Download - Role of drugs and devices in patients at risk of sudden cardiac death

doi: 10.1111/j.1472-8206.2010.00853.x

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A R T I C L E

Themed series on‘Sudden Cardiac Death –Cardiovascular Therapy’Meeting June 18–19, 2009Copenhagen, Denmark

Role of drugs and devices in patients at riskof sudden cardiac death

Giuseppe Boriania*, Igor Diembergera, Cinzia Valzaniaa, Mauro Biffia,Cristian Martignania, Emanuel Raschib, Valentina Mantovania,Matteo Ziacchia, Matteo Bertinia, Fabrizio De Pontib, Angelo Branzia

aInstitute of Cardiology, University of Bologna, Azienda Ospedaliera S. Orsola-Malpighi, Bologna, ItalybDepartment of Pharmacology, University of Bologna, Bologna, Italy

I N T R O D U C T I O N

Sudden cardiac death (SCD) is defined as an unexpected

death from cardiac causes following sudden cardiac

arrest occurring within 1 h of the onset of acute

symptoms [1]. Despite important progress, SCD contin-

ues to represent an important clinical challenge for

contemporary cardiology, and this is related to a series of

complex issues related to the extent of SCD epidemiology,

the variety of pathophysiological factors and mecha-

nisms that may lead to ventricular fibrillation as a

common final pathway, the incomplete knowledge of the

role of genetic factors in facilitating the occurrence of

malignant ventricular tachyarrhythmias, as well as the

difficulties in demonstrating the efficacy and effectiveness

of pharmacological or non-pharmacological interven-

tions (Figure 1).

A large number of studies have been dedicated to the

pathophysiology of SCD, and a specific experimental

model of SCD was developed to test the effect of various

classes of drugs [2]. In view of the complex interactions

among the mechanisms of arrhythmogenesis, the

anatomical and functional myocardial substrates, the

transient initiating events and genetic factors (Figure 1),

Keywords

anti-arrhythmic drugs,

cardioverter defibrillator,

sudden cardiac death,

ventricular fibrillation

Received 25 January 2010;

revised 19 March 2010;

accepted 4 May 2010

*Correspondence and reprints:

[email protected]

A B S T R A C T

The search for effective treatment for preventing sudden cardiac death (SCD) initially

started with anti-arrhythmic agents in high-risk patients, but the use of randomized

controlled trials clearly led to the conclusion that an approach based on anti-

arrhythmic agents is not useful, and sometimes potentially harmful (the risk of

arrhythmic death was increased up to 159% in CAST study). Today the approach to

SCD prevention includes considering both the setting of patients who have already

presented a cardiac arrest or a malignant ventricular tachyarrhythmias (secondary

preventions of SCD) and the much broader setting of primary prevention in patients

at variable degrees of identifiable risk. For secondary prevention of SCD, implantable

cardioverter defibrillation is now the standard of care (the risk of overall mortality

may be reduced by 20–31%), and anti-arrhythmic agents, specifically amiodarone,

have only a complementary role (for reducing device activations or for preventing

atrial fibrillation). For primary prevention of SCD in high-risk patients, cardioverter

defibrillators have nowadays specific indications in patients with left ventricular

dysfunction (often in combination with cardiac resynchronization therapy), where

the risk of overall mortality may be reduced by 23–54%. For the large number of

subjects who have some risk of SCD, but are not identified as at high risk of SCD, a

series of drugs could exert a favorable effect (beta-blockers, angiotensin-converting

enzyme inhibitors, angiotensin receptor blocker agents, statins, omega-3 fatty acids

and aldosterone antagonists), and for some of them evidence is emerging, from

subgroup analysis, of possible SCD prevention capabilities.

ª 2010 The Authors Fundamental and Clinical Pharmacology ª 2010 Societe Francaise de Pharmacologie et de TherapeutiqueFundamental & Clinical Pharmacology 24 (2010) 575–594 575

Fund

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tal &

Cli

nica

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y

randomized clinical trials are currently the crucial step to

validate any therapeutic intervention. Therefore, in this

review, we will focus on the clinical evaluation of the

therapeutic approaches for reducing SCD, with specific

reference to the result of randomized clinical trials.

The epidemiology of SCD as the basis for

therapeutic approaches

SCD is the most common cause of death in developed

Western countries where it is responsible every year for

more victims than AIDS (acquired immune deficiency

syndrome) or stroke [1,3,4], with around 460,000 SCDs

in the United States in 1998, accounting for nearly 60%

of all cardiac deaths.[5]. Worldwide, more than 3 million

people are estimated to die from SCD each year and only

<1–3% of SCD events are non-fatal [2]. It is estimated

that in Western countries, the overall incidence of SCD in

an unselected adult population is 1–2 per 1000 per year.

The incidence of SCD increases according to age, and

also the underlying heart disease varies according of the

age of patients presenting with SCD (Figure 2). While

coronary artery is largely the dominating etiology at an

age higher than 50 years, cardiomyopathies and pri-

mary electrical diseases (i.e. channelopathies) are the

prevalent etiology at an age below 30-40 years [6].

A careful evaluation of the epidemiological profile of

SCD should represent the basis for any rational approach

to prevention of SCD (Figure 3) [1,5]. Indeed, according

to the overall incidence of SCD, a treatment or an

intervention designed for the general population should

be applied to 1000 people to potentially prevent SCD in 1

out of these 1000 people, but with the costs and risks of

applying this treatment/intervention to 999 people who

will not experience SCD [1]. As shown in Figure 3, it is

possible to identify, on the basis of clinical factors, some

subgroups of patients at high risk of SCD, for whom the

Anatomic andfunctional substrate:

C

Transient initiating events:• Ischemia

• CAD• DCM, HCM, ARVD• Valvular HD

Congenital HD

• Reperfusion• Stretch• Overload••

• Hypertensive HD• Inflammatory, infiltrative,

•

• Drugs• Neuro-endocrine

stimulationdegenerative alterationsVF, VT

AsystoleEMD

Arrhythmia mechanisms:• Re-entry• Automaticity

Genetic factors influencing:• Ionic channels• Coronary risk factors

Ath i• Triggered activity• Block• Cell uncoupling

• Atherogenic processand plaque vulnerability

• Thrombosis of coronaryarteries

• Inflammation

Electrolytes, pH, pO2

Figure 1 Factors involved in the complex chain of events that may

lead to sudden cardiac death. Modified from ref. [1].

Figure 2 Incidence of sudden cardiac death according to age, in

general population (top) and in subjects aged less than 50 years

(bottom). CAD: coronary artery disease; CMP, cardiomyopathy; ED,

primary electrical disease (channelopathy). Modified from ref. [6].

Figure 3 The epidemiology of sudden cardiac death (SCD) in the

context of the overall adult population of the United States. The

picture illustrates the risk of SCD in various subgroups of patients

and in the general adult population in terms of incidence per year

(left panel) and total number of events per year (right panel). The

categories of patients who are potential candidates for device

therapy and to upstream therapy are shown. Modified from ref. [1].

