Critical review of the approaches to the prevention of sudden death

Critical Review of the Approaches to the Prevention of Sudden Death Salim Yusuf, MBBS, DPhil, FRCP, Govindarajan Venkatesh, MD,FRCP(C)

and Koon K. Teo, MBBCh, PhD, FRCP

lhe types of cardiac rhythm in patients wtth sudden death may vary considerably, depending on the underiying cardiac disease. Although ven-

tricular tachyarrhythmtas are likely to be the most common causes, a stgntficant proportion of

pattents may die suddenly due to asystoie, electromechanical dtssociatii, or cardiac rupture.

Therefore, the approaches to preventhg sudden death may have to be multifactorial. The ctassk approach of arrhythmta suppression by emptrk

antiarrhythmk drugs has not resutted in a decrease in sudden death mortaltty. Atthough f3

blockers have only a modest effect in suppressing arrhythmias, they have been clearly proven to prevent sudden death. Other promising ap-

proaches that require further evaluation bwlude modulation of the autonomic balance between

the sympathettc and parasympathetk nervous systems (perhaps by f3 biockers, exercise training, or iow-dose atropine or scopolamine), re5ef

of ischemia by medk~l or surgical therapy, magnesium supplementation, and mechanical de-

vices, such as the impiantable defibriltator. (Am J Cardlol1553;72:5lF--55F)

From the Division of Cardiology and Program of Preventive Cardiology and Therapeutics, Hamilton Civic Hospitals Research Centre, McMaster University, Hamilton, Ontario, Canada (S.Y., G.V.) and Division of Cardiology, University of Alberta, Edmon- ton, Alberta, Canada (K.K.T.).

Address for reprints: Salim Yusuf, MBBS, DPhil, 252 HGH- McMaster Clinic, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2.

S udden cardiac death refers to natural cardiac death, heralded by an abrupt loss of con- sciousness within a brief period of the onset

of acute symptoms in an individual with or without known preexisting heart disease, but in whom the time and mode of death were unexpected. Sudden cardiac death is believed to account for about 50% of deaths in patients with evidence of cardiovascular disease. Various estimates suggest that about 300,000 sudden cardiac deaths occur annually in the United States alone.’ Epidemiologic studies such as the Framingham Heart Study2 have suggested that approximately 67% of all deaths classi- fied as sudden and of cardiac origin occur in individuals who previously were not known to have any evidence of cardiac disease. In the general population, the risk factors associated with sudden death are those related to the development of coronary artery disease. Therefore, preventive measures aimed at modifying risk factors are likely to lead to reductions in sudden death.

Several studies conducted primarily in subjects with cardiac disease have reported a relation between the frequency of ventricular arrhythmia and subsequent mortality.3 Several other studies have reported that 75% of sudden deaths are due to ventricular tachycardia or fibrillation.4 This led to the traditional view on preventing sudden death- that suppression of ambient ventricular arrhythmias should lead to a reduction in sudden death and consequently a reduction in total mortality. This view was the impetus for the pharmacologic approach to preventing sudden death by utilizing antiarrhythmic agents to suppress ambient or in- duced ventricular arrhythmias. This rationale has been tested in several randomized trials over the last 2 decades, and the data from the available randomized trials are reviewed in the next section.

OVERVIEW OF 7RtN.S OF ARRARRtfy7RMIC DRUG5

Figure 1 summarizes data from the various randomized trials evaluating the effects of a num-

A SYMPOSIUM: ARRHYTHMIAS AND REPOLARIZATION !iiF

ber of different antiarrhythmic drugs in patients with myocardial infarction (MI).5 Eighteen trials evaluated class 1A drugs (quinidine, procainamide, disopyramide, imipramine, and moricizine) in a total of 6,582 patients. There were 253 deaths among 3,292 treated patients compared with 217 among 3,290 control patients. Thirty-two trials evaluated class 1B drugs (lidocaine, tocainide, phenytoin, and mexiletine) in a total of 14,013 patients. There were 306 deaths among 7,068 treated patients, compared with 275 among 6,945 control subjects. There have been 8 trials of class IC agents (aprindine, encainide, and flecainide) in a total of 2,538 patients. There were 97 deaths among 1,303 treated patients compared with 74 among 1,235 control patients (odds ratio, 1.31; 95% confidence limits, 0.95-1.79). Separate exami- nation of the data on each agent also does not show any evidence of benefit. Therefore, individually and collectively there is no evidence that class I agents reduce the risk of death.

