3 Prevention of Sudden Cardiac Death

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From: Contemporary Cardiology: Cardiopulmonary Resuscitation Edited by: J. P. Ornato and M. A. Peberdy © Humana Press Inc., Totowa, NJ

3 Prevention of Sudden Cardiac Death

Joseph E. Marine, ^MD

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INTRODUCTION

Since the 1960s, important advances have been made in resuscitation of patients from sudden cardiac death (SCD). Despite these advances, rates of survival to hospital dis- charge range from only 2 to 30% (generally 5–10%); rates of survival with intact neuro- logical status are even lower (1). Approximately 400,000 out-of-hospital sudden deaths occur in the United States each year (2). These grim statistics point to the importance of prevention in approaching the problem of SCD from a public health standpoint.

It has been estimated that one-half to two-thirds of out-of-hospital sudden death is caused by ventricular arrhythmias (VA) (ventricular tachycardia [VT] and ventricular fibrillation [VF]) (3). Bradyarrhythmias, such as complete atrioventricular block and asystole, are a less frequent cause of arrhythmic sudden death. A substantial minority of cases of apparent SCD may be because of nonarrhythmic causes, such as massive pulmo- nary embolus, ruptured aortic aneurysm or dissection, or stroke (4). Because most research into prevention of SCD has focused on VA, this subject will form the basis for this chapter.

Preventive strategies will be considered according to the etiology of cardiac disease.

CORONARY ARTERY DISEASE

Coronary artery disease (CAD) is the leading cause of death in Western countries and

the most common cardiac substrate for SCD. It is now recognized that CAD is a systemic

disease of the cardiovascular system that is often far advanced by the time it is clinically

manifest. The first signs of atheroma formation may begin in adolescence. As CAD

progresses, atheromas may encroach on the coronary artery lumen, causing flow-limiting

stenosis. At this stage, patients may develop ischemia in the absence of infarction, often

with exertion or stress. Ischemia in turn may lead to arrhythmias, particularly polymor-

phic VT and VF. Ischemic VA may also occur in the absence of significant atheroscle-

rosis, usually associated with coronary artery spasm or congenital coronary anomalies.

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

Primary Prevention of CAD

Approximately 12.6 million people in the United States have CAD and about 1 million suffer AMIs annually (2). Given the scope of the problem, effective primary prevention of CAD could have a substantial impact on prevention of SCD. Particularly important is changing modifiable risk factors, especially cigarette smoking, dyslipidemia, athero- genic diet, obesity, and physical inactivity (5). Optimal control of predisposing medical conditions, such as systemic hypertension and diabetes mellitus, may also reduce the incidence of coronary disease and related SCD. Hopefully, improved public education regarding primary prevention of CAD will ultimately translate into reduction of SCD rates as well as CAD incidence.

There is evidence that improvements in treatment of AMI are also reducing rates of SCD. Both fibrinolytic therapy and primary percutaneous coronary intervention reduce all-cause mortality as well as SCD. Moreover, by reducing infarct size, acute revascularization in AMI likely reduces late risk of SCD by modifying the substrate for arrhythmogenesis. Modification of the arrhythmic substrate may also account for some of the mortality benefit of angiotensin-converting enzyme (ACE) inhibitors in treatment of AMI. The Coronary Artery Surgery Study showed that coronary artery bypass grafting (CABG) leads to improved survival in selected high-risk patients with CAD. Further analysis of this trial has shown reduction in SCD in high-risk patients who underwent surgery (6).

Medical Therapy for Prevention of SCD After Myocardial Infarction Table 1 summarizes the outcomes of nine large trials of antiarrhythmic therapy after AMI. Probably the most important aspect of medical treatment of AMI survivors for prevention of SCD is `-blocker therapy. These agents block the `-1 adrenergic receptor in the heart, blunting the pro-arrhythmic effects of the sympathetic nervous system and circulating cathecholamines, and reducing myocardial oxygen consumption and ischemia.

In addition to reducing incidence of late coronary events, `-blockers have been shown in several trials to reduce all-cause mortality as well as life-threatening VAs (7–10). The antiarrhythmic action of `-blockers was also demonstrated in a recent small trial, which showed that sympathetic blockade was superior to standard antiarrhythmic drugs for treatment of recurrent VF in AMI (11).

Prospective observational studies published in the early 1980s established that fre-

quent isolated ventricular premature contractions and nonsustained VT are markers of

increased mortality risk after MI, particularly in patients with left ventricular (LV) sys-

tolic dysfunction (12). Further studies showed that type I antiarrhythmic drugs effec-

tively suppressed these VAs in this setting, leading to the organization of the Cardiac

Arrhythmia Suppression Trial (CAST). Publication of the results of this trial, which

showed a doubling of mortality rates in patients receiving flecainide, encainide, or

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

Trial Year of publication Result

BHAT (7) 1981 Improved survival with propranolol

ISIS-1 (8) 1986 Improved survival with atenolol

CAPRICORN (9) 2001 Improved survival with carvedilol

CAST-I (13) 1989, 1991 Increased mortality with flecainide or encainide CAST-II (14) 1992 Increased mortality with moricizine

SWORD (15) 1996 Increased mortality with D-sotalol DIAMOND (16) 2000 No effect of dofetilide on mortality EMIAT (19) 1997 No effect of amiodarone on mortality CAMIAT (20) 1997 No effect of amiodarone on mortality

moricizine, led to a re-examination of the use of these agents in patients with CAD and other forms of structural heart disease (13,14). There is now general agreement that type I antiarrhythmic drugs, particularly type Ic agents, should be avoided in patients with CAD because of the pro-arrhythmic effects demonstrated in CAST.

