The Primary Prevention of Sudden Death in Patients with Coronary Artery Disease

Which Patients with Coronary Artery Disease Are Most Likely To Benefit from Primary Prevention of Cardiac Arrest?

The ideal risk factor is one that separates those persons destined to suffer cardiac arrest in the overall population (highly sensitive) from those who will not (highly specific). In addition, screening programs to detect these factors must be inexpensive and free from risk. Certain factors are consistently and independently associated with the highest risk for cardiac arrest. An ejection fraction of less than 0.40 is the single most important predictor of sudden cardiac death [1]. Frequent or complex ventricular ectopy, particularly after myocardial infarction, is also an important risk factor [6]. Figure 2 in the article by Myerburg and colleagues shows the interaction between ventricular ectopy and ejection fraction in generating increased risk in patients who have had a myocardial infarction. Despite the absence of definitive studies, programmed electrical stimulation (PES) of the heart to induce sustained ventricular tachycardia has been used both for risk stratification and for guidance of antiarrhythmic drug therapy. In most patients resuscitated from cardiac arrest in the absence of a new Q-wave myocardial infarction, a sustained ventricular tachycardia can be induced [7-9]. Suppression of inducibility by an antiarrhythmic drug regimen is possible in some patients, although reports vary substantially in what percentage can be suppressed [7-9]. Study results suggest that the risk for sudden cardiac death is less than 10% in the next year in the patients in whom inducibility of the arrhythmia is suppressed but that it remains substantially higher (approximately 30% during the next year) in those in whom it is not [7-9]. The risk for sudden cardiac death is also high in survivors of cardiac arrest who are not inducible into ventricular tachycardia before beginning antiarrhythmic therapy.

More recently, abnormalities of the signal-averaged electrocardiogram have been shown to be an independent risk factor for ventricular tachycardia [10, 11]. Signal-averaging refers to averaging depolarization signals over multiple cardiac cycles. With appropriate analysis, this process improves the signal-to-noise ratio of the electrocardiographic recording, permitting the detection of very-low-amplitude signals [12, 13]. Late ventricular potentials (defined as QRS complex > 114 ms, root-mean-square voltage during the last 40 ms of the filtered QRS complex < 20 microvolts, and duration of the filtered QRS complex > 38 ms after the voltage had decreased to < 40 microvolts) have been associated with an increased risk for sustained and inducible ventricular tachycardia in patients who have had a myocardial infarction. Farrel and colleagues [10] reported a relative risk of 2.21 (95% CI, 1.2 to 4.0) for sustained ventricular tachyarrhythmias or arrhythmic death in patients with a history of myocardial infarction. Consequently, the signal-averaged electrocardiogram has been used as a risk stratification tool.

Strategies of Primary Prevention of Cardiac Arrest

The identification of patients at risk for cardiac arrest, such as those with ventricular ectopy, is of little practical value in the absence of effective intervention. Because ventricular ectopy is a risk factor for cardiac arrest in patients with a history of myocardial infarction, it was believed that drugs that suppressed ventricular ectopy would prevent ventricular tachyarrhythmia-based cardiac arrest. The most frequently used drugs were the type I antiarrhythmics (quinidine, procainamide, disopyramide [type IA] and encainide, flecainide, moricizine [type IC]). The Cardiac Arrhythmia Suppression Trial (CAST) was designed to determine whether the type I agents could reduce the risk for sudden cardiac death in patients at high risk because of previous myocardial infarction and the presence of ventricular ectopy [14, 15]. Patients whose ectopy was suppressed by encainide, flecainide, or moricizine were randomly assigned to placebo or to drug treatment. The patients randomly assigned to active treatment experienced a 2.5-fold increase in mortality (encainide and flecainide) or no survival benefit (moricizine) compared with those randomly assigned to placebo. These results showed a dissociation between the ability of the type IC agents to suppress ventricular ectopy and their ability to prevent sudden cardiac death after acute myocardial infarction. The study also showed the inadequacy of ventricular ectopy suppression as a marker for prevention of sudden cardiac death.