576 G. Boriani et al.

ª 2010 The Authors Fundamental and Clinical Pharmacology ª 2010 Societe Francaise de Pharmacologie et de TherapeutiqueFundamental & Clinical Pharmacology 24 (2010) 575–594

incidence of SCD events at 1 year may be at least 10-fold

greater than in the general population. These subgroups

of patients at high risk traditionally have been the

subject of investigations targeted to assess the risk and

cost-benefit ratio of a series of pharmacological and non-

pharmacological treatments (beta-blockers, amiodarone

and other anti-arrhythmic agents and, more recently,

implantable cardioverter defibrillators [ICDs]). These

subjects correspond to patients with coronary artery

disease, previous myocardial infarctions (MIs) associated

with left ventricular (LV) dysfunction and other high-risk

markers; patients with a recent ventricular tachyar-

rhythmia or recent cardiac arrest; and patients with LV

dysfunction or heart failure. However, approaches

directed to these high-risk patients will inevitably have

a limited effect on the overall number of SCD occurring

in the general population, as can be easily predicted by

data on the number of annual SCD events reported in

Figure 3 (right panel). The focus on high-risk patients

implies limiting the potential benefit of applied treat-

ments/interventions to a small fraction of the overall

number of subjects at risk. It is estimated that at least

two-thirds of all the events of SCD related to coronary

artery disease occur as the first clinical event in subjects

belonging to the general population or considered to be

at relatively low risk for SCD [(often relatively young

subjects with no more than one established cardiovas-

cular risk factor) [1,5]. For these reasons, although

present consensus guidelines [7] recommend highly

selective evidence-based SCD prevention strategies to

target the patients identified as at high risk for SCD, with

specific indications for ICDs, it should be highlighted that

this approach has the inherent limitation of targeting

only a relatively small proportion of all expected cases of

SCD. In this perspective, the ICD can be considered as

just one of the tools we have for fighting SCD: it is

obviously confined to high-risk subgroups and based on

prompt termination of ventricular tachyarrhythmias,

with an intervention which is ‘downstream’ of the chain

of events leading to life-threatening arrhythmias (i.e.

with effects acting directly on the electrophysiological

properties of cardiac fibers or specialized conducting

tissue). For patients at lower risk of SCD, or as a

complementary treatment in high-risk patients, there is

now increasing interest in the efficacy, effectiveness, and

cost-benefit ratio of a series of treatments that do not

have specific electrophysiological or anti-arrhythmic

effects, but may exert an ‘upstream’ effect on the

complex chain of events involved in SCD pathophysiol-

ogy, including interactions between substrate, triggers

and modulating factors [8]. As ‘upstream therapy’, we

can define all the pharmacological treatments without

electrophysiological actions on cardiac muscle or spe-

cialized conducting tissue [7]. In a rational approach to

SCD prevention, these upstream interventions (non-anti-

arrhythmic agents, such as b-blockers, aldosterone

antagonists, angiotensin-converting enzyme (ACE)

inhibitors, angiotensin II receptor blockers (ARB) agents,

statins and omega-3 fatty acids) should be considered as

attempts to prevent SCD in the much broader group of

patients at relatively low risk who have only coronary

risk factors, without specific markers of arrhythmic risk.

In this review, we will consider the evidence support-

ing the clinical use of anti-arrhythmic agents, ICDs and

non-anti-arrhythmic agents for upstream therapy, as a

rational and broad, full-spectrum approach to the

complex problem of SCD prevention. We will consider

both the selected setting of secondary prevention of SCD

[i.e. in patients with a previous aborted cardiac arrest or

a previous life-threatening ventricular tachycardia (VT)],

as well as the topical, larger setting of primary preven-

tion of SCD (i.e. in patients who had not previously

experienced life-threatening events but are identified as

patients at risk of SCD).

Anti-arrhythmic drugs: no evidence of benefit in

secondary and primary prevention of SCD

As ventricular fibrillation is the final common pathway

of a wide range of events leading to SCD (Figure 1), the

search for pharmacological agents to prevent SCD was

initially focused on agents that directly interact with the

ion channels of myocardial cells. Anti-arrhythmic agents

with characteristics typical of class I and class III

(including amiodarone) of the Vaughan Williams clas-

sification have been tested over time, also on the basis of

a series of considerations on the ‘vulnerable parameters’

that could be the most suitable targets for pharmaco-

logical interventions [9].

The observation in intensive care units, that ventric-

ular fibrillation is preceded by frequent premature

ventricular beats (PVB) and initiated by PVBs with very

short coupling, coupled with the observations that the

occurrence of frequent PVBs in survivors of MI is

associated with increased risk of SCD led in the 1980s

to the concept of reducing SCD through PVB suppres-

sion. This concept was applied to the field of primary

prevention of SCD in patients with a previous MI, and

class I anti-arrhythmic agents of the Vaughan Williams

classification, which are potent suppressors of PVBs,

were tested in a series of studies, including randomized

Prevention of sudden cardiac death 577


trials [10–14]. Two controlled studies, named CAST I

and II [11–13], tested a series of class I anti-arrhythmic

drugs (encainide, flecainide, moricizine) vs. placebo in

post-infarction patients with frequent PVBs. The CAST

study was prematurely terminated in 1989 with regard

to encainide and flecainide arm [11], because a 10-

month follow-up showed evidence of harm, because of

increase in both arrhythmic and non-arrhythmic death

in patients treated with encainide or flecainide

[11,12](Table I). The evidence that excess mortality

occurred, despite effective suppression of PVBs, clearly

indicated that the approach to SCD prevention through

PVB suppression was wrong. The moricizine arm (CAST

II study) was also subsequently terminated because of

evidence of early proarrhythmia [13]. The studies on

primary prevention of SCD using anti-arrhythmic agents

Table I Main controlled trials on anti-arrhythmic agents in prevention of mortality and sudden cardiac death (excluding ICD trials).

NS = P > 0.1.

Study, year, ref

No.

patients Comparison Follow-up End-point P-value Relative risk reduction

Class I anti-arrhythmic agents

IMPACT: International mexiletine and

placebo anti-arrhythmic coronary trial

(1984) [10]

630 Mexiletine vs. placebo 12 months All-cause death NS Risk increased by 58%

CAST I; Cardiac arrhythmia suppression

Trial I (1991) [12]

1498 Encainide or Flecainide

vs. placebo

10 months Arrhythmic death 0.0004 Risk increased by 159%

Non-arrhythmic

cardiac death

0.01 Risk increased by 228%

CAST II: Cardiac arrhythmia suppression

Trial II (1992) [13]

2699 Moricizine vs. placebo 18 month All-cause death NS Risk increased by 13%

Class III anti-arrhythmic agents (except amiodarone)

Julian et al. (1982) [15] 1456 Sotalol vs. placebo 12 months All-cause death NS 22%

SWORD: Survival with oral d-sotalol in

patients with left ventricular

dysfunction after myocardial

infarction (1996) [16]

3121 D-sotalol vs. placebo 2.25 years All-cause death 0.006 Risk increased by 65%

Arrhythmic death 0.008 Risk increased by 77%

DIAMOND: Danish investigations of

arrhythmia and mortality on dofetilide

(2000) [116]

1510 Dofetilide vs. placebo 15.2 month All-cause death NS 1%

Arrhythmic death NS 6%

ALIVE: Azimilide post-infarct survival

evaluation (2004) [18]

3717 Azilimide vs. placebo 12 months All-cause death NS 0%

Amiodarone

GESICA: Grupo de estudio de la

sobrevida en la insuficiencia cardiaca

en Argentina (1994) [19]

516 Amiodarone vs. control 24 months All-cause death 0.024 28%;

Sudden death NS 27%

STAT CHF: Survival trial of

anti-arrhythmic therapy in congestive

heart failure (1995) [20]

674 Amiodarone vs. placebo 45 months All-cause death NS 2%

Sudden death NS 7%

EMIAT: European myocardial infarct

amiodarone trial investigators

(1997) [21]


Arrhythmic death 0.05 35%

CAMIAT: Canadian amiodarone

myocardial infarction arrhythmia

trial (1997) [22]



GEMICA: Grupo de estudios

multicentricos en Argentina.

