Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group

The potential for proarrhythmic responses to the class IC sodium channel-blocking drugs encainide and flecainide has not been well described in young patients. Therefore, data were retrospectively collected from 36 institutions regarding 579 young patients who were administered encainide or flecainide for treatment of supraventricular tachycardias (encainide 86 patients, flecainide 369 patients) or ventricular arrhythmias (encainide 21 patients, flecainide 103 patients) to assess the frequency of proarrhythmia, cardiac arrest and death during therapy (adverse events). The two drugs were similar in regard to efficacy (flecainide 71.4%, encainide 59.8%) and rate of proarrhythmic responses (flecainide 7.4%; encainide 7.5%). However, patients receiving encainide more frequently experienced cardiac arrest (encainide 7.5% vs. flecainide 2.3%, p less than 0.05) or died during treatment (encainide 7.5% vs. flecainide 2.1%, p less than 0.05). Detailed data were provided for 44 patients experiencing one or more adverse events. Patient age, previous drug trials, concomitant therapy and days of inpatient monitoring were similar for patients receiving encainide or flecainide. However, echocardiographic left ventricular shortening before treatment was lower among patients receiving encainide (0.23 +/- 0.09) than among those receiving flecainide (0.34 +/- 0.06, p less than 0.05). Plasma drug concentrations were rarely elevated. Cardiac arrest (12 patients) and deaths (13 patients) occurred predominantly among patients with underlying heart disease, particularly among patients receiving flecainide for supraventricular tachycardia (8.3% vs. 0.3%, p less than 0.001). Fifteen patients with an ostensibly normal heart and normal ventricular function experienced proarrhythmia during treatment for supraventricular tachycardia, but only 3 of the 15 had a cardiac arrest or died. The relatively high incidence of adverse events should be considered when contemplating treatment with encainide or flecainide, particularly among patients with underlying heart disease.     

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in the entire population enrolled

To test the hypothesis that suppression of ventricular arrhythmias by antiarrhythmic drugs after myocardial infarction improves survival, the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. Suppression was evaluated before randomization during an open label titration period. Patients whose arrhythmias were suppressed were randomized in the main study and those whose arrhythmias were partially suppressed were randomized in a substudy. Overall survival and survival free of arrhythmic death or cardiac arrest were lower [corrected] in patients treated with encainide or flecainide than in patients treated with placebo. However, the death rate in patients randomized to placebo therapy was lower than expected. This report describes the survival experience of all patients enrolled in CAST and compares it with mortality in other studies of patients with ventricular arrhythmias after myocardial infarction. As of April 18, 1989, 2,371 patients had enrolled in CAST and entered prerandomization, open label titration: 1,913 (81%) were randomized to double-blind, placebo-controlled therapy (1,775 patients whose arrhythmias were suppressed and 138 patients whose arrhythmias were partially suppressed during open label titration); and 458 patients (19%) were not randomized because they were still in titration, had died during titration or had withdrawn. Including all patients who enrolled in CAST, the actuarial (Kaplan-Meier) estimate of 1-year mortality was 10.3%. To estimate the "natural" mortality rate of patients enrolled in CAST, an analysis was done that adjusted for deaths that might be attributable to encainide or flecainide treatment either during prerandomization, open label drug titration or after randomization. Because the censoring procedure excluded patients treated with encainide or flecainide after randomization, the mortality estimate will be less than the unadjusted mortality estimate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.

The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.     

Clinical aspects of trial design: What can we expect from the cardiac arrhythmia suppression trial?

