Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation.

We evaluated the efficacy and safety of azimilide, a new class III antiarrhythmic agent that blocks both the slow and fast components of the cardiac-delayed rectifier potassium currents in 4 randomized, double-blind, placebo-controlled trials with similar protocols. The purpose of this study was to assess the relation between dose and effect. A total of 1,380 patients with a documented history of symptomatic atrial fibrillation (AF), atrial flutter, or both, were enrolled. After a 3-day loading period during which the assigned dose was given twice a day, subjects received placebo or azimilide (35, 50, 75, 100, or 125 mg once a day) for the duration of the study period. The primary end point of the studies was the time to symptomatic arrhythmia recurrence with a transtelephonic electrocardiogram typical of AF, atrial flutter, or paroxysmal supraventricular tachycardia. For each study, Kaplan-Meier estimates of the median time to recurrence were computed for placebo and for each azimilide dose. Cox proportional-hazards modeling was used to estimate hazard ratios for each active dose. Each of the 2 highest azimilide doses (100 and 125 mg/day) significantly prolonged the time to recurrence of arrhythmia. For the 100 mg/day dose, the hazard ratio was 1.34, 95% confidence interval 1.05 to 1.72; p = 0.02. For the 125 mg/day dose, the hazard ratio was 1.32, 95% confidence interval 1.07 to 1.62; p = 0.01. Patients with a history of either ischemic heart disease or congestive heart failure had a significantly greater treatment effect from azimilide than those without it. Torsades de Pointes occurred in 0.9% of patients receiving either of the 2 effective doses. Thus, doses of azimilide <100 mg/day are not effective for control of AF, whereas doses of 100 and 125 mg/day are effective with an acceptable risk of serious toxicity.

Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose-response. Azimilide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators.

OBJECTIVES: The purpose of this study was to assess the effectiveness of azimilide, a class III antiarrhythmic drug, in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation, atrial flutter or both. BACKGROUND: Atrial fibrillation is an increasingly common disorder of the heart rhythm, and most patients with this problem are identified because they have symptoms associated with their arrhythmia. New antiarrhythmic therapies are needed to treat patients with this problem. METHODS: A total of 384 patients with a history of atrial fibrillation, atrial flutter or both were randomly assigned to receive once daily doses of placebo or azimilide; recurrent symptomatic arrhythmias were documented using transtelephonic electrocardiogram (ECG) recording. Azimilide 50 mg, 100 mg or 125 mg was tested; the primary efficacy analysis compared the time to first symptomatic recurrence in the combined azimilide 100 mg and 125 mg dose groups with that in the placebo group using the log-rank test. RESULTS: In the primary efficacy analysis, the time to first symptomatic arrhythmia recurrence was significantly prolonged in the combined azimilide 100 mg and 125 mg daily dose group compared with the placebo group (chi-square 7.96, p = 0.005); the hazard ratio (placebo: azimilide) for this comparison was 1.58 (95% confidence interval [CI] = 1.15, 2.16). In comparisons between individual doses and placebo, the hazard ratio for the 50 mg daily dose was 1.17 (95% CI = 0.83, 1.66; p = 0.37); for the 100 mg group, dose was 1.38 (95% CI = 0.96, 1.98; p = 0.08), and for the 125 mg group, dose was 1.83 (95% CI = 1.24, 2.70; p = 0.002). CONCLUSIONS: Azimilide significantly lengthened the symptomatic arrhythmia-free interval in patients with a history of atrial fibrillation, atrial flutter or both.

Observations on the transition from intermittent to permanent atrial fibrillation.