A similar increased risk of death was seen in a trial of the class III antiarrhythmic

-sotalol in postinfarction patients (15). The Survival With Oral

-Sotalol trial recruited 3121 patients with LV ejection fraction (EF) of 0.40 or less and prior MI. Patients were randomly assigned to long-term treatment with

-sotalol (a pure type III anti-arrhythmic agent with no `-blocking activity) or matching placebo. After a mean follow-up period of 150 days and halfway into recruitment, the trial was stopped early because of a 65% increased relative risk of mortality in the

-sotalol treatment arm (5 vs 3.1% in placebo group, p = 0.006).

The excess mortality was felt to be because of an increase in arrhythmic deaths.

In contrast, a large trial of dofetilide, another pure class III antiarrhythmic drug, found no increase in mortality on survivors of MI (16). The Danish Investigations of Arrhyth- mia and Mortality on Dofetilide (DIAMOND) Study Group randomized 1510 patients with recent MI and LVEF of 0.35 or less to treatment with dofetilide (dose based on creatinine clearance) or matching placebo. After a median follow-up of 456 days, mor- tality was nearly identical in the two groups (31 vs 32%, respectively, p = 0.61).

Amiodarone, a unique antiarrhythmic drug that exhibits actions of all four Vaughn- Williams drug classes, was originally developed as an anti-anginal medication. On the basis of its efficacy in the treatment of recurrent VA and its safety compared with other antiarrhythmic drugs in survivors of cardiac arrest (CA), two large trials were organized to test its efficacy in high-risk survivors of AMI (17,18). The European Myocardial Infarction Amiodarone Trial (EMIAT) enrolled 1486 patients 5 or more days after MI only on the basis of depressed LVEF of 0.40 or less (19). Patients were treated with amiodarone (200 mg per day after loading) or placebo. After a median follow-up period of 21 months, overall mortality was identical in the two groups (14% in each, p = 0.96).

The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) stud-

ied 1202 patients enrolled 6–42 days after AMI, who had frequent ventricular premature

contractions or nonsustained VT; LV systolic dysfunction was not required for entry into

the trial (20). Patients were treated with amiodarone (200 mg per day after loading) or

placebo and followed for a mean of 1.8 years. No significant difference in overall mortal-

ity was found (9.4% in the amiodarone group vs 11.4% in the placebo group, p = 0.129).

Both EMIAT and CAMIAT did find a reduction in death ascribed to arrhythmia, but the significance of this finding in the absence of overall mortality benefit has been ques- tioned. A posthoc analysis of both trials suggested a possible synergistic benefit of amiodarone and `-blockers, but this remains to be demonstrated prospectively.

In summary, proven medical therapy for primary prevention of sudden death in patients with CAD is limited to `-blocker use. Type I antiarrhythmic drugs and

-sotalol have been shown to be harmful in this population. Amiodarone and dofetilide had a neutral effect on all-cause mortality and are relatively safe to use for treatment of symp- tomatic arrhythmias in patients with CAD.

Role of the Implantable Cardioverter Defibrillator in CAD

The implantable cardioverter defibrillator (ICD) has had a major impact on clinical approach to prevention of SCD. Conceived by Morton Mower and Michel Mirowski and introduced after a decade of preclinical development, the ICD was first used in humans in the late 1970s (21). Implantation initially required thoracotomy to place epicardial patches and rate-sensing electrodes. First generations of pulse generators were large (>250 g) and required implantation in an abdominal pocket. Pacing function and pro- grammability were extremely limited. Rapid evolution of the ICD ensued, leading to a succession of improved lead systems and smaller generators with greater functionality (22).

Current ICD systems can be implanted transvenously via subclavian or cephalic vein access, similar to pacemakers, using a single 8–10 French lead and a pectorally implanted generator as small as 75 g. They are capable of all bradycardia-pacing functions, includ- ing, with addition of one or more leads, dual-chamber and biventricular pacing. They are also capable of detecting arrhythmias in several different programmable rate zones and delivering a different series of programmable therapies for each zone (Fig. 1). They have capacity to store large amounts of information regarding each arrhythmia episode for later analysis. Finally, they incorporate increasingly sophisticated algorithms for distin- guishing supraventricular from VAs.