Summary The controlled clinical trial, i.e., a prospective study that compares the effect of one or more interventions against a control in human subjects, is the most definitive method to determine the benefit/risk ratio for a treatment. Some of the elements are a clear statement of the primary and secondary hypotheses, carefully defined end points, randomization, double blinding, and concomitant controls for the experimental treatment using either placebo or standard treatment. Randomization tends to produce study groups that are comparable with respect to both known and unknown factors that influence the outcome, and also removes bias in the assignment of subjects to treatments to ensure that statistical hypothesis testing will have valid significance levels. An adequate sample size is critically important for a successful trial.The Cardiac Arrhythmia Suppression Trial (CAST) is a randomized, placebo-controlled, double-blind, international, multicenter clinical trial to determine whether suppression of ventricular arrhythmias after myocardial infarction with long-term antiarrhythmic drug treatment will reduce arrhythmic death. Survivors of myocardial infarction who are <80 years of age and have six ventricular premature depolarizations (VPD) per hour on a 24-hour continuous ECG recording obtained between 6 days and 2 years after myocardial infarction are eligible for CAST. A sample size of 4400 patients was calculated for the main study using the following assumptions: average follow-up of 3 years, arrhythmic death or cardiac arrest has a 3-year incidence of 11% in the placebo group, suppression of ventricular arrhythmias with antiarrhythmic drugs will reduce sudden death by 30%, type I () error=0.025 (one tail), power (1–)=0.85, a drop-in rate of 6%, and a drop-out rate of 30%. The primary end point for CAST is arrhythmic death or cardiac arrest. On April 17, 1989, the CAST Data and Safety Monitoring Board recommended that encainide and flecainide be removed from CAST because of strong evidence that these drugs increased the death rate compared to placebo. The 730 patients randomized to encainide or flecainide and the 725 randomized to a corresponding placebo were followed an average of about 300 days. There were 78 deaths or cardiac arrests. Patients taking encainide or flecainide were 3.6 times as likely to experience arrhythmic death or nonfatal cardiac arrest as those treated with placebo. There were no imbalances between the encainide/flecainide group and the placebo group with respect to baseline risk variables that might confound the apparent adverse treatment effect. The increase in the death rate for patients treated with encainide or flecainide was observed consistently in the various subgroups within the study. The relative risk of dying or experiencing a nonfatal cardiac arrest was almost identical for the two drugs (2.3 for encainide and 2.7 for flecainide). The CAST finding clearly indicates that marked suppression of ventricular arrhythmias after myocardial infarction by encainide or flecainide does not predict improved survival. CAST continues to enroll patients and to randomize them to moricizine or placebo.     

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.     

Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo-treated patients

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events). On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction. The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.     

Comparisons of efficacy and tolerance of moricizine with other antiarrhythmic agents in the treatment of chronic ventricular arrhythmias

Comparative trials of a new drug with standard antiarrhythmic agents are important for establishing relative efficacy and tolerance. For moricizine, such trials have included comparisons with propranolol, disopyramide and quinidine. Furthermore, the Cardiac Arrhythmia Pilot Study compared moricizine in postinfarction patients with encainide and flecainide. These trials show moricizine to be superior in efficacy to a beta blocker (propranolol) and disopyramide and equivalent to quinidine. Although the class IC drugs (encainide and flecainide) showed somewhat greater efficacy in the Cardiac Arrhythmic Pilot Study, they are now known to increase the risk of mortality in postinfarction patients. Moricizine was also shown to be well tolerated in these trials and associated with fewer discontinuations than propranolol, disopyramide and quinidine. Thus, moricizine is a promising new agent when profiled against other drugs frequently used for therapy of chronic ventricular arrhythmias.     

Prevalence, characteristics and significance of ventricular premature complexes and ventricular tachycardia detected by 24-hour continuous electrocardiographic recording in the Cardiac Arrhythmia Suppression Trial. CAST Investigators.

The prevalence, characteristics and significance of ventricular arrhythmias detected by ambulatory electrocardiography were evaluated in 1,498 patients who were randomized to encainide, flecainide or placebo in the Cardiac Arrhythmia Suppression Trial. The mean ventricular premature complex (VPC) frequency at baseline was 133 +/- 257 VPCs/hour. Nonsustained ventricular tachycardia (VT) (rate greater than or equal to 120 beats/min) was present in 22% of patients. Accelerated idioventricular rhythm (rate less than 120 beats/min) occurred in 22% of subjects. There were 63 deaths/resuscitated cardiac arrests in the active treatment (encainide/flecainide) group and 26 in the placebo group. In the treatment group mortality increased with increasing VPC frequency, (p = 0.006), whereas in the placebo group such a relation was not present. Mortality/resuscitated cardiac arrest increased in patients with greater than or equal to 2 VT episodes than in those with less than or equal to 1 episode in the active treatment group (p = 0.04). There was no significant association between VT and mortality/resuscitated cardiac arrest in the placebo group. The presence of accelerated idioventricular rhythm was not associated with increased mortality/resuscitated cardiac arrest in either the active treatment or placebo groups. However, mortality was lower in patients with accelerated idioventricular rhythm rates less than 100 beats/min than in those with rates greater than or equal to 100 beats/min (p = 0.05). Thus, in the Cardiac Arrhythmia Suppression Trial the previously described association between mortality/resuscitated cardiac arrest and ventricular arrhythmias (VPC and VT) were only observed in the active treatment group. In addition, based on the results obtained in this highly selected population, it is suggested that the definition of accelerated idioventricular rhythm should be a rate less than 100 beats/min, and at a rate greater than or equal to 100 beats/min it should be categorized as VT.     