BACKGROUND: Quantitative data on the frequency with which transition from intermittent to permanent atrial fibrillation occurs are lacking. We conducted this study to determine the proportion of patients with intermittent atrial fibrillation who progress to permanent atrial fibrillation and to investigate baseline clinical characteristics that might predict such a progression. METHODS: This retrospective cohort study included 231 patients who were seen with intermittent atrial fibrillation at a university hospital-based clinic from January 1978 through December 1997. Patients' medical records and electrocardiograms were reviewed and data were collected for all clinic visits through May 1998. The proportion of patients who remained free of transition from intermittent to permanent atrial fibrillation was calculated by the Kaplan-Meier method. A Cox proportional hazards model was used to determine the effect of some baseline characteristics on this transition. RESULTS: The number of patients who remained free of transition from intermittent to permanent atrial fibrillation was 92% (95% confidence interval 88%-96%) at 1 year and 82% (95% confidence interval 75%-88%) at 4 years. Among 5 baseline characteristics (age, sex, structural heart disease, atrial fibrillation at presentation, and use of an antiarrhythmic medicine before presentation), the 2 significant predictors of progression from intermittent to permanent atrial fibrillation were age (P =.0003) and being in atrial fibrillation at presentation (P =.0006). The hazard ratio associated with 10 years of advancing age was 1.82 (95% confidence interval 1.31-2.51), and the hazard ratio associated with atrial fibrillation at presentation was 3.56 (95% confidence interval 1.73-7.34). CONCLUSIONS: Approximately 18% of patients who had intermittent atrial fibrillation were permanently in atrial fibrillation after 4 years of follow-up. Age and being in atrial fibrillation at presentation were the only 2 important clinical variables identified in predicting such a progression.

Effect of dofetilide on survival in patients with supraventricular arrhythmias.

OBJECTIVES: This study compared survival between patients taking dofetilide and patients taking placebo in a pooled analysis of randomized clinical trials of patients with supraventricular arrhythmias. BACKGROUND: Clinical trials of antiarrhythmic drugs used to treat supraventricular arrhythmias rarely include enough patients to assess whether the drug being tested has an effect on survival. Pooling data from many trials provides useful information on safety. METHODS: Data from randomized clinical trials of antiarrhythmic drug therapy of supraventricular arrhythmias were pooled to assess the effect on survival of dofetilide (n = 1346) compared with placebo (n = 677) in this patient population. RESULTS: The unadjusted hazard ratio for risk of death (dofetilide/placebo) was 1.4 with 95% confidence interval 0.4-5.1. After adjusting for effects of arrhythmia diagnosis, age, sex, and structural heart disease, the hazard ratio was 1.1 (confidence interval 0.3-4.3). CONCLUSIONS: The pooled survival analysis provided reassurance regarding the safety of dofetilide in patients with supraventricular arrhythmias.

Clinical features of Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White syndrome is the most common form of ventricular preexcitation. Understanding this syndrome is fundamental for anyone interested in learning about arrhythmias. This review addresses (1) the historic sequence of events that led to the understanding of this syndrome; (2) the pathologic, embryologic, and electrophysiologic properties of accessory pathways; (3) the epidemiology and genetics of this syndrome; (4) the clinical diagnosis of this syndrome, with special emphasis on the arrhythmias that patients with ventricular preexcitation are predisposed to; and (5) the therapy for patients with Wolff-Parkinson-White syndrome.

Evolution and revolution in drug labeling: regulation of antiarrhythmic drugs by the Food and Drug Administration 1962-1996.

Between 1962, when the Kefauver-Harris Drug Amendments were passed, and 1996, 20 pharmaceutical compounds were approved and labeled by the FDA as effective antiarrhythmic drugs for some specified cardiac arrhythmia. Drug research and development in the 1970s and 1980s were focused on treatment of premature ventricular beats as a marker for sudden cardiac death and ventricular tachycardia. The Cardiac Arrhythmia Suppression Trial in 1989 irrevocably altered this approach. Recent drug development programs have targeted atrial fibrillation (AF) as epidemiologic data have predicted an increase in the incidence of AF as the United States population ages, and as treating premature ventricular beats has fallen from favor. The FDA, the scientific community, and the pharmaceutical industry have all participated in and been affected by this evolution in drug development.

Pharmacologic management of atrial fibrillation.

