Steven Singh

Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia

BACKGROUND Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. METHODS We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). RESULTS There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. CONCLUSIONS Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT)

BACKGROUND In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period. METHODS AND RESULTS Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%, P<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%, P=0.001), at 6 months (18%, P=0.001), and at 12 months (16%, P=0.006). Maximal VR was reduced 22% (P=0.001) at 2 weeks, 19% (P=0.001) at 6 months, and 14% (P=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (chi2=9.23, P=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (chi2=12.88, P=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (P=0. 04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug. CONCLUSIONS In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.

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

BackgroundThis 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 ResultsPatients with AF or AFl (n=325) were randomized to 125, 250, or 500 &mgr;g dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (ClCr). Pharmacological cardioversion rates for 125, 250, and 500 &mgr;g dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 &mgr;g 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 &mgr;g dofetilide, respectively, and 0.25 for placebo (500 &mgr;g 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). ConclusionsDofetilide, 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 ClCr are necessary to minimize a small but nonnegligible proarrhythmic risk.

Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter

OBJECTIVES This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide, a pure class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. BACKGROUND Dofetilide is a highly selective blocker of the rapid component of the delayed rectifier current causing action potential prolongation. These effects, and preliminary clinical data, suggest that it may be effective in the treatment of atrial fibrillation and flutter. METHODS Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 micrograms/kg body weight) or placebo. RESULTS Dofetilide effectively terminated the arrhythmia in 31% of patients receiving 8 micrograms/kg, a statistically significant difference from those receiving 4 micrograms/kg (conversion rate 12.5%, p < 0.05) or placebo (no conversion, p < 0.01). Patients with atrial flutter had a greater response to dofetilide (54% conversion rate) than those with atrial fibrillation (14.5% conversion rate, p < 0.001). CONCLUSIONS Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. However, its efficacy is greater in flutter--a response that contrasts with the poorer response seen with class I agents. This finding potentially represents an important advance in the pharmacologic termination of atrial flutter.

Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure

BACKGROUND Although trials of amiodarone therapy in patients with congestive heart failure have produced discordant results with regard to effects on survival, most studies have reported a significant rise in left ventricular ejection fraction during long-term therapy. In the present study, we determined whether this increase in ejection fraction is associated with an improvement in the symptoms and/or physical findings of heart failure or a reduction in the number of hospitalizations for heart failure. METHODS AND RESULTS In the Department of Veterans Affairs cooperative study of amiodarone in congestive heart failure, 674 patients with New York Heart Association class II through IV symptoms and ejection fractions of < or = 40% were treated with amiodarone or placebo for a median of 45 months in a randomized, double-blind, placebo-controlled protocol. Clinical assessments and radionuclide ejection fraction were performed at baseline and after 6, 12, and 24 months. Compared with the placebo group, ejection fraction increased more in the amiodarone group at each time point (8.1 +/- 10.2% [mean +/- SD] versus 2.6 +/- 7.9% at 6 months, 8.0 +/- 10.9% versus 2.7 +/- 8.0% at 12 months, and 8.8 +/- 10.1% versus 1.9 +/- 9.4% after 24 months, all P < .001). However, this difference was not associated with greater clinical improvement, lesser diuretic requirements, or fewer hospitalizations for heart failure (11.1% for amiodarone and 13.6% for placebo group; overall relative risk in the amiodarone group, 0.81 [95% CI, 0.56 to 1.10], P = .18). Of note is the trend toward a reduction in the combined end point of hospitalizations and cardiac deaths (relative risk, 0.82 [CI, 0.65 to 1.03], P = .08), which was significant in patients with nonischemic etiology (relative risk, 0.56 [CI, 0.36 to 0.87], P = .01) and absent in the ischemic group (relative risk, 0.95). CONCLUSIONS Although amiodarone therapy resulted in a substantial increase in left ventricular ejection fraction in patients with congestive heart failure, this was not associated with clinical benefit in the population as a whole. The substantial reduction in the combined end point of cardiac death plus hospitalizations for heart failure in the nonischemic group suggests possible benefit in these patients.

Prevalence and Significance of Nonsustained Ventricular Tachycardia in Patients With Premature Ventricular Contractions and Heart Failure Treated With Vasodilator Therapy