Of the various studies, the Cardiac Arrhythmia Suppression Trial (CAST)6 and the overview of lidocaine trials by MacMahon et al7 deserve elabo- ration. CAST used 24-hour Holter recordings as the means of identifying post-MI patients with arrhythmias and selected the best drug and dose to yield arrhythmia suppression. CAST showed a statistically significant 2- to 3-fold increase in both total and sudden arrhythmic deaths in the patients treated with encainide or flecainide compared with those on placebo. The increase in total mortality is of particular importance, given the difficulty in clearly defining arrhythmic death. The substantial increase in presumed arrhythmic deaths and nonfa-

14

12

10

$6

:

ii ap =

4

2

0

tal cardiac arrests implies a proarrhythmic action of these drugs. The increase in nonarrhythmic cardiac mortality suggests that these drugs may also have other adverse consequences, such as worsening of ventricular function. The excess in mortality and cardiac arrests was seen in all identi- fied subgroups of patients (e.g., those with normal and impaired left ventricular ejection fraction, frequent and infrequent arrhythmia, presence or absence of previous MI, presence or absence of other medications). The second part of CAST, which evaluated the drug moricizine, was prema- turely terminated because of a trend toward higher mortality in treated patients.

CAST has several implications for assessment of antiarrhythmic therapy. First, only large studies are likely to have sufficient events to provide adequate information regarding benefit or harm. Previous smaller studies and databases regarding encainide or flecainide were not able to do so conclusively. Indeed, the latter sets of data suggested the drugs were safe. Second, although the drugs were found to be associated with an increased risk of death, they were quite effective in suppressing ventricular arrhythmias. Therefore, studies using only suppression of ventricular arrhythmia as the primary endpoint may be mislead- ing. Third, although limited extrapolations might be made to other class IC agents, or perhaps to all class I drugs, it may not be appropriate, at the current time, to generalize the CAST findings to all antiarrhythmic drugs. Each agent may need to be evaluated for its effects or clinical outcomes. Be- cause the risk-benefit ratio of antiarrhythmic drugs may vary in different types of patients who may

class 1 class 2

short-term long-term

class 3

I class 4

FIRURE I Mortality In random Iad trhle ofantkurhythmlc drugs. (Modlf&d from C&Ma-

-.3

52F THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 NOVEMBER 26, 1993

have different underlying conditions and “arrhythmic” substrate, there may be an additional need to evaluate these drugs in different populations. Nevertheless, the adverse trends seen in several of the other trials of class I agents in MI patients are disturbing and must make us exceed- ingly cautious in using any agent from this class. It appears unlikely that any of the class I agents tested thus far will reduce mortality.

Class I drugs have also been evaluated during acute MI. Lidocaine, in particular, has been shown to reduce the incidence of ventricular fibrillation.8 However, there is no significant decrease (in fact, there is a trend toward an increase) in total mortality, which appears to be due to an increase in asystole.