(2000) [23]

1073 Amiodarone vs. placebo 6 months All-cause death 0.004 Risk increased by 60%

with high-dose

amiodarone

All-cause death NS Risk reduction by 30%

with low-dose

amiodarone

ICD, implantable cardioverter defibrillator; NS, non-significant.



were analyzed in a meta-analyses published by Teo el al.

[14], resulting in clear evidence that use of class I anti-

arrhythmic agents was associated with harm, expressed

by increased mortality in treated patients. The results of

these studies led to the conclusion of no role for class I,

and specifically for class Ic anti-arrhythmic agents in

SCD prevention in the setting of patient with previous

MI.

Agents with class III anti-arrhythmic properties have

been tested in a relatively small number of studies, while

much more data are available on amiodarone, a multi-

channel blocker that also exerts class III effects [15–26]

(Table I). Sotalol is a racemic mixture of a beta-blocker

and Ikr blocker, and in the study by Julian at al., its use

in post-infarction patients did not result in a significant

improvement in the outcome [15] (Table I). The SWORD

study tested d-sotalol, the isomer with pure class III

activity, in a population of patients with previous MI and

the result was negative, because of increased mortality

and only anti-arrhythmic death vs. placebo [16]

(Table I). Dofetilide is a class III anti-arrhythmic agent

developed to treat atrial fibrillation, which was tested in

a controlled study in post-infarction patients with LV

dysfunction, with evidence of no difference in overall

mortality and anti-arrhythmic mortality vs. placebo

[17]. More recently, azimilide, a complex class III anti-

arrhythmic agent, resulted in no improvement in the

outcome in a controlled study performed on post-

infarction patients with LV dysfunction [18].

Amiodarone has been the subject of several studies,

both in the field of primary and secondary prevention of

SCD. This agent has class III anti-arrhythmic properties,

but also exerts a broad spectrum of anti-arrhythmic

effects, through its multichannel activity, with a low rate

of proarrhythmic effects [9]. As shown in Table I, many

randomized, controlled trials were designed to assess the

efficacy of amiodarone either in patients with a previous

MI or in patients with heart failure [19–23]. As evident

from the results of the individual studies and from the

meta-analysis published in 1997 on more than 6500

patients [24], although amiodarone may reduce

arrhythmic death, there is no straight evidence that this

translated into a significant reduction in overall mortal-

ity. In the meta-analysis published in 1997, the reduc-

tion in overall mortality [13% relative risk (RR)

reduction] was significant or not significant depending

on the approach to meta-analysis (fixed effect or random

effect technique, respectively) [24]. A recent meta-

analysis on randomized studies on amiodarone was

published in 2009, based on 15 trials involving over

8500 patients [25]. This meta-analysis also confirms

that amiodarone treatment is associated with a signifi-

cant reduction in SCD and cardiovascular mortality (RR

reductions 28% and 18%, respectively), but without any

significant reduction in all-cause mortality [25].

Amiodarone was investigated also in SCD-HeFT trial, a

trial on the role of ICDs in primary prevention of SCD in

heart failure [26]. The lack of any significant improve-

ment in survival in the amiodarone arm vs. the placebo

arm of the SCD-HeFT trial (the trial with the largest

number of amiodarone-treated patients) strengthens the

notion that nowadays amiodarone has no role in

improving outcomes in patients at high risk [26]. For

this reason, and the evidence emerging from a series of

trials reported in Table II [27–35], amiodarone does not

currently represent a valid alternative to ICD therapy

which, unless not indicated for specific reasons [7], has

emerged as the landmark treatment for prevention of

SCD in high-risk patients, in the setting of either

secondary or primary prevention (the latter in patients

with LV dysfunction either of ischemic or of non-

ischemic etiology) [7,36–38].

Amiodarone has traditionally been the reference

treatment for patients with ventricular tachyarrhyth-

mias, i.e. in the setting of secondary prevention of SCD

(Table II). Its role in improving survival was initially

tested against anti-arrhythmic therapy guided by elec-

trophysiological testing in the CASCADE study, pub-

lished in 1993 [39]. In this study, 228 survivors of out-

of-hospital cardiac event were randomized to empiric

amiodarone or anti-arrhythmic therapy (predominantly

quinidine or procainamide) guided by the results of

programmed electrical stimulation. At 2 years, amioda-

rone treatment was associated with a significant lower

occurrence (8% vs. 31%, P = 0.007) of the combined

end-point of cardiac mortality, resuscitated cardiac event

or syncope because of ICD shock.

More recently, the development of ICDs has required

validation through randomized, clinical trials of ICD

therapy, and amiodarone has been the traditional

comparator in the field of either secondary or primary

prevention of SCD. The landmark trials comparing

amiodarone to ICD in the setting of secondary prevention

are shown in Table II, which also includes the results of a

meta-analysis [30]. Based on all the available trials, it

emerges that in the setting of secondary prevention, the

outcome of patients is improved by implanting an ICD,

which nowadays represents the standard of care for

secondary prevention of SCD, according to consensus

guidelines [7,38].



It is clear that anti-arrhythmic agents, including

amiodarone, currently play a minor role in SCD preven-

tion. However, it should be stressed that in patients

implanted with an ICD, for secondary or primary

prevention of SCD, there may be a role for anti-

arrhythmic therapy, with amiodarone in most case and

with sotalol in a minority of cases, with the aim of

reducing the number of ICD shocks (in the case of

frequent recurrences of ventricular tachyarrhythmias) or

for preventing atrial fibrillation, a frequent cause of

inappropriate ICD interventions [36].

Dronedarone is a non-iodinated analog of amiodarone

that like amiodarone exerts the properties of class III

anti-arrhythmic agents, as well as multichannel-block-

ing efficacy [40]. Although this agent reduces the

incidence of ventricular fibrillation in several experimen-

tal models, it has undergone thorough clinical evalua-

tion in the setting of atrial fibrillation and has recently

been approved for treatment of non-permanent atrial

fibrillation and is not approved for ventricular tachyar-

rhythmias treatment or for SCD prevention [40].

Implantable cardioverter defibrillators: efficacy in

secondary and primary prevention of SCD

The role of ICD therapy has impressively expanded

since this device therapy was first conceived by Dr.

Table II Main controlled trials on cardioverter defibrillators (ICDs) vs. amiodarone or other controls in secondary and primary prevention of

sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.

patients Comparison Follow-up End-point P-value

Relative risk

reduction

Secondary prevention trials

AVID: Anti-arrhythmics vs. implantable

defibrillators (1997) [27]

1016 ICD vs. anti-arrhythmic drugs

(amiodarone in 96%)

18 months All-cause death <0.02 31%

CIDS: Canadian implantable defibrillator

study (2000) [28]

659 ICD vs. amiodarone 36 months All-cause death NS 20%


CASH: Cardiac arrest study Hamburg

(2000) [29]

288 ICD vs. amiodarone,

propafenone

or metoprolol

57 months All-cause death 0.081 23%

Meta-analysis AVID, CASH, CIDS

(2000) [30]

1866 ICD vs. amiodarone 28 months All-cause death <0.001 27%

Arrhythmic death <0.001 51%

Primary prevention trials

MADIT: Multicenter automatic

defibrillator implantation trial

(1996) [31]

196 ICD vs. control 27 months All-cause death 0.009 54%

MUSTT: Multicenter unsustained

tachycardia trial (1999) [32]

704 Anti-arrhythmic drugs or ICD

(guided by

electrophysiological

study) vs. Control

ICD vs. anti-arrhythmic drugs

39 months Cardiac arrest or

arrhythmic death

0.04 27%

All-cause death 0.06 20%

Cardiac arrest or

arrhythmic death

<0.001 76%

All-cause death <0.001 60%

MADIT II: Multicenter automatic

defibrillator implantation trial II

(2002) [33]

1232 ICD vs. control 20 months All-cause death 0.016 31%

COMPANION: Comparison of medical

therapy, pacing, and defibrillation in

heart failure trial (2004) [34]

1634 CRT-D vs. control 16 months All-cause death

or hospitalization

0.01 20%

All-cause death 0.003 36%

SCD-HeFT: Sudden cardiac death in

heart failure trial (2004) [26]

2521 ICD vs. amiodarone vs.

placebo

45.5 months All-cause death 0.007 23% ICD vs.

placebo

NS Risk increased by

6% amiodarone

vs. placebo

MADIT CRT: Multicenter automatic

defibrillator implantation trial – cardiac

resynchronization therapy (2009) [35]

1820 ICD vs. CRT-D 4.5 years All-cause death or

heart failure event

0.001 36%

Heart failure event <0.001 41%

CRT-D: cardiac resynchronization therapy with defibrillation back up; ICD: implantable cardioverter defibrillator; NS: non-significant.