The recently completed Conventional versus Amiodarone Drug Evaluation (CASCADE) study suggests that the CAST results may not be generalizable to other antiarrhythmic drugs [16]. In this secondary prevention trial, patients with out-of-hospital ventricular fibrillation not occurring during an acute Q-wave myocardial infarction were studied. Eighty-one percent of the CASCADE patients had coronary disease, and the mean left ventricular ejection fraction of the entire patient group was 0.35. Patients were randomly assigned to empiric treatment with amiodarone or to treatment with other antiarrhythmic drugs (including flecainide and moricizine, which were used in CAST, and eight other antiarrhythmic agents) guided by Holter monitoring or electrophysiologic study. Ventricular fibrillation, syncope-associated defibrillator discharge, and cardiac death were significantly less in the amiodarone-treated group (P < 0.007).

The Multicenter Unsustained Tachycardia Trial (MUSTT), with 53 enrolling centers, is examining a strategy for the prevention of cardiac arrest based on the ability of a drug to suppress PES induction of ventricular tachycardia. Patients at high risk for cardiac arrest because of a left ventricular ejection fraction less than 0.40, the presence of nonsustained ventricular tachycardia, and inducibility into sustained ventricular tachycardia by PES are being studied. Patients are randomly assigned to a conservative or to an interventional approach. In the interventional arm, patients receive drug therapy to try to suppress PES ventricular tachycardia induction; patients randomly assigned to the conservative arm do not. Patients whose ventricular tachycardia is suppressed or rendered hemodynamically stable are followed on the suppressing drug; those who are not receive an implantable defibrillator. The strategies being tested were based on current clinical practice when the trial began. Various antiarrhythmic drugs, including acebutolol, disopyramide, procainamide, propafenone, and sotalol, are being used. This study will provide insight into the usefulness of programmed stimulation to guide therapy to prevent cardiac arrest.

The limitations of pharmacologic therapy have led to widespread enthusiasm for the implantable cardioverter-defibrillator. Since its introduction in the 1980s, the technology of the implantable cardioverter-defibrillator has evolved rapidly, and the number of implants has steadily increased because of their effectiveness in aborting lethal ventricular tachyarrhythmias [17-20]. The sudden cardiac death rate is reported to be less than 2% per year when implantable cardioverter-defibrillators are used rather than the 30% discussed above. However, these reports describe outcome in patients with a variety of clinical presentations, including cardiac arrest, ventricular tachycardia, and syncope. Further, the perioperative mortality associated with placement of an implantable cardioverter-defibrillator has declined from about 5% with systems that require a thoracotomy for placement to less than 1% using nonthoracotomy-based lead systems (those in which the electrodes are not placed on the epicardial surface of the heart) [17-20]. In the future, devices will be introduced that use the battery casing as one electrode and an endocardial lead as the other (much like today's antibradycardia pacing systems), which will make them even easier and safer to implant.

The CABG Patch trial is investigating a strategy of primary prevention using the implantable cardioverter-defibrillator. Patients having coronary bypass surgery who are at increased risk for cardiac arrest because of a low ejection fraction (<0.35) and an abnormal signal-averaged electrocardiogram are randomly assigned to placement or no placement of an implantable cardioverter-defibrillator at the time of their operation. This study is especially interesting in that it is a truly placebo-controlled trial of the prevention of cardiac arrest by placement of an implantable cardioverter-defibrillator. Of particular importance is that both perioperative mortality and revascularization are controlled for because all patients receive a thoracotomy and coronary bypass.

The Multicenter Automatic Implantable Defibrillator Trial is another primary prevention study of patients at high risk for cardiac arrest. Inclusion criteria are the presence of a previous Q-wave myocardial infarction, nonsustained ventricular tachycardia, an ejection fraction of less than 0.35, and sustained ventricular tachycardia inducible by programmed stimulation (when the inducibility cannot be suppressed by procainamide). Patients are randomly assigned to defibrillator placement or to conventional pharmacologic therapy. The primary end point is total mortality.

Whereas the implantable cardioverter-defibrillator holds great promise for preventing total mortality, its effect will be mitigated to some degree by progression of the underlying disease, occasional failure of the device to revert lethal arrhythmias, and that not all sudden death results from ventricular tachyarrhythmias. The study of primary prevention of cardiac arrest is still in its initial phase. Research should now be directed toward more effective, cost-efficient identification of at-risk patients in the total population. Research on safer and more effective antiarrhythmic drugs is also important as is the continuing improvement in safety and effectiveness of the implantable cardioverter-defibrillator. Clinical trials to define optimal screening and treatment strategies will continue to be central to the overall effort. The success of these studies depends on the referral of high-risk patients from practicing internists.