ICDs detect VAs from the tip electrode of the lead, usually implanted at the right ventricular apex. When a ventricular rate is detected that exceeds the programmed detection rate (usually 150–200 beats per minute [bpm]) for the programmed number of beats (usually 10–20), the ICD begins charging the capacitors. This generally takes between 1 and 5 seconds, after which the device confirms continuation of tachycardia before delivering the programmed energy (anywhere from 1–40 J) between the metal shell of the generator and one or more coils on the ICD lead (Fig. 2A). The ICD then re-analyzes the ventricular rate to determine if therapy was successful. If the rate has not fallen below the arrhythmia detection limit, the ICD proceeds to deliver the next therapy.

This process continues until the arrhythmia is terminated or all programmed therapies (usually a maximum of six to eight) are exhausted.

In addition to delivering shock therapies, ICDs may be programmed to deliver sequences of antitachycardia pacing (ATP), usually 8–12 beats, to terminate sustained monomorphic (regular) VT (Fig. 2B). This therapy has the advantage of being delivered more rapidly and being entirely painless. Potential disadvantages of ATP include possibility of accel- erating the tachycardia to a more unstable type and delaying delivery of shock therapy if ATP is unsuccessful. ATP is not useful for treating VF or polymorphic VT.

When first released for clinical use in the early 1980s, ICDs were targeted toward

patients who had survived multiple CAs with recurrent VAs that were refractory to

conventional anti-arrhythmic drug treatment. As the design of ICDs improved over the

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

next decade, and the limitations of anti-arrhythmic drugs were exposed through random- ized clinical trials, the ICD gained increasing favor for treatment of CA survivors. In this setting, several clinical trials were organized to test the efficacy of the ICD in secondary prevention (for patients who had survived a sustained life-threatening VA) and primary prevention (for high-risk patients without history of sustained arrhythmia) of SCD (Tables 2 and 3).

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The first published trial comparing the ICD and conventional medical therapy for secondary prevention of SCD was the Anti-arrhythmics Versus Implantable Defibrillator (AVID) trial (23). This National Institutes of Health (NIH)-sponsored multicenter study enrolled 1016 patients in 56 North American centers who were resuscitated from VF or sustained VT between 1993 and 1997. The mean age of enrolled patients was 65 years and the mean LVEF was 0.32. Eighty-one percent of patients had CAD and 67% had a history of MI. Patients were randomly assigned to receive an ICD or to treatment with anti-arrhythmic drug therapy, predominantly amiodarone (96% of assigned patients).

Over a mean follow-up period of 18 months, 122 of 509 patients (24%) in the anti-

arrhythmic drug therapy group died vs only 80 of 507 patients (16%) assigned to receive

an ICD. This difference corresponds to a 33% relative risk reduction and an 8% absolute

risk reduction in total mortality in favor of the ICD (p < 0.02). Of note, this treatment

effect was demonstrated despite a significant crossover to ICD therapy in the drug therapy

arm, reaching 25% at 3 years.

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

Strengths of the AVID trial include its relatively large size, NIH sponsorship, and its use of total mortality as an unambiguous and unquestionably important primary end- point. Because the trial included only a small proportion of patients without CAD, it is difficult to draw conclusions about benefit of ICD in other subgroups. No placebo group was used, raising the question of whether the some of the apparent benefit of the ICD was because of a detrimental effect of amiodarone; other trials, however, have demonstrated the safety of amiodarone in patients with structural heart disease. Finally, `-blocker use was much greater in the ICD arm (about 40%) compared to the drug therapy arm (10–

15%), probably because of the bradycardic effects of amiodarone; this discrepancy might account for some of the apparent benefit of the ICD. Despite these criticisms, the AVID trial has led to the ICD becoming the treatment of choice for survivors of CA without contraindications to its use.

Two smaller trials of ICD therapy in secondary prevention of SCD have been reported

since the AVID trial was published. The first, the Canadian Implantable Defibrillator

Study (CIDS), enrolled 659 patients with an episode of unstable sustained VA in 24

centers in Canada, Australia, and the United States between 1990 and 1997 (24). Baseline

patient characteristics were similar to those of the AVID population, with a mean age of

63.5 years, mean LVEF of 0.34, and an 82% prevalence of CAD. After a mean follow-

up period of 3 years, 98 of 331 patients (29.6%) assigned to amiodarone had died vs 83 of 328 patients assigned to ICD therapy (25.3%). On an annualized basis, the absolute risk reduction for death was 1.9% per year in favor of the ICD arm, with a relative risk reduction of 19.7% (p = 0.142).

The Cardiac Arrest Study Hamburg (CASH) enrolled 288 CA survivors (84% with VF) in eight centers in northern Germany between 1987 and 1996 and randomly assigned them to ICD implantation, amiodarone therapy, or metoprolol treatment in a 1:1:1 fash- ion (25). The trial had originally included a propafenone treatment arm, which was discontinued in 1992 because of the 61% higher all-cause mortality in that group. Over a mean follow-up period of 57 months, the crude death rates were 36.4% in the ICD arm and 44.4% in the two drug treatment arms, an absolute reduction of 8% and a relative risk reduction of 18% (p = 0.081). The relative risk reduction was 42% at 1 year and 28% at 3 years. Secondary analysis showed that this nonsignificant reduction in total mortality appeared to be due entirely to a significant reduction in sudden death (p = 0.005). As in CIDS, there was a trend toward increased efficacy of the ICD in higher risk subgroups with lower LVEF and higher New York Heart Association (NYHA) heart failure class.

