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Chapter
31
Contemporary Management
of Sudden Cardiac Death
SN Narasingan
ABSTRACT
Sudden cardiac death (SCD) is a major public health problem. It is
estimated that approximately 50% of all cardiac deaths are sudden
and unexpected. Sudden cardiac death is a direct consequence of
cardiac arrest, which may be reversible if addressed promptly. Solid
evidence has been obtained from Randomized Clinical Trials (RCTs),
which had changed the approach in the recent guidelines. There are
limitations in determining the true estimate of SCD, as there is a lack of
uniform criteria for definition and classification of mode of death. Most
studies define SCD as death occurring within 1 hour of symptom onset.
This chapter focuses on risk stratification, prevention of ventricular
arrhythmias and sudden cardiac arrest with pharmacotherapy, and
implantable cardioverter-defibrillator (ICD).
INTRODUCTION
Cardiovascular disease (CVD) is a leading cause of global mortality,
accounting for almost 17 million deaths annually, which is 31%
of all global mortality. In developing countries, it causes twice as
many deaths as human immunodeficiency virus (HIV), malaria
and tuberculosis (TB) combined. It is estimated that about 40–50%
of all cardiovascular (CV) deaths are SCDs and about 80% of these
are caused by ventricular tachyarrhythmias. About 6 million SCDs
occur annually due to ventricular tachyarrhythmias. Sudden cardiac
death remains a major public health problem. The survival rate
from sudden cardiac arrest is less than 1% worldwide and close
to 5% in the United States (US). Prevention of CVD by increasing
awareness of risk factors such as lack of exercise, inappropriate diet
and smoking has reduced CV mortality in the US over the past few
decades. However, there is still a huge CVD burden globally as well as
in India. Hence, there is a need to develop complementary strategies
for management of SCD. The data from several trials conclusively
indicate that implantable defibrillators improve mortality in patients
who have experienced an episode or are at high risk of developing
ventricular tachyarrhythmias. These devices are reimbursed, and are
being used frequently in the developed countries for management
of SCD. Cost of ICDs are prohibitive, their implant rates are very
low in developing countries including India. The automatic external
defibrillators (AED) and Emergency Medical Response Services
equipped with AEDs provide complementary as well as alternative
opportunities for management of SCD. There are several challenges
associated with the adoption of these strategies. The global problem
of SCD as well as Indian data with various options for its management
from pharmacotherapy to ICD will be discussed in this chapter.
DEFINITION OF SUDDEN CARDIAC DEATH
Sudden cardiac death is defined as “natural death due to cardiac
causes in a person who may or may not have previously recognized
heart disease but in whom the time and mode of death are
unexpected. In the context of time, sudden is defined for most clinical
and epidemiologic purposes as 1 hour or less between a change in
clinical status heralding the onset of the terminal clinical event and
the cardiac arrest itself”.1 An exception is witnessed deaths, in which
pathologists may expand the definition of time to 24 hours after the
victim was last seen to be alive and stable.
ETIOLOGY OF SUDDEN CARDIAC DEATH
The incidence of SCD increases markedly with age regardless of sex
or race. The most common electrical event with SCD is progression
of ventricular tachycardia (VT) to ventricular fibrillation (VF).2 The
most important common causes are:
• Coronary artery disease (CAD)
• Anomalous origin of coronary arteries
• Cardiomyopathies
• Left ventricular (LV) hypertrophy due to hypertension
• Infiltrative myocardial diseases: Amyloidosis
• Congenital cardiac anomalies
• Primary electrophysiologic abnormalities like long QT syndrome
(LQTS).
