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Aims: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy., Methods and Results: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR., Conclusion: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Energy levels for electrocardioversion in atrial fibrillation (AF) have been empiric, and the influence of antiarrhythmic therapy compared with placebo is largely unknown., Objective: The purpose of this study was to determine systematically the energy levels for electrocardioversion in patients with persistent AF and to define the influence of antiarrhythmic therapy., Methods: Patients (n = 665) with persistent AF were randomized to amiodarone, sotalol, or placebo. Rate control, if necessary, was achieved with digoxin, diltiazem, or verapamil. Among the 665 patients, 504 who did not achieve sinus rhythm at day 28 had electrocardioversion systematically by a prespecified four-step protocol as follows: monophasic shocks-100, 200, 360, 360 J; or biphasic shocks-150, 175, 200, 200 J sequentially. Energy levels and shock waveforms (monophasic/biphasic) for successful electrocardioversion (sinus rhythm for at least 1 minute) and use of antiarrhythmic therapy and calcium channel blockers were recorded., Results: Electrocardioversion was successful in 371 (71.6%) of 504 patients: 72%, 73.5%, and 67.9% for patients assigned to amiodarone, sotalol, and placebo, respectively. Overall, after adjustments for age, body mass index (BMI), history of AF, shock waveforms, left atrial size, and ejection fraction, both amiodarone (odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.24-3.77, P <.01) and sotalol (OR: 1.92, 95% CI: 1.11-3.33, P = .02) significantly facilitated successful electrocardioversion compared with placebo. Calcium channel blockers had no effect on the success rate of electrocardioversion. Success of electrocardioversion was associated with lower BMI, AF history < or =1 year, and older age. Compared with placebo, patients taking amiodarone were significantly more likely to achieve successful electrocardioversion in step 1 (OR: 2.73, 95% CI: 1.11-6.74, P = .03) and step 3 (OR: 1.86, 95% CI: 1.00-3.44, P = .05) but not in steps 2 and 4. Sotalol was superior to placebo in step 4 (OR: 2.58, 95% CI: 1.02-6.52, P = .05) and trended in step 2 (OR: 1.7, 95% CI: 0.98-3.07, P = .06). Successful electrocardioversion was seen in 11%, 29%, 38%, and 29% in steps 1, 2, 3, and 4, respectively. Compared with monophasic shocks, biphasic shocks achieved higher success rates for step 1 (P <.001) and step 2 (P <.01), respectively. Antiarrhythmic therapy did not influence the total number of energy steps used for the patients with successful electrocardioversion. However, biphasic shocks, lower BMI, and AF duration < or =1 year were associated with less energy step used for successful cardioversion., Conclusion: Amiodarone and sotalol facilitated successful electrocardioversion, which could be achieved in a stepwise fashion. Upon achievement of successful electrocardioversion, amiodarone is superior to placebo, and sotalol has a lesser effect. Antiarrhythmic drugs had no effect on the total number of energy step use in patients who had successful electrocardioversion. Calcium channel blockers had no influence on the success rate in achieving sinus rhythm. Successful electrocardioversion was associated with lower BMI and AF history < or =1 year. Lower energy use was associated with biphasic shocks, lower BMI, and AF duration < or =1 year.

Background: Many patients receiving amiodarone therapy are male. The long-term risk for amiodarone-induced thyroid dysfunction in these patients has not been systematically and prospectively investigated. The purpose of this study was to determine the extent of amiodarone-induced thyroid dysfunction in a large male cohort., Methods: This is a substudy of a prospective randomized controlled trial (SAFE-Trial) in which amiodarone, sotalol, and placebo for persistent atrial fibrillation were evaluated. For the purpose of this substudy, sotalol and placebo groups were combined into a control group. Serial thyroid function tests were performed over 1-4.5 years. Of the 665 patients enrolled in the SAFE-Trial, 612 patients were included in this sub-study., Results: Subclinical hypothyroidism, thyroid-stimulating hormone (TSH) level 4.5-10 mU/L, was seen among 25.8% of the amiodarone-treated patients and only 6.6% of controls (P <.0001). Overt hypothyroidism, TSH level >10 mU/L, was seen among 5.0% of the amiodarone-treated patients, and only 0.3% of controls (P <.001). By 6 months, 93.8% of the patients who developed TSH elevations above 10 mU/L on amiodarone had been detected. There was a trend toward a greater proportion of hyperthyroidism, defined as a TSH <0.35 mU/L, in the amiodarone group compared with the control group (5.3% vs 2.4%, P=.07)., Conclusions: Hypothyroidism developed in 30.8% of older males treated with amiodarone and in only 6.9% of the controls. Hypothyroidism presented at an early stage of therapy. Hyperthyroidism occurred in 5.3% of amiodarone treated patients, and was a subclinical entity in all but 1 case.