Figure 1 also summarizes the data from all the trials of short-term P-blocker therapy in acute M19Jo and long-term therapy in the first l-2 years following an infarction. In both groups of studies, there was a significant reduction in total mortality. In addition, the short-term studies indicated a reduction in nonfatal cardiac arrest (p < 0.02) and the long-term studies demonstrated a reduction in sudden death (p < 0.001) suggesting that major arrhythmic events were indeed being prevented. A recent prospective, randomized trial” compared empirical P-blocker therapy to electrophysiologi- tally (EP)-guided antiarrhythmic drug therapy in patients with symptomatic sustained ventricular tachyarrhythmias. Of 170 patients, 115 had electrophysiologically inducible ventricular arrhythmias and 61 of these patients were randomly allocated to EP-guided antiarrhythmic drug therapy and the other 54 patients were randomly allocated to metoprolol, empirically. Fifty-five patients whose arrhythmia was noninducible electrophysiologically were also treated with metoprolol, empirically. Of the 61 patients randomized to the EP-guided antiarrhythmic drug arm, 29 patients were treated with the first antiarrhythmic drug that rendered the arrhythmia noninducible, whereas the other 32 patients remained inducible despite antiarrhythmic drug therapy. The incidence of symptomatic arrhythmia and sudden death combined was virtu- ally the same in the 2 groups. These data indicate that empirical p-blocker therapy is likely to be as effective as EP-guided antiarrhythmic drug therapy.

and clinical complications in a total of 613 high-risk post-MI patients, ineligible for p-adrenergic block- ing drugs. The cardiac mortality (19 vs 33, p = 0.048) and Lo wn class IV ventricular arrhythmia (7.5% vs 19.7%, p < 0.001) were significantly reduced. The Cardiac Arrest in Seattle: Conven- tional Versus Amiodarone Drug Evaluation (CAS- CADE)r4 studied antiarrhythmic drug treatment in survivors of out-of-hospital ventricular fibrillation. A total of 228 patients were randomized either to empiric treatment with amiodrone or conventional therapy with antiarrhythmic drugs guided by electrophysiologic testing or Holter monitoring, or both. Conventional therapy consisted mainly of class I drugs (lone exception, P-blocker use). This study essentially compared empiric amiodarone versus class I agents. Survival, free of cardiac death or sustained arrhythmias, was 78% in the amiodarone group versus 52% in the conventional group at 2 years, 52% and 36% at 3 years, and 41% and 20% at 4 years, respectively; p < 0.001.

ELEClROPHYSlOLOGlC STUDY VERSUS HOLTER MONITOR-GUIDED THERAPY

The data on amiodarone also appear to be encouraging.12 In trials published before 1992, there were 55 deaths among 577 treated patients compared with 73 deaths among 575 controls. A recent randomized, double-blind, placebo-controlled study from Poland13 evaluated the effect of amiodarone on mortality, ventricular arrhythmias,

Electrophysiologic study (EPS) is commonly used in the management of ventricular tachyarrhythmia, not only for diagnosis, but also as a guide to the selection of antiarrhythmic drug therapy. The suppression of inducible ventricular tachycardia by short-term drug therapy was thought to indicate a good prognosis based on several small, nonrandomized studies, followed by some larger case series.rs-l7 The Electrophysiologic Study Ver- sus Electrocardiographic Monitoring (ESVEM) investigators18 conducted a randomized comparison of selection of antiarrhythmic drug therapy by EPS versus electrocardiographic monitoring in patients with ventricular tachyarrhythmias. A total of 486 patients with ventricular tachyarrhythmia, who also had reproducibly inducible tachyarrhythmia at EPS and 2 10 premature ventricular complexes per hour on Holter monitor were randomly as- signed to serial drug testing by EPS or Holter monitoring. They received up to 6 antiarrhythmic drugs (5 class I agents and sotalol) in random order until 1 was predicted to be effective by suppression of arrhythmia inducibility in the EPS limb or premature ventricular complexes in the Holter monitoring limb. In the EPS limb 108 patients received an efficacy prediction, compared with 188 in Holter monitoring limb. There were no significant differences in rates of arrhythmia recurrence or death between the EPS and Holter monitoring groups. Among patients with drug efficacy prediction, the risk of arrhythmia recurrence was signifi-

A SYMPOSIUM: ARRHYTHMIAS AND REPOLARIZATION 53F

TABLE I Heart Rate Variability as a Prognostic Indicator of Postmyocardial Infarction

% Events

Reference Patients tn)