Sudden Cardiac Death: Indian
Epidemiological Data
In 2011, a study by Madhavan SR et al. reported that CVD was the
underlying cause in majority of SCD events during a study period
of 22 months involving total deaths of 1,916. Prevalence of CV risk
factors among sudden cardiac and non-sudden deaths was evaluated
in this study. The majority of SCD events are due to CV causes even
in the absence of a history of cardiac disease. The majority of Indian
population lives in rural India. This study in rural India showed that
subjects experiencing SCD were significantly more likely to have
hypertension, diabetes and a history of myocardial infarction (MI)/
CAD (P < 0.0001 for all)3 (Figure 1).
Sudden Cardiac Death Following ST-Segment Elevation
Myocardial Infarction
Study by Rao BH et al. in India, reported that SCDs occurred
after acute ST-segment elevation myocardial infarction (STEMI)
(Figure 2). Interestingly, the study revealed that sudden deaths
constituted about 10% of total mortality in a population from
Southern India and 33.5% of cases had past history of MI. It involved
Cardiology
Section 4
Figure 1: Prevalence of cardiovascular (CV) risk factors among sudden cardiac and non-sudden deaths
Figure 2: Sudden cardiac death (SCD) following ST-segment elevation myocardial infarction (STEMI). Abbreviations: SCD, Sudden cardiac death;
STEMI, ST-segment elevation myocardial infarction; MI, Myocardial infarction. Source: Rao BH, Sastry BK, Chugh SS, et al. Contribution of sudden
cardiac death to total mortality in India: a population-based study. Int J Cardiol. 2012;154(2):163-7. Epub 2010.
younger population and most of SCDs occurred within 1 month after
MI. Out of 159 total deaths reported, 78 were due to SCD and 81 were
due to nonsudden death. This study has shown that SCDs following
STEMI accounts for about 50% of total deaths.
Sudden Cardiac Death in Patients with Myocardial
Infarction and Left Ventricular Dysfunction,
Heart Failure or Both
The results of an analysis of a study published in the New England
Journal of Medicine (NEJM) (Figure 3) confirm that patients with LV
dysfunction, heart failure (HF) or both after MI are at high risk for
SCD or cardiac arrest with resuscitation. The risk of SCD from cardiac
148
causes is increased among survivors of acute MI with reduced LV
systolic function. The risk of sudden death is highest in the first 30
days after MI among patients with LV dysfunction, HF or both. Thus,
earlier implementation of strategies for preventing sudden death
may be warranted in selected high-risk patients.
First Cardiac Rhythm Documented at
the Time of Sudden Cardiac Death
The most common cardiac rhythm abnormality seen at the time
of SCD is VT, which accounts for nearly 63% in a study recently
published.4 Thirteen percent were due to torsade de pointes, 16%
were bradycardia and 8% were due to primary VF.
Section 4
Chapter 31 Contemporary Management of Sudden Cardiac Death
Figure 3: Sudden death in patients with myocardial infarction (MI) and left ventricular (LV) dysfunction, heart failure (HF) or both.
Abbreviations: MI, Myocardial infarction; EF, Ejection fraction; LVEF, Left ventricular ejection fraction. Source: Solomon SD, Zelenkofske S, McMurray JJ,
et al. Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators. N Engl J Med. 2005;352(25):2581-8.
BETA-BLOCKERS AND PREVENTION OF
SUDDEN CARDIAC DEATH
Beta-blockers are the agents most frequently studied in post-MI
patients for the prevention of SCD. More than 12 large RCTs were
reported. A meta-analysis of the beta-blocker trials showed a
significant reduction in mortality.5 Highly significant 30% reduction
in SCD was seen. The risk of non-sudden death was also decreased
by 12%. Recent beta-blocker trials in congestive heart failure (CHF)
patients also show a reduction in both overall deaths and SCD. Betablockers are effective against arrhythmic death (20–30% reduction)
and nonarrhythmic deaths, and reduce overall mortality significantly.
Beta-blocker therapy is indicated in all patients at high risk for SCD.