OBJECTIVES: This study sought to determine the prevalence and significance of nonsustained ventricular tachycardia (NSVT) in patients with premature ventricular contractions (PVCs) and heart failure treated with vasodilator therapy. BACKGROUND: Heart failure patients with ventricular arrhythmia and NSVT have a significantly increased risk of premature cardiac death. Recently there has been the question of whether these arrhythmias are expressions of a severely compromised ventricle or are they independent risk factors. We, therefore, determined the prevalence and significance of NSVT in patients with PVCs and heart failure and on vasodilator therapy. METHODS: Twenty-four hour ambulatory recordings were done at randomization, at 2 weeks, at months 1, 3, 6, 9 and 12 and then every 6 months in 674 patients with heart failure and on vasodilator therapy. The median period of follow-up was 45 months (range 0 to 54). RESULTS: Nonsustained ventricular tachycardia was present in 80% of all patients. Patients without (group 1) and with (group 2) NSVT were balanced for variables: age, etiology of heart disease, New York Heart Association (NYHA) functional class, use of amiodarone and diuretics and left ventricular diameter by echocardiogram. However, group 1 patients had significantly less beta-adrenergic blocking agent use and higher ejection fraction (EF) (p < 0.002 and p < 0.001, respectively). Survival analysis for all deaths showed a greater risk of death among group 2 patients (p=0.01). Similarly, sudden death was increased in group 2 patients (p=0.02, risk ratio 1.8). After adjusting for the above variables, only EF (p=0.001) and NYHA class (p=0.01) were shown to be independent predictors of survival. Nonsustained ventricular tachycardia showed a trend (p=0.07) as an independent predictor for all-cause mortality but not for sudden death. Only EF was an independent predictor for sudden death. CONCLUSIONS: Nonsustained ventricular tachycardia is frequently seen in patients with heart failure and may be associated with worsened survival by univariate analysis. However, after adjusting other variables, especially for EF, NSVT was not an independent predictor of all-cause mortality or sudden death. These results have serious implications in that suppression of these arrhythmias may not improve survival.

Treatment of frequent ventricular arrhythmia with encainide: assessment using serial ambulatory electrocardiograms, intracardiac electrophysiologic studies, treadmill exercise tests, and radionuclide cineangiographic studies.

The effects of encainide on ventricular arrhythmia and left ventricular function were studied in 21 patients with chronic, high-grade ventricular arrhythmia using a prospective, 3-month, placebo-controlled, single-blind trial design. Encainide caused a 96% decrease in the average hourly frequency of ventricular premature complexes (VPCs) and comparable reductions in salvos of nonsustained ventricular tachycardia (VT) and episodes of sustained VT. Intracardiac electrophysiologic testing showed prolonged intraatrial and intraventricular conduction times and increased atrial, atrioventricular nodal, and ventricular refractory periods with both i.v. and oral encainide without His-Purkinje block, despite marked prolongation of HV and QRS intervals. Induced repetitive ventricular beating after ventricular extrastimuli in 15 patients showed persistent repetitive ventricular beating with chronic oral encainide in seven patients, four of whom had sustained VT within 2 months of treatment on encainide. Encainide did not reduce exercise capacity or left ventricular ejection fraction at rest or during supine exercise. Minor adverse effects of encainide in 11 of 21 patients included dose-related visual disturbances, dizziness and sinus pauses (< 3 seconds). Major adverse effects included the new appearance of sustained VT in three of 20 patients (15%). Oral encainide effectively reduces the frequency and grade of VPCs, prolongs intracardiac conduction times, and does not impair left ventricular performance. However, it is associated with frequent minor side effects and uncommon but potentially severe major side effects (sustained VT), both of which apparently have a direct relationship to the size of the dose.

Meta-analysis of antiarrhythmic therapy in the prevention of postoperative atrial fibrillation and the effect on hospital length of stay, costs, cerebrovascular accidents, and mortality in patients undergoing cardiac surgery.

