Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study.

BACKGROUND: This double-blind, multicenter, placebo-controlled study determined the efficacy and safety of dofetilide in converting atrial fibrillation (AF) or atrial flutter (AFl) to sinus rhythm (SR) and maintaining SR for 1 year. METHODS AND RESULTS: Patients with AF or AFl (n=325) were randomized to 125, 250, or 500 microgram dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (Cl(Cr)). Pharmacological cardioversion rates for 125, 250, and 500 microgram dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 microgram versus placebo; P=0.015 and P<0.001, respectively). Seventy percent of pharmacological cardioversions with dofetilide were achieved in 24 hours and 91% in 36 hours. For the 250 patients who successfully cardioverted pharmacologically or electrically, the probability of remaining in SR at 1 year was 0.40, 0.37, 0.58 for 125, 250, and 500 microgram dofetilide, respectively, and 0.25 for placebo (500 microgram versus placebo, P=0.001). Two cases of torsade de pointes occurred, 1 on day 2 and the other on day 3 (0.8% of all patients given active drug); 1 sudden cardiac death, classified as proarrhythmic, occurred on day 8 (0.4% of all patients given active drug). CONCLUSIONS: Dofetilide, a new class III antiarrhythmic agent, is moderately effective in cardioverting AF or AFl to SR and significantly effective in maintaining SR for 1 year. In-hospital initiation and dosage adjustment based on QTc and Cl(Cr) are necessary to minimize a small but nonnegligible proarrhythmic risk.

Comparison based on age of baseline electrocardiographic abnormalities in non-Q-wave myocardial infarction. VANQWISH Trial Research Investigators. Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital.

OBJECTIVE: To compare the incidence of electrocardiographic abnormalities between older (age > or = 70 years) and younger patients presenting with acute non-Q-wave myocardial infarction. DESIGN: Retrospective review of qualifying electrocardiograms in 918 patients enrolled in the multicenter Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study. SETTING: Seventeen Department of Veterans Affairs medical centers. PARTICIPANTS: A total of 918 patients (224 > or = 70 years old) with acute non-Q-wave myocardial infarction. MEASUREMENTS: Comparison of electrocardiograms in patients aged > or = 70 years and younger patients for presence of left ventriculary hypertrophy, widened QRS complex, ST and T wave abnormalities, rhythm other than sinus, heart rate > or = 80 beats/minute, and location of acute non-Q-wave myocardial infarction. RESULTS: Left ventricular hypertrophy and ST depression > or = 1 mm were significantly more frequent in older than in younger patients. CONCLUSIONS: Older patients presenting with non-Q-wave myocardial infarction have a greater incidence of left ventricular hypertrophy and ST depression on their electrocardiograms than younger patients. Both of these electrocardiographic findings have previously been associated with increased risk of death and recurrent myocardial infarction and may help account for the worse prognosis of non-Q-wave myocardial infarction in older patients.

Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators.

BACKGROUND: Non-Q-wave myocardial infarction is usually managed according to an "invasive" strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). METHODS: We randomly assigned 920 patients to either "invasive" management (462 patients) or "conservative" management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non-Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. RESULTS: During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The number of patients with one of the components of the primary end point (death or nonfatal myocardial infarction) and the number who died were significantly higher in the invasive-strategy group at hospital discharge (36 vs. 15 patients, P=0.004, for the primary end point; 21 vs. 6, P=0.007, for death), at one month (48 vs. 26, P=0.012; 23 vs. 9, P=0.021), and at one year (111 vs. 85, P=0.05; 58 vs. 36, P= 0.025). Overall mortality during follow-up did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group (hazard ratio, 0.72; 95 percent confidence interval, 0.51 to 1.01). CONCLUSIONS: Most patients with non-Q-wave myocardial infarction do not benefit from routine, early invasive management consisting of coronary angiography and revascularization. A conservative, ischemia-guided initial approach is both safe and effective.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Chronobiology of acute myocardial infarction: cardiac arrhythmia suppression trial (CAST) experience.