PREVENTION OF VENTRICULAR ARRHYTHMIAS AND
SUDDEN CARDIAC DEATH
Ventricular ectopy is considered an electrical trigger of sustained
ventricular arrhythmias and potentially SCD. Suppression of
ventricular arrhythmia and prevention of SCD are effectively
controlled by antiarrhythmic drugs in various trials.
Class I Antiarrhythmic Agents
Mexiletine, encainide, flecainide or moricizine have been abandoned
for the reduction of the risk of SCD in patients with ischemic
cardiomyopathy and nonsustained ventricular arrhythmia. Class
I antiarrhythmic drugs are harmful, and are prescribed in patients
with ischemic heart disease and reduced LV ejection fraction (LVEF)
rarely.
Class III Antiarrhythmic Agents
Amiodarone
Class III antiarrhythmic agents were tested in a series of randomized
trials. The two largest trials using amiodarone are: (1) the Canadian
Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT)6
and (2) the European Myocardial Infarction Amiodarone Trial
(EMIAT).7 Both showed a reduction in arrhythmic death but no
significant reduction in overall death. Meta-analysis of data from
all 13 randomized controlled trials (RCTs) of amiodarone in which
89% of patients were after MI, showed a significant reduction in
total mortality and a significant reduction in arrhythmic death.8,9
Amiodarone has a moderate effect against SCD and a neutral effect
on other deaths. The overall effect on total mortality is modest. In
Valsartan in Acute Myocardial Infarction Trial (VALIANT) Study, a
randomized comparison of valsartan, captopril, or both in patients
with acute MI with HF and/or LV systolic dysfunction were analyzed.
Amiodarone use was associated with excess early and late all-cause
mortality and CV mortality.10
Positive relationship between beta-blocker use and amiodarone
effect,11 such that patients on beta-blockers received a significantly
greater benefit from amiodarone than those not on beta-blockers.
More recently, the association of amiodarone and beta-blockers has
been demonstrated to markedly reduce the incidence of appropriate
ICD therapy. In the Optimal Pharmacological Therapy in Cardioverter
Defibrillator Patients (OPTIC) Trial,12 amiodarone plus beta-blocker
significantly reduced the risk of appropriate ICD shocks compared
with beta-blocker alone.
D-Sotalol
D-sotalol, a pure Class III agent, was evaluated in a multicenter
double-blind randomized study. The mortality was 18% lower in
the sotalol than in the placebo group, but this difference was not
statistically significant. D-sotalol is actually a harmful drug.
ROLE OF UPSTREAM THERAPY IN THE PREVENTION
OF SUDDEN CARDIAC DEATH
Angiotensin-Converting-Enzyme Inhibitors
The effect of angiotensin-converting-enzyme inhibitors (ACEs) on
the risk of SCD following MI has been demonstrated in randomized
trials.13-15 A recent meta-analysis of 15 trials that included 15,104
patients having 900 SCD,15 ACEI therapy resulted in a significant
reduction in total mortality, CV death and SCD. The exact mechanism
by which ACEIs reduce SCD is not known. Proposed mechanism
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Cardiology
is attenuation of remodeling, thereby reducing the substrate
for ventricular tachyarrhythmia. They also provide significant
neurohumoral modulation and protection from future ischemic
events.
Angiotensin II Receptor Blockers
The Angiotensin II receptor blockers (ARBs) are potentially
antiarrhythmic. They inhibit the proarrhythmic effects of
Angiotensin II.16 Several trials of different ARB have demonstrated
equivalent effects to those of ACEIs on cardiac and overall mortality.
Except for the Candesartan in Heart Failure Assessment of Reduction
in Mortality and Morbidity (CHARM) Trial results, the addition
of an ARB to ACEI has not yielded any additional benefits.17 The
Angiotensin II receptor blockers should be used as an alternative
therapy in patients who are intolerant to ACEIs.
