therapy in this study is most likely
due to the overall low event rate in the cohort that was
studied.
A MIODARONE VERSUS IMPLANTABLE CARDIOVERTER
DEFIBRILLATOR (AMIOVIRT) 435
The AMIOVIRT was a randomized trial for primary prevention of SCD in patients with nonischemic, dilated cardiomyopathy and LVEF of ≤35% who had asymptomatic NSVT. A
total of 103 patients with nonischemic dilated cardiomyopathy were randomized in this trial; 52 patients treated with
amiodarone had 1- and 3-year survival rates of 90% and 87%,
respectively. Fifty-one patients treated with ICDs had 1- and
3-year survival rates of 96% and 88%, respectively. The differences were not statistically significant (p = .8).
The CAT and AMIOVIRT trials questioned the benefit of
the use of ICD in nonischemic dilated cardiomyopathy. The
DEFINITE, which was a larger trial, showed a strong trend
toward improved survival with an ICD. In the SCD-HeFT,
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chapter
which was the largest primary prevention trial in patients
with ischemic or nonischemic cardiomyopathy, ejection fraction ≤35% and NYHA class II to III CHF symptoms, showed
a significant survival benefit from an ICD. It seems that the
smaller randomized trials did not show this benefit due to a
less than expected mortality rate in patients with nonischemic dilated cardiomyopathy. Furthermore, the small size of
these clinical trials did not give them enough statistical
power to answer this question.
Secondary Prevention
In patients with a history of sustained VT/VF, aborted SCD
or both, antiarrhythmic drugs have been in the cornerstone
of therapy for several years. Different studies were performed
to determine the best method to guide antiarrhythmic
therapy.436–440 Several studies have been performed to determine whether antiarrhythmic drugs or ICDs are the therapy
of choice to prolong survival.441–446
Role of Antiarrhythmic Drugs
The debate on whether antiarrhythmic therapy is best guided
by Holter monitoring or invasive EP study led to prospective
trials.
CALGARY STUDY437
This study randomized patients with a history of sustained
VT to receive antiarrhythmic therapy guided by Holter monitoring or EP study. By intention-to-treat analysis, the recurrence of symptomatic sustained VT/VF or sudden death was
at 19% in the invasive arm and 47% in the noninvasive arm
(p = .02). It showed the superiority of the invasive approach
in decreasing the frequency of recurrent VT/VF.
T HE ELECTROPHYSIOLOGIC STUDY VERSUS
ELECTROCARDIOGRAPHIC MONITORING T RIAL
The Electrophysiologic Study versus Electrocardiographic
Monitoring (ESVEM) study438,439 was performed to determine
whether Holter monitoring or EP drug testing is superior in
predicting long-term efficacy of different antiarrhythmic
drugs. A total of 486 patients with sustained VT/VF who
were inducible during EP study and had more than 10 PVCs
per hour during 48-hour monitoring were randomized to EP
drug testing or ambulatory ECG monitoring while on antiarrhythmic therapy. Drug efficacy was defined in the Holter
arm as 100% suppression of VT runs of more than 15 beats,
80% suppression of pairs, and 70% suppression of PVCs. EP
study efficacy was defined as suppression of inducible VT (no
inducible VT of more than 15 beats in duration). The primary
end point was recurrence of arrhythmia in a patient receiving
a drug that was predicted to be more effective by serial
testing. Secondary end points were death from any cause,
death from cardiac cause, and death from arrhythmia. Fortyfive percent of patients in the EP arm (108 of 242 were
included in this limb of the study) and 77% (187 of 244) in
the Holter monitoring arm achieved efficacy. There was no
substantial difference between the two methods in predicting arrhythmia recurrence, which was 58% at 2 years.439
Patients received up to six drugs in a random order. Amiodarone was not used in this study. Sotalol was found to be more
CAR098.indd 2070
98
effective than other drugs tested and statistically had a lower
recurrence rate of arrhythmia (p < .001), all-cause mortality
(p < .004), cardiac death (p < .02), and arrhythmic death (p =
.04).439 The ESVEM investigators therefore concluded that
Holter monitoring was equally predictive of arrhythmia
recurrence as EP testing.