The onset of acute myocardial infarction (AMI) has been shown to occur in a reproducible pattern with a peak in mid-morning and a secondary peak in late afternoon and early evening. More detailed information on the timing of this catastrophic event may provide important pathophysiologic information. Using the database from the Holter Registry of the Cardiac Arrhythmia Suppression Trial (CAST) (n = 22,516), the day of the week, the month, and season of the onset of AMI was obtained and correlated with demographic characteristics. The pattern of the day of onset for the entire population was significantly nonuniform (p <0.0001) with a Monday peak and a weekend nadir. This pattern was observed in most of the examined subgroups. Analysis of seasonal data revealed nonuniform distribution (p <0.001) with a peak in winter and autumn. We conclude that AMI is not a random event but occurs in definite patterns related to the day of the week and the season of the year. These patterns were observed in a wide variety of patient subgroups and appear related to climate, occupation, and other factors.

Relation of circadian ventricular ectopic activity to cardiac mortality. CAST Investigators.

The relation between the circadian occurrence of ventricular premature depolarizations (VPD) and sudden arrhythmic death was examined in a subset of patients entered into the Cardiac Arrhythmia Suppression Trial (CAST). Ambulatory electrocardiographic recordings with hourly measurement of VPD frequency were available in 357 patients. Forty percent of the patients (142 of 357) demonstrated circadian variation in VPD frequency between 6:00 A.M. and 9:59 A.M. that was significantly higher (p < 0.05) than what could randomly be expected from an overall 24-hour average for that patient. The only baseline characteristics in patients with circadian VPDs were age (p < 0.04), history of cardiac arrest (p < 0.01), presence of higher frequency of VPDs (p < 0.002), more frequent episodes of ventricular tachycardia (p < 0.04), and more frequent episodes of slow runs (p < 0.04). There was no difference in mortality in patients with or without circadian VPD variation; drug treatment did not effect mortality. These data indicate that the presence of circadian VPDs is not a predictor of sudden arrhythmic death in patients with a high frequency of VPDs.

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study.

OBJECTIVES: Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND: Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS: The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS: The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS: These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. dl-Sotalol Atrial Fibrillation Study Group.

To establish the value of adjuvant dl-sotalol to digoxin for control of the ventricular response in chronic atrial fibrillation, 60 patients were evaluated in a multicenter, randomized, double-blind, parallel, placebo-controlled study. Patients were evaluated with serial ambulatory ECG monitoring and exercise testing during stable digoxin dosing and then with the addition of either a placebo or dl-sotalol, 80 mg/day, or dl-sotalol, 160 mg/day. The combination of digoxin and dl-sotalol, at either 80 or 160 mg/day, resulted in a statistically significant reduction in heart rate at rest and with exercise during both exercise testing and ambulatory monitoring. No significant difference was observed between the two doses of dl-sotalol. There was no significant difference with regard to symptoms or side effects among the three groups. In summary, dl-sotalol was noted to be a safe and effective adjuvant to digoxin for control of the ventricular response in chronic atrial fibrillation.

Identification of a secondary peak in myocardial infarction onset 11 to 12 hours after awakening: the Cardiac Arrhythmia Suppression Trial (CAST) experience.

