Intrapericardial Ibutilide Administration Fails to Terminate Pacing-Induced Sustained Atrial Fibrillation in Dogs

PURPOSE: The hypothesis that intrapericardial (ip.) ibutilide administration would terminate pacing-induced sustained atrial fibrillation (AF) and ibutilide distribution were tested. METHODS AND RESULTS: Sustained (> or =24 hours) AF was induced by 59 +/- 20 day rapid atrial pacing in 19 dogs. After sustained AF was present, the atrial pacemaker was turned off and 9 open chest dogs received 0.015 mg/kg ibutilide (37 degrees C) in 30 ml saline into the pericardial sac. Ten control dogs received 30 ml saline (37 degrees C) ip. QT intervals, right ventricular monophasic action potential duration at 90% of repolarization (RV-MAPD(90)), AF mean cycle length (AFCL(m)), systolic- and diastolic intraarterial blood pressures, intrapericardial-, right atrial- and ventricular pressures, cardiac output and ibutilide concentrations were measured. If AF persisted after the 1st drug infusion, dual site rapid atrial pacing (DRAP) simultaneously from the high right atrium and coronary sinus was performed to terminate AF. If it was ineffective, a 2nd ip. drug infusion in the same fashion as the 1st one, was attempted. There was no significant difference in AF termination [5/9 (56%) in ibutilide treated and 3/10 (30%) in control dogs] between the two groups. DRAP never terminated AF. The AF duration did not differ between the two groups. Compared with control, ibutilide treatment prolonged significantly AFCL(m) (p < 0.001) and non-significantly QT, RV-MAPD(90). No significant difference was found in systolic and diastolic blood pressure and cardiac output between the two groups. The two orders of magnitude greater ibutilide concentration in the pericardial fluid than that in the femoral vein decreased rapidly over time, drug concentration was greatest in the atria, smaller in the ventricular myocardium, with a trend decreasing from the epi- to endocardium. CONCLUSIONS: Despite a significant atrial electrophysiological effect, ip. delivery of ibutilide did not result in higher AF termination rate compared with control.     

心房颤动的药物治疗进展

心房颤动是临床上最常见的心律失常类型,患病率随年龄增长而增加,药物是心房颤动治疗的首选,由于传统抗心律失常药物潜在的致心律失常作用及心脏外的不良反应,故而在心房颤动的治疗中受限。近年一些新药的研制给心房颤动的治疗带来了新的希望,也为临床医生提供了更多的选择。现就心房颤动药物治疗进展做一综述。     

Persistent Atrial Flutter in Patients Treated for Atrial Fibrillation with Amiodarone and Propafenone:

INTRODUCTION: Antiarrhythmic drugs have been reported to promote the conversion of atrial fibrillation to atrial flutter in patients with paroxysmal atrial fibrillation. However, information about the electrophysiologic mechanism and response to radiofrequency ablation of these drug-induced atrial flutters is limited. Furthermore, the determinants of the development of persistent atrial flutter in patients treated for atrial fibrillation with antiarrhythmic drugs are still unknown. METHODS AND RESULTS: Among the 136 patients treated for atrial fibrillation with amiodarone (n = 96) or propafenone (n = 40), 15 (11%, mean age 65.5 +/- 12.3 years) were identified to have subsequent development of persistent atrial flutter based on surface ECG characteristics during antiarrhythmic drug treatment. The mean interval between the beginning of drug treatment and the onset of atrial flutter was 5.0 +/- 5.5 months. Intracardiac mapping and entrainment studies revealed that 11 patients had counterclockwise typical atrial flutter, and 4 had clockwise typical atrial flutter. All 15 patients underwent successful ablation with creation of complete bidirectional isthmus conduction block. After a mean follow-up of 12.3 +/- 4.2 months, 14 (93%) of 15 patients who underwent successful ablation and continued taking antiarrhythmic drugs have remained in sinus rhythm. Univariate analysis of clinical variables demonstrated that only atrial enlargement was significantly related to the occurrence of persistent atrial flutter. CONCLUSION: In patients with atrial fibrillation, persistent typical atrial flutter might occur during antiarrhythmic drug treatment, and atrial enlargement was a risk factor for the development of such an arrhythmia. Radiofrequency ablation and continuation of pharmacologic therapy offered a safe and effective means of achieving and maintaining sinus rhythm.     