Encainide—An updated safety profile

The safety of encainide has been evaluated using retrospective analyses of the Bristol-Myers Supraventricular and Ventricular Arrhythmias data base and of the Post-Marketing Adverse Experience Report data and prospective analyses of the Cardiac Arrhythmia Suppression Trial (CAST), the Cardiac Arrhythmia Pilot Study (CAPS), and the Ventricular Tachycardia/Heart Disease and Boston studies. CAST, a randomized, placebo-controlled study in patients with a history of myocardial infarction with asymptomatic or minimally symptomatic ventricular arrhythmias, showed that sudden death or nonfatal cardiac arrest occurred more frequently on encainide (24/418, 5.7%) than on placebo (7/416, 1.7%). The highest sudden death/cardiac arrest rates were found in patients with a left ventricular ejection fraction of less than 0.30, those with a ventricular premature beat count of more than 50/hr and those with a myocardial infarction of more than 90 days. Similar sudden death/cardiac arrest rates were seen in the flecainide-treated group of the study but not in the moricizine-treated group. A retrospective analysis of the data collected from a similar cohort of patients in the Bristol-Myers data base showed a 1-year cumulative incidence of 10.2% in patients with a history of myocardial infarction. A retrospective analysis of mortality data in patients with supraventricular arrhythmias (301 patients) showed this to be slightly lower than in a matched sample of the general U.S. population. The sudden death mortality in the Ventricular Tachycardia/Heart Disease and Boston studies were similar to those reported with other antiarrhythmic agents. Abnormal laboratory findings caused four patients to be discontinued prematurely, but there have been no reported cases of any blood dyscrasias. Thus, there are currently no data showing that patients with symptomatic reentry supraventricular and life-threatening ventricular arrhythmias are at increased risk with encainide therapy. Encainide should be reserved for those patients who are refractory or intolerant to other antiarrhythmic agents. Encainide is not indicated in patients with symptomatic ventricular arrhythmias and structural heart disease. In patients without structural heart disease and symptomatic ventricular arrhythmias, the benefit and risks of encainide therapy should be carefully considered before it is prescribed.     

The Cardiac Arrhythmia Suppression Trial: background, interim results and implications

The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular premature complexes (VPCs) in survivors of acute myocardial infarction would reduce arrhythmic death risk. Instead, a preliminary finding from the CAST was that the encainide and flecainide groups had a 3.6-fold increase in arrhythmic death compared with their placebo group. These unfortunate results were especially surprising in that the CAST population represented patients in whom the risk of arrhythmic death was only moderate and the risk of proarrhythmia was thought to be low. In contrast, the arrhythmic death rate of the CAST placebo group was unusually low, to the extent that it paralleled the arrhythmic death rate in previous clinical trials of patients surviving myocardial infarction with no ventricular arrhythmia. The excessive arrhythmic death rate in patients taking encainide and flecainide occurred over the duration of the CAST, implying a proarrhythmic effect that may be due to mechanisms that are unique in this population, and thus challenging traditional concepts of proarrhythmia. The existing knowledge regarding the proarrhythmic and negative inotropic effects of encainide and flecainide are reviewed. The previous pharmaceutical database experience with these 2 antiarrhythmic drugs exceeded 3,000 patients; however, there was no indication of this serious proarrhythmic effect. In contrast, the CAST population taking encainide and flecainide totaled only 725 patients who were followed for 10 months and had an extremely high proarrhythmic event rate. The reasons for this discrepancy are discussed. The results of the CAST emphasize the power of a randomized, placebo-controlled clinical trial to uncover previously unsuspected benefits or liabilities of traditional therapies.     

Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group

Paroxysmal atrial fibrillation (PAF) is a problematic clinical arrhythmia that is usually symptomatic. Unfortunately, few adequate trials and trial methods are available for assessment of the value of therapy, and traditional treatment has often been ineffective or associated with unacceptable side effects. Transtelephonic monitoring is a new method that allows evaluation of paroxysmal arrhythmias and arrhythmia-related symptoms in outpatients. We used a patient-initiated transtelephonic monitor system to evaluate the potential of flecainide, a class 1C antiarrhythmic, in prevention of symptomatic recurrences of PAF. Sixty-four patients qualified for the study (two or more PAF attacks documented within a 4-week baseline period) and entered a dose-finding phase to determine drug tolerance. Dose was incremented at weekly intervals from 200-300 and finally to 400 mg/day. The largest dose that was well tolerated was selected for the 4-month, double-blind, randomized, crossover comparison with placebo. Fifty-five patients entered and 53 received both treatments in the double-blind phase; 48 of these patients without protocol violations were evaluable for efficacy comparisons. Evaluable patients had undergone an average of 3.8 previous drug trials (range, 1-8); 30 were men, 18 had hypertension, and 14 had ischemic heart disease. The study demonstrated a highly significant correlation (p less than 0.0001) between perceived symptoms and documented PAF by transtelephonic monitoring. The rate of symptoms and PAF attacks was also significantly reduced by therapy (median dose, 300 mg/day). The first PAF attack occurred after a median of 3 days on placebo versus 14.5 days on flecainide (p less than 0.001) therapy. Similarly, the time interval between attacks was lengthened, from a median of 6.2 days on placebo to 27.0 days on flecainide (p less than 0.001) therapy. PAF was prevented in 15 patients (31%) during flecainide and four (9%) during placebo therapy (p = 0.013). However, during the study, 13 patients dropped out, seven because of adverse effects (five cardiac), five for other reasons, and one because of cardiac arrest/death. Adverse cardiac events occurred in a total of seven patients (11%) during flecainide therapy. Thus, transtelephonic monitoring is a useful method for documentation of the occurrence of paroxysmal arrhythmias such as PAF and its related symptoms during daily living and for assessment of new therapies in an outpatient setting.     

Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. The Flecainide Supraventricular Tachycardia Study Group

Oral flecainide acetate was administered to 34 patients with documented symptomatic paroxysmal supraventricular tachycardia (PSVT) with a double-blind, placebo-controlled, 8-week crossover trial design. PSVT was defined as a regular tachycardia of at least 120 beats/min without evidence of atrioventricular dissociation. The study required considerable patient cooperation. Patients first entered a 4-week qualifying phase followed by a 3-week, open label, flecainide dose-ranging phase. They were then randomized in a blind fashion to receive either placebo or tolerated flecainide dose for an 8-week treatment period and then crossed over after four symptomatic documented episodes of PSVT or at the end of the treatment period. By all efficacy parameters analyzed, flecainide was superior to placebo. Flecainide was associated with an actuarial 79% freedom from symptomatic PSVT events compared with only 15% on placebo at 60 days (p less than 0.001). Of the 34 patients, 29 had recurrence of symptomatic PSVT at least once during the placebo phase; only eight patients had a recurrence during the flecainide phase (p less than 0.001). The median time to the first symptomatic PSVT event was 11 days in the placebo group and greater than 55 days in the flecainide group (p less than 0.001). Likewise, the interval between attacks was a median of 12 days on placebo compared with more than 55 days on flecainide (p less than 0.001). Finally, the flecainide slowed symptomatic PSVT heart rates to 143 +/- 12 beats/min from 178 +/- 12 on placebo (p less than 0.02) in the seven patients who had events in the placebo and flecainide treatment phases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Congestive heart failure after acute myocardial infarction in patients receiving antiarrhythmic agents for ventricular premature complexes (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 an ejection fraction greater than 0.20 and at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. Patients were followed for 1 year and the incidence of new or worsened congestive heart failure (CHF) was evaluated. Heart failure in the 1-year follow-up was gauged by the development (in order of increasing severity) of new symptoms (grade 1), the need for a change in therapy, including addition of digitalis, addition or increase of dose of diuretics or afterload reduction agents or discontinuation of beta-blocking agents (grade 2), or by hospitalization (grade 3). Sixty-one of 502 patients (12%) required hospitalization for CHF in the 1-year follow-up. One hundred five of 403 patients (26%) in the active treatment group and 18 of 99 patients (18%) in the placebo group (difference not significant) developed CHF requiring hospitalization or a change in therapy or both. Although patients with severely impaired ejection fraction were excluded, new or worsened CHF was common in follow-up during CAPS.     