Michel Mirowski over 30 years ago for secondary SCD

prevention in selected patients with documented ven-

tricular tachyarrhythmias [41]. The first ICD was

implanted in a human in 1980, and in 1985, the

Food and drug administration approved use of this

device for patients who had survived two episodes of

cardiac arrest. Impressive technological advances have

made ICDs easier and safer to implant and better

accepted by patients, with the possibility of performing

the implant in a subcutaneous pectoral pocket, without

the need for thoracotomy [36,42]. In parallel, a series

of randomized, controlled trials tested the efficacy of

ICD in reducing SCD and improving overall survival,

not only in the selective field of secondary prevention

but also in high-risk patients without previous ventric-

ular tachyarrhythmias [26–35] (Table II). For all these

studies, the main criterion for selecting patients at high

risk of SCD was the presence of a depressed LV

function. Demonstrated efficacy of ICDs in primary

prevention was initially established in patients with

previous MI associated with LV dysfunction (MADIT I,

MUSTT, MADIT II trials) [31–33] and was then

extended to patients with LV dysfunction and heart

failure (NYHA class II and III) of either ischemic or

non-ischemic etiology (SCD-HeFT trial) [26]. These

findings were progressively translated into the recom-

mendations for ICD implantation provided by consen-

sus guidelines [7,38]. Considering the evidence from

the individual trials alongside the results of various

meta-analyses of efficacy [36,38], it seems clear that

ICDs are effective in improving overall survival at

2–5 years in appropriately selected patients with LV

dysfunction at high risk of SCD and that the number of

patients who need to be treated to prevent one death

ranges between 1 and 14 in a time perspective ranging

from 1 to 5 years [43].

Device therapy for SCD prevention has had a

substantial improvement since the development and

validation of cardiac resynchronization therapy, ini-

tially in patients with moderate to severe heart failure,

and more recently also in mild heart failure [35,44].

In patients with moderate to severe heart failure,

cardiac resynchronization therapy, through continuous

biventricular pacing, has been shown to improve

overall survival, as well as providing favorable effects

in terms of quality of life, exercise capacity and

reductions in hospitalization because of heart failure

[44]. In view of current guidelines [7,38] and the most

recent studies, definite indications are now available

for device therapy, i.e. ICDs or devices providing both

defibrillation and resynchronization therapy (CRTD

devices), both in the field of secondary and primary

preventions of SCD. In Table III, indications to device

treatment for primary prevention of SCD and for heart

failure treatment are shown for a wide spectrum of

patients, including patients presenting with heart

failure and LV dysfunction. The presence of a wide

QRS complex (QRS duration ‡ 120 ms) is considered

an electrocardographic marker of ventricular dyssyn-

chrony and identifies those patients with heart failure

and LV dysfunction who can benefit from CRT [44].

As reported in Table III, patients with LV dysfunction

in the first 40 days following an acute MI are not

candidates to a prophylactic ICD, and this is in line

with the results of both DIAMOND and IRIS study

[45,46].

Some groups of patients are at risk of SCD even in the

absence of LV dysfunction, and specific indications for

ICD implant have been developed [7,38] for high-risk

subgroups of patients with hypertrophic cardiomyo-

pathy, arrhythmogenic right ventricular dysplasia, long

QT syndrome, Brugada syndrome or other clinical

entities, as indicated in Table III.

The challenging issue is now to what extent current

indications for device therapy for SCD prevention can be

applied in ‘real-world’ clinical practice, where health

care systems have to face the global financial and

economic crisis [36,43]. In this perspective, ICD is

commonly perceived as a rather expensive therapy, in

view of its high up-front costs at the time of device

implant, followed by maintenance costs for device

replacement and possible complications [43]. Despite

marked price reductions in the last decade, the cost issue

limits full acceptance and adoption of ICD therapy,

especially as regards widespread use for primary preven-

tion of SCD [36]. Even in economically developed

countries, the use of ICDs for primary prevention of

SCD represents an important public health consider-

ation, and implementation of consensus guidelines on

ICD use for primary prevention of SCD is fairly hetero-

geneous across Europe [36,43].

There is increasing interest on the role of VT

ablation, as a way for controlling ventricular tachyar-

rhythmias, either in patients who already have an

indication to ICD treatment [47,48] or in very selected

patients, as the unique intervention for preventing

recurrences of ventricular tachyarrhythmias [49]. The

latter application of VT ablation is still a matter of

clinical investigation, with regard to its impact on

patients’ outcomes at long term.



Non-anti-arrhythmic ‘upstream’ therapy: a

potential role in primary prevention of SCD

Beta-blockers

Beta-blockers have strong evidence in support of their

use. These agents exert multiple actions, both ‘upstream’

and at an electrophysiological (potentially anti-

arrhythmic) level. In addition, beta-blockers exert an

anti-ischemic action by reducing heart rate, cardiac

contractility and systolic blood pressure. Improvement in

LV structure and function (by decreasing ventricular size

and increasing ejection fraction) also plays an important

role in the prevention of arrhythmic events.

Several trials have shown that beta-blockers reduce

the risk of hospitalizations and death in patients with

heart failure. Table IV summarizes available evidence

derived from clinical trials regarding the effects of beta-

Table IV Main controlled trials on beta-blockers in prevention of mortality and sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.


Relative risk

reduction (%)

CIBIS: Cardiac insufficiency bisoprolol study

(1994) [50]

641 Bisoprolol vs. placebo 1.9 years All-cause death NS 21

SCD NS 11

CIBIS II: Cardiac insufficiency bisoprolol study II

(1999) [51]

2647 Bisoprolol vs. placebo 1.3 years All-cause death <0.0001 32

SCD 0.0011 43

MERIT-HF: Metoprolol CR/XL randomised

intervention trial in congestive heart failure

(1999) [52]

3991 Metoprolol vs. placebo 1 year All-cause death 0.00009 32

SCD 0.0002 39

BEST: Beta-blocker evaluation of survival trial

investigators (2001) [53]

2708 Bucindolol vs. placebo 2.0 years All-cause death 0.10 8

SCD NS 11

CAPRICORN: Carvedilol post-infarct survival

control in left ventricular dysfunction (2001) [54]

1959 Carvedilol vs. placebo 1.3 years All-cause death 0.031 22

SCD 0.098 26

COPERNICUS: Carvedilol prospective randomized

cumulative survival study (2001) [55]

2289 Carvedilol vs. placebo 10.4 months All-cause death 0.0014 33

COMET: Carvedilol or metoprolol European trial

(2003) [56]

1511 Carvedilol vs. placebo 58 months All-cause death 0.002 14

NS: non-significant; SCD: sudden cardiac death.