A Review of Clinical Trials Assessing the Efficacy and Safety of Newer Antiarrhythmic Drugs in Atrial Fibrillation

Clinical trials assessing the efficacy of anti- arrhythmic drugs for terminating atrial fibrillation have demonstrated that rate control drugs have little to no added efficacy compared to placebo; however, spontaneous conversion of recent-onset atrial fibrillation is common. Antiarrhythmic drugs such as oral dofetilide, oral bolus-flecainide and propafenone and intravenous ibutilide all have a role in terminating atrial fibrillation. Active comparator trials have demonstrated that amiodarone is more efficacious in maintaining sinus rhythm than propafenone and sotalol. Multiple trials have demonstrated the safety of amiodarone, sotalol, dofetilide and azimilide in a post-myocardial infarction population and amiodarone and dofetilide in a congestive heart failure population. Newer antiarrhythmic agents, some with novel mechanisms of action, will add to the pharmacologic armamentarium in treating atrial fibrillation.     

The Future of Atrial Fibrillation Therapy

Today management of atrial fibrillation (AF) centers on restoration and maintenance of normal sinus rhythm or control of the ventricular rate response to AF. Current guidelines state that rhythm and rate control strategies should be considered therapeutically equivalent, but recognize that no "one size fits all," an approach consistent with growing recognition of the heterogeneity of AF. As data from the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial clearly demonstrate, conventional antiarrhythmics have a role in highly symptomatic AF accompanied by decreased quality of life. However, for many AF patients such drugs lack efficacy, have potentially serious side effects, and are poorly tolerated. In parallel with the development of more effective and safer antiarrhythmics, nontraditional approaches to prevention and treatment of AF are being explored. Treatments not considered "antiarrhythmic" that may prevent or forestall AF include aggressive antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and some, but not all, beta-blockers and calcium channel antagonists, especially when used as adjunctive therapy. Other approaches include statins, steroids, and fish oil to reduce atrial fibrosis and inflammation, and pacemakers to prevent bradycardia-mediated AF and as a pacing preventive strategy in selected patients. Ablative techniques with potential to cure AF are gaining popularity, but are not yet simple, straightforward, and risk-free procedures. In the future, treatment of AF will progress beyond today's focus on AF as a purely electrocardiographic disease toward a patient and context-specific management strategy involving multiple treatment modalities.     

Pharmacotherapy of Atrial Fibrillation

Atrial fibrillation is a common medical problem that has a wide clinical spectrum ranging from a benign condition, such as “lone” atrial fibrillation, to a life-threatening arrhythmia, when there is an accessory pathway. There is a striking contrast between the frequency of atrial fibrillation and the absence of well-defined, scientifically based medical management. At least four considerations guide the pharmacological treatment of patients with atrial fibrillation: (1) restoration of sinus rhythm; (2) acute and long-term control of the ventricular rate; (3) maintenance of sinus rhythm; and (4) anticoagulation. Pharmacological cardioversion is best achieved with intravenous flecainide, intravenous propafenone, or intravenous ibutilide. During episodes of atrial fibrillation, the drugs of first choice for control of the ventricular rate are calcium antagonists and beta-blockers. Digitalis is helpful in elderly patients and in cases with congestive heart failure. Maintenance of sinus rhythm is a complex task, owing to the proarrhythmic potential of antiarrhythmic drugs, and the treatment should be tailored to the individual patient's needs. No one drug is clearly better than another. As for amiodarone, its benefit/risk ratio remains to be evaluated prospectively. Usually, most of the patients benefit from serial electrical cardioversion, with the longest possible interval between cardioversion sessions being sought. The question about whether the aim of the treatment of atrial fibrillation should be to control the ventricular rate or to restore sinus rhythm will be answered by ongoing trials. The effectiveness of low-dose anticoagulation in preventing stroke in patients with nonrheumatic atrial fibrillation has been validated by seven separate studies. Anticoagulation with warfarin should be monitored carefully in order to achieve an International Normalized Ratio (INR) of between 2.0 and 3.0. This targeted INR decreases the embolic rate and eliminates the risk of intracranial bleeding. The role of aspirin alone in decreasing the risk of stroke remains to be established. Pharmacological management of patients with atrial fibrillation has to be improved, by better risk stratification and the development of new drugs with an optimal benefit/risk ratio. Ongoing trials are expected to provide important guidelines, corresponding to the needs of the many different types of patients with atrial fibrillation.     