Wolf et aP6 176

Kleiger et alz8 808

Casolo et aP7 54

Farrell et aids 416

HRV Index

sdNN ~32 msec (30 RR intervals)

sdNN < 50 msec (24.hr Halter)

sdNN < 50 msec (24.hr Halter)

Baseline width < 20 msec (24.hr Halter)

Outcome

In-hospital death

All cause mortality

In-hospital death

Arrhythmic events

HRV “Normal”

4.1

12.0

0

0

HRV “Abnormal”

15.5

27.0

11.1

5.7

Baseline width = width of baseline of histogram of RR: HRV = heart rate variability; sdNN = standard deviation of RR intervals.

cantly higher in patients who received drugs other than sotalol (risk ratio = 2.48). These results suggest that EPS-guided therapy is unlikely to be superior to Holter monitoring-guided therapy. However, since Holter-guided therapy itself has not been shown to reduce mortality, the collective data imply that EPS-guided therapy may not be beneficial. It may well be that identification of patients in whom arrhythmia is suppressed by any method simply selects patients with inherently better prognosis.

ALTERNATIVE APPROACHES TO PREVENTION OF SUDDEN DEATH

Relief of myocardial ischemia: The risk factors for sudden cardiac death among a general population are the same as those for the development of ischemic heart disease. It is, therefore, reasonable to assume that avoidance or treatment of common risk factors such as cigarette smoking, elevated cholesterol, hypertension, or prevention of thrombosis may prevent sudden death. This assumption is supported by some observational, pathologic, and interventional studies that are all suggestive of the important role of ischemia in the causation of sudden death. For example, studies of the prognostic significance of ischemic changes during exercise testing indicate that patients with a positive exercise test are at a greater risk of death but not of recurrent infarction. Some pathologic studies have demonstrated extensive atherosclero- sis and platelet microthrombi in the coronary vessels of patients dying from sudden cardiac death. Moreover, at least 3 randomized trials of antiplatelet drugs reported a significant reduction in nonfatal cardiac arrest or sudden death.19-21 These data suggest a role for ischemia (due either to coronary narrowing or acute platelet microdepos- its) in the pathogenesis of sudden death.

Several studies22,23 have indicated that electro- lyte disturbances such as hypokalemia and hypo- magnesemia may be associated with frequent ven-

tricular arrhythmia. Magnesium is important for the maintenance of adequate intracellular levels of potassium and may, therefore, be crucial in ventricular arrhythmia prevention. Some studies have indicated that in areas deficient in magnesium in the drinking water, cardiovascular mortality is increased.24 Several randomized trials2s have indicated that an intravenous infusion of magnesium reduces the frequency of ventricular arrhythmia in the acute phase and also several weeks after MI. In an overview of all randomized trials,26 intravenous infusion of magnesium was associated with a significant reduction in mortality. Large prospective randomized trials currently are underway to evaluate the effect of intravenous magnesium infusion in acute MI.

Role of autonomic newous system: Experi- mental and clinical evidence indicates that the role of the autonomic nervous system is critical in triggering ventricular fibrillation.27 High vagal tone appears to be protective. Valid methods, including heart rate variability and baroreceptor reflex sensitivity, provide indirect measures of balance in autonomic tone.28,29 Decrease in heart rate variability (time domain measures) or flattened high frequency power and heightened low frequency power (power spectral analysis of heart rate variability) have been shown to be associated with higher mortality from sudden death30 in patients following MI. Table I summarizes the studies of heart rate variability post-MI. Apart from post-MI patients, heart-rate variability is also decreased in patients with congestive heart failure,31y32 but the value of heart rate variability in predicting mortality in this population has not yet been studied.

Baroreflex sensitivity is a test of reflex vagal activity. LaRovere et aP3 prospectively studied 78 patients, < 65 years of age, after a first MI. During a mean follow-up of 24 months, there were 6 cardiovascular system deaths, 4 of which were sudden. The baroreflex sensitivity was markedly lower among the deceased patients compared with


survivors (2.4 + 1.7 vs 8.2 + 4.8 msec mm Hg). The mortality rate rose sharply from 2.9% to 40% in the presence of a markedly depressed baroreflex sensitivity < 3.0 msec mm Hg.