Effects of advancing age on the efficacy and side effects of antiarrhythmic drugs in post-myocardial infarction patients with ventricular arrhythmias. The CAST Investigators.

OBJECTIVE: To determine the effect of age on the response to anti-arrhythmic drugs. DESIGN: Randomized controlled trial comparing particular drugs. SETTING: Multi-institutional (The Cardiac Arrhythmia Suppression Trial, CAST). PARTICIPANTS: 2,371 patients, age less than 80, with ventricular arrhythmias after a recent myocardial infarction. Subjects classified by age as less than or equal to 55, 56-65, and 66-79 years. INTERVENTION: Upwardly titrated doses of encainide, flecainide or moricizine. After identification of a tolerated and effective dose of one of the drugs, participants were randomized to that drug and dose versus its placebo for up to 10 months. MAIN OUTCOME MEASURES: Efficacy of drug (suppression of ventricular premature depolarizations and/or non-sustained ventricular tachycardia), side effects and mortality. RESULTS: Older patients had more previous MIs, congestive heart failure (CHF), hypertension, NSVT, repolarization abnormalities, digitalis use, and diuretic use. They had less pathologic Q-waves or electrocardiographic injury pattern, and their left ventricular ejection fraction (LVEF) was lower. First dose VPD suppression with the first drug averaged 53% and is not associated with age (P = 0.29). Adverse events including death are more frequent in older patients taking study drugs (P less than 0.001). This trend is consistent in all three study drugs and at varying LVEFs. History of prior MI, low LVEF, VPD (in log scale), and digitalis therapy also correlates with adverse events (all P less than 0.05). Following adjustment for these factors, older age is an independent predictor of adverse events (relative risk 1.30 per decade of age, P less than 0.001). CONCLUSIONS: Older age increases the susceptibility to adverse cardiac events from a class of relatively toxic antiarrhythmic agents.     

Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I.

OBJECTIVE--To determine whether an interaction between encainide or flecainide and intercurrent ischaemia could account for the observed increase in cardiac and sudden deaths in the study group in the Cardiac Arrhythmia Suppression Trial (CAST) I. DESIGN--CAST I was a randomised, double blind, placebo controlled study in which patients received the drug which suppressed at least 6 premature ventricular contractions per minute by 80% or episodes of non-sustained ventricular tachycardia by 90%. Arrhythmic sudden death or aborted sudden death were the study end points. Measured secondary end points included recurrent myocardial infarction, new or increasing angina pectoris, congestive heart failure, and syncope. The CAST I database was analysed to determine which of three end points occurred first--cardiac death or cardiac arrest, angina pectoris, or non-fatal recurrent infarction. They were regarded as mutually exclusive end points. The triad of cardiac or sudden arrhythmic death plus congestive heart failure and syncope was similarly analysed. RESULTS--It was assumed that recurrent non-fatal infarction and new or increasing angina pectoris were ischaemic in origin. The sum of these non-fatal ischaemic end points and sudden death were nearly identical in the placebo group (N = 129) and the treatment group (N = 131). The one year event rate in each group was 21%. However, the treatment group had a much greater fatality rate (55 v 17; P < 0.0001) than the placebo group. The same relation was found when the data were examined on the basis of drug exposure rather than intention to treat. The temporal and circadian events were similar in each group and were consistent with an ischaemic pattern. No such patterns emerged from analysis of the presumed non-ischaemic end points of congestive heart failure and syncope. CONCLUSIONS--These data suggest that the interaction between active ischaemia and treatment with encainide or flecainide may have been responsible for the increased mortality seen in the treatment group in CAST I. This conversion of a non-fatal to a fatal event emphasises the need for future antiarrhythmic drugs to be screened in ischaemic models.     