Aldosterone Antagonists
In the Randomized Aldactone Evaluation Study (RALES),18
aldactone was evaluated in patients, having New York Heart
Association (NYHA) III–IV. After a mean follow-up for 24 months,
the incidence of SCD was significantly decreased. The magnitude
of this effect was similar to the effect on total mortality. In the
Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS) Trial, patients with an
acute MI complicated by symptomatic LV dysfunction were
randomized to standard therapy plus eplerenone.19 Eplerenone
significantly reduced all-cause mortality, CV death and the risk
of CV death and hospitalization. Interestingly, SCD was also
significantly reduced. Either spironolactone or eplerenone is
recommended as adjunctive therapy in patients with HF with LV
dysfunction and NYHA Class III–IV.
N-3 Polyunsaturated Fatty Acids
Alpha-linolenic acid is an essential n-3 polyunsaturated fatty acid
(PUFA) derived from plant sources. Long-chain n-3 PUFA include
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
predominantly derived from seafood consumption. In animalexperimental and in vitro studies, n-3 PUFA directly affects myocyte
electrophysiology (e.g. altering the function of membrane sodium
channel, L-type calcium channel, and sodium-calcium exchanger).
Such effects might contribute to reduced myocyte excitability and
cytosolic calcium fluctuations, particularly in ischemic or damaged
cells susceptible to partial depolarization and triggered arrhythmia.
In a larger study, the Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto miocardico (GISSI)-Prevenzione Trial,20
treatment with n-3 PUFA in 11, 324 post-MI patients significantly
decreased the incidence of SCD, and also significantly decreasing
total cardiac mortality and coronary mortality by a similar extent.
This is the largest secondary prevention clinical trial with n-3 PUFAs
and the first trial to show significant coronary heart disease (CHD)
benefit from supplementation with EPA and DHA alone. The benefits
also were seen in addition to standard therapy including statins,
aspirin, ACEIs and β-blockers. Finally, GISSI was the first study to
document a marked sudden death benefit from supplementation
with omega-3 fatty acids (FAs).
A recent systematic review of 48 RCTs (36,913 participants) and
41 cohort studies did not document a clear effect of omega-3 fats on
total mortality, combined CV events or cancer. The pooled estimate of
this meta-analysis showed no strong evidence of reduced risk of total
mortality or combined CV event in participants taking additional
omega-3 fats. When data from the subgroup of studies of long-chain
omega-3 fats were analyzed separately, total mortality and CV events
were not clearly reduced.
150
Section 4
The effects of fish oils on SCD and CV morbidity and mortality
remain debated. The protective effect of fish oils may be limited to
patients with a previous MI. Current guidelines recommend that
patients with documented CAD consume approximately 1 g of EPA
+ DHA per day, preferably from oily fish; although supplements can
also be considered.
Implantable Cardioverter-Defibrillator Therapy
for Prevention of Sudden Cardiac Death
Number of clinical trials have shown efficacy of ICD therapy for SCD
prevention in various clinical settings. Highly selected and highrisk individuals have shown benefits of ICD therapy. The primary
indication is LVEF, which is less than or equal to 35%. The American
College of Cardiology (ACC)/American Heart Association (AHA)/
Heart Rhythm Society (HRS) 2008 Guidelines for current indication
for ICD therapy is the presence of a persistently depressed LVEF of
35% or less in patients with ischemic cardiomyopathy who are on
appropriate medical therapy at least 30 days beyond MI. In some
instances, the presence of nonsustained VT or the induction of
VT during programmed electrical stimulation have been used as
inclusion criteria.
However, the limitations of ICD therapy have to be taken into
account. Implantable cardioverter-defibrillator shocks may be
associated with increased mortality and sometimes ICD shocks may
change the mode of death from arrhythmic to nonarrhythmic or
HF death. Implantable cardioverter-defibrillator malfunction may
interfere with success of therapy. It is not uncommon to witness
patients having ICD to develop states of anxiety and depression. Cost
may be prohibitive apart from the longevity of the device.