In an era when many electrophysiologic problems are routinely treated with invasive procedures or implantable devices, drugs remain the cornerstones of treatment for atrial fibrillation. Atrial fibrillation may present as an episodic rhythm in patients who are primarily in sinus rhythm or it may be manifested as rhythm disorder that is permanent. Patients who appear to have an episodic rhythm disorder may be found to be in atrial fibrillation permanently when followed for long periods of time, and prognosis in the two forms is similar. It is, therefore, useful to consider them different manifestations in the same spectrum of disease. This review will address pharmacologic approaches designed to: (1) slow ventricular response; (2) restore sinus rhythm; (3) reduce occurrences of atrial fibrillation; and (4) prevent thromboembolic complications. Nonpharmacologic approaches to treating atrial fibrillation will be briefly reviewed.

Cost effectiveness of inpatient initiation of antiarrhythmic therapy for supraventricular tachycardias.

This study assessed the cost effectiveness of inpatient antiarrhythmic therapy initiation for supraventricular tachycardias using a metaanalysis of proarrhythmic risk and a decision analysis that compared inpatient to outpatient therapy initiation. A MEDLINE search of trials of antiarrhythmic therapy for supraventricular tachycardias was performed, and episodes of cardiac arrest, sudden or unexplained death, syncope, and sustained or unstable ventricular arrhythmias were recorded. A weighted average event rate, by sample size, was calculated and applied to a clinical decision model of therapy initiation in which patients were either hospitalized for 72 hours or treated as outpatients. Fifty-seven drug trials involving 2,822 patients met study criteria. Based on a 72-hour weighted average event rate of 0.63% (95% confidence interval, 0.2% to 1.2%), inpatient therapy initiation cost $19,231 per year of life saved for a 60-year-old patient with a normal life expectancy. Hospitalization remained cost effective when event rates and life expectancies were varied to model hypothetical clinical scenarios. For example, cost-effectiveness ratios for a 40-year-old without structural heart disease and a 60-year-old with structural heart disease were $37,510 and $33,310, respectively, per year of life saved. Thus, a 72-hour hospitalization for antiarrhythmic therapy initiation is cost effective for most patients with supraventricular tachycardias.

Evaluation of the effect of transthoracic cardioversion from ventricular tachycardia to sinus rhythm on left atrial mechanical function.

We measured left atrial function during sinus rhythm before and after ventricular tachycardia was induced in an electrophysiology laboratory, using peak transmitral A-wave velocity from pulsed-Doppler transthoracic echocardiography as a marker of left atrial mechanical function. The results of this prospective study do not support the hypothesis that a transthoracic shock of mild to moderate energy diminishes atrial mechanical function.

Heart rate during spontaneous and induced paroxysmal supraventricular tachycardia.

It is generally assumed that paroxysmal supraventricular tachycardia (PSVT) induced during invasive electrophysiological study reproduces the patient's spontaneous, clinical arrhythmia. Even in the absence of antiarrhythmic drugs, however, there may be significant differences in characteristics of the induced and spontaneous arrhythmias. We compared the heart rate of PSVT in 38 patients who had undergone electrophysiological study with induction of PSVT who also had a spontaneous episode of PSVT documented by transtelephonic ECG monitoring during a period when all antiarrhythmic drugs were withheld. The heart rate during spontaneous PSVT was faster than the heart rate of PSVT induced during electrophysiological study; the mean difference was 16 beats/min (P < 0.001). We conclude that heart rate of PSVT induced during electrophysiological study generally underestimates the heart rate of spontaneous PSVT in the antiarrhythmic drug-free state. This may be due to differences in the autonomic and hemodynamic states during spontaneous and induced arrhythmias.

Incidence of symptomatic atrial fibrillation in patients with paroxysmal supraventricular tachycardia.