Although neither CIDS nor CASH reached statistical significance, the degree of treat- ment effect was similar to that seen in AVID and these trials are generally viewed a supportive for ICD treatment in secondary prevention of SCD.

Table 2

ICD Trials for Primary and Secondary Prevention of SCD Primary or Year Number Mean Relative Absolute

secondary of of follow-up risk risk

Trial prevention publication patients (months) reduction reduction p-value

AVID (23) Secondary 1997 1016 18 33% 8% p < 0.02

CIDS (24) Secondary 2000 659 36 28% 4.3% p = 0.14

CASH (25) Secondary 2000 288 57 18% 8% p = 0.08

MADIT (26) Primary 1996 196 27 59% 23% p = 0.009

MUSST (27) Primary 1999 704 39 60% 31% p < 0.001

CABG-Patch (28) Primary 1997 900 32 –8% –1.7% p = NS

MADIT-II (29) Primary 2002 1232 20 28% 5.6% p = 0.016

Table 3

Nonischemic Cardiomyopathies Associated With Sudden CA Dilated cardiomyopathies

Idiopathic Postviral Alcohol-related Valvular heart disease Postpartum

Familial Chagas’ disease

Hypertrophic cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy Cardiac sarcoidosis

Cardiac amyloidosis

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With the rapid evolution of the ICD and its clear effectiveness in treating VAs, it was reasonable to presume that the ICD might be effective in primary prevention of SCD in high-risk patients. Several trials were designed to test this hypothesis. The first to be published was the Multicenter Automatic Defibrillator Implantation Trial (MADIT) (26). This device industry-sponsored study enrolled 196 high-risk CAD patients in 32 US and European centers from 1990 to 1996 and randomly assigned them to implantation of ICD or to conventional therapy (determined by treating physician, with amiodarone in 74%). Eligible patients had a documented MI greater than 3 weeks prior to enrollment and an episode of asymptomatic nonsustained VT of 3 to 30 beats with a rate of at least 120 bpm. Patients with NYHA class IV symptoms were excluded because of a known high mortality from pump failure. Eligible patients then underwent invasive electro-physi- ologic study, with delivery of one, two, and three-paced ventricular premature beats at increasingly close coupling intervals. If sustained VT or VF was induced, stimulation was repeated after giving intravenous procainamide. If the arrhythmia remained induc- ible, then the patient became eligible for randomization. The mean age of randomized patients was 64 years, the mean LVEF was 0.26, and 65% had NYHA class II or III symptoms.

After a mean follow-up of 27 months, the trial was stopped early because of a marked treatment effect in favor of the ICD. Over the follow-up period, 39 of 101 patients (39%) in conventional treatment group died vs only 15 of 95 patients (16%) assigned to ICD, an absolute risk reduction of 23% and a relative risk reduction of 59%. The relative hazard for overall mortality was 0.46 in the ICD arm (p = 0.009).

Despite the results, MADIT initially met with skepticism owing to its small sample size, ICD industry-sponsorship, and low use of `-blockers (5–8%) in the conventional therapy arm. These criticisms were largely answered with the publication of the Multicenter Unsustained Tachycardia Trial (MUSTT) 3 years later (27). This study involved 704 patients with CAD enrolled at 85 centers in the United States and Canada between 1990 and 1996, and was sponsored by the NIH, with additional grant support from several drug and ICD manufacturers. Similar to MADIT, eligible patients had CAD with depressed LVEF (0.40 or less), and a qualifying episode of nonsustained VT of three or more beats at least 96 hours after a MI or revascularization procedure. Potential patients underwent invasive electrophysiologic (EP) study and, if inducible for sustained VA, were eligible for randomization to either electrophysiologically guided anti-arrhyth- mic therapy or to no anti-arrhythmic therapy. Patients in the therapy arm were then randomly assigned to a Food and Drug Administration-approved class I or class III anti- arrhythmic drug followed by repeat EP testing. If no effective anti-arrhythmic drug was found, an ICD was implanted. ICD therapy was permitted, at investigator discretion, after one to three failed drug trials. Out of 351 patients, 202 in this arm (58%) ultimately received an ICD. `-Blocker and ACE inhibitor treatment was encouraged in all patients, and 40% of all patients were receiving `-blockers at hospital discharge. The median age of enrolled patients was 66 years and the median LVEF was 0.30.

After a median follow-up period of 39 months, the 2- and 5-year rates of overall mortality were 28% and 48% in the group assigned to no anti-arrhythmic therapy and 22% and 42% in the EP-guided therapy arm (relative risk 0.80 at 5 years, p = 0.06).