Assessment of Rhythm and Rate Control in Patients with Atrial Fibrillation

A recent series of randomized prospective clinical trials that compared rate control with rhythm control in patients with atrial fibrillation (AF) found no significant difference in primary outcome between the two strategies. However, these trials lacked clear criteria for defining "successful" rate or rhythm control. Various measures have been used to gauge the success of antiarrhythmic drug therapy, including time to first recurrence of AF, any AF recurrence, AF burden, and a reduction in symptoms. Determining the success of antiarrhythmic therapy can be relatively straightforward by using how patients feel during therapy as a key endpoint. Most patients are satisfied with a major reduction in symptomatic AF episodes and can live comfortably with occasional episodes of AF. For those who are bothered by even infrequent, brief AF episodes, a treatment regimen that eliminates nearly all AF recurrences is required, although often hard to achieve. Catheter ablation may be necessary to achieve a successful outcome in these patients. Suppression of AF in a patient at high risk of stroke does not, however, remove the need for concomitant warfarin therapy. The endpoints of ventricular rate control are not clear, and the recently published rhythm versus rate control trials lacked standard criteria for judging acceptable rate control. One relatively simple method is to try and achieve a 24-hour heart rate that mimics expected normal sinus rhythm. It is important to achieve good rate control to minimize symptoms and the risk of tachycardia-mediated cardiomyopathy.     

Chronic Atrial Fibrillation

ABSTRACT One hundred consecutive patients admitted in 1980–82 for direct current conversion of chronic atrial fibrillation (AF) were followed. The first attempt to convert was made without the institution of class I antiarrhythmics. If AF relapsed, patients were selected for further conversions, in connection with which quinidine or disopyramide treatment was instituted. The proportion of patients maintaining sinus rhythm (SR) one and two years after the first conversion was 23% and 16%, after the second conversion 40% and 33% and after any number of conversions [1–12] 54% and 41%. Fifty-three per cent of the patients were symptomless before at least one conversion. Of the patients maintaining SR two years after conversion, 46% did not receive antiarrhythmic therapy. More than two conversions should be exceptional since symptoms of AF are often absent and the additional effect of further conversions is minor. A first attempt to convert without antiarrhythmics identifies a substantial proportion of patients maintaining SR without any prophylactic antiarrhythmic therapy.     

Atrial Ectopics Prior to Atrial Fibrillation Onset

Background: This study examined the possible role of atrial ectopics and short runs of atrial tachycardia in the initiation of episodes of paroxysmal atrial fibrillation (PAF). Methods: Holter recordings from patients participating in pharmacotherapy trials for the prevention of PAF were examined. Treatment comprised placebo, digoxin, disopyramide, or atenolol. The frequency of atrial ectopic beats during each 30 seconds over the 5 minutes prior to PAF and whether this was also associated with atrial tachycardia (3 or more ectopics in succession) was calculated. Results: The mean number of ectopics was 4.1 in the final minute, but patients receiving disopyramide or atenolol had significantly more ectopics than those on placebo (P > 0.05 for both). Those on digoxin had a similar number of ectopics to placebo patients. There was no relationship between heart rate at PAF onset and ectopic frequency, nor any association between the presence of one or more episodes of atrial tachycardia and ectopic frequency. Conclusion: Atrial ectopics increase in frequency prior to PAF onset, and this study suggests that antiarrhythmic therapy may increase the number of ectopics required to initiate PAF.     