CARDIAC A RREST STUDY IN SEATTLE: CONVENTIONAL
VERSUS A MIODARONE DRUG EVALUATION T RIAL
In the Cardiac Arrest Study in Seattle: Conventional versus
Amiodarone Drug Evaluation (CASCADE) study,447 228
cardiac arrest survivors (out-of-hospital VF not associated
with a Q-wave MI) were randomly assigned to receive empirical amiodarone or a conventional class I antiarrhythmic drug
guided by EP studies or Holter monitoring. Patients were
included in this study if they had 10 PVCs or more per hour
on Holter monitoring and had inducible sustained VT or VF.
The primary end point was cardiac survival, which was
defined as being free of syncope/ICD shock, resuscitated
cardiac arrest, and/or cardiac death.
During a follow-up of 6 years, the rate of cardiac survival
was 30%. The patients treated with amiodarone had a better
outcome (amiodarone, 41% survival rate; conventional class
I agent, 20% survival rate; p < .001). There was no significant
difference in outcomes between conventionally treated
patients whose inducible arrhythmias were or were not
suppressed.
Based on the findings of the ESVEM, CASCADE, and
CAST trials as we discussed earlier, it should be concluded
that therapy with class I antiarrhythmic drugs for VT/VF
was either ineffective or caused more harm. Although class
III agents, sotalol in the ESVEM trial, and amiodarone in the
CASCADE trial were more effective than class I agents, the
chance of long-term event-free survival (no cardiac death or
sustained ventricular arrhythmia) was less than 50% during
follow-up. Therefore, ICD therapy was considered as an alternative for the secondary prevention of SCD. Several studies
evaluated the role of ICDs for secondary prevention.
A NTIARRHYTHMIC VERSUS IMPLANTABLE
DEFIBRILLATOR T RIAL
The Antiarrhythmic Versus Implantable Defibrillator (AVID)
trial442,443 was designed to determine whether the best antiarrhythmic drug (empiric amiodarone or guided sotalol) or ICD
therapy is superior in reducing mortality rates in patients
with a history of sustained VT/VF. Secondarily, the study
considered the cost-effectiveness of the two arms and a
quality-of-life assessment (Table 98.6).
The study enrolled 1016 patients who had either been
resuscitated from VF (45%) or undergone cardioversion from
sustained VT (55%). The patients who had VT also had
syncope or other serious cardiac symptoms and LVEF of
0.40 or less. The patients were randomized to either class
III antiarrhythmic drugs, primarily amiodarone, or ICD
implantation.
The study was terminated prematurely in April 1997
after data analysis and safety monitoring revealed a significant survival advantage in the ICD group.445 The survival
rates in the ICD group were 89.3%, 81.6%, and 75.4% at 1, 2,
and 3 years, respectively. The survival rate in the drug group
was 82.3%, 74.4%, and 64.1% at 1, 2, and 3 years, respectively.
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TABLE 98.6. Prospective Multicenter Intracardiac Defibrillator Secondary Prevention Trials
Study
Patient inclusion criteria
End points
Treatment arms
Key results
AVID442
VF or sustained VT with syncope or
sustained VT without syncope and
LVEF ≤0.40 and SBP <80 mm Hg,
Chest pain, or near-syncope
Overall mortality
Quality of life
Cost and cost
effectiveness
ICD therapy (n = 29)
EP or Holter-guided
sotalol or empiric
amiodarone
ICD reduced total mortality 39%
after 1 y, 27% after 2 y and 31%
after 3 y compared with
antiarrhythmic drugs
CASH441
Survivors of sudden cardiac death
Documented to be associated with
VF or hemodynamically
significant sustained VT
Total mortality
Recurrence of sudden
cardiac death
Arrhythmic mortality
ICD
Propafenone
Metoprolol
Amiodarone
CIDS444
Survivors of sudden cardiac death
Documented to be associated with
VF or VT with syncope or
sustained VT and LVEF ≤0.35
Syncope of unknown cause and
inducible VT in EPS and LVEF
<0.35
All-cause mortality
Arrhythmic death
ICD
Amiodarone
Propafenone arm was associated
with excess mortality and was
discontinued
No significant mortality difference
between amiodarone and
metoprolol
ICD decreased total mortality by
63% in 1 y and 37% in 2 y
compared with combination arms
of amiodarone and metoprolol
ICD decreased all-cause mortality
slightly but not significantly
Results were consistent with AVID
and CASH
AVID, Antiarrhythmic Versus Implantable Defibrillator; CASH, Cardiac Arrest Study Hamburg; CIDS, Canadian Implantable Defibrillator Study; EP, electrophysiology; EPS, electrophysiologic study; ICD, implantable converter-defibrillator; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia.