Table III Indications for device therapy, for primary prevention of SCD.

Patients with left ventricular dysfunction (ejection fraction £ 35%)

NYHA class I QRS interval < 120 ms QRS interval ‡ 120 ms

ICD if LVEF £ 30% & previous MI ICD if previous MI ‡ 40

days + LVEF 31-35% + nSVT + VT/VF inducibility at

electrophysiological study

CRT-D if LVEF £ 30% & previous MI

NYHA class II ICD CRT-D

NYHA class III ICD CRT-D

NYHA class IV No device (CRT if dyssynchrony assessed with echocardiography ?) CRT/CRT-D

Patients without left ventricular dysfunction

Patients with HCM with at least one major risk factor for SCD

Patients with ARVD with at least one major risk factor for SCD

Patients with Long QT syndrome who have syncope under treatment with beta-blockers

Patients with Brugada syndrome with syncope

Non-hospitalized patients awaiting heart transplantation

Patients with cardiac sarcoidosis, giant cell myocarditis or Chagas disease

Patients with syncope and advanced HD when invasive + non-invasive investigations fail to define a cause

ARVD, arrhythmogenic right ventricular dysplasia; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy with defibrillation back up;

HCM, hypertrophic cardiomyopathy; HD, heart disease; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial

infarction; nSVT, non-sustained ventricular tachycardia; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.



blocker therapy on SCD and all-cause mortality [50–56].

The CIBIS II trial [51] demonstrated that treatment with

bisoprolol is associated with reduced all-cause mortality

in patients with heart failure symptoms and ejection

fraction of 35% or less (apparently irrespective of the

severity of heart failure etiology), and a reduction in SCD

was also recorded. In the MERIT-HF trial [52], addition

of metoprolol to standard therapy significantly reduced

both all-cause mortality in patients with NYHA func-

tional class II-IV symptoms and ejection fraction of

40% or less, and again seemed to lead to a reduction in

SCD.

Several meta-analyses [57–59] have reported that

beta-blocker therapy is associated with clinically mean-

ingful reductions in mortality in patients with congestive

heart failure. For example, in a meta-analysis [57] of 18

double-blind, placebo-controlled, parallel-group trials of

beta-blockers in heart failure, treatment with beta-

blockers provided a 32% reduction in the risk of death

and a 37% reduction in the combined risk of death or

hospitalization for heart failure.

Based on the evidence of benefit, beta-blockers have to

be considered the mainstay of therapies for improving

patients’ outcome and for SCD prevention, both in

patients with and without heart failure [3–5,7].

Angiotensin-converting enzyme (ACE) inhibitors

The anti-arrhythmic effects of ACE inhibitors seem to be

mediated by several mechanisms [60]. A long series of

clinical trials have uniformly shown that ACE inhibitors

provide survival benefits in patients with congestive

heart failure or MI. Table V shows the trial results of the

main trials [61–74]. In a meta-analysis [75] of 15

randomized, controlled trials comparing ACE inhibitors

with placebo in patients following acute MI, ACE

inhibitor therapy resulted in a significant reduction in

risk of death (odds ratio: 0.83; 95%CI 0.71, 0.97),

cardiovascular death (odds ratio: 0.82; 95%CI 0.69,

0.97), and SCD (odds ratio: 0.80; 95%CI 0.70, 0.92).

The reduction in SCD risk seems therefore to be an

important component of the survival benefit observed

with ACE inhibitor therapy. A further systematic over-

view [76] of 5 long-term randomized trials comparing

ACE inhibitor treatment with placebo showed that ACE

inhibitors lower rates of mortality, MI, and hospital

admission for heart failure in patients with LV dysfunc-

tion with or without a recent MI, thus suggesting the use

of ACE inhibitors in patients with LV dysfunction

irrespective of the proximity to a MI. ACE inhibitors

now have an established role in improving the outcome

both of heart failure and post-infarction patients (with or

without LV dysfunction), but the preventive effect on

SCD does not appear to be a determinant of treatment

selection.

The impact of ACE inhibitors on the outcome of

larger groups of patients, such as patients with vascular

disease and preserved LV function has been evaluated

mainly in 3 large randomized, placebo-controlled trials:

HOPE [71,72], EUROPA [73], and PEACE [74], with

non-homogeneous results. A systematic review of these

three large trials [77] confirmed the benefits of ACE

inhibitors in patients with vascular disease without

heart failure or LV systolic dysfunction in terms of

reduced all-cause mortality (odds ratio: 0.86; 95%CI

0.79, 0.94) and cardiovascular mortality (odds ratio:

0.82; 95%CI 0.73, 0.91). Furthermore, two further

meta-analyses regarding randomized, controlled trials

of ACE inhibitors [78,79] showed beneficial effects on

total mortality and major cardiovascular end-points in

patients with coronary artery disease and preserved LV

function.

Based on the evidence of benefit, ACE inhibitors have a

crucial role for improving patients’ outcome and pre-

venting worsening of LV dysfunction in all the stages of

heart failure, including also the presence of LV dysfunc-

tion without overt heart failure; the overall benefit of

these agents may involve also favorable effects on the

risk of SCD [7].

Angiotensin receptor blocker agents

The potential benefit of angiotensin receptor blocker

agents (ARBs) is related to a series of neurohormonal

and haemodynamic mechanisms [60]. The main con-

trolled trials on ARBs in prevention of mortality and SCD

are shown in Table VI [80–88].

The ELITE trial [80] compared losartan with captopril

in elderly patients with heart failure: treatment with

losartan was associated with a significant decrease in

all-cause mortality (Table VI) [59–64]. The ELITE II

study [81] enrolled a larger number of patients with

heart failure but was unable to find any significant

difference between losartan and captopril in terms of all-

cause mortality or SCD. Similar results were obtained in

the OPTIMAAL trial [82]. The effects of adding an ARB

to the standard therapy for heart failure were investi-

gated in the Val–HeFT trial [83]. Overall mortality was

similar in the intervention and the placebo-controlled

arms. Subgroup analysis suggested significant survival

benefits from valsartan in patients not taking an ACE

inhibitor.



In the VALIANT trial [85], the angiotensin receptor

blocker valsartan, administered alone or in combination

with the ACE inhibitor captopril, was reported not to be

inferior to captopril in terms of all-cause mortality in

patients with heart failure and/or LV dysfunction after

acute MI. The LIFE study [84] compared losartan with

atenolol as antihypertensive treatments: a significant

reduction in the primary composite end-point of cardio-

vascular morbidity and mortality was seen in the

losartan arm.

In a meta-analysis [89] of 17 randomized, controlled

trials comparing ARBs with either placebo or ACE

inhibitors in patients with symptomatic heart failure,

ARBs were not superior to controls in reducing all-cause

mortality (odds ratio:0.96; 95%CI 0.75, 1.23). Stratified

analysis, however, revealed a non-significant trend in

benefit of ARBs over placebo in reducing mortality when

an ARB was given in the absence of ACE inhibitor

therapy. The combination therapy of ARBs and ACE

inhibitors was superior to ACE inhibitors alone in

reducing hospitalizations, but not mortality.

In a subsequent meta-analysis [90] of 24 trials

(including CHARM), use of ARBs in patients with

chronic heart failure was associated with reduced all-

cause mortality (odds ratio 0.83; 95%CI 0.69, 1.00)

when compared with placebo, but no difference was seen

Table V Main controlled trials on angiotensin-converting enzyme inhibitors in prevention of mortality and sudden cardiac death.

NS = P > 0.1.

Study, year, ref

No.