Amiodarone in Atrial Fibrillation

ABSTRACT Twenty-seven patients with atrial fibrillation without any concomitant conduction abnormality have been treated with oral amiodarone in a daily maintenance dose of 200 mg. The drug has been used for three purposes: 1) to block atrioventricular conduction, thereby decreasing the ventricular rate during atrial fibrillation (9 patients), 2) as prophylaxis against paroxysmal atrial fibrillation (8 patients), 3) as prophylaxis against recurrence of atrial fibrillation after DC conversion to sinus rhythm (13 patients). All patients were considered refractory to other antiarrhythmic drugs in these respects. In the second group, 4 of the 8 patients reported complete cessation of attacks and the others a marked reduction of the attack rate. In the third group, 10 of the 13 patients have maintained sinus rhythm for a longer period on treatment with amiodarone than with other drugs, resulting more than a triple prolongation of the time in sinus rhythm. In 3 patients the drug has been discontinued because of side-effects. In conclusion, amiodarone affords protection from episodes of paroxysmal atrial fibrillation, as well as from recurrence of atrial fibrillation after DC conversion to sinus rhythm. If the drug is ineffective in either of these respects, it may still be useful as a means of moderating the ventricular response in atrial fibrillation.     

Medical Management of Atrial Fibrillation: State of the Art

Predominantly a disease of advancing age, atrial fibrillation (AF) is the most common sustained arrhythmia. Its prevalence is rising as the proportion of elderly people in the population continues its inexorable rise. Without more effective therapeutic interventions, AF-related cardiovascular and cerebrovascular morbidity and mortality will also continue to rise. Antiarrhythmic drugs are an essential tool in the management of AF and may be used as premedication before cardioversion; together with cardioversion to help or assist cardioversion; or given afterward to prevent recurrence. If AF recurs after one or two cardioversions, then it is usual to adopt a rate control strategy; highly symptomatic patients who fail cardioversion may benefit from ablation therapy. We are already on the threshold of a large expansion in the use of ablation therapy, a strategy that has potential to deliver dramatic improvements in outcome. Not only can AF be cured by ablative therapy, but there is also evidence that it confers functional improvement as well. It will not, however, be appropriate for all AF patients and pharmacological therapies will continue to have an important place in the management of AF. The plethora of antiarrhythmic drugs currently available for the treatment of AF is a reflection that none is wholly satisfactory, each having limited efficacy combined with poor safety and tolerability. Improved class III antiarrhythmic agents, such as dronedarone; new classes of antiarrhythmic agents, such as atrial repolarization delaying agents; and upstream therapies dealing with substrate represent potential sources of new pharmacological therapies for AF.     

Pharmacological Conversion of Atrial Fibrillation of Ten-Years Duration with Flecainide

A case of idiopathic atrial fibrillation of ten-years duration refractory to quinidine therapy, but successfully converted to sinus rhythm following flecainide therapy is presented. With the availability of newer more potent antiarrhythmic drugs, such as flecainide, conversion of previously refractory atrial fibrillation may be possible.     

Analysis of the Surface Electrocardiogram for Monitoring and Predicting Antiarrhythmic Drug Effects in Atrial Fibrillation

Specific antiarrhythmic therapy with class I and III drugs for atrial fibrillation (AF) conversion and prevention of its recurrence is frequently utilized in clinical practice. Besides being only moderate effective, the utilization of antiarrhythmic drugs may be associated with serious side effects. In the clinical setting it is difficult to directly evaluate the effects of antiarrhythmic drugs on the individual patient’s atrial electrophysiology, thereby predicting their efficacy in restoring and maintaining sinus rhythm. Analysis of the surface electrocardiogram in terms of P-wave signal averaged ECG during sinus rhythm and spectral characterization of fibrillatory waves during AF for evaluation of atrial antiarrhythmic drug effects is a new field of investigation. Both techniques provide reproducible parameters for characterizing atrial electrical abnormalities and seem to contain prognostic information regarding antiarrhythmic drug efficacy. Further research is needed which elucidates the most challenging clinical questions in AF management whom to place on antiarrhythmic drug treatment and what antiarrhythmic drug to prescribe. Analysis of the surface ECG might have the potential to answer these questions.     

