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(Circulation. 1997;95:2694-2699.)
© 1997 American Heart Association, Inc.

Articles

Treatment of Sudden Cardiac Death

Current Understandings From Randomized Trials and Future Research Directions

Michael J. Domanski, MD; Douglas P. Zipes, MD; Eleanor Schron, MS

From The Clinical Trials Scientific Research Group, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (M.J.D., E.S.), and the Division of Cardiology, Indiana University School of Medicine (Indianapolis) (D.P.Z.).

Correspondence to Michael J. Domanski, MD, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.

Key Words: death, sudden • cardiovascular disease • arrhythmias

	Introduction

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
Sudden cardiac death (SCD) occurs in 300 000 individuals each year in the United States.¹ This represents about half of the deaths caused by cardiovascular disease,² which in turn represents almost half of all deaths in the United State annually. Because of this, SCD is recognized as an important public health problem, and substantial research has been directed at its prevention. This research has been directed at primary and secondary prevention of diseases that cause fatal arrhythmias as well as at treatment of the arrhythmias.

Central to this research have been a number of randomized trials in patients known to be at risk for SCD. Taken together, the studies that have been reported and those that will be reported in the near future will paint a coherent picture of the role of the currently available modalities for SCD prevention. It is timely to review the available data and define future research directions.

	Pharmacological Treatment

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
ß-Blockers
Historically, the ß-blockers were the first family of drugs shown to help prevent SCD. Their ability to reduce ventricular arrhythmias^{3 4} led to studies in the early 1980s of their usefulness in the prevention of SCD in survivors of myocardial infarction.

Among the important studies demonstrating the usefulness of ß-blockers in the prevention of SCD is the Beta-Blocker Heart Attack Trial (BHAT), which was a randomized, double-blind, placebo-controlled study that tested whether the administration of propranolol in patients with a history of at least one myocardial infarction could reduce subsequent mortality.⁵ A total of 3837 patients were randomized to receive propranolol (180 or 200 mg/d) or placebo. The trial was stopped 9 months before planned termination because of the significant improvement in total mortality in the ß-blocker treatment group. Total mortality at 25.1 months was 7.2% in the propranolol-treated patients and 9.8% in the placebo group. SCD was significantly less frequent in the propranolol-treated patients (3.3% versus 4.6%). Patients with a history of congestive heart failure experienced a 47% reduction in SCD (5.5% versus 10.4%).⁶

In the Norwegian Multicenter Study, in which a different ß-blocker was used, treatment with timolol was compared with the use of placebo in post–myocardial infarction patients.⁷ A total of 1884 survivors of acute myocardial infarction were randomized to timolol (10 mg BID) or placebo 7 to 28 days after infarction. After an average of 17.3 months, there were 152 deaths (16%) in the placebo-treated group and 98 (10%) in the timolol-treated group (P<.001). SCD was also reduced in the timolol group (13.9% versus 7.7%; P=.0001).

These studies and others⁸ have demonstrated the efficacy of ß-blockers in the prevention of SCD as well as in the reduction of total mortality in patients with a history of myocardial infarction. The striking benefit in BHAT patients with a history of congestive heart failure suggests a possible role in SCD prevention for these agents in patients with chronic coronary disease and reduced ejection fraction.

ACE Inhibitors
Although the role of ACE inhibitors in reducing mortality in patients with heart failure and in patients with reduced ejection fraction has been demonstrated in a number of prospective, randomized trials,^{9 10 11 12} only in the Trandolapril Cardiac Evaluation Trial (TRACE) did the data suggest that the ACE inhibitor reduced SCD.¹²

Nonamiodarone Antiarrhythmic Drugs
Although benign in the absence of structural heart disease, premature ventricular complexes (PVCs) are a risk factor for SCD in patients after myocardial infarction.^{13 14 15 16} The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test whether suppression of PVCs with antiarrhythmic therapy (encainide, flecai-nide, or moricizine) could prevent mortality in patients with asymptomatic or mildly symptomatic ventricular ectopy.¹⁷ In this study, 1789 patients were found to have one of the three study drugs suppress their PVCs, as assessed by Holter monitoring, and were randomly assigned to receive active drug or placebo. During 10 months of follow-up, a higher death rate was observed in the active treatment (encainide or flecainide) group than in the placebo-treated patients. The relative risk of total mortality was increased (relative risk, 2.5; 95% confidence interval, 1.6 to 4.5), as was the relative risk of nonfatal cardiac arrest or death from arrhythmia (relative risk, 3.6; 95% confidence interval, 1.7 to 8.5). The CAST investigators concluded that neither encainide nor flecainide was appropriate treatment of patients with asymptomatic or minimally symptomatic arrhythmia after myocardial infarction, even when they proved capable of suppressing ventricular ectopy. The moricizine arm of the study was subsequently stopped because of excess mortality in the first 14 days of treatment and estimates of conditional power that indicated a high probability that a beneficial effect of moricizine would not be shown.¹⁸