Immediate Risk-Stratification Improves Survival (IRIS) Trial had
shown the benefit of the ICD in reducing SCD and this was negated by
the higher rate of mortality due to nonarrhythmic death. Defibrillator
in Acute Myocardial Infarction Trial—ICD therapy did not reduce
mortality in high-risk patients early after MI. The ICD significantly
reduced arrhythmic death by more than 50%. However, this was
offset by a significant increase in nonarrhythmic death. It may be that
the use of an ICD in patients early after MI changes the mode of death
from arrhythmic to nonarrhythmic. Interpretation of Multicenter
Automatic Defibrillator Implantation Trial (MADIT I and II) is that
patients who are vulnerable to malignant ventricular arrhythmias
early post-MI are also likely to have more HF and increased risk
for other cardiac nonarrhythmic mortality. Although SCD may be
aborted with ICD therapy, recent studies have demonstrated that
ICD shocks may be associated with increased mortality.
Adjunctive therapy for the prevention of recurrent shocks has
clinical relevance primarily by improving quality of life by preventing
both appropriate and inappropriate shocks. Amiodarone and betablocker have both shown significant reductions in device therapy,
and are recommended for patients with recurrent shocks.
Long QT Syndrome
The long QT syndrome (LQTS) is frequently associated with SCD.
Long-term therapy with beta-blockers, permanent pacing or left
cervicothoracic ganglionic sympathectomy, have been reported to
reduce cardiac events.21-23 A number of clinical markers have been
suggested as risk-stratifiers for SCD. History of syncope, family
history of SCD, cardiac arrest, torsade de pointes and type of LQTS
have been suggested by some investigators as markers of SCD.22 ICD
is recommended for patients who have a recurrence of syncope or
VF while receiving beta-blockers. Genetic analysis may in the future
aid in identifying patients at higher risk of SCD, and may justify
implanting an ICD for primary prevention.21,23
Section 4
Chapter 31 Contemporary Management of Sudden Cardiac Death
Cardiac Resynchronization Therapy and
Implantable Cardioverter-Defibrillator for
Sudden Cardiac Death Prevention
Whether ICD therapy alone or combined with cardiac
resynchronization therapy (CRT) in appropriate HF candidates
has an impact on SCD remains a matter of debate. The Cardiac
Resynchronization Heart Failure (CARE-HF) Study randomized 813
patients with advanced HF, QRS prolongation (> 120 msec) and LVEF
less than 35% who were followed for a mean of 29.4 months. The
primary endpoint was significantly reduced in the CRT compared
to medical therapy group. Death was also significantly reduced in
the CRT compared to medical therapy group.24 The extension of the
study observed a significant reduction in SCD. Hence, it is reasonable
to recommend CRT + ICD, when there is an overlapping indication
(advanced HF, EF < 35%, QRS duration > 120 msec).25
CONCLUSION
Sudden cardiac death is a major public health problem. There is
increased incidence of SCD in developing countries including India.
Indian data revealed that SCD was commonly seen following STEMI.
It is estimated that about 40–50% of all CV deaths are SCDs and about
80% of these are caused by ventricular tachyarrhythmias. The survival
rate from sudden cardiac arrest is less than 1% worldwide. There is a
need to develop complementary strategies for management of SCD.
Implantable defibrillators improve mortality in patients who have
experienced an episode or are at high risk of developing ventricular
tachyarrhythmias. Patients with EF less than 35% derive benefit
from ICD. Beta-blocker therapy is indicated in all patients at high
risk for SCD. Suppression of ventricular arrhythmia and prevention
of SCD are effectively controlled by antiarrhythmic drugs. More
recently, the association of amiodarone and beta-blockers has been
demonstrated to markedly reduce the incidence of appropriate ICD
therapy. Accumulated evidence supports the use of ACEI, ARBs,
aldosterone antagonists and n-3 PUFA as upstream interventions in
appropriate patients to prevent SCD.
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