Early Antiarrhythmic Therapy Is No Better than Rate Control Therapy Alone for Suppression of Atrial Fibrillation After Cardiac Surgery

Background: Despite recent advances in therapy for atrial fibrillation (AF) following cardiac surgery, the potential superiority of antiarrhythmics over rate control therapy for suppression of AF has not been convincingly demonstrated. We sought to determine whether early treatment of AF following cardiac surgery with antiarrhythmics improves clinical outcome, as measured by recurrence rate, length of stay, and adverse events. Methods: Out of 1100 consecutive patients undergoing cardiovascular surgery from July 1997 to June 1998, AF was identified in 425 (38.6%) prior to discharge. Patients with a history of chronic AF prior to cardiovascular surgery and patients who died within 48 hours of cardiovascular surgery were excluded from the analysis; 365 patients were studied. Group I patients received rate control alone; Group II received antiarrhythmic drugs within 24 hours of the first onset of AF. Results: With the exception of frequency of pulmonary disease (4 vs 17, P = 0.009), CABG rate (35 vs 45%, P = 0.045), and rate of valve surgery (24 vs 15%, P = 0.028), there were no significant differences in clinical characteristics between the two groups. The rate of return to sinus rhythm within 24 hours (80 vs 82%), and the percentage of patients leaving the hospital in sinus rhythm (90 vs 92%) were similar between the two groups, as were total length of stay (10.6 ± 6.0 vs. 11.4 ± 5.8, P = 0.159) and postoperative length of stay (8.4 ± 15.0 vs. 9.4 ± 5.3, P = 0.061). Embolic event rates were similar in both groups (eight in Group I and three in Group II). Proarrhythmia occurred in two patients receiving early antiarrhythmic therapy. Conclusion: Traditional use of early antiarrhythmic therapy appears to provide no clear advantage to rate control after cardiovascular surgery in terms of length of stay, freedom from AF at discharge, and other common clinical outcomes. Routine use of antiarrhythmics for suppression of AF should be carefully reconsidered. A.N.E. 2000;5(4):365–372     

心律平与氟卡胺预防阵发性心房颤动的对比观察

比较心律平与氟卡胺对阵发性心房颤动的疗效发现,心律平(n=66)1个月、6个月及1年的有效率分别为30.3％、37.5％和34.4％;氟卡胺(n=36)则分别为47.2％、61.8％和69.7％。氟卡胺6个月及1年有效率均高于心律平(P<0.05)。本研究提示氟卡胺对阵发性心房颤动有较好的预防作用。     

Long-term Efficacy of Flecainide in Paroxysmal Atrial Fibrillation

Abstract. The efficacy and safety of flecainide for long-term prevention of paroxysmal atrial fibrillation (AF) were studied in an open trial. Twenty patients with very frequent attacks (mean 13 per month) of paroxysmal AF for many years (mean 8 years) participated. Before inclusion, the patients had unsuccessfully been treated with an average of 3.3 antiarrhythmic drugs. Efficacy was jugded from a carefully kept diary in which the patients made daily notes of any AF attacks and possible side-effects from 1 month before treatment until the end of a follow-up period of 6 months. Twelve patients (60%) were completely free from AF and 11 of these are still successfully treated with flecainide after 11–38 months (mean 24 months). Flecainide plasma levels did not differ between responders and non-responders. Eleven patients (55%) had adverse effects but these were usually mild and well tolerated, necessitating withdrawal or dose reduction resulting in relapse of AF only in three patients (15%). No proarrhythmic events were seen.     

Evaluation of Atrial Refractoriness and Atrial Fibrillation Inducibility Immediately after Internal Cardioversion in Patients with Chronic Persistent Atrial Fibrillation

Summary. Objective: To prospectively evaluate right atrial refractoriness and sustained atrial fibrillation (AF) inducibility at programmed electrical stimulation in two groups of patient: a series of patients with chronic