Subsequent analysis of the data showed that this treatment effect was entirely attributable

to treatment with the ICD; the overall mortality rate at 5 years was 24% in patients

receiving an ICD and 55% in those who did not (adjusted relative risk of overall mortality 0.40, p < 0.001). In fact, patients treated with anti-arrhythmic drugs without an ICD had a trend toward higher mortality than the control arm of the study, possibly because of a high use of type I anti-arrhythmic agents in the drug-therapy group (26% at initial hospital discharge). Thus, although MUSTT had a complex design, which was not primarily intended to test the efficacy of the ICD, its results supported the apparent benefit of the ICD for primary prophylaxis demonstrated in MADIT and led to widespread use of the ICD in high-risk coronary patients for this indication.

In contrast to MADIT and MUSST, the Coronary Artery Bypass Graft (CABG) Patch trial used a different test (signal-averaged ECG) to identify high-risk CAD patients and found no benefit to prophylactic epicardial ICD implantation in the population studied (28). This NIH-sponsored study screened patients less than 80 years old with LVEF of 0.35 or less who were scheduled for CABG surgery at 37 centers in the United States and Germany between 1990 and 1996. Patients were screened with signal-averaged electro- cardiography (SAECG), a variation of the standard surface ECG used to analyze QRS complexes for prolongation or the presence of late potentials, which reflect myocardial scarring and substrate for VAs. A pilot study had shown that patients with abnormal SAECG had a mortality rate in the 2 years after CABG surgery twice as high as patients with normal SAECG, which is in line with previous studies of this technique. Neither nonsustained VT nor invasive EP study was required for study entry.

After screening, 900 patients were assigned randomly to receive an epicardial ICD system at the time of CABG surgery (446 patients) or to CABG surgery alone (454 patients). Baseline characteristics were similar to MADIT patients, with a mean age of 64 years, mean LVEF of 0.27, and 73% with NYHA class II or III heart failure symptoms.

Ninety-one percent of patients had two- (36%) or three- (55%) vessel CAD. After an average follow-up of 32 months, the trial was terminated because of a lack of efficacy, at which point 101 of 446 (22.6%) patients in the ICD arm had died vs 95 of 454 (20.9%) patients in the control arm. No subgroups were identified that appeared to benefit from the ICD.

There are several possible explanations for the difference in outcome between the CABG-Patch Trial and other trials, which demonstrate efficacy of the ICD for primary prophylaxis. These include relatively low mortality rate in the control arm, an indepen- dent anti-arrhythmic effect of complete revascularization, use of epicardial devices, and potential harmful effect of prolonging operative time with ICD implant and testing.

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) was

recently published and may significantly expand the population eligible for primary

prophylaxis of SCD with the ICD (29). This industry-sponsored trial randomized 1232

patients in 76 US and European centers with prior MI (1 month or more before entry) and

LVEF of 0.30 or less to receive a transvenous ICD or usual medical therapy. Patients were

not required to have any spontaneous or induced arrhythmias for entry. Enrolled patients

had a mean age of 64 years and a mean LVEF of 0.23. In contrast to MADIT, `-blocker

use was high (70% in each arm). After a mean follow-up of 20 months, 19.8% of patients

in the usual therapy group had died, and 14.2% of patients in the ICD arm (p = 0.016),

indicating a hazard ratio of 0.69 in favor of the ICD arm, and an absolute risk reduction

of 5.6%. There were no statistically significant interactions with baseline characteristics,

but patients with lower LVEFs and those with wider QRS duration showed trend toward

greater benefit from the ICD. An unexplained trend toward higher rates of hospitalization

for heart failure was also present in the ICD arm.

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The MADIT-II trial, for the first time, demonstrated efficacy of the ICD in reducing all-cause mortality in a population defined solely by cardiac substrate (prior MI and reduced LVEF) and not by presence of any arrhythmia. Other ongoing trials are testing the ability of the ICD to reduce SCD mortality in other populations, including all patients with heart failure and reduced EF from any cause, and in other lower risk populations with CAD. The health care cost implications of such expansion of ICD indications are substan- tial. The MADIT-II authors estimated that up to 4 million patients in the United States might qualify for ICD therapy under the new indication, with addition of up to 400,000 new patients annually (29). At a conservative estimate of $25,000 per ICD implant, it would cost $100 billion to implant all current MADIT-II eligible patients in the United States, and $10 billion to implant newly eligible cases each year. There would be addi- tional costs associated with follow-up, generator replacements, and management of late complications and device/lead malfunction.

Cost-effectiveness analysis of ICD therapy has been performed based on MADIT and AVID data. Analysis of MADIT results, which had initial ICD implantation cost of

$18,000–$27,000, showed a cost-effectiveness ratio of $27,000 per year of life saved, based on a survival advantage of 0.8 years in the ICD group (30). Patients in the ICD arm had higher initial costs, which were later balanced by higher medication costs in the medically treated group after 4 years. Total net health care costs over follow-up were about $98,000 in the ICD group and $76,000 in the control group; the difference was largely because of a longer survival in the ICD group. Corresponding economic analysis of the AVID study showed estimated 3-year medical costs of $87,000 in the ICD group and $73,000 in the anti-arrhythmic drug group (31). As in MADIT, initial hospital costs were higher in the ICD arm and medication costs were higher in the drug arm. Because the mortality difference was smaller in AVID (about 0.21 years advantage for ICD), the cost-effectiveness ratio was higher—about $67,000 per year of life saved. These cost- effectiveness ratios, although high, are comparable to other accepted health care inter- ventions.