Usefulness of either or both left and right bundle branch block at baseline or during follow-up for predicting death in patients following acute myocardial infarction

The presence or onset of bundle branch block (BBB) is associated with increased mortality in patients after acute myocardial infarction (AMI). The risk increases with age. We assessed the prognostic power of BBB patterns for predicting clinical outcomes in patients after high-risk AMI. In the OPTIMAAL trial, the effects of losartan versus captopril were compared in 5,477 patients with heart failure and/or evidence of left ventricular dysfunction after MI. The association between clinical outcomes and the presence of left or right BBB at randomization (median 3 days after AMI) or occurring during follow-up (mean 2.7 years) was assessed using Cox regression models. At randomization, 8% of patients (n = 438) showed BBB patterns; 3.7% (n = 203) showed left BBB and 4.3% (n = 235) showed right BBB patterns. In patients with left BBB, there was an increased risk of all-cause death and cardiovascular death. In patients with right BBB, there was increased risk of sudden cardiac death/resuscitated cardiac arrest. During follow-up, another 4.9% (n = 272) developed BBB patterns; 2.8% (n = 153) developed left BBB and 2.17% (n = 119) developed right BBB. Left BBB was associated with increased risk for all-cause death, cardiovascular death, and sudden cardiac death/resuscitated cardiac arrest, whereas right BBB was related to increased risk of sudden cardiac death/resuscitated cardiac arrest. In conclusion, our results confirm and quantify previous observations showing substantially increased mortality in patients with BBB patterns at baseline or occurring soon after AMI.     

Circadian pattern of arrythmic death in patients receiving encainide,Flecainide or moricizine in the cardiac arrhythmia

Objectives. The purpose of this study was to assess the effect of antiarrhythmic drugs on the timing of arrhythmic death.Background. Sudden cardiac death remains a problem of epidemic proportions. Delineating its pathophysiology is an important step in devising preventive measures. Previous studies have shown a circadian pattern of onset of sudden cardiac death. The effect of antiarrhythmic drugs on this pattern has not been systematically studied.Methods. The Cardiac Arrhythmia Suppression Trial (CAST) was a multicenter double-blind, placebo-controlled study designed to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs (encainide, flecainide or moricizine) after acute myocardial infarction would reduce the incidence of arrhythmic death.Results. The trial was terminated prematurely because of an unexpectedly high mortality rate in the active treatment group. The onset of arrhythmic death in this group (in patients not receiving beta-adrenergic blocking agents) displayed a bimodal variation, with significant peaks in midmorning and late afternoon/early evening. More than half of the symptomatic events were accompanied by anginalike symptoms. Approximately 30% of all events occurred within 2 h of awakening.Conclusions. Our data suggest the possibility of a complex interaction among antiarrhythmic drags, sympathetic nervous system activation and acute myocardial ischemia. Planning of future antiarrhythmic drug trials will need to take this information into account.     

Encainide versus flecainide for chronic atrial and junctional ectopic tachycardia

For treatment of chronic atrial and Junctional ectopic tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in most patients. Both the intravenous efficacy and the oral efficacy of 2 class IC, were studied in 16 patients with atrial ectopic tachycardia and in 3 patients with junctional ectopic tachycardia, using exercise testing, 24-hour long-term electrocardiography and programmed electrical stimulation. All patients had been previously treated unsuccessfully with several antiarrhythmic drugs. In 5 patients, tachycardia was persistent; in the remaining patients, it occurred intermittently for more than 12 hours/day. Intravenous encainide, in doses ranging from 0.3 to 2.0 mg/kg body weight, was given to 5 patients with atrial ectopic tachycardia, and it terminated atrial ectopic tachycardia in all patients. Intravenous flecainide was given to 9 patients, and it terminated atrial tachycardia in 4 and slowed the tachycardia rate in 2. It terminated Junctional tachycardia in 2 patients and slowed tachycardia rate in 1. During a follow-up period of 10 ± 5 months, oral encainide, in dosages between 150 and 225 mg/day, completely suppressed atrial ectopic activity in 4 patients. In the remaining patient, encainide reduced the number of tachycardia episodes markedly but had to be withdrawn because of intolerable side effects. During a 12 ± 11-month (median 6) follow-up, oral flecainide at dosages between 200 and 300 mg/day, completely suppressed ectopic activity in 7 patients and improved symptoms in 5. Only 1 patient failed to respond to oral flecainide. The results of this study indicate that both encainide and flecainide are effective in the treatment of chronic ectopic atrial and junctional tachycardia.     