Relative risk

reduction (%)

CONSENSUS: Cooperative north

Scandinavian enalapril survival

study (1987) [61]

253 Enalapril vs. placebo 188 days All-cause death 0.003 27

SCD NS 1

SOLVD: Studies on left ventricular

dysfunction (1991) [62]

2569 Enalapril vs. placebo 41.4 months All-cause death <0.003 11

Arrhythmic death NS 7

SOLVD: Studies on left ventricular

dysfunction (1992) [63]

4228 Enalapril vs. placebo 37.4 months All-cause death NS 6

Arrhythmic death NS 8

V-HeFT II: Veterans administration

cooperative vasodilator-heart

failure trial (1991) [64]

804 Enalapril vs. placebo 42 months All-cause death 0.08 14

SCD 0.015 35

SAVE: Survival and ventricular

enlargement trial (1992) [65]

2231 Captopril vs. placebo 42 months All-cause death 0.019 17

SCD NS 16

AIRE: Acute infarction ramipril

efficacy study (1993) [66]

2006 Ramipril vs. placebo 15 months All-cause death 0.002 25

GISSI-3: Gruppo italiano per lo

studio della sopravvivenza

nell’infarto miocardico (1994) [67]

19394 Lisinopril vs. placebo 6 weeks All-cause death 2P=0.03 11

SMILE: Survival of myocardial

infarction long-term evaluation

(1995) [68]

1556 Zofenopril vs. placebo 6 weeks All-cause death NS 22

SCD NS 64

TRACE: Trandolapril cardiac

evaluation study (1995) [69]

6676 Trandolapril vs. placebo 24–50 months All-cause death 0.001 18

SCD 0.03 21

ISIS-4: Fourth international study of

infarct survival (1995) [70]

58050 Captopril vs. placebo 5 weeks All-cause death 2P = 0.02 6

HOPE: Heart outcomes prevention

evaluation study (2000) [71,72]

9297 Ramipril vs. placebo 5 years All-cause death 0.005 15

SCD 0.072 20

EUROPA: European trial on

reduction of cardiac events with

perindopril in stable coronary

artery disease (2003) [73]

13655 Perindopril vs. placebo 4.2 years All-cause death 0.1 12

Cardiovascular

mortality, MI

or cardiac arrest

0.0003 19

PEACE: Prevention of events with

angiotensin converting enzyme

inhibition (2004) [74]

8290 Trandolapril vs. placebo 4.8 years Overall mortality NS 12

CHF, chronic heart disease; NS, non-significant; SCD, sudden cardiac death.



between ARBs and ACE inhibitors in terms of reduction

in all-cause mortality and heart failure hospitalizations.

The combination of ARBs plus ACE inhibitors did not

provide a significant reduction in all-cause mortality

when compared with ACE inhibitors alone.

More recently, the ONTARGET study [87] showed that

the ARB telmisartan was as effective as ramipril, in terms

of vascular protection, with good tolerability. Telmisar-

tan was also evaluated, in the TRANSCEND study [88],

in a similar population of patients who were intolerant of

ACE inhibitors: no significant effect was found on the

primary end-point (death, MI, stroke or heart failure

hospitalization), but there was a trend to a benefit for the

combined secondary end-point of cardiovascular death,

MI, and stroke.

Taken together, evidence generated by randomized

multicenter trials did not show any superiority of ARBs

over ACE inhibitors, although use of ARBs may be

suggested in patients who are intolerant to ACE

inhibitors.

Statins

The influence of statins on clinical events is related to

their pleiotropic effects [60]. Their cholesterol-lowering

and antioxidant properties help attenuate endothelial

dysfunction, prevent plaque rupture in vascular walls,

and inhibit platelet aggregation and thrombus forma-

tion. Statins also reduce the levels of C-reactive protein,

and their anti-inflammatory properties could contribute

to their plaque-stabilization effects [60].

Table VI Main controlled trials on angiotensin II antagonists in prevention of mortality and sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.

patients Comparison Follow-up End-point P value

Relative risk

reduction

ELITE: Evaluation of losartan in the

elderly study (1997) [80]

722 Losartan vs. placebo 48 weeks All-cause death 0.035 44%

SCD <0.05 63%

ELITE II: Losartan heart failure survival

study (2000) [81]

3152 Losartan vs. placebo 555 days All-cause death NS )11%

SCD or resuscitated

cardiac arrest

0.08 )23%

Val-HeFT: Valsartan heart failure trial

(2001) [82]

5010 Valsartan vs. placebo 23 months All-cause death NS )2%

OPTIMAAL: Optimal trial in myocardial

infarction with the angiotensin II

antagonist losartan (2002) [83]

5477 Losartan vs. placebo 2.7 years All-cause death 0.069 )11%

SCD or resuscitated

cardiac arrest

0.072 )18%

LIFE: Losartan intervention for end-point

reduction (2002) [84]

9193 Losartan vs. placebo 4.8 years Cardiovascular

morbidity and

Mortality

0.009 14%

VALIANT: Valsartan in acute myocardial

infarction trial investigators (2003) [85]

14 808 Valsartan and valsartan

+ captopril vs, captopril

25 months All-cause death NS 0% valsartan

vs. captopril

NS 2% valsartan

vs. valsartan

+ captopril

CHARM: Candesartan in heart failure

assessment of reduction in mortality

and morbidity (2004) [86]

4576 Candesartan vs. placebo 40 months All-cause death 0.018 10%

Cardiovascular mortality 0.005 13%

ONTARGET: Ongoing telmisartan alone

and in combination with ramipril global

end-point trial (2008) [87]

24 620 Telmisartan vs. ramipril vs.

telmisartan + ramipril

56 month Combined end-point

(MI, stroke, death

from cardiovascular

causes or heart

failure hospitalization)

NS 1% ramipril

vs. telmisartan

NS 1% telmisartan

+ ramipril vs.

ramipril

TRASCEND: Telmisartan

randomised assessment study in

angiotensin-converting enzyme

intolerant subjects with

cardiovascular disease (2008) [88]

5926 Telmisartan vs. placebo 56 month Combined end-point

(MI, stroke, death

from cardiovascular

causes or heart

failure hospitalization)

NS 8%

MI, myocardial infarction; NS, non-significant; SCD, sudden cardiac death.



Table VII Main controlled trials on statins in prevention of mortality and sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.


Relative risk

reduction

4S: Scandinavian simvastatin survival

study (1994) [91]

4444 Simvastatin vs. placebo 5.4 years All-cause death 0.0003 27%

WOSCOPS: West of Scotland coronary

prevention study group (1995) [92]

6595 Pravastatin vs. placebo 4.9 years All-cause death 0.051 25%

CARE: Cholesterol and recurrent events

trial (1996) [93]

4159 Pravastatin vs. placebo 5 years All-cause death NS 9%

LIPID: Long-term intervention with

pravastatin in ischaemic disease (1998)

[94]

9014 Pravastatin vs. placebo 6.1 years All-cause death <0.001 21%

AFCAPS TexCAPS: Air force/Texas

coronary atherosclerosis prevention

study (1998) [95]

6605 Lovastatin vs. placebo 5.2 years Acute major coronary

event (MI, unstable

angina or SCD)

<0.001 36%

MIRACL: Myocardial ischemia reduction

with aggressive cholesterol lowering

study (2001) [96]

3086 Atorvastatin vs. placebo 16 weeks Combined end-point

(death, non-fatal MI,

cardiac arrest,

symptomatic

myocardial ischemia)

NS 12%

HPS: Heart protection study (2002) [97] 20 536 Simvastatin vs. placebo 5 years All-cause death 0.0003 13%