Economic analysis of MADIT-II is currently in progress. Review of currently pub- lished data suggests that the cost-effectiveness ratio may be higher than in MADIT, because of a smaller absolute survival advantage, higher costs for heart failure hospital- izations in the ICD group, and lower costs for anti-arrhythmic drugs in the control arm.

Regardless of the ratio, the absolute cost of expanding ICD indications will have to be considered by health care payers. Some investigators have expressed hope that market competition will reduce costs of ICD therapy and that expanding indications for the ICD will spur manufacturers to design and market a lower cost model for primary prophylaxis in lower risk patients (32).

DILATED CARDIOMYOPATHY

Although not as common as CAD, several other forms of cardiomyopathy (listed in

Table 2) are associated with an elevated risk of SCD. The most prevalent of these is

dilated cardiomyopathy (DCM). Numerous studies have shown that patients with DCM

have significantly elevated risk of all-cause mortality and SCD, and that degree of risk

correlates with heart failure class (33). Interestingly, although patients with the most

severe heart failure symptoms have the highest mortality rates, the proportion of deaths

classified as because of SCD is lower than in those with lower heart failure class; the

proportion of deaths because of pump failure rises accordingly. Other important risk factors for arrhythmic mortality in DCM include degree of LV dilatation, impairment of LV systolic function, and increased QRS duration, especially with left bundle branch block. Frequency of nonsustained VT has also been shown to increase risk of mortality in one study (34), but another failed to show this association (35). Syncope, regardless of etiology, was shown in one study to increase risk of mortality nearly fourfold (36).

Although recognized as an insensitive marker, inducibility of sustained VAs at invasive EP study also seems to confer elevated risk of death (37).

Medical Therapy of DCM

Several medications without anti-arrhythmic action have been shown to improve all- cause mortality in DCM, and also may reduce SCD because of a modification of the underlying arrhythmic substrate. These medications include ACE inhibitors, hydrala- zine-isosorbide, metoprolol, carvedilol, and spironolactone. Digoxin use, even though improving heart failure symptoms and modestly reducing hospitalization, does not appear to significantly affect survival (38). In contrast, several positive inotropic drugs, including enoximone, amrinone, and high-dose vesnarinone, have been shown to increase mortality in heart failure patients, possibly through ventricular proarrhythmic effects. Several stud- ies of type I (sodium-channel blocking) anti-arrhythmic drugs have shown that these agents are associated with excess mortality in patients with heart failure and structural heart disease (13,14,39). Sodium-channel blocking drugs have both negative-inotropic and proarrhythmic side effects in this population. On the basis of these trials, these drugs should generally be avoided in patients with DCM.

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DCM

There have been two large trials of amiodarone for primary prophylaxis of SCD in heart failure patients. The GESICA trial was conducted in 26 hospitals in Argentina between 1989 and 1993. Patients (N = 516, mean age 59 years) with stable chronic class II, III, and IV congestive heart failure on appropriate medical treatment with LVEF of 0.35 or less (mean = 0.20) were randomized to receive amiodarone (300 mg/day chroni- cally) or usual treatment (40). Forty percent of patients had prior MI and 10% had Chagas’

disease. After a mean 13 months of follow-up, 87 of 260 patients (33.5%) treated with amiodarone died vs 106 of 256 control patients (41.4%), a relative risk reduction of 28%

and an absolute risk reduction of 7.9% (p = 0.024). Subsequent substudies of GESICA showed particular benefit in patients with baseline heart rate above 90 bpm.

The STAT-CHF trial was a US-based trial conducted in Veteran’s Affairs medical centers enrolling 674 patients (99% men) with LVEF of 0.40 or less, class II, III, or IV congestive heart failure symptoms, and 10 or more ventricular premature contractions per hour on Holter monitor (41). Patients were randomized to amiodarone (300 mg per day) or placebo and were followed for a mean of 4 years. In contrast to GESICA, this trial showed no significant difference in outcome between the two groups, either in total mortality or in sudden death.

The explanation for the discrepancy between the two trials has been attributed to the

difference in populations studied. GESICA included a higher proportion of patients with

nonischemic cardiomyopathy, including Chagas’ disease in 10%. In CHF-STAT, there

was also a trend toward improved survival with amiodarone in the smaller subgroup

without CAD. Additionally, mortality in the placebo group at 2 years was higher in

GESICA (50%) than in CHF-STAT (30%), suggesting that amiodarone may only benefit

those at very high risk. Alternatively, CHF-STAT included a much longer follow-up period, and hence GESICA might have shown less benefit for amiodarone if patients had been followed longer. No clear consensus exists for utility of amiodarone for primary prevention of SCD in the heart failure population because of the conflicting results of these two trials. Preliminary results of the Sudden Cardiac Death in Heart Rate Failure Trial (SCD-HeFT; see below) also suggest that amiodarone does not prolong survival in heart failure patients.