OBJECTIVES: This study was performed to determine the incidence of symptomatic, sustained atrial fibrillation in a group of patients with paroxysmal supraventricular tachycardia. The effects of the mechanism of paroxysmal supraventricular tachycardia (atrioventricular [AV] node reentry vs. AV reentry through an accessory pathway) and heart rate during the tachycardia on the occurrence of atrial fibrillation were also assessed. BACKGROUND: There is a substantial incidence of atrial fibrillation in patients with paroxysmal supraventricular tachycardia, but the precise incidence and the factors that determine it are unknown. METHODS: One hundred sixty-nine patients with paroxysmal supraventricular tachycardia were followed up by regular clinic visits and transtelephonic electrocardiographic monitoring during symptomatic episodes of arrhythmia. The Kaplan-Meier product-limit method was used to estimate the proportion of patients remaining free of atrial fibrillation during the observation period. The Cox proportional hazards model was used to assess the effect of mechanism and heart rate during paroxysmal supraventricular tachycardia on the atrial fibrillation-free period. RESULTS: Thirty-two (19%) of the 169 patients had an episode of atrial fibrillation during a mean follow-up period of 31 months. The cumulative percent of patients experiencing an episode of atrial fibrillation was 6% within 1 month, 9% within 4 months and 12% within 1 year. The mechanism of paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio corresponding to classification in the AV node reentry group was 0.8 (p > 0.6). The heart rate during paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio associated with an increase in heart rate of 50 beats/min during the tachycardia was 1.15 (p > 0.5). CONCLUSIONS: This study suggests that atrial fibrillation will develop in approximately 12% of patients with paroxysmal supraventricular tachycardia during a 1-year follow-up period. The occurrence of atrial fibrillation is not related to the mechanism or heart rate of the paroxysmal supraventricular tachycardia.

Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly.

BACKGROUND: Our goal was to determine whether patient age affects a physician's reported likelihood of using anticoagulant therapy or the intensity of anticoagulant therapy for patients with nonvalvular atrial fibrillation. METHODS: We surveyed a nationwide sample of 1189 randomly selected office-based practitioners in three strata: primary care (geriatrics, internal medicine, family practice, and general practice), cardiology, and neurology. A vignette-based questionnaire was used to measure attitudes and beliefs regarding anticoagulation risks and effectiveness, barriers to anticoagulation in clinical practice, and likelihood of using anticoagulation and target intensity of anticoagulation at three patient ages (55, 65, and 75 years) for four clinical scenarios (chronic non-valvular atrial fibrillation with mild left atrial enlargement, intermittent or paroxysmal atrial fibrillation, recent-onset atrial fibrillation, and atrial fibrillation with recent [3 months] embolic stroke). RESULTS: The overall response rate was 38%. The mean likelihoods of using anticoagulation for the three ages were unequal (P < .0001) for each scenario. Most physicians were "very" or "somewhat" likely to use anticoagulant therapy for a 65-year-old with left atrial enlargement (71%), intermittent or paryoxysmal atrial fibrillation (68%), recent-onset atrial fibrillation (86%), or embolic stroke (96%). Fewer physicians were likely to use anticoagulant therapy for a 75-year-old with left atrial enlargement (63%), intermittent or paroxysmal atrial fibrillation (56%), recent-onset atrial fibrillation (80%), or embolic stroke (93%). Among physicians equally likely to use anticoagulation for 65- and 75-year-old patients, intensity of anticoagulant therapy (target international normalized ratio or prothrombin time ratio) was lower (P < .04) for the 75-year-old. CONCLUSION: Anticoagulant therapy may be less often and less intensively used for elderly patients with nonvalvular atrial fibrillation.

Flecainide acetate for paroxysmal supraventricular tachyarrhythmias. The Flecainide Supraventricular Tachycardia Study Group.