PROSPER: Pravastatin in elderly

individuals at risk of vascular disease

(2002) [98]

5804 Pravastatin vs, placebo 3.2 years Combined end-point

(death from CHD,

non-fatal MI, stroke)

0.014 13%

ALLHAT-LLT: Antihypertensive and

lipid-lowering treatment to prevent

heart attack trial (2002) [99]

10 355 Pravastatin vs. control 4.8 years All-cause death NS 2%

ASCOT: Anglo-Scandinavian cardiac

outcomes trial-lipid lowering arm

(2003) [100]

10 305 Atorvastatin vs. placebo 3.3 years All-cause death NS 12%

PACT: Pravastatin in acute coronary

treatment (2004) [101]

3408 Pravastatin vs. placebo 4 weeks Combined end-point

(death, recurrence of

myocardial infarction

or unstable angina)

NS 6%

SCD NS 20%

PROVE IT-TIMI 22: Pravastatin or

atorvastatin evaluation and infection

therapy-thrombolysis in myocardial

infarction 22 (2004)[102]

4162 Pravastatin vs. atorvastatin 24 months Combined end-point

(all-cause death, MI,

unstable angina,

revascularization,

stroke)

0.005 16% atorvastatin

vs. pravastatin

TNT: Treating new targets trial (2005)

[103]

10 001 Atorvastatin 10 mg vs.

atorvastatin 80 mg

4.9 years All-cause death NS 0

CORONA: Controlled rosuvastatin

multinational trial in heart failure

(2007) [104]

5011 Rosuvastatin vs. placebo 32.8 months All-cause death NS 5%

GISSI HF: Gruppo italiano per lo studio

della sopravvivenza nell’infarto (2008)

[105]

4631 Rosuvastatin vs. placebo 3.9 years All-cause death NS 0%

JUPITER: Justification for the use of

statins in prevention: an intervention

trial evaluating rosuvastatin (2008) [106]

17 802 Rosuvastatin vs. placebo 1.9 years All-cause death 0.02 20%

CHD, coronary heart disease; MI, myocardial infarction; NS, non-significant; SCD, sudden cardiac death.



Many trials have shown significant reductions in all-

cause mortality after statin therapy (Table VII) [91–106].

These benefits were mostly paralleled by reduced SCD,

although few specific data on this outcome measure were

separately reported.

In a meta-analysis of 15 lipid trials [107], statin

therapy significantly reduced the RR of coronary events

[RR 0.73; 95%CI 0.68, 0.77], cardiovascular disease

mortality (RR 0.78; 95%CI 0.73, 0.84), and all-cause

death (RR 0.85; 95%CI 0.81, 0,89). Another meta-

analysis of 10 outcome trials of statins [108] showed

that statin therapy reduces major coronary events by

27% (95%CI 23%, 30%), stroke by 18% (95%CI 10%,

25%), and all-cause mortality by 15% (95%CI 8%, 21%).

Coronary events were reduced by 23% (95%CI 18%,

29%) in pravastatin trials and 29% (95%CI 25%, 33%)

in five trials with other statins.

More recently, the ability of statins to improve

outcomes has been tested also independently of choles-

terol levels, i.e. in subjects with no conventional indica-

tion to statins. In patients with chronic heart failure,

GISSI-HF showed that rosuvastatin did not affect clinical

outcomes [105], while the CORONA trial [104] showed

that in older patients, rosuvastatin did not reduce

mortality, although the drug did reduce the number of

cardiovascular hospitalizations.

In JUPITER, rosuvastatin significantly reduced the

incidence of major cardiovascular events and death in

apparently healthy persons without hyperlipidemia but

with elevated high-sensitivity C-reactive protein levels

[106].

Based on the evidence from trials, statins have an

established therapeutic role in patients with coronary

artery disease, but the potential role in reducing SCD for

the broader population of patients at risk has still to be

assessed.

Omega-3 fatty acids

Omega-3 fatty acids may provide cardiovascular health

benefits derived from several effects, including decrease

in very low density lipoprotein and thereby in plasma

triglyceride levels; improvement in endothelial function;

cell membrane stabilization; platelet aggregation inhibi-

tion; suppression of smooth muscle cell proliferation; and

prevention of calcium overload [60].

Several clinical trials support the concept that omega-

3 fatty acids can reduce the risk of overall and

cardiovascular mortality in patients with coronary heart

disease [105,109–112] (Table VIII). In the GISSI-Preven-

tion study [112], the use of omega-3 fatty acids

significantly reduced the primary combined end-point

of death, non-fatal MI and non-fatal stroke, with a

benefit attributable to a decrease in the risk of overall

and cardiovascular death.

A systematic review has shown that the evidence for

the outcome benefits of n ) 3 fatty acids is stronger

in secondary- than in primary prevention trials [113].

Based on a literature review [114], Mozzafarian reported

that modest consumption of fish or fish oil substantially

reduces the risk of SCD and coronary deaths, with little

additional benefit with higher intakes.

Remarkably, no significant effect on all-cause death

was reported by a randomized, placebo-controlled trial

that evaluated the effects of n ) 3 fatty acids in patients

with ICDs [115].

A recent meta-analysis [116] of randomized trials on

omega-3 fatty acids in patients with coronary heart

disease, related to more than 20,000 patients, shows

that this treatment may reduce the incidence of SCD in

patients with previous MI (RR = 0.43; 95% CI:

0.20–0.91) but may have adverse effects in patients

with angina, where the risk of SCD may increase

(RR = 1.39; 95% CI: 1.01–1.92). Overall, the relative

risk for all-cause mortality was 0.77 (95% CI:

0.58–1.01), suggesting the need for further investiga-

tions in the setting of patients with angina. In patients

with chronic heart failure of New York Heart Associ-

ation class II–IV, GISSI-HF [105] reported that treat-

ment with n ) 3 PUFA (polyunsaturated fatty acid)

provided a significant beneficial advantage in terms of

mortality and admission to hospital for cardiovascular

reasons.

Based on the evidence derived from trials, omega-3

fatty acids result to be beneficial for patients with a

previous MI (with or without LV dysfunction). Their role

in other settings has still to be defined.

Aldosterone antagonists

On a pathophysiological basis, aldosterone antagonists

may have beneficial effects on cardiovascular mortality

and SCD through at least three mechanisms: a sympatho-

lytic effect, the reduction in both vascular and cardiac

fibrosis, and prevention of the negative effects of angio-

tensin II at vascular level, with reduction in vascular

endothelial dysfunction [60]. The effects of aldosterone

antagonists on SCD have been assessed in two random-

ized, placebo-controlled trials (Table IX). The RALES trial

evaluated the effects of spironolactone in patients with

congestive heart failure [117], while EPHESUS focused on

the use of eplerenone in MI survivors with LV dysfunction



[118]. Both interventions were associated with relevant

reductions in both all-cause mortality and SCD. According

to available evidence, aldosterone antagonists are bene-

ficial for both patients with heart failure and post-

infarction patients (with or without LV dysfunction).

C O N C L U S I O N S

SCD is an important public health problem, more often

occurring associated with coronary artery disease

(frequently in an asymptomatic phase), but also occur-

ring in many different types of heart diseases, as well as

in apparently healthy subjects (who may or may not

have identifiable risk factors). SCD is an extremely

complex phenomenon with many factors potentially

facilitating the occurrence of ventricular fibrillation,

most often in combination with myocardial ischemia.

Ventricular fibrillation, the event leading to SCD, is the

final common pathway of a complex network of inter-

actions between multiple factors related to the substrate,

the triggers and modulating factors, which may be

variously related (in terms of proximity and causation)

with its onset.

