Debra S. Echt

Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.

BACKGROUND AND METHODS In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. RESULTS Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs. 5 receiving placebo). Almost all cardiac deaths not due to arrhythmia were attributed to acute myocardial infarction with shock (11 patients receiving drug and 3 receiving placebo) or to chronic congestive heart failure (4 receiving drug and 2 receiving placebo). There were no differences between the patients receiving active drug and those receiving placebo in the incidence of nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a permanent pacemaker, congestive heart failure, recurrent myocardial infarction, angina, or need for coronary-artery bypass grafting or angioplasty. CONCLUSIONS There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

Clinical experience, complications, and survival in 70 patients with the automatic implantable cardioverter/defibrillator.

Seventy patients received the automatic implantable defibrillator, five original devices and 72 modified second-generation devices using only bipolar rate sensing and delivering an R wave synchronous cardioverting/defibrillating shock, for either ventricular tachycardia or fibrillation. The primary clinical arrhythmia was sustained ventricular tachycardia in 32 patients, ventricular fibrillation in 20 patients, and both ventricular tachycardia and fibrillation in 18 patients. Before implantation of the device the patients had survived 3.1 +/- 2.3 arrhythmic episodes, including 1.9 +/- 1.7 cardiac arrest, and had received 4.0 +/- 2.1 antiarrhythmic drugs without improvement. Sixty-eight patients ultimately received devices. After a follow-up period of 8.9 +/- 7.7 months (range 1 to 33), 37 patients received a total of 463 discharges. Inability to determine the precise reason for most discharges and the unpleasant nature of the discharges were the major clinical problems encountered. Complications included postoperative death (one patient), lead problems (six patients), inadequate energy requiring explanation (two patients), and pocket infection (one patient. Life-table analysis revealed 6 and 12 month cardiovascular survival of 95.0% and 89.9% and sudden death survival of 98.2%. In our experience, survival with the automatic implantable cardioverter/defibrillator exceeds that with other forms of therapy.

Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (The Cardiac Arrhythmia Pilot Study)

The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. CAPS tested the feasibility of performing a larger study to determine if suppression of ventricular ectopic activity after acute myocardial infarction could improve survival. Patients in CAPS were followed for 1 year. All death or cardiac arrest events were evaluated by at least 2 investigators using a classification scheme that characterized the underlying mechanism as cardiac arrhythmic, cardiac nonarrhythmic or noncardiac. Forty-five patients (9%) died or had cardiac arrest during the 1-year follow-up, 29 (64%) within 1 hour from the onset of symptoms and 16 greater than 1 hour from the onset of symptoms. Twenty-three deaths (51%) were classified as arrhythmic, 19 (42%) as nonarrhythmic and 3 (7%) as noncardiac. Acute myocardial ischemia or infarction was associated with the death/cardiac arrest event in 16 patients (36%), 8 in the arrhythmic death group. Discrepancies in classification among reviewers were particularly common in patients with long-standing symptoms of congestive heart failure, in whom it was frequently difficult to identify the precise moment of the onset of symptoms in the death/cardiac arrest event. Using only the temporal relation of symptoms to categorize deaths or cardiac arrests, the mechanism of 12 (27%) of the 45 patients was in disagreement with the classification based on the Events Committee review. Classification of death as sudden or nonsudden is not equivalent to the classification of death as arrhythmic or nonarrhythmic.

Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs. Sodium channel block and action potential prolongation.

Antiarrhythmic drugs have been reported to produce variable effects on defibrillation energy requirements. However, the relation between the in vitro electrophysiologic effects of these agents and the changes in defibrillation energy requirements have not been systematically examined. Therefore, we evaluated the effects of the sodium channel blocking drugs lidocaine and procainamide, the action potential prolonging drugs N-acetyl procainamide and clofilium, and the potassium current blocker cesium in acute canine models with the same internal spring and epicardial patch electrodes used in humans for ventricular defibrillation testing. Ten series of experiments were performed in 78 dogs. Nonlinear regression was used to derive curves of energy dose versus percent successful defibrillation attempts and the 50% and 90% effective energy dose for each experimental condition. Saline control experiments indicated that the preparation was stable throughout the 6-hour duration of the experiments. Lidocaine doubled the defibrillation energy requirement (p less than 0.001) at a mean plasma concentration of 8.2 micrograms/ml. The effect of lidocaine on defibrillation energy was reversible, present at therapeutic plasma concentrations, linearly related to plasma concentration (r = 0.69, p less than 0.002), and present even after only 5-second episodes of ventricular fibrillation. In contrast, procainamide had no effect on defibrillation energy at mean plasma concentrations of 8.5 and 13 micrograms/ml, even after prolonged (30-second) episodes of ventricular fibrillation, whereas N-acetyl procainamide, clofilium, and cesium all decreased the energy requirement for defibrillation by 13-27%. Moreover, with the addition of N-acetyl procainamide, there was a trend toward diminishing the increase in defibrillation energy requirement caused by lidocaine. All agents prolonged the mean ventricular fibrillation cycle length. Lidocaine shortened the QT interval, whereas all other agents increased the QT (p less than 0.05). The major electrophysiologic effect of lidocaine is of sodium channel blockade, whereas, N-acetyl procainamide, clofilium, and cesium predominantly increase the action potential duration, and procainamide exerts both effects. Thus, these data indicate that sodium channel block and action potential prolongation exert significant and antagonistic modulating effects on defibrillation energy requirements.