Flecainide has been shown to be effective in short-term, controlled studies for prevention of paroxysmal supraventricular tachycardia (SVT) and paroxysmal atrial fibrillation (AF). However, it is unknown whether this beneficial response is maintained during long-term chronic therapy. Forty-nine patients were studied who enrolled in double-blind, placebo-controlled, short-term studies of safety and efficacy and subsequently received long-term, open-label therapy for > or = 6 months (mean duration of therapy, 17 months). To evaluate chronic efficacy, events during long-term therapy were documented by a transtelephonic monitor for either 4 or 8 weeks, comparable to the corresponding 4- or 8-week placebo-baseline periods in the same patients. Results during chronic therapy were compared with those at baseline and after the initial (short-term) treatment period. Compared with placebo-baseline results, the number of patients free of arrhythmic attacks increased significantly for both patients with SVT (from 24% to 82%, p = 0.013, n = 17) and patients with AF (from 12% to 68%, p < 0.001, n = 25). Mean time to first attack and mean number of days between attacks also showed significant and parallel increases during the chronic efficacy period. In patients with paired short- and long-term efficacy evaluations with the same dose of flecainide, end points were maintained at equivalent levels or showed further improvement (i.e., mean rate of AF attacks decreased further with chronic therapy, p = 0.036). No proarrhythmic events, death, or myocardial infarction occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of outpatients experiencing implantable cardioverter defibrillator shocks associated with minimal symptoms.

Patients receiving minimally symptomatic shocks from their implantable cardioverter defibrillators were studied prospectively using transtelephonic ECG loop monitoring. The time course to the first subsequent shock was evaluated. Twenty-nine consecutive patients who received a shock preceded by mild palpitations or no symptoms were given a transtelephonic ECG loop monitor and instructed to activate the monitor if a subsequent shock occurred. Kaplan-Meier analysis was used to quantitate the time to first shock during the study period. The point estimate +/- standard error of patients receiving a shock during the study period was 31% +/- 9% at 30 days, 41% +/- 9% at 60 days, and 60% +/- 9% at 120 days. The ECG was successfully transmitted in 7 of 13 patients who had shocks in the 60-day monitoring period, and demonstrated inappropriate shocks in 6 of 7. Determination of the cause of shock led to a change in subsequent management in all 7 patients. We conclude that the incidence of inappropriate shocks may be higher than estimated previously in patients with minimal symptoms prior to the shock. There are thousands of patients with implantable cardioverter defibrillators that have no storage function for treated tachycardias; transtelephonic ECG loop monitoring can determine the cause of implantable cardioverter defibrillator discharge in these patients, and the diagnosis is invaluable in their management.

Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia.

BACKGROUND: Paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia are recognized clinically when patients seek treatment for symptoms due to recurrent arrhythmias; atrial fibrillation also increases the risk of stroke. The frequency with which asymptomatic arrhythmias occur in patients with these arrhythmias is unknown. METHODS AND RESULTS: Twenty-two patients with paroxysmal atrial fibrillation (n = 8) or paroxysmal supraventricular tachycardia (n = 14) were studied for 29 days with two different ambulatory ECG-monitoring techniques to measure the relative frequency of asymptomatic and symptomatic arrhythmias. All class I antiarrhythmic drugs, calcium channel blockers, beta-blockers, and digitalis were withheld. Sustained asymptomatic arrhythmia events (defined as lasting at least 30 seconds) were documented using continuous ambulatory ECG monitoring once weekly for a total of 5 of the 29 study days; symptomatic arrhythmia events were documented using transtelephonic ECG monitoring for all 29 days of the study. In the group of patients with paroxysmal atrial fibrillation, asymptomatic arrhythmia events occurred significantly more frequently than symptomatic arrhythmia events; the mean rates, expressed as events/100 d/patient (95% confidence interval), were 62.5 (40.4, 87.3) and 5.2 (2.7, 9.0) (P < .01); the ratio of the mean rates was 12.1 (5.8, 26.4). In contrast, in the group of patients with paroxysmal supraventricular tachycardia, asymptomatic arrhythmia events were significantly less frequent than symptomatic arrhythmia events; the mean rates were 0.0 (0.0, 5.3) and 7.4 (5.0, 10.6) (P = .02). The ratio of the mean rates was 0.0 (0.0, 0.8). CONCLUSIONS: In a group of patients with paroxysmal atrial fibrillation, sustained asymptomatic atrial fibrillation occurs far more frequently than symptomatic atrial fibrillation. However, it is not known whether asymptomatic atrial fibrillation is a potential risk factor for stroke even when patients are not having symptomatic arrhythmias.