Therapeutk interventions to modulate autonomic balance: Nonpharmacologic methods, such as exercise training, have been shown to reduce total and cardiovascular mortality from sudden death.34 An overview of the trials of physical rehabilitation following MI indicates that exercise training leads to a significant reduction in the risk of sudden death.34 Exercise training increases vagal tone, in normal individuals as well as in post-MI and congestive heart failure patients. Psychosocial factors affect both heart-rate variability and mortality, post-MI. Further, behavioral modification of adverse psychosocial factors by biofeedback or self-management training can increase vagal tone and decrease preexisting sympathetic overactivity as measured by spectral and nonspectral analysis of heart-rate variability in the electrocardiogram of survivors of sudden cardiac death.3s

Pharmacologic interventions that modulate autonomic balance favorably seem to reduce mortality from sudden death. Apart from reducing sympathetic activity, l3 blockers seem to increase heart- rate variability, reflecting augmented vagal activity.36 Scopolamine (or low-dose atropine) has been shown to increase heart-rate variability in post-MI and congestive heart failure patients.37-39 Zuaneti et a140 studied the effect of various antiarrhythmic drugs on heart-rate variability. No change was noted with amiodarone, but a significant decrease in heart-rate variability occurred in patients treated with flecainide or other class I agents (which were, however, shown to be associated with an increase in mortality in randomized trials).

Although preliminary, the collective data appear to indicate that interventions that reduce sympathetic tone or increase parasympathetic tone decrease sudden death, whereas agents that have an adverse effect on the balance in autonomic tone increase sudden death rates.

Use of implantable cardiac defibdlator: Given the disappointing results of most pharmacologic approaches to preventing sudden death, many investigators have turned to nonpharmacologic approaches, such as surgery (endocardial resec- tion, stellate ganglionectomy, etc.) or the implanta- tion of devices that recognise ventricular tachycardia or fibrillation and deliver a shock. The greatest interest has been generated by the implantable cardiac defibrillator (ICD). Many workers in this field believe that the available data indicate that an

ICD reduces the incidence of sudden death41 (and consequently overall mortality) markedly and that the available data are so compelling that formal evaluation in prospective studies may not be neces- sary. The types of studies that have been conducted fall into the 6 categories, outlined in Table II. Studies that belong to categories 5 and 6 are likely to be the most reliable, those in categories 3 and 4 are of intermediate reliability, and those in categories 1 and 2 are the least reliable. The problems associated with each category of study are also outlined in Table II. The claims of benefit for ICD are largely based on patient series (categories 1 and 2) that have major limitations in evaluating any therapy. Therefore, even the direction of effect from these studies is unreliable. The case control series by Newman et a143 ccsmpared the outcome among patients who received the ICD versus patients receiving amiodarone. Although this study attempted to overcome some of these problems, even this study was not free from potential biases. There may be differences in prognostic features that were not used in matching, ancillary therapies may have been different, and there may be differences in the time elapsed from the index event to entry into the series. For example, there may be a longer delay from the index cardiac arrest to receiving an ICD (due to delay in referrals, electrophysiologic testing, etc.), so that a higher proportion of the early deaths may have occurred prior to receiving the ICD. Conversely, pharmacologic treatment may have started earlier in patients receiving amiodarone and, therefore, this group may include a proportion of the high-risk group that were excluded from the ICD arm. Therefore, no true intent-to-treat analysis can be carried out in such a design. Ideally, studies that randomize patients to receive an ICD or alternative therapy are required. A preliminary report from one small randomized study indicates no benefit on total mortality. How- ever, larger studies of longer duration are needed to address this question reliably. Several such studies are underway (Table III).