Hemodynamic effects of encainide in patients with ventricular arrhythmia and poor ventricular function

Gated cardiac scanning was used to evaluate the hemodynamic effects of encainide in 19 patients (1 woman) with complex ventricular arrhythmia and depressed left ventricular (LV) function (ejection fraction less than 45%). Patients were 36 to 80 years old (average 61). All were candidates for long-term encainide therapy after having failed with currently available antiarrhythmics. Sixty-three percent had congestive heart failure before they received encainide. All were evaluated in the hospital before encainide therapy by a gated cardiac scan performed at least 3 days after discontinuing all antiarrhythmic drugs. Patients received oral encainide in doses of 75 to 200 mg. Gated cardiac scans were repeated 1 to 2 weeks later when an 80% reduction in frequency of premature ventricular complexes was observed on a 24-hour Holter recording. No patient had worsening of congestive heart failure during encainide therapy. Encainide did not significantly affect ejection fraction, which averaged 22 +/- 10% before and 25 +/- 14% (SD) after encainide (difference not significant [NS]). Other hemodynamic variables, including heart rate, blood pressure, stroke volume and end-diastolic volume, remained unchanged during encainide therapy. Digoxin blood levels in 10 patients averaged 1.04 +/- 0.43 before and 1.22 +/- 0.47 mg/ml (NS) during encainide therapy. Thus, encainide given orally in clinically effective doses does not appear to have significant hemodynamic effects in patients with ventricular arrhythmia and depressed LV function.     

New aspects of the clinical use of anti-arrhythmia agents with special reference to acute therapy of ventricular tachycardia (lidocaine vs. ajmaline)

Antiarrhythmic treatment is based on the hypothesis that ventricular premature beats (VPBs), in the presence of underlying cardiac disease and impaired ventricular function, may predispose to sudden cardiac death. The effectiveness of treatment, however, has not been proven. For acute treatment of paroxysmal ventricular tachycardia, on comparison of the effectiveness of lidocaine and ajmaline, some new aspects have been rendered. VENTRICULAR PREMATURE BEATS (VPB): Isolated VPBs can be found in 40 to 75% of healthy subjects; if their number is substantial, investigation is warranted. For VPBs with subjective symptoms, beta-receptor blockers or specific antiarrhythmic agents, if necessary in combination, may be given. In several studies it has been shown that the prognosis of patients with frequent and complex VPBs, that is couplets and salvos, without heart disease is not compromised. In one long-term study over an average of 6.5 years, sudden death was observed in only one of 70 subjects who had 566 VPBs/24 hours, 60% additionally couplets and 26% salvos in the Holter ECG. Accordingly, treatment for the sake of prognosis is not warranted. For patients with mitral valve prolapse or only mildly impaired ventricular function and asymptomatic arrhythmias, treatment is not necessary since it has not been shown to be beneficial. Coronary artery disease is the most frequent cause of ventricular arrhythmias and sudden death. In numerous studies in patients after myocardial infarction, a relationship has been recognized between frequent and complex VPBs and overall mortality as well as sudden death. Particularly at risk are patients with very frequent and complex VPBs with additional impairment of ejection fraction to less than 30 to 40% but this group only accounts for 10% of patients after infarction. Only in one interventional study, carried out with aprindine, there was a significant reduction in overall mortality from 12.5 to 7.8% with an adverse reaction rate, however, of 21%. In high-risk patients with a low ejection fraction and numerous, complex VPBs as well, in a further study with aprindine, after one year, there was no decrease in overall mortality as compared with the placebo group. The cause for the insufficient effectiveness of the antiarrhythmic agents in various interventional studies has been attributed to a limited number of patients, rigid dosing regimens, inadequate suppression of VPBs and a high incidence of adverse reactions. In the multicenter, randomized, placebo-controlled CAST study with newer substances, a total of 2309 patients with essentially asymptomatic VPBs at a rate of more than 6/hour and an ejection fraction less than 55% or 40% admitted more than 90 days after infarction, respectively, were followed from six days to two years after myocardial infarction to determine if the significant suppression of VPBs in patients with coronary artery disease with antiarrhythmic agents leads to a reduction in arrhythmia-associated deaths. Flecainide, encainide and moricizine led to a significant suppression of VPBs in 75% of the patients. After an average of ten months, the rate of arrhythmia-induced deaths of 4.5% in those treated with encainide or flecainide was significantly higher than the 1.2% observed in the placebo group. These results appear attributable to a proarrhythmic effect of the class IC drugs during long-term treatment.(ABSTRACT TRUNCATED AT 400 WORDS)