Comparison of monophasic and biphasic defibrillating pulse waveforms for transthoracic cardioversion

All transthoracic defibrillators on the US market use nominally monophasic shock waveforms. However, biphasic waveforms have a lower defibrillation threshold than monophasic waveforms for transthoracic defibrillation of animals and for defibrillation of humans by implantable cardioverter defibrillators. The relative efficacies of Edmark monophasic and Gurvich biphasic transthoracic cardioversion waveforms (200 J into 50 omega) were compared for transthoracic cardioversion in 171 patients undergoing electrophysiologic study for evaluation of ventricular arrhythmias. Patients were randomized in a blinded fashion to receive either a monophasic or a biphasic waveform for the initial shock for conversion of induced ventricular arrhythmias (ventricular fibrillation [VF] = 53, monomorphic ventricular tachycardia [VT] = 80, polymorphic VT = 30, ventricular flutter = 8). Delivered energies for the Edmark and Gurvich waveforms were 215 +/- 11 and 171 +/- 11 J, respectively. There were no significant differences in patient characteristics, use of antiarrhythmic agents, arrhythmia cycle length, or duration of arrhythmia prior to shock for monophasic and biphasic waveform groups. The first shock for all arrhythmias was successful in 75 of 88 patients (85.2%) for the monophasic waveform compared with 81 of 83 patients (97.6%) for the biphasic waveform, p = 0.0054. The first shock for VF was successful in 22 of 28 patients (78.6%) for the monophasic waveform compared with 25 of 25 (100%) for the biphasic waveform, p = 0.0241. The Gurvich biphasic waveforms delivering a mean of 171 J were superior to Edmark monophasic waveforms delivering a mean of 215 J for transthoracic cardioversion of arrhythmias of short duration. This finding may have important implications for the development of future transthoracic defibrillators.

Prolongation of the human cardiac monophasic action potential by sotalol

Sotalol and propranolol are nonselective beta-adrenergic blocking agents. Sotalol at low concentration, unlike propranolol, prolongs the duration of the transmembrane action potential. In a double-blind study, the electrophysiologic effects of intravenous sotalol (0.30 or 0.60 mg/kg; n = 9) were compared with intravenous propranolol (0.15 or 0.20 mg/kg; n = 8) in 17 patients with use of bipolar suction electrodes in the right atrium and right ventricle to determine whether sotalol prolongs the monophasic action potential duration in man. After administration of sotalol, there were significant increases (paired t test) in the Q-T interval (p less than 0.001), right atrial effective refractory period (p less than 0.05), right ventricular effective refractory period (p less than 0.005), right atrial monophasic action potential duration at 90% repolarization (p less than 0.01), and right ventricular monophasic action potential duration at 90% repolarization (p less than 0.005). Prolongation of the monophasic action potential duration was dependent on plasma sotalol concentration. There were no significant changes in these variables after propranolol. The spontaneous cycle length and Wenckebach cycle length increased significantly in both groups, and the mean blood pressure decreased in both, although not significantly after propranolol. In summary, sotalol but not propranolol prolonged atrial and ventricular effective refractory periods and lengthened the monophasic action potential and the Q-T interval of human myocardium after intravenous infusion. The ability to acutely prolong repolarization at therapeutic plasma concentration is unique among known competitive beta-adrenergic receptor antagonists.

Measurement of cardioversion/defibrillation thresholds in man by a truncated exponential waveform and an apical patch-superior vena caval spring electrode configuration.