ICD

DCM

Patients with DCM who are resuscitated from sustained VT or VF warrant strong consideration for ICD therapy based on AVID and the other secondary prevention studies discussed above. ICDs are also appropriate for patients with symptoms consis- tent with VA (such as syncope) who have inducible VAs at EP study. Based on natural history studies, unexplained syncope is considered by some to constitute an indication for an ICD in patients with DCM. Other indications for ICD implantation in this group need to be defined.

To date, there have been no completed large-scale randomized trials of the ICD for primary prevention of SCD in patients with DCM. One small pilot trial conducted in Germany randomized 104 patients with DCM and LV ejection of 0.30 or less to ICD or usual therapy (42). After 5 years of follow-up, there was no significant difference in mortality between the two groups. Lack of efficacy of the ICD was ascribed to lower- than-expected mortality in this group. The Amiovert trial, recently reported in abstract form, compared ICD therapy with amiodarone in 178 patients with nonischemic cardi- omyopathy and nonsustained VT (43). This trial also appeared to be underpowered to detect a treatment effect of the ICD, and was terminated prematurely having shown no significant difference in outcome between the two groups.

The SCD-HeFT is a multicenter study that has enrolled approx 2500 patients with DCM because of any cause with LVEF of 0.35 or less and class II or III heart failure symptoms (44). Patients were randomly assigned to ICD implantation, amiodarone therapy, or placebo in a 1:1:1 fashion. Follow-up was completed in 2003 and prelimi- nary results were presented at the annual Scientific Sessions of the American College of Cardiology in March 2004 (available at www.sicr.org). After a mean follow-up period of 45 months, there was a statistically significant 23% relative reduction in all- cause mortality in the patients assigned to ICD therapy. Patients with ischemic and non- ischemic etiologies of heart failure appeared to benefit equally. There was no significant mortality difference in patients assigned to amiodarone treatment. Assuming these results are confirmed in the final published report, SCD-HeFT may result in significant expansion in patients eligible for ICD therapy for primary prevention of SCD.

OTHER FORMS OF CARDIOMYOPATHY

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

Hypertrophic Cardiomyopathy

HCM is a group of diseases caused by inherited mutations in genes encoding protein

components of the cardiac sarcomere (45). To date, 11 different HCM-associated genes

have been identified; others likely remain to be discovered. The disease results in myo- cyte disorganization, progressive myocardial wall thickening, and diastolic dysfunction.

Increased LV wall thickening develops during childhood and adolescence and is usually present by young adulthood in affected individuals. Some forms may develop systolic dysfunction late in the course of disease. The disease was first characterized in patients that had disproportionate thickening of the interventricular septum with dynamic LV outflow tract gradient (idiopathic hypertrophic subaortic stenosis [IHSS]). Further stud- ies have demonstrated that neither septal hypertrophy nor outflow tract gradient is a requirement for the disease, and numerous different patterns of LV wall thickening have been identified.

SCD as a result of VAs is believed to be the most common cause of death in HCM, with annual incidence ranging from 1% per year in all patients and up to 5% per year in high- risk subgroups. The highest risk is present in patients who have survived a CA or episode of sustained VT. These patients generally warrant ICD therapy for secondary prophy- laxis. Other proposed markers of risk include extreme LVH with wall thickness greater than 30 mm, frequent runs of nonsustained VT on Holter monitoring, history of unex- plained syncope, hypotensive response to exercise, and malignant family history. Pre- liminary data suggest that some genotypes, particular certain mutations in `-myosin heavy chain and cardiac troponin T, confer increased risk of SCD. Genotyping, however, is not widely available and not currently practical for risk stratification. Younger patients appear to be at higher risk, although a cut-off age indicating low risk has not been defined.

Resulting from the relative rarity of the disease and the overall low mortality rate, it has been difficult to define effective therapies for prevention of SCD in HCM.

Vigorous physical exertion and participation in competitive sports should be pro- scribed. `-Blockers have been used based on their efficacy in other cardiac substrates;

a retrospective study also suggests effectiveness (46). Amiodarone has been used to treat nonsustained and sustained VAs, but the potential for extracardiac adverse effects with lifelong treatment in relatively young patients is substantial (47). There are no controlled trials of ICD use in patients with HCM. Criteria for secondary prevention are applied generally as with other AVID-eligible patients. There are no prospectively defined criteria for ICD implantation for primary prophylaxis in this disease.

A retrospective cohort study of 128 patients with HCM who had ICDs implanted for perceived high risk of SCD was recently reported (48). This study found that, over a mean follow-up period of 3 years, 19 of 43 patients (44%) implanted for secondary prophylaxis had appropriate ICD discharges for VT or VF, and 10 of 85 patients (12%) implanted for primary prophylaxis did as well. This percentage is lower than that seen in primary prophylaxis trials in patients with CAD or DCM. Because the ICD cannot distinguish between truly life-threatening arrhythmias and VT which would terminate spontane- ously without treatment, it is difficult to draw conclusions regarding mortality reduction in this study. Moreover, 18 of 128 patients (14%) had device-related complications in the 3-year follow-up period, including 12 ICD lead failures. Thirty-two patients (25%) had inappropriate ICD discharges for sinus tachycardia, atrial fibrillation, or ICD lead failure;

25 of these patients did not receive an appropriate discharge from the device. These data

underscore the potential complications of ICD therapy, particularly applied to young

people with long life expectancy. Thus, while this study suggests that some HCM patients

may benefit from ICD therapy, definitive data to guide patient selection for primary

prophylaxis are not currently available.