T have been 13 randomized controlled trials of prophylactic antiarrhythmic therapy in patients undergoing cardiac surgery that have assessed its effects on hospital length of stay.1–13 These have shown consistent and marked decreases in the incidence of atrial fibrillation (AF), but the effects on hospital stay have been less concordant. Correlation of a decreased incidence of this arrhythmia with a reduction in hospital length of stay, costs, morbidity, or mortality would help determine how much continuing effort should be placed on its prevention. To determine whether this decreased incidence translates into clinically important outcomes, we conducted a meta-analysis of various antiarrhythmic therapies and their effects on the length of hospitalization, costs, stroke, and mortality. • • • We conducted a review of reports (in English) in the MEDLINE database, using the keywords “antiarrhythmics” and “postoperative atrial fibrillation” between January 1977 and March 2001. Published reviews, computerized literature search, and analysis of references identified potentially eligible studies. Only published data were included in this analysis. Unpublished studies and results reported in abstracts were excluded. Studies were included if they met the following criteria: (1) randomized comparison of an intervention to placebo; (2) evaluation of pacing modality or drug administration excluding calcium channel blockers, digoxin, and magnesium; (3) reported hospital length of stay; (4) AF identified as the arrhythmia. Thirteen randomized trials met the criteria and are included in this analysis. Forty trials were excluded because they did not include data on hospital length of stay, 14 because they did not include a placebo group, 7 because they evaluated atrial flutter or supraventricular arrhythmias as a group, and 4 because they were retrospective studies. Data were also extracted on 3 additional outcomes when available (costs, stroke, and death). Six studies had data on costs, 5 had data on the incidence of stroke, and 9 had data on mortality. All trial analyses were double-blinded and performed on an intention-to-treat basis. In the study by Dorge et al,8 the 2 different dosing regimens of amiodarone were considered as a single treatment group when evaluated for outcomes in the meta-analysis. In cases where different pacing modalities resulted in no significantly different effect on the incidence of atrial fibrillation, the results for outcomes were averaged before statistical analysis.3 In trials of different pacing modalities that showed superiority of 1 treatment group in decreasing the incidence of atrial fibrillation, only this group was included in the analysis of outcomes.10,11 The trials by Guanieri et al5 and Fan et al9 did not have SDs for the cost analysis; therefore, we approximated the SD to be 70% to 75% of the total cost, based on an evaluation of other studies in this meta-analysis that included data on SDs. Our primary outcomes for analysis were the effects on duration of hospitalization, defined as the number of days from surgery to hospital discharge, as well as hospital costs. The clinically important outcomes of the incidence of stroke and mortality were also assessed. For quantitative outcomes, the difference in the outcomes between the patient and the intervention groups was computed along with 95% confidence intervals. These were checked for consistency with an analysis of variance. By taking a weighted average of the differences, the results from the separate studies were combined, the weight being inversely proportional to the square of the width of the confidence interval. The values were combined using a method described by Fleiss.14 For dichotomous outcome variables, odds ratios and confidence intervals were computed, and these were combined on the basis of the weighted logarithms of the odds ratio, as described in the aforementioned source.14 In the 13 studies, a total of 1,783 patients were enrolled and included in the meta-analysis. Of these patients, 1,038 were assigned to the antiarrhythmic group and 745 were assigned to the control group. One thousand five hundred and sixty-nine patients underwent isolated coronary artery bypass grafting, 87 underwent only valvular surgery, 117 underwent both coronary artery bypass grafting and valvular surgery, and 10 underwent other types of cardiac surgery. The incidence of AF varied from 8% to 37% in the treatment groups and 29% to 53% in the control groups, From the Department of Cardiology, Veterans Affairs Medical Center; and Georgetown University Medical Center, Washington, DC. Dr. Singh’s address is: Department of Cardiology, Veterans Affairs Medical Center, 50 Irving Street, NW, Room 1E301, Washington, DC 20422. E-mail: singh@va.med.gov. Manuscript received September 24, 2002; revised manuscript received and accepted January 22, 2003.

Exercise Capacity and Blood Pressure Associations With Left Ventricular Mass in Prehypertensive Individuals

Prehypertensive individuals are at increased risk for developing hypertension and cardiovascular disease compared with those with normal blood pressure. Early compromises in left ventricular structure may explain part of the increased risk. We assessed echocardiographic and exercise parameters in prehypertensive individuals (n=790) to determine associations between exercise blood pressure and left ventricular structure. The exercise systolic blood pressure at 5 metabolic equivalents (METs) and the change in blood pressure from rest to 5 METs were the strongest predictors of left ventricular hypertrophy. We identified the systolic blood pressure of 150 mm Hg at the exercise levels of 5 METs as the threshold for left ventricular hypertrophy. There was a 4-fold increase in the likelihood for left ventricular hypertrophy for every 10-mm Hg increment in systolic blood pressure beyond this threshold (OR: 1.15; 95% CI: 1.12 to 1.18). There was also a 42% reduction in the risk for left ventricular hypertrophy for every 1 MET increase in the workload (OR: 0.58; P<0.001). When compared with low-fit, moderate, and high-fit individuals exhibited significantly lower systolic blood pressure at an exercise workload of 5 METs (155±14 versus 146±10 versus 144±10; P<0.05), lower left ventricular mass index (48±12 versus 41±10 versus 41±9; P<0.05), and prevalence of left ventricular hypertrophy (48.3% versus 18.7% versus 21.6%; P<0.001). This suggests that moderate improvements in cardiorespiratory fitness achieved by moderate intensity physical activity can improve hemodynamics and cardiac performance in prehypertensive individuals and reduce the work of the left ventricle, ultimately resulting in lower left ventricular mass.

Comparison of sotalol versus amiodarone in maintaining stability of sinus rhythm in patients with atrial fibrillation (Sotalol-Amiodarone Fibrillation Efficacy Trial [Safe-T])

The Sotalol-Amiodarone Fibrillation Efficacy Trial (SAFE-T) is a randomized, double-blind, multicenter, placebo-controlled trial in which the effects of sotalol and amiodarone in maintaining stability of sinus rhythm are being examined in patients with persistent atrial fibrillation at 20 Veterans Affairs medical centers. The time to the occurrence of atrial fibrillation or flutter in patients with atrial fibrillation converted to sinus rhythm is the primary outcome measure, with a number of parameters as secondary end points. SAFE-T had randomized 665 patients when enrollment terminated on October 31, 2001. Follow-up of patients continued until October 31, 2002, for a maximum period of 54 months and a minimum period of 12 months for all patients.