Principal Findings:

This trial was unusual because its primary objective was to compare testing methods instead of treatments. This necessitated using a subset of the original randomized groups for sensible analysis of the clinical question. Nevertheless, the two groups appeared to be well balanced. The absence of a difference in outcome could be verified by several analyses. In addition, confidence intervals were narrow, indicating the high precision and reliability of the findings. However, the comparison of antiarrhythmic drugs is problematic because the trial was not designed to address this issue. There were differences in the distribution of clinical characteristics between the groups who received different antiarrhythmic drugs. Nevertheless, using both univariate analyses and a variety of adjustments for important prognostic variables, treatment with sotalol appeared to be a significant predictor of reduced arrhythmia recurrence, and sotalol was consistently associated with a trend for nearly a 50% reduction in sudden death and all-cause mortality as compared with the other drugs administered in the trial.

However, this study was not placebo-controlled, and amiodarone was not included as one of the antiarrhythmic drugs in the trial. Randomized comparative trials between sotalol and amiodarone are available, but the results are inconclusive mainly because of small sample sizes. Because of the specific pharmacokinetics of amiodarone, sotalol has become the first-line agent in the management of ventricular arrhythmias. Because this policy is based on expediency rather than follow-up data, the long-term efficacy, morbidity, and safety of sotalol should be compared with those of amiodarone as well as of nonpharmacological treatment modes for ventricular tachyarrhythmias, such as implantable cardioverter defibrillator therapy in prospective trials. Until these issues are resolved, it is incorrect to say that sotalol should be the first-line agent in the management of ventricular arrhythmias.

A repeat 24-hour Holter monitor, following the one that predicted drug efficacy, was available in 119 patients. Ninety-nine patients (83%) also had suppression that met efficacy criteria on the second Holter monitor. There were no significant differences in arrhythmia recurrence (p = 0.612) or mortality (p = 0.638) in patients with concordant Holter results (n = 99; 1-year arrhythmia recurrence = 45%; 1-year mortality = 10%) compared with those with discordant Holter results (n = 20; 1-year arrhythmia recurrence = 45%; 1-year mortality = 16%).

Although analysis of the large amount of ECG data collected is in progress, initial studies have provided information about unsustained ventricular tachycardia (VTu), heart period (R-R) variability, and the signal-averaged ECG. VTu has been reported to have prognostic implications in several disorders, but its clinical significance in patients with sustained ventricular tachyarrhythmias is unknown. The significance of VTu recorded in the baseline (antiarrhythmic drug-free) 48-hour ECG recording in ESVEM study patients was examined; no variable representing the presence of VTu, the frequency of VTu events, or the duration of the longest episode of VTu was a significant predictor of arrhythmia recurrence, arrhythmic death, or all-cause mortality, although a trend was present for worse all-cause mortality in patients with VTu.

R-R variability provides powerful prognostic information after acute myocardial infarction (AMI) and in patients with chronic ischemic heart disease. In general, R-R variability decreases dramatically at the time of AMI and recovers somewhat during the year after infarction. Although most patients in the ESVEM trial had chronic ischemic heart disease, R-R variability, which has been determined in about three fourths of the patients, was much lower than that reported in patients 1 year after MI. Instead, the mean values were closer to the more depressed values observed shortly after MI. This suggests a greater degree of autonomic dysfunction in patients with sustained ventricular tachyarrhythmias, frequent ventricular ectopic activity, and low ejection fractions, as compared with that for patients with chronic ischemic heart disease in general.

Signal-averaged ECGs have also been shown to predict arrhythmic events in patients with ischemic heart disease. In a subset of the ESVEM patients, antiarrhythmic drugs that block sodium channels were found to prolong the filtered, signal-averaged QRS duration, especially the late potential portion. This correlated with prolongation of the cycle length of induced ventricular tachycardia. Sotalol appeared to have a differential effect on the signal-averaged ECG; the signal-averaged QRS shortened slightly in patients in whom induction of VT was suppressed by sotalol, whereas it appeared to lengthen slightly in patients in whom VT remained inducible despite sotalol. This suggests that sotalol may affect conduction in diseased tissue in some patients, which may affect suppression of ventricular arrhythmia induction by programmed stimulation.