The CAST has important implications and raises a number of questions. Among these is the inappropriateness of Holter-assessed ventricular ectopy suppression as a surrogate end point for mortality in trials of antiarrhythmic therapy. It is also clear that the drugs used in this study do not have a role in preventing SCD in patients after myocardial infarction. Whether the conclusions of the CAST apply only to these specific drugs or to all class IC drugs, or even to all antiarrhythmics, could not be determined on the basis of this study. Also, whether a method of guiding drug therapy other than Holter monitor would be more appropriate was not determined.

The Cardiac Arrest Study Hamburg (CASH) is a randomized, controlled study of the treatment of survivors of SCD due to documented ventricular tachycardia or ventricular fibrillation unrelated to acute myocardial infarction.¹⁹ Patients are enrolled within 3 months of cardiac arrest. After electrophysiological testing, patients are randomly assigned to receive treatment with propafenone, amiodarone, or metoprolol or implantation of an implantable cardioverter-defibrillator (ICD). The propafenone arm of the study has been stopped because of a significantly higher rate of SCD or cardiac arrest in the propafenone compared with the ICD-treated group; the other arms of the study continue.

The Survival With ORal D-sotalol (SWORD) study²⁰ trial was designed to test the hypothesis that D-sotalol would reduce the mortality in high-risk survivors of a myocardial infarction. This study enrolled patients with left ventricular ejection fraction of 40% and a history of myocardial infarction with congestive heart failure. The study was designed to enroll 6400 patients but was stopped after the enrollment of 3400 patients because of excess mortality in the D-sotalol group (mortality, 4.6% in the sotalol group and 2.7% in the placebo group; P=.005).

A meta-analysis of randomized trials of antiarrhythmic therapy, published or unpublished, available at the time was reported in 1993 by Teo et al.⁸ Mortality data were collected on 98 000 patients entered into 138 trials. The mortality of patients randomized to receive class I agents was significantly higher than that of patients receiving placebo (odds ratio, 1.14; 95% confidence interval, 1.01 to 1.28; P=.03).

No study reported to date has shown a benefit with the use of any of the nonamiodarone antiarrhythmic agents in the prevention of SCD; in fact, the results suggest that the proarrhythmic potential of these agents increases, rather than decreases, mortality.

It is possible that the mode of guidance—Holter monitor versus treatment based on electrophysiological study (EPS)—makes an important difference. The Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) study randomized 486 patients who had documented ventricular tachyarrhythmias inducible with EPS and 10 PVCs/h during Holter monitoring to serial testing of antiarrhythmic drug efficacy by Holter monitoring or by EPS.²¹ There was no difference in the recurrence of ventricular tachyarrhythmia in patients who received antiarrhythmic drugs predicted to be effective by Holter monitor versus EPS.

Thus, the results of ESVEM suggest that the lack of benefit of conventional antiarrhythmic drugs is not related to the approach to guiding therapy (EPS or Holter monitoring) but rather to lack of efficacy, or even detrimental effects, of these drugs.

It should be added that the ESVEM investigators concluded that DL-sotalol was more effective than other drugs tested in this study in the prevention of ventricular tachyarrhythmias. Drug assignment was, however, nonrandom, making the result of this part of the study hard to assess.

Amiodarone
A possible role for amiodarone in SCD prevention has been extensively studied in patients at increased risk of SCD because of a history of myocardial infarction or congestive heart failure.

The Basel Antiarrhythmic Study of Infarct Survival (BASIS) was reported in 1990.²² BASIS investigated prophylactic antiarrhythmic drug therapy in patients with asymptomatic, complex arrhythmias after myocardial infarction. The 3127 patients randomized were assigned to treatment with low-dose amiodarone; individualized antiarrhythmic drug therapy, starting with procainamide; or no antiarrhythmic drug therapy (control). During the 1-year follow-up, amiodarone-treated patients had a significantly greater survival than control subjects (95% versus 87%; P=.048), and antiarrhythmic events were significantly reduced. No other statistically significant differences between groups were found.