Heterogeneity of sudden death: In an earlier section, we discussed the disappointing results of antiarrhythmic therapy. Such results may stem from the possibility that clinically recognized sudden cardiac death may actually be a composite of some quite different processes. It is possible that some drugs may be beneficial on some of these processes and yet may be harmful on others. Therefore, the net clinical effect may depend on the balance between potential benefit (e.g., antifi- brillatory) and harm (e.g., increased risk of asys-


TABLE II Overview of Types of Studies Evaluating the Efficacy of the Implantable Cardiac Defibrillator (ICD) on Survival: Different

Approaches and their Limitations

Type of Study Results Limitations

1. Comparison of a series with ICD vs a sepa- Claims for reduced sudden death. However, 1. Marked differences in patient selection, con- rate series of historical controls from the lower nonsudden death with ICD is apparent comitant therapy and CABG surgery same or another center in some series, suggesting biases in patient 2. Biases due to differences in time from cardiac

selection (Winkle et al411 arrest to entry into study, e.g., may be longer in studies of ICD, so highest risk patients may have died before entry

2. Comparison of actual with projected sudden Claims for reduced sudden death 1. Validity of ascertaining appropriate shock death rates based on number of “appropri- dubious

ate” shocks 2. Large number of shocks may be inappropri- ate

3. ?Reversible episodes of VT or fast AF may be shocked

3. Comparison with historical matched controls Reduced sudden death. But increase in deaths 1. No assurance that all prognostic features within the same institution due to heart failure. Difference in mortality matched

only apparent for about 2 years (Newman et 2. No assurance that all treatments similar ai@) 3. Biases due to differences in time from cardiac

arrest to entry into study 4. Concurrent matched controls No study No guarantee that selection biases or referral

biases can be avoided 5. Concurrent randomized controls Preliminary results of an ongoing study (Kuck et Primary endpoint should be CV or total mortality

aI@) shows no benefit on total mortality, but to avoid classification biases. Need for study of apparent effect on sudden death at least 600 to 800 patients who survive car-

diac arrest 6. Concurrent randomized controls + use of No study Would be ideal study if it has 600 to 800 survi-

devices that can record the rhythm at the vors of cardiac arrest and uses CV or total time of ICD discharge mortality as endpoint

AF = atrial fibrillation; CV = cardiovascular; VT = ventrlculat tachycardia. Reprinted with permission from J Card Ekctrophysiol.49

tole). Study of the exact initiating or terminal arrhythmic event has been extremely difficult and has been limited by the practicalities of obtaining the recordings of the cardiac rhythms preceding and during episodes of sudden and nonsudden cardiac deaths. Currently, limited data are available from the following sources: (1) recordings at the time of resuscitation of out-of-hospital cardiac arrests; (2) recordings during the early hours of MI before patients are admitted to a hospital; (3) recordings among patients admitted to the hospital with acute MI; and (4) recordings obtained by chance among patients who have a Holter monitor and are being evaluated or treated with antiarrhythmic therapy.

A summary of the results from several studies in each category is provided in Table IV.44,45 Most studies are “convenience” rather than random samples. Therefore, the “representativeness” of

most studies must be questioned. The results may be confounded by the effects of concomitant therapy, the differences in disease processes, and the delay from the onset of the event to the beginning of recording. For example, in patients receiving a drug that is proarrhythmic, the proportion of deaths ascribed to ventricular tachycardia or fibrillation may be exaggerated. Conversely, drugs that increase the risk of asystole or heart block might alter the proportions of the various causes of death. Some studies have suggested that if recordings are obtained earlier during a cardiac arrest, ventricular tachycardia or fibrillation is more likely to be recorded, whereas with increasing delay, asystole is likely to be observed. Table IV shows considerable variation in the proportion of sudden deaths that were ascribed to ventricular tachyarrhythmia (range, 15-7.5%) in various conditions. A significant proportion was due to asystole

TABLE Ill Summary of Randomized Controlled Trials of Implantable Cardiac Defibrillator I

Trial Type of Problem Endpoint 2N

CIDS (vs amiodarone) CASH (vs amiodarone, 8 blocker, propafenone) NHLBI 01s amiodarone, sotalol) CABG-Patch MADIT (vs conventional)