Defibrillation/cardioversion thresholds were measured in 33 patients undergoing defibrillator implants. Each patient had a 12 cm2 patch placed near the left ventricular apex via a thoracotomy and a 10 cm2 spring lead placed pervenously at the right atrial-superior vena caval junction. Ventricular tachycardia of stable morphology, polymorphic ventricular tachycardia, or ventricular fibrillation was induced four times in each patient and 1, 5, 10, and 25 J truncated exponential shocks with 60% tilt were given in a random sequence. The conversion rate was constant (77%, 86%, 87%, 85%) with increasing energy for ventricular tachycardia but progressively increased for polymorphic ventricular tachycardia and ventricular fibrillation (8%, 33%, 58%, 92%). The ventricular tachycardia acceleration rates for 1, 5, 10, and 25 J were 23%, 14%, 10%, and 15%. Patients not reliably converted with 25 J may require repositioning of leads or two patches. We conclude that for the spring-patch electrodes, increasing energy from 1 to 25 J improves the conversion rate for polymorphic ventricular tachycardia and ventricular fibrillation; the ventricular tachycardia conversion rate is constant. Acceleration of ventricular tachycardia occurs at all energies. Defibrillator implantation requires extensive intraoperative electrophysiologic testing to ensure safe and reliable termination of ventricular tachycardia and fibrillation.

The automatic implantable defibrillator: local ventricular bipolar sensing to detect ventricular tachycardia and fibrillation.

The first-generation automatic implantable defibrillator implanted in man sensed arrhythmias by monitoring a transcardiac electrocardiographic signal. This sensing system reliably detected ventricular fibrillation and sinusoidal ventricular tachycardia but failed to sense all nonsinusoidal ventricular tachycardias. To solve this problem, a new ventricular tachycardia detection scheme was developed using a local ventricular bipolar electrogram and electronic circuits using rate averaging and automatic gain control to permit sensing of electrograms down to 0.1 mV. This detection scheme was tested during electrophysiologic studies in 11 patients with ventricular tachycardia and fibrillation. All 22 episodes of induced ventricular tachycardia with a rate above the selected cutoff were detected after an average of 5.1 +/- 1.8 seconds. No episodes below the rate cutoff were detected. The bipolar circuits also reliably detected ventricular fibrillation. Arrhythmia detection and signal quality in 9 patients receiving automatic defibrillators using the new bipolar rate detection circuit were compared with the findings in 5 patients previously receiving units that sensed arrhythmias using the transcardiac electrocardiographic signal. Compared with the transcardiac monitoring units the newer bipolar units had shorter and more uniform sense times (5.5 +/- 1.4 versus 12.2 +/- 7.1 seconds). It is concluded that malignant ventricular tachyarrhythmias can be sensed accurately using bipolar rate detection and that this system has numerous advantages over the previously used transcardiac electrocardiographic signal.

Clinical factors predicting successful electrophysiologic-pharmacologic study in patients with ventricular tachycardia

Data from 142 patients who had sustained ventricular tachycardia or ventricular fibrillation were analyzed to determine if clinical variables predict response to antiarrhythmic drugs at electrophysiologic study. Effective antiarrhythmic drugs were identified for 43 patients (30%). Ten of 25 variables analyzed were univariate predictors of drug response at the probability (p) level of less than 0.05. Stepwise logistic regression identified three variables independently predictive of drug response: fewer coronary arteries with 70% or greater stenosis (p less than 0.001), female sex (p less than 0.002) and fewer episodes of arrhythmia (p less than 0.03). A function incorporating these three variables was constructed to predict the probability of drug response, and ranges of the predictor function corresponding to high, intermediate and low probabilities of drug response were identified. Response rates in the high (greater than 50%), intermediate and low (less than 10%) probability ranges were 28 (58%) of 48, 10 (27%) of 37 and 5 (9%) of 57, respectively. Thus 40% of the patients who had a less than 10% likelihood of benefit from electrophysiologic-pharmacologic study were classified into the low probability range. When the predictor function was applied prospectively to 25 additional patients, response rates in the three probability ranges were 3 (50%) of 6, 1 (12%) of 8 and 0 (0%) of 11. These data show that analysis of clinical variables can be used to estimate the probability of benefit from electrophysiologic-pharmacologic study.

Finite element analysis of cardiac defibrillation current distributions

A two-dimensional finite element model of the canine heart and thorax developed to examine different aspects of the distribution of current through cardiac tissue during defibrillation is discussed. This model allows comparison of the various electrode configurations for the implantable cardioverter/defibrillator. Since the electrical criteria for predicting defibrillation thresholds are not known, defibrillation energy in dogs was measured to determine the voltages to apply to the model for calculating current distribution. Analyzing isopotential contours, current lines, power distributions, current lines, power distributions, current density histograms, and cumulative current distributions allowed the critical fraction and threshold current density for defibrillation to be estimated, various electrode configurations to be compared, and the sensitivity of the defibrillation threshold to electrode position, patch size, and tissue conductivity to be assessed. It was found that blood can shunt defibrillation current away from the myocardium, that myocardial tissue conductivity strongly affects the current distributions, and that epicardial patch size is more important than subcutaneous patch size.<<ETX>>