OBJECTIVES: The purpose of this study was to assess the relation between the time of awakening and the time of onset of acute myocardial infarction. BACKGROUND: Previous investigation has shown the onset of symptoms of acute myocardial infarction to have a primary peak 1 to 2 h after awakening. In studies not corrected for time of awakening, there appears to be a late afternoon/early evening peak, but data correlating the onset of symptoms with awakening have been limited by small numbers of patients, perhaps precluding identification of a secondary peak. METHODS: In the Cardiac Arrhythmia Suppression Trial (CAST), 3,549 patients had a documented myocardial infarction and entered antiarrhythmic drug titration. Of these, 3,309 had data on the onset of symptoms relative to the time of awakening and form the basis of this report. RESULTS: A total of 870 patients (26.3%) were awakened by symptoms. Of the remaining 2,439 patients who were not awakened by symptoms, 798 (32.7%) experienced the onset of symptoms in the 1st 4 h after awakening (with the highest number in the 1st h), after which the incidence of symptom onset decreased in a linear fashion, with a secondary peak 11 to 12 h after awakening. Both peaks are statistically significant. A similar pattern was seen in most of the subgroups examined (based on age, gender and various other demographic characteristics). CONCLUSIONS: Analysis of the very large CAST data base confirms the relation between awakening and onset of symptoms of myocardial infarction, suggesting involvement of the morning catecholamine surge. A secondary peak in symptom onset, occurring 11 to 12 h after awakening, is a new observation and may relate to ingestion of the evening meal or other trigger factors concentrated in those hours.

Pharmacokinetic and pharmacodynamic evaluation of propafenone in patients with ventricular arrhythmia. Propafenone Research Group.

Propafenone, a class IC antiarrhythmic agent, is metabolized into two active metabolites: 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP). In a placebo-controlled, double-blind study, we examined trough plasma concentrations of propafenone and its two metabolites in 169 subjects. Patients were randomized to one of five parallel treatment groups: placebo and 337.5, 450, 675, or 900 mg/day propafenone with 24-hour ambulatory ECG monitorings, 12-lead ECGs, and plasma samples obtained at frequent intervals. Nonlinear kinetics were noted for propafenone and NDPP but not for 5-OHP. The ratio of NDPP to propafenone was about 10% at all doses, but the ratio of 5-OHP to propafenone decreased from 33% at 337.5 mg/day to 18% at 900 mg/day. Propafenone suppression of ventricular ectopy was dependent on concentration, with pairs and VT beats selectively suppressed at lower concentrations than VPBs. The PR interval and QRS duration increased significantly at propafenone concentrations above 100 ng/ml, while minimal heart rate slowing was noted at concentrations above 1,000 ng/ml.

Comparative effects of nadolol-digoxin combination therapy and digoxin monotherapy for chronic atrial fibrillation.

In some patients with chronic atrial fibrillation, treatment with digitalis alone may fail to produce a satisfactory decrease in heart rate at rest or during exercise or emotional stress. Findings of a few clinical studies suggest that beta blockade in combination with digitalis therapy may be of benefit in these patients. In a randomized, double-blind, placebo-controlled, parallel-group, 8-week study of 32 patients with chronic atrial fibrillation, the effects of digoxin therapy alone were compared with a combination of digoxin and nadolol. Criteria for entry into the study included ventricular rate at rest greater than or equal to 80/min or greater than or equal to 120/min with exercise, and serum digoxin levels within the therapeutic range. After digoxin dose titration to produce therapeutic levels, digoxin dosage remained constant throughout the balance of the study. After a 2-week, single-blind placebo lead-in period, patients were randomized to receive either digoxin plus placebo or a combination of digoxin and nadolol. The dose of nadolol/placebo was titrated from 20 to 120 mg daily as tolerated. Twenty-four hour ambulatory electrocardiographic (Holter) recordings, symptom-limited exercise treadmill tests and serum digoxin and nadolol levels were obtained at the end of the single and double-blind treatment periods. Comparing endpoint with baseline, results from Holter recordings showed that patients treated with a combination of digoxin and nadolol had significant (p less than 0.001) decreases in 24 hour average (78 +/- 4 to 63 +/- 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Polyurethane sheath disintegration causing impaction of pacer lead and shock during attempted removal.

Steady traction to remove a lead whose polyurethane sheath had disintegrated caused displacement of the heart and caused hypotension; the bared lead uncoiled and impacted in the wall of the subclavian vein. The tension on the intrathoracic lead was relieved via immediate anterior thoracotomy and compartmentalization of the superior vena cava.