Ceremuzynski et al²³ also studied the effect of amio-darone on mortality after myocardial infarction. These investigators randomized 613 patients after infarction who were ineligible to receive ß-blockers to amiodarone or placebo. There were fewer deaths in the amiodarone group. Although a statistically significant reduction in overall mortality (the primary end point) was not achieved (P=.095), the reduction in cardiac mortality was significant (P=.048). Although this was a small study with borderline statistical significance, the conclusion is similar to that reached in BASIS.

Further support for the usefulness of amiodarone in the postinfarction patient came from the meta-analysis of Teo et al.⁸ They combined mortality data from 98 000 patients who had been entered into 138 trials. Class I agents were associated with an increased risk of death (51 trials; odds ratio, 1.14; 95% confidence interval, 1.01 to 1.28; P=.03). This was entirely consistent with the results of studies discussed above. Amiodarone, on the other hand, was associated with improved survival (8 trials; odds ratio, 0.71; 95% confidence interval, 0.51 to 0.97; P=.03). As would be expected, ß-blockers also improved survival.

A small study (368 patients) reported by Navarro-Lopez et al²⁴ examined postinfarction patients randomized to amiodarone, metoprolol, or no antiarrhythmic therapy. In this study, the amiodarone-treated patients showed no improvement compared with control subjects but had a significantly better survival than metoprolol-treated patients. This unexpected finding relative to metoprolol is probably related to chance in this small study.

The possibility that amiodarone might be more effective than conventional antiarrhythmic drugs was addressed in the Cardiac Arrest in Seattle: Conventional Antiarrhythmics Versus Amiodarone Drug Evaluation (CASCADE).²⁵ Survivors of out-of-hospital cardiac arrest unassociated with Q-wave myocardial infarction were randomized to empiric therapy with amiodarone or treatment with other antiarrhythmic drugs guided by EPS, Holter monitoring, or both (conventional therapy group). The primary study end points were cardiac mortality, resuscitated cardiac arrest due to documented ventricular fibrillation, or syncope followed by a shock from an ICD. Survival free of this end point was 53% in the amiodarone-treated group and 40% in the conventional antiarrhythmic group (P=.007). Rates of survival free of cardiac death or significant ventricular arrhythmias were also significantly better in the amiodarone-treated patients.

Participants in the Grupo de Estudio de la Sobrevida en la Insufficiena Cardiaca en Argentina (GESICA) trial examined the prophylactic use of amiodarone in SCD prevention in patients at risk because of the presence of heart failure.²⁶ This study randomized 516 patients with advanced heart failure to treatment with amiodarone and standard heart failure therapy or just standard heart failure therapy. At an average follow-up of 13 months, control group mortality was 41.4% compared with 33.5% in the amiodarone-treated patients (P=.02).

Amiodarone treatment of heart failure patients was also studied in the Survival Trial of Amiodarone in Patients with Congestive Heart Failure (CHF-STAT).²⁷ In this study, 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 PVCs/min, and left ventricular ejection fraction of 40% were randomly assigned to receive amiodarone or placebo. The primary end point of this study was total mortality, and the median follow-up was 45 months. No significant difference in mortality was seen between the two groups (P=.6).

The dramatic difference between this study and GESICA cannot be explained with absolute assurance. However, there were far more patients with coronary disease in CHF-STAT than in GESICA. That the difference in etiology of heart failure might be important in causing the different results of the two trials is supported by the fact that amiodarone-treated patients in CHF-STAT who had a nonischemic heart failure etiology had a strong trend toward improved survival (P=.07). These data also suggest that the etiology of arrhythmia may be an important factor in the effectiveness of amiodarone.

The European Myocardial Infarct Amiodarone Trial (EMIAT)²⁸ was designed to study the efficacy of amio-darone in reducing mortality in patients with decreased left ventricular function after myocardial infarction. Patients were enrolled 5 to 21 days after myocardial infarction if their left ventricular ejection fraction was 40% and randomized to treatment with amiodarone or placebo. This trial enrolled 1486 patients.²⁹ There was no difference in all-cause mortality, the primary end point of the study, or in cardiac mortality. Arrhythmic death was reduced from 7.0% in the placebo group to 4.0% in the amiodarone group (P=.05). Retrospective analysis of the data demonstrated a significant reduction in cardiac deaths in amiodarone-treated patients who were also treated with ß-blockers, suggesting that they confer an additional benefit beyond that of amiodarone alone. The failure of an improvement in arrhythmic death to translate into an improvement in cardiac or all-cause mortality may be related to the limited power of the study.

