Can Antiarrhythmic Drugs Survive Survival Trials?

Abstract

Sudden cardiac death due to arrhythmic events is the major cause of mortality among early post-myocardial infarction (MI) patients, accounting for >250,000 deaths annually in the United States alone. Antiarrhythmic drugs can be used in such patients as well as in those who have not had a recent MI but are at high risk for sudden cardiac death (e.g., those with ventricular tachycardia/fibrillation, or who have survived cardiac arrest). Most antiarrhythmic drugs available, however, have limitations arising from their toxic and proarrhythmic potential. Thus, research and development of new agents and treatment modalities are desirable. This article seeks to enumerate the lessons of past clinical trials with these agents and to provide guidelines for future trials. That a variety of antiarrhythmic drugs have been associated with an increased mortality has been a disturbing observation. It is therefore imperative that candidates for antiarrhythmic therapy be selected appropriately. We recommend that future clinical trials use stringent criteria for the identification of patients at “high risk” for arrhythmia or sudden cardiac death, and limit recruitment to such patients. Traditional markers, such as the increased frequency and complexity of ventricular premature beats, and low left ventricular ejection fraction, have not been successful in identifying these high-risk patients. However, decreased heart rate variability and cardiac late potentials recorded on a signal-averaged electrocardiogram appear to be more specific markers of post-MI arrhythmia or sudden cardiac death and may, in conjunction with the traditional markers, be used to improve selection of trial populations. Since the risk of sudden cardiac death diminishes with time after MI, it is also recommended that the temporal window of treatment with antiarrhythmic agents be limited to 1 year post-MI. It is also important to define clearly the endpoints of efficacy evaluations. A short-term reduction on markers like ventricular ectopic beats, for example, does not translate into a long-term decrease in arrhythmia-related mortality. Therefore, a reduction in overall mortality is the only meaningful endpoint to define the true risk–benefit ratio. To limit exposure to the potentially adverse effects of these agents, target populations for prophylactic antiarrhythmic drugs should be limited to recent post-MI patients at high risk for sudden cardiac death due to arrhythmia. Avoiding exposure of low-risk patients to antiarrhythmic drugs is equally imperative. “Low risk” of all-cause mortality includes the group of post-MI patients with a left ventricular ejection fraction >36%. Risk must be continuously evaluated in the setting of other pharmacologic (angiotensin-converting enzyme [ACE] inhibitors, aspirin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [“statins”], and others) and/or nonpharmacologic interventions (coronary artery bypass graft, angioplasty, implantable cardioverter/defibrillator). There is also a need to improve noninvasive techniques for identifying patients in the high-risk category—at present, the presence of ventricular premature beats and a left ventricular ejection fraction <36% is considered somewhat predictive of sudden cardiac death. Thus, patients with a recent MI and moderately low left ventricular ejection fraction (≤36% but not <20%) may be considered for antiarrhythmic therapy. A subset analysis of patients with low heart rate variability can provide valuable additional information. It is important to note that although all-cause mortality is a valid endpoint for such trials, stratification by specific cause of mortality is desirable.