Trial analysis has yielded seven principal findings concerning treatment of patients with ventricular tachyarrhythmias: (1) similar accuracy of electrophysiologic study (EPS), Holter monitoring (HM), and EPS combined with HM for predicting antiarrhythmic drug efficacy; (2) greater efficiency and lower cost of HM; (3) improved survival associated with predicted drug efficacy; (4) predictors of response to EPS and HM; (5) greater efficacy and lower cost of therapy with sotalol compared with drugs with class-l sodium channel-blocking effects; (6) lack of a relationship between presenting and recurring arrhythmia; and (7) preponderance of nonarrhythmic deaths in trial participants. The original ESVEM HM criteria, new set 1 (reduction of total PVC’s by 70%, of pairs by 80%, and of all VT by 100%), and new set 2 (reduction of total PVC’s by 80%, of pairs by 90%, and of all VT by 100%) yielded predicted drug efficacy rates of 77%, 68%, and 58%, respectively; however, arrhythmia recurrence rates were unchanged. Similarly, arrhythmia recurrence rates for patients tested with triple versus less than triple extra stimuli (p=.238), more aggressive versus identical protocols (p=.955), and 0 to 5 vs 6 to 10 vs more than 10 induced beats (p=.263) or 0 vs 3 to 15 induced beats (p=.106) were unchanged. In the 215 (of 286) patients with coronary disease and not receiving beta blockers, there was still no difference in arrhythmia recurrence or mortality between the noninvasive and invasive limbs in ESVEM. Lastly, in patients with drug efficacy predictions by EPS testing, there was no difference in outcome in patients who had concordant versus discordant efficacy prediction by simultaneously obtained HMs. The use of more stringent testing methods and efficacy criteria would not have significantly improved the predictive accuracy of drug assessment by HM or EPS in the ESVEM trial. Additionally, excess noncoronary disease in EP-guided patients and excess beta-blocker used in HM-guided patients did not influence the results in the ESVEM trial.

At the time of the first drug trial, concordance of Holter and electrophysiological predictions of drug efficacy was observed in 46% of patients (both techniques predicted efficacy in 23%; neither predicted efficacy in 23%). Discordant results were observed in 54% (Holter suppression without electrophysiological suppression in 44%; electrophysiological suppression without Holter suppression in 10%). At the time of an electrophysiology study predicting drug efficacy, 68 of the 100 patients without inducible ventricular tachyarrhythmias also had suppression of spontaneous ventricular arrhythmias on the Holter recorded at the time of the electrophysiological study. Neither arrhythmia recurrence nor mortality was significantly different in patients with suppression of both inducible and spontaneous ventricular arrhythmias compared with those with only suppression of inducible arrhythmias. Comparison of patients with suppression of both inducible and spontaneous ventricular arrhythmias with the 188 patients in the Holter limb, in whom efficacy was predicted by Holter monitoring only, revealed no difference in outcome.

Of 1,102 episodes of spontaneous ventricular tachycardia, 73 (6.6%) were type 1 [events of ventricular tachycardia initiated by configurationally distinct, possibly triggering, complexes]; 1,012 (91.8%) were type 2 [events in which the initial QRS waveforms were identical to subsequent complexes, suggesting no requirement for premature ventricular beats]; and 17 (1.5%) were uncertain. Of 59 patients only 14 (24%) had only type 1 episodes (group 1), whereas 37 patients (63%) had predominantly type 2 events (group 2) (p< 0.0001). Sustained ventricular tachycardia was inducible in all group 1 patients, and in most (57%) the induced rhythm was similar to the spontaneous rhythm. Ventricular tachycardia could not be induced in 7 patients from group 2 (19%), and in 18 patients (49%) the induced and spontaneous rhythms were dissimilar. Recurrence of arrhythmia rates differed according to the guidance method in group 2.

In the electrophysiologic-study group, 108 of 242 patients (45 percent) received a prediction of efficacy, as compared with 188 of 244 patients (77 percent) in the Holter-monitoring group (P <0.001). Over a six-year follow-up period, there were 150 recurrences of arrhythmia and 46 deaths among the 296 patients receiving drugs predicted to be effective. Thirty-four of the deaths were from arrhythmic causes, and eight were from cardiac causes. There was no significant difference between the two study groups in the actuarial probabilities of these events. The risk of a recurrence of arrhythmia was significantly lower in patients who received sotalol than in those who received other antiarrhythmic drugs, and the risk was lower in those who had not previously failed to respond to antiarrhythmic drugs than in those who had.

In the electrophysiologic-study group, the percentage of patients who had predictions of drug efficacy was higher with sotalol (35 percent) than with the other drugs (16 percent, P< 0.001). There was no significant difference among the drugs in the Holter-monitoring group. The percentage of patients with adverse drug effects was lowest among those receiving sotalol. The actuarial probability of a recurrence of arrhythmia after a prediction of drug efficacy by either strategy was significantly lower for patients treated with sotalol than for patients treated with the other drugs (risk ratio, 0.43; 95 percent confidence interval, 0.29 to 0.62; P < 0.001). With sotalol, as compared with the other drugs combined, there were lower risks of death from any cause (risk ratio, 0.50; 95 percent confidence interval, 0.30 to 0.80; P = 0.004), death from cardiac causes, (0.50; P = 0.02), and death from arrhythmia (0.50; P = 0.04). The cumulative percentage of patients in whom a drug was predicted to be effective and in whom it remained effective and tolerated was higher for sotalol than for the other drugs (P < 0.001).