The corresponding reductions in mortality rates in the ICD
group were 39% at 1 year, 27% at 2 years, and 31% at 3 years
(Fig. 98.21). The majority of ICD benefit occurred in the first
9 months. The ICD survival benefit was most prominent in
patients with an LVEF of less than 0.35. No significant statistical benefit of the ICD was noted with an LVEF of more
than 0.35.
CARDIAC A RREST STUDY H AMBURG T RIAL
The Cardiac Arrest Study Hamburg (CASH) trial441 was initiated in 1987 and designed to compare the efficacy of empiric
antiarrhythmic therapy with amiodarone, propafenone, or
1.0
Proportion surviving
Defibrillator group
0.8
Antiarrhythmic-drug group
0.6
0.4
0.2
0.0
0
1
2
3
Years after randomization
Patients at risk:
1016
Percent surviving
Defibrillator group
Antiarrhythmic-drug group:
644
333
104
89.3
81.6
75.4
82.3
74.7
64.1
FIGURE 98.21. The difference in mortality rates between two
treatment groups was significant at 1, 2, and 3 years after
randomization.
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metoprolol compared with an ICD in survivors of SCD not
related to MI. The primary end point was total mortality. The
secondary end points were hemodynamically unstable VT
and the incidence of drug withdrawal. The mean LVEF was
0.46, and approximately 75% of the patients had CAD. The
main exclusion criterion was MI within 72 hours of SCD.
In July 1992, an interim analysis showed an excessive
mortality rate in the propafenone arm compared with the
ICD group, and the propafenone arm was dropped. The other
three arms of the trial continued, and follow-up evaluation
was conducted for a minimum of 2 years after the randomization of 349 patients. The analysis revealed that ICD
implantation significantly decreased overall mortality rates
in the first year of follow-up (63% decrease in overall mortality rats). The 2-year mortality rate was 12.1% in the ICD
group and 19.6% in the combined drug therapy group (37%
reduction in 2-year overall mortality rates, p = .047). There
was no significant difference in mortality rate between the
amiodarone and metoprolol groups.
The results of this trial were consistent with the results
of the AVID trial.
CANADIAN IMPLANTABLE DEFIBRILLATOR STUDY
The Canadian Implantable Defibrillator Study (CIDS) trial444
randomized 659 patients with a prior history of cardiac arrest
or hemodynamically unstable VT to receive either ICD
therapy (n = 328) or amiodarone (n = 331). The inclusion criteria were documented VF, out-of-hospital cardiac arrest
requiring defibrillation, documented sustained VT at a rate
of 150 beats/min or greater causing presyncope or angina in
a patient with an LVEF of 0.35 or less, syncope with documented spontaneous VT of 10 seconds or greater duration, or
inducible sustained VT in EP laboratory.
The study end point was all-cause mortality in a
comparison of the two therapeutic options. The study also
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considered arrhythmic death. By the end of 5 years after
enrollment, 22% of patients in the amiodarone group received
an ICD and 30% of the ICD patients had been started on
amiodarone.
ICD therapy trended toward overall improvement in survival. Overall mortality rate was approximately 27% at 4
years with ICD versus approximately 33% with amiodarone
(p = .07).
The trial showed a modest, but not statistically significant, reduction in mortality rates with ICD. These results
are consistent with the AVID and CASH results that showed
a beneficial effect of ICD therapy for the secondary prevention of SCD.
Although insight into the mechanism and circumstances
of SCD is increasing, the majority of patients who suffer an
SCD are not identified as high risk before the event. A search
for more effective methods must continue to identify patients
at risk of SCD and to predict the efficacy of our preventive
measures, as SCD remains a major health care issue.448
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