Implantable cardioverter defibrillators (ICDs) are increasingly used for the prevention of sudden cardiac death in patients with life-threatening ventricular arrhythmias (VAs); however, there is a potential for severe and debilitating anxiety caused by symptoms associated with ICD therapy and anticipation of shocks. Anxiety is a psycho-logic stressor, including physiologic components that may lead to adrenergic excitation triggering new arrhythmias and ICD therapies. This often requires concomitant antiarrhythmic medication to reduce the frequency of shocks and symptomatic arrhythmias treated by anti-tachycardia pacing. Although published studies have documented the efficacy of currently available antiarrhythmics, they have limitations in patients with heart failure, may affect the defibrillation threshold, and/or have been associated with major side-effects. In conclusion, for the patient with an ICD experiencing symptomatic ventricular tachycardia (VTs) episodes or ICD shocks, there is a need for pharmacologic therapy to reduce the incidence of such events without affecting the performance of the ICD or causing major side-effects.

Background: Therapy for chronic atrial fibrillation (AF) focuses on rate versus rhythm control, but little is known about the effects of common therapeutic interventions on exercise tolerance in AF., Methods: Six hundred fifty-five patients with chronic AF underwent maximal exercise testing at baseline and 8 weeks, 6 months, and 1 year after randomization to sotalol, amiodarone, or placebo therapy and attempted direct current cardioversion. Analyses of baseline determinants of exercise capacity, predictors of change in exercise capacity at 6 months and 1 year, and the short- and long-term effects of cardioversion on exercise capacity were made., Results: Age, obesity, and presence of symptoms accompanying AF were inversely associated with baseline exercise capacity, but these factors accounted for only 10% of the variance in exercise capacity. Patients most likely to benefit from cardioversion were those most limited initially, younger, not obese or hypertensive, and with an uncontrolled ventricular rate at baseline. Conversion to sinus rhythm (SR) resulted in significant reductions in resting (approximately 25 beat/min) and peak exercise (approximately 40 beat/min) heart rates at 6 months and 1 year (P < .001). Successful cardioversion improved exercise capacity by 15% at 8 weeks, and these improvements were maintained throughout the year. This improvement was observed both among those who maintained SR and those with intermittent AF., Conclusion: Cardioversion resulted in a sustained improvement in exercise capacity over the course of 1 year, and this improvement was similar between those in SR and those with SR and recurrent AF. Patients most likely to improve with treatment tended to be younger and nonobese and have the greatest limitations initially.

Background: Heart failure complicated by atrial fibrillation (AF) is associated with excessive mortality and morbidity. The aim of the study was to determine the role of amiodarone or implantable cardioverter/defibrillator (ICD) in patients with AF and heart failure., Methods: Patients were determined to be in sinus rhythm (SR) or AF on the baseline electrocardiogram. Mortality, ICD discharge, or change in rhythm was assessed., Results: Of the 2521 patients at baseline, 2328 were in SR and 173 were in AF. Overall, after adjusting for differences in baseline variables, there was no difference in mortality between patients with SR and patients with AF (P = .98), nor within assigned groups: placebo (P) (P = .82), amiodarone (A) (P = .68), and ICD (P = .40). For patients with SR, ICD decreased mortality (P vs ICD, P = .004; A vs ICD, P = .004; P vs A, P = .75). For patients with AF, there were no differences in mortality among groups (P vs ICD, P = .99; A vs ICD, P = .88; P vs A, P = .88). Of patients with SR at baseline, 11% (264) developed AF by any electrocardiogram during follow-up (P 12%, A 8%, ICD 15%; A vs P, P = .019; A vs ICD, P = .001; P vs ICD, P = .044). Of patients with AF, 70% (121) developed SR during follow-up (P 66%, A 67%, ICD 75%, all P = not significant against each other). Any ICD shock was seen in 52% (34) of patients with AF vs 30% (222) of patients with SR (P = .001). Inappropriate shocks were seen in 37% (24) of patients with AF vs 14% (107) of patients with SR (P = .001). Appropriate shocks were more often seen in AF vs SR (P = .03)., Conclusion: After adjustments for baseline differences, patients with AF and patients with SR have similar overall mortality rates. Compared to P or A, ICD improves survival in patients with SR, but may not in patients with AF. Amiodarone is effective in reducing new AF, but not in converting AF to SR. Implantable cardioverter/defibrillator, inappropriate, and appropriate shocks were more often seen in AF than in SR.