A similar study, the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), has been reported.^{30 31} In this study, 1202 patients with a history of myocardial infarction and frequent ventricular ectopy (10 PVCs/h or at least one episode of ventricular tachycardia) were randomized to receive treatment with amiodarone or with placebo.^{30 31} The primary outcome was the composite of resuscitated ventricular fibrillation or arrhythmic death. This primary outcome variable was reduced from 6.0% in the placebo group to 3.3% in the amiodarone group (P=.03). There was no difference in all-cause mortality. As in EMIAT, amiodarone-treated patients appeared to derive added benefit from treatment with ß-blockers.

On the basis of available studies, it appears that amiodarone reduces the mortality from SCD, at least in high-risk postinfarction patients and in some populations of heart failure patients, but an overall mortality benefit has not been demonstrated. An additional benefit may be conferred by ß-blocker treatment.

	Nonpharmacological Therapy

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
Defibrillators
In 1980, Mirowski et al³² were the first to implant an ICD. In patients with current devices in place, the annual SCD rate is 1% to 2%.^{32 33} Advanced systems offer tiered therapy of ventricular tachycardia, with competitive pacing, synchronized cardioversion, and defibrillation if necessary. Electrogram storage provides a retrievable record of the onset and termination of the arrhythmia.

With thoracotomy-based systems, the implant mortality was 3% to 5%, but current transvenously placed systems have implant mortality rates of <1%.^{33 34} These devices also provide backup antibradycardia pacing. Future systems may use electrical approaches to prevent ventricular arrhythmias.

The Multicenter Automatic Defibrillator Implantation Trial (MADIT) is the first randomized study to report a direct comparison between ICD and antiarrhythmic drugs.^{35 36} In MADIT, 196 patients at high risk for cardiac arrest but without prior cardiac arrest were randomized to ICD (11% were on class I antiarrhythmic agents) or antiarrhythmic drugs. These patients had a history of myocardial infarction, nonsustained ventricular tachycardia, ejection fraction of 35%, and sustained ventricular tachycardia induced at EPS that was not suppressed with procainamide. Patients were assigned to drug treatment (74% received amiodarone) or ICD placement. The trial was stopped before planned completion because of a highly significant reduction in mortality in the ICD group; there were 39 deaths (39%) in the antiarrhythmic drug treatment group and 11 (12%) in the ICD treatment group (P=.009).

The Antiarrhythmics Versus Implantable Defibrillators (AVID) study examined the relative effectiveness of the ICD and amiodarone in patients resuscitated from life-threatening ventricular tachyarrhythmias.³⁷ In this study, patients at risk for cardiac arrest because of a history of ventricular fibrillation or sustained ventricular tachycardia and low ejection fraction or sustained ventricular tachycardia and hemodynamic compromise were randomized to receive ICD implantation or initial drug therapy with either empiric amiodarone or sotalol (guided by Holter or EPS). The study goal was to randomize 1200 patients, with study completion scheduled for 1999. However, the study was stopped in April 1997 because of a statistically significant benefit of the ICD compared with drug therapy. AVID will have an important impact on medical practice because, given these results, the ICD will become the initial treatment for most patients who have a cardiac arrest. Because in-hospital drug trials and titration may no longer be needed for most patients, overall length of hospitalization for these patients may be substantially reduced. Amiodarone, if instituted after ICD implantation to reduce the number of defibrillator shocks, could be started in the outpatient setting.

Although these data suggest that at least in patients at high or moderate risk for SCD who fit the MADIT or AVID entry criteria the ICD is superior to amiodarone, the capacity of the ICD to affect overall mortality depends in part on the degree to which death is caused by a ventricular tachyarrhythmia in a particular population. The less the contribution, the less likely it will be that a benefit of the ICD can be demonstrated over amiodarone. As a result, the effect on total mortality of a reduction in SCD may be variable; therefore, additional studies are required in other at-risk populations.

	What Will Trials in Progress Add to the Current Knowledge?

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
The Canadian Implantable Defibrillator Study (CIDS) is similar to AVID and should provide complementary information.³⁸ Six hundred fifty patients with (1) documented ventricular fibrillation, (2) out-of-hospital cardiac arrest requiring defibrillation or cardioversion, (3) documented sustained ventricular tachycardia causing syncope, (4) documented sustained ventricular tachycardia at a rate of 150 bpm causing presyncope or angina in a patient with ejection fraction of 35%, or (5) syncope with subsequent documentation of spontaneous ventricular tachycardia of 10 seconds or sustained monomorphic ventricular tachycardia induced at EPS are randomized to receive treatment with amiodarone or ICD. The study will be completed by 1998.