The search for effective treatment for preventing SCD

initially started with anti-arrhythmic agents in high-risk

patients, but the use of randomized, controlled trials as

the tool for demonstrating the validity of any hypothesis

clearly led to the conclusion that an approach based on

anti-arrhythmic agents is not useful, and sometimes

potentially harmful. Today the approach to SCD preven-

tion includes considering both the setting of patients who

have already presented a cardiac arrest or a malignant

ventricular tachyarrhythmias (secondary preventions of

SCD) and the much broader setting of primary preven-

tion in patients at variable degrees of identifiable risk. For

secondary prevention of SCD, implantable devices (ICDs

and CRT-D devices) are now the standard of care, and

anti-arrhythmic agents, specifically amiodarone, have

only a complementary role (in reducing device activa-

tions or preventing atrial fibrillation). For primary

prevention of SCD in high-risk patients, ICDs now have

specific indications in patients with LV dysfunction (often

Table VIII Main controlled trials on omega-3 fatty acids in prevention of mortality and sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.


Relative risk

reduction (%)

DART: Diet and reinfarction trial

(1989) [109]

2033 Diet advice to increase

fatty fish intake vs. control

2 years Cardiovascular Mortality <0.01 32

All-cause death <0.05 27

Indian: Indian experiment of infarct

survival (1997) [110]

404 Fish oil vs. placebo 1 year SCD NS 76


Lyon: Lyon diet heart study (1999) [111] 605 Mediterranean diet vs. control 46 months All-cause death 0.03 46

GISSI Prevenzione: Gruppo italiano per

lo studio della sopravvivenza nell’infarto

(1999) [112]

11 324 n ) 3 polyunsaturated fatty

acids vs. control

3.5 years SCD 0.010 24


GISSI HF: Gruppo italiano per lo studio della

sopravvivenza nell’infarto (2008) [105]

7046 n ) 3 polyunsaturated fatty

acids vs. placebo

3.9 years All-cause death 0.041 9

NS, non-significant; SCD, sudden cardiac death.

Table IX Main controlled trials on aldosterone antagonists in prevention of mortality and sudden cardiac death. NS = P > 0.1.

Study, year, ref

No.

patients Comparison Follow-up End-point P value

Relative risk

reduction (%)

RALES: Randomized aldactone

evaluation study investigators

(1999) [117]

1663 Spironolactone vs. placebo 1 year SCD 0.02 20


EPHESUS: Eplerenone post-acute

myocardial infarction heart failure

efficacy and survival study

(2003) [118]

6642 Eplerenone vs. placebo 16 months SCD 0.03 24

All-cause death 0.008 25

NS, non-significant; SCD, sudden cardiac death.



in combination with CRT), although implementation in

clinical practice of this approach is still incomplete.

Moreover, both epidemiological and pathophysiologi-

cal considerations suggest that limiting the target of SCD

preventive strategies to the relatively limited number of

high-risk subjects (who are currently proposed for a

strictly ‘downstream’ intervention like the implantable

cardioverter defibrillator) will necessarily have a limited

impact on the overall number of SCD events occurring in

the general population. For the large number of subjects

who have some risk of SCD, but are not identified as at

high risk of SCD, a series of drugs that were initially

thought to be devoid of what is usually termed a true

‘anti-arrhythmic’ effect could conceivably help prevent

Table X Relevant pharmacokinetic and pharmacodynamic properties of drugs for upstream therapya.

Therapeutic

dose (mg)bBioavailability

(%)

Protein

binding (%) T½ (h)c Other properties

b-Blockers

Non-selective b-antagonists

Propranolol 80–320 30–70 93 3–4 MSA, high lipophilicity

Pindolol 10–40 87–90 40–60 3–4 ISA, high lipophilicity

Nadolol 40–80 20–40 28–30 20–24 Low lipophilicity

Sotalol 80–160 60–100 NA 7–18 Class III anti-arrhythmic properties

Selective b-antagonists

Atenolol 50–200 46–60 <5 6–7 Low lipophilicity

Bisoprolol 2.5–20 82–94 30–36 10–12.4 Moderate lipophilicity

Metoprolol 100–400 50 12 3–7 High lipophilicity

Nebivolol 40 12 98 12–19 Antoxidant and vasodilating properties

Mixed a- and b-antagonists

Labetalol 200–400 25 50 5–8 ISA, a1-blocking properties

Carvedilol 25–50 25–35 95–98 6–10 MSA, a1-blocking and antioxidant properties

Angiotensin-converting enzyme inhibitors

Captopril 25–450 70–75 20–30 1.9 Inactive metabolite

Enalapril 10–40 60 50–60 1.3 (11) Active metabolite

Lisinopril 20–40 6–60 minimal 12 No active metabolite

Perindopril 4–8 20–30 60 0.8–1 (3–10) Active metabolite

Ramipril 2.5–20 60 73 1–1.5 (13–17) Active metabolite

Trandolapril 2–4 10 80 0.6–1.3 (6–24) Active metabolite

Angiotensin receptor blockers

Losartan 25–100 25 98.7 1.5–2 (4–9) Metabolized by CYP2C9, CYP3A4

Valsartan 80–320 25 94–95 6–9 No active metabolite

Irbesartan 150–300 60–80 90 (11–15) Metabolized by CYP 2C9

Candesartan 8–32 15 >99 (5.1–10.5) Metabolized by CYP 2C9

Telmisartan 20–80 42 99.5 24 No active metabolite

Eprosartan 400–800 13 98 6 No active metabolite

Aldosterone antagonists

Spironolactone 50–400 73 90 1.3–1.4 (8.9–23) Active metabolite

Eplerenone 50–100 69 50 4–6 Metabolized by CYP3A4

Statins

Atorvastatin 10–80 14 98 7–14 (9–32) Metabolized by CYP3A4, lipophilicity

Fluvastatin 20–80 20–30 98 (<3) Metabolized by CYP2C9 (75%), lipophilicity

Lovastatin 10–80 5 >95 2.9 Metabolized by CYP3A4, lipophilicity

Pravastatin 40–80 17 43–55 2.6–3.2 Metabolized by sulfation

Rosuvastatin 5–40 20 88 (19) Metabolized by CYP2C9, CYP2C19 (minor)

Simvastatin 5–80 5 95 2–3 Metabolized by CYP3A4, lipophilicity

NA, not appreciable; ISA, intrinsic sympathomimetic activity; MSA, membrane-stabilizing activity; CYP, cytochrome P450.aData from refs [119–123].bDaily per os maintenance dose of the immediate-release formulation in adult. Data from ref. [119].cIn parenthesis half-lives of active metabolite.



SCD in an attempt to reduce the overall SCD burden. As

a consequence of such an approach, for the large group

of patients at relatively low risk who have only coronary

risk factors, it could be possible to target the processes of

the complex cascade leading to SCD at an ‘upstream’

level. Such ‘upstream’ interventions could conceivably

include non-anti-arrhythmic agents, such as beta-block-

ers, angiotensin-converting enzyme inhibitors, angioten-

sin receptor blocker agents, statins, omega-3 fatty acids,

and aldosterone antagonists. The clinical use of these

agents should be based on an appropriate knowledge

of their pharmacokinetic/pharmacodynamic profile,

summarized in Table X [119–123]. Some of these agents

have already shown survival benefits in clinical trials,

largely focused on patients at relatively high risk of SCD,

and evidence is emerging from subgroup analysis of

possible SCD prevention capabilities. In patients at higher

risk of SCD, who are treated with an ICD or CRT-D

device, agents with ‘upstream’ effects can be associated

in an attempt to obtain additional, and synergetic, effects

on the outcome.

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