Arrhythmogenic Right Ventricular Cardiomyopathy

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

Cardiac Sarcoidosis and Amyloidosis

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

Long QT Syndrome

The long QT syndrome (LQTS) is the most common of the cardiac ion channel dis- eases that cause SCD. The acquired form is most commonly caused by medications, which prolong cardiac repolarization. For a complete updated list of medications asso- ciated with LQTS, the reader is referred to www.torsades.org. Other causes of acquired LQTS include hypokalemia and hypomagnesemia; severe bradycardia, such as during complete AV block; and neurological insults, such as subarachnoid hemorrhage and stroke. The congenital form of the disease is associated with mutations in one of at least six identified gene loci (LQT 1–6) (55). LQT1, LQT2, LQT5, and LQT6 are all caused by mutations in different genes encoding for components of cardiac potassium channels, but LQT3 is caused by mutations in the cardiac sodium channel. All result in prolonged repolarization of the cardiac action potential with resulting prolongation of the QT inter- val and predisposition to torsades de pointes, which may in turn degenerate into VF.

Recognition of the ECG pattern in patients presenting with symptoms is an impor-

tant component of sudden death prevention in this disorder (56). The ECG in LQTS is

highly variable in degree of QT prolongation and morphology of the T wave, which

may make recognition difficult. Detection of LQTS is an important reason for careful

review of the ECG in any patient presenting with palpitations or syncope. Occasion-

ally, the syndrome presents as a seizure disorder in young children. Once an affected individual has been identified, family members should be screened for the disease.

The most important medical component of treatment for congenital LQTS is `-blocker therapy. This medication has been shown to reduce incidence of syncope and sudden death in congenital LQTS patients (57). Other treatments that have been shown to reduce symptoms include left cardiac sympathectomy and permanent atrial pacing. Preliminary data suggest that sodium channel blockade may be beneficial in the LQT3 subtype.

Criteria for ICD implantation are controversial, and the decision is difficult in young patients with long life expectancy. Patients resuscitated from CA and those with recurrent syncope because of torsade de pointes despite `-blockade are the most obvious candi- dates. Patients with syncope of undetermined etiology and patients with malignant family history are often considered as well.

Brugada Syndrome

The Brugada syndrome is a recently described inherited disease consisting of an abnormal ECG pattern (incomplete right bundle branch block with coved ST segment elevation in leads V

–V

) and idiopathic VF (58). In some cases, the ECG pattern is elicited only after sodium-channel blockade. Patients usually present after resuscitation from CA or, less commonly, with recurrent syncope. ICD implantation is currently the only effective therapy for symptomatic individuals. Evaluation and treatment of asymp- tomatic patients and affected family members is controversial. One report suggests that VT or VF inducibility at EP study has prognostic value (59). Although another report reached the opposite conclusion (60).

Commotio Cordis

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

FUTURE DIRECTIONS

Recent efforts to reduce the public health burden of SCD have focused on expansion of indications for ICD therapy. These trials have clearly shown efficacy of the ICD in the high-risk groups in which it has been studied. It has been noted that the majority of victims of SCD do not have risk factors that would currently make them eligible for an ICD (62).

Although further reduction in implant-related complications may make the ICD effective in lower risk patients, the cost-effectiveness ratios associated with this approach would be prohibitively high without a reduction in ICD costs. Additionally, the long-term economic, psychological, and health effects of chronic ICD therapy in low-risk popula- tions are not yet well-understood, and it is unclear to what degree low-risk populations would accept ICD therapy.

The disappointing history of anti-arrhythmic drug trials for prevention of SCD make

these agents unattractive for primary prophylaxis of SCD in lower risk groups. To be

useful for this purpose, an agent should have low cost and side-effect profile and negli-

gible proarrhythmic risk. Preliminary studies of t-3 polyunsaturated fatty acids (“fish oils”) have shown marked protective effect against VF in animal models of ischemia and infarction, possibly because of stabilizing effects on the membrane of the cardiomyocyte (63). Further trials in humans will be required to demonstrate clinical efficacy.

In order to better target preventive therapies, others have worked on identifying novel markers of high risk of SCD. A recent report has observed that patients with congestive heart failure and depressed LVEF who had elevated brain natriuretic peptide levels (>130 pg/mL) had more than 10-fold higher risk of sudden death than those with lower values (64). Other noninvasive electrocardiographic markers of risk include microvolt T-wave alternans, heart rate variability, and heart rate turbulence. Whether any of these markers can predict benefit of ICD or other preventive strategies remains to be proven (65).

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