SD/VT + syncope SD + inducible SD/VT EF <0.35 + SA ECG + Nonsustained VT, EF co.35 Inducible VT/VF resistant to IV procainamide

SD 600 Total mortality 400 Cardiac deaths 1,000 Total mortality 250 Total mortality 280

CABG = coronary afierY bypass gratting; CASH = Cardiac Arrest Study Hamburg; CIDS = Canadian Implantable Defibrdlabon Study! ECG = electrocardiogram; EF = ejection fraction; IV = intravenous; MADIT = MultIcenter Automatic Defibrillator lmplantabon Trial; NHLBl = National Heart, Lung, and Blo@d lwt,t&; SD = sudden death: VF = ventricular fibrillation; VT = ventricular tachycardia.

S6F THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 NOVEMBER 26, 1993

TABLE IV Projected Percentages of Sudden Deaths Due to

Various Causes in Different Conditions

EM Dissoclatlon

VT/VF* Asystole Cardiac Condition (%) (%) Rupture (%)

Out of hospital cardiac arrest 65-75 10-15 10-15 (Schaffer and Cobb4)

Prehospital acute MI 80 10 10 (Schaffer and Cobb41

Inhospital acute MI Wolpi et al47 15-20 10-15 60-65 Severe heart failure (Luu et al42) 20-30 60-70 5-10

*The proporbon of sudden deaths due to ventrular tachycardia (VT) or ventricular fibrlllatlon WF) may be exaggerated If proarrhflhmlc drugs are used. Some drugs may increase the risk of asystole. EM = electromechanical; MI = myocardial InfarctIon.

Reprmted wth permission from J Cardiovasc Electrophysiol.49

or electromechanical dissociation in patients hospi- talized after MI or among those with heart failure. Moreover, the proportion of sudden cardiac deaths compared to other cardiac deaths varies by the type of patient or the presence and severity of heart failure. The contribution of ventricular tachyarrhythmia to all cardiac deaths may be small, perhaps as low as 10-S% in some patients with severe left ventricular dysfunction, heart failure, or late after MI. It could also be as high as 30-40% among those resuscitated from out-of-hospital cardiac arrest. Consequently, even if 90% of deaths due to ventricular tachyarrhythmias are prevented by an ideal and highly effective therapy (that has no adverse effects and does not merely change the mode of death), the maximum theoretical benefit is likely to be only about 3040% reduction in cardiac mortality (unless the intervention has beneficial effects on other mechanisms of death). Of course, if an intervention is used in a population where the contribution of tachyarrhythmic deaths to all cardiac deaths is lower, or if the intervention is only partially effective in preventing tachyarrhythmic deaths, or produces some increase in deaths due to other mechanisms, or changes the mode of death (some patients destined to have ventricular fibrillation may die due to heart failure), then the ex- pected benefit is likely to be less. These general considerations would suggest that effective approaches to the prevention of sudden death may have to be multifactorial and even varied in different populations.

CONCLUSION The classic approach of suppressing ambient

arrhythmias with antiarrhythmic drugs has not been shown to reduce sudden death. The approaches to prevent sudden cardiac death have to be multifactorial, given the heterogeneity of this clinical entity. There is convincing evidence that

P-adrenergic blockers reduce sudden death not only by an antiarrhythmic effect, but also by reducing heart rate, maintaining a favorable autonomic balance, relieving ischemia, and preventing cardiac rupture. Relief of ischemia by medical or surgical therapy, including antiplatelet drugs, is important. Potassium and magnesium homeostasis, or supplementation, may be beneficial. Nonpharmacologic and pharmacologic measures that increase vagal tone as measured by heart-rate variability hold promise. Device therapy (e.g., ICD) may be a useful adjunct in high-risk patients. However, rigor- ous trials are needed before many of these interventions become routine therapy to prevent cardiac death.

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Critical review of the approaches to the prevention of sudden death