The Coronary Artery Bypass Graft (CABG) Patch trial is studying primary prevention of cardiac arrest in patients at high risk because of the presence of coronary disease, ejection fraction of <36%, and abnormal signal-averaged ECG who are to receive bypass surgery.³⁹ Patients are randomized at the time of surgery to implantation of an ICD or no implantation. An interesting feature of this study is that inducible ischemia should not be a common trigger for a ventricular tachyarrhythmia in these patients because they are all revascularized at the time of randomization.

Another study that examines an at-risk population of particular importance because of its present and increasing size is the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Patients with class II and III heart failure will be randomized to receive placebo, amio-darone, or ICD implantation. The primary end point is total mortality, and the result of this study should define the role of antiarrhythmic prophylaxis in reducing total mortality as well as the relative effectiveness of amio-darone and the ICD. The study is just beginning.

The Multicenter Unsustained Tachycardia Trial (MUSTT)⁴⁰ randomized patients with coronary disease and nonsustained ventricular tachycardia who have sustained inducible ventricular tachycardia to a conservative approach of standard treatment of coronary disease versus an aggressive approach of EPS-guided therapy. Patients whose arrhythmia is suppressed with drugs or whose inducible ventricular tachycardia is rendered hemodynamically stable are treated with that drug; otherwise, an ICD is placed. This study is important because it will provide insight into the role of EPS in guiding therapy as well as the usefulness of the ICD in this population.

	Where Do We Stand in 1997?

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
The reported studies suggest that the ICD is highly effective in terminating malignant ventricular tachyarrhythmias. Conventional antiarrhythmic drugs offer no protection against and may even increase the risk of SCD. Preliminary data suggest that amiodarone may exert a protective effect. At least in some high-risk populations, the ICD is more effective than antiarrhythmic therapy (predominantly amiodarone) in preventing SCD. This conclusion, however, may not be applicable to all at-risk populations. The effect of SCD prevention by drug or device on total mortality will depend on the population studied (competing risks of death in each at-risk population) and is not currently understood. The critical importance of ongoing studies (CIDS, MUSTT, SCD-HeFT, CABG Patch) cannot be overemphasized, nor can the need for the cardiology community to support these studies. This knowledge should make it possible to define a strategy for the various at-risk populations that makes use of one or the other or the appropriate combination of the two.

	Future Directions

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 
Further progress depends on fundamental progress in several areas. Regarding ICD development, better sensing algorithms and sensors, smaller devices, improved lead systems, and other engineering improvements are likely to increase the safety and efficacy of these devices. Furthermore, improved telemetry capability will assist in the study of SCD.

Progress must be made in understanding the underlying substrates of fatal arrhythmias and the triggers that cause them to occur. Drugs currently available for antiarrhythmic treatment were brought into use through observations of their capacity to suppress ventricular ectopy rather than through any real understanding of the mechanism by which they might actually prevent a sudden fatal arrhythmia. To develop new drugs that specifically target the cellular and molecular mechanisms of arrhythmia genesis, these mechanisms must be much better understood. This will involve study of the structure-function relations of cell entities such as ion channels and understanding of the electrophysiolog-ical substrate of fatal arrhythmias and their mechanisms in the intact organism. A fuller understanding of the electrical events and activation pathways present in the at-risk myocardium and during ventricular tachyarrhythmias could lead to more effective catheter ablation strategies. Furthermore, elucidation of the genomic dysfunction that causes abnormality of structure and/or function could lead to the development of novel therapies. Such work would be materially benefited by the development of suitable animal models.

A number of factors exist that predict increased risk of a fatal arrhythmia, including reduced systolic function, coronary disease, hypertension, male sex, and ventricular arrhythmias.⁴¹ Furthermore, triggers such as ischemia, electrolyte imbalance, and sympathetic discharge can precipitate ventricular tachyarrhythmias in patients with the appropriate substrate.⁴² The mechanisms by which these risk factors and triggers result in ventricular tachyarrhythmias are not well defined. An understanding of these mechanisms might lead to new, specifically targeted therapy.

A series of clinical trials both completed and under way will elucidate the role of currently available therapeutic modalities. The next series of therapeutic advances will require a much improved understanding of fundamental arrhythmia mechanisms, and emphasis should be placed on the development of this understanding.

	References

Top Introduction Pharmacological Treatment Nonpharmacological Therapy What Will Trials in... Where Do We Stand... Future Directions References

 

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