Objectives: The purpose of this study was to determine quality of life (QOL) and exercise performance (EP) in patients with persistent atrial fibrillation (AF) converted to sinus rhythm (SR) compared with those remaining in or reverting to AF., Background: Restoration of SR in patients with AF improving QOL and EP remains controversial., Methods: Patients with persistent AF were randomized double-blind to amiodarone, sotalol, or placebo. Those not achieving SR at day 28 were cardioverted and classified into SR or AF groups at 8 weeks (n = 624) and 1 year (n = 556). The QOL (SF-36), symptom checklist (SCL), specific activity scale (SAS), AF severity scale (AFSS), and EP were assessed., Results: Favorable changes were seen in SR patients at 8 weeks in physical functioning (p < 0.001), physical role limitations (p = 0.03), general health (p = 0.002), and vitality (p < 0.001), and at 1 year in general health (p = 0.007) and social functioning (p = 0.02). Changes in the scores for SCL severity (p = 0.01), functional capacity (p = 0.003), and AFSS symptom burden (p < 0.001) at 8 weeks and in SCL severity (p < 0.01) and AF symptom burden (p < 0.001) at 1 year showed significant improvements in SR versus AF. Symptomatic patients were more likely to have improvement. The EP in SR versus AF was greater from baseline to 8 weeks (p = 0.01) and to 1 year (p = 0.02). The EP correlated with physical functioning and functional capacity except in the AF group at 1 year., Conclusions: In patients with persistent AF, restoration and maintenance of SR was associated with improvements in QOL measures and EP. There was a strong correlation between QOL measures and EP.

Background: The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial., Methods: In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring., Results: Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial fibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups., Conclusions: Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance., (Copyright 2005 Massachusetts Medical Society.)

Objectives: The purpose of this study was to assess the effect of oral azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial., Background: Previous clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF., Methods: A total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12., Results: Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04)., Conclusions: Azimilide was safe and effective AF therapy in patients with depressed LV function after an MI.

Despite the recent results of the AFFIRM trail showing that either strategy of rate control or rhythm control is acceptable, there is general agreement that therapy must be individualized. Antiarrhythmic drugs while being effective in maintaining sinus rhythm are not without side effects. Thus, there continues to be a search for safer and better tolerated agents. Azimilide is a novel class 3 agent that blocks both components of the delayed rectifier current, while dofetilide blocks only the slow component. Dronedarone is somewhat similar to aminodarone, but perhaps with the side effects. Tedisamil is a complex class 3 agent, blocking multiple channels. Piboserod is a selective 5-HT receptor antagonist that is being investigated in clinical trials.

Dofetilide is a class III antiarrhythmic drug (potassium channel blocker) that has been approved by the regulatory agencies in the United States and throughout the world to convert atrial fibrillation and maintain sinus rhythm. Therapy is initiated in-hospital during heart rhythm monitoring. Doses are selected according to the QT interval and estimated creatinine clearance. In patients with heart failure and prior myocardial infarction, dofetilide was very effective in converting atrial fibrillation and maintaining normal sinus rhythm. In patients with persistent atrial fibrillation, dofetilide compared to placebo was significantly better in converting atrial fibrillation and maintaining sinus rhythm. This was especially true for the highest dose of 500 microg twice-a-day. Caution must be used when initiating dofetilide therapy to avoid torsade de pointes ventricular tachycardia, especially in patients with heart failure, hypertrophy, bradycardia and female gender.

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.

BACKGROUND: Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. METHODS: In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. RESULTS: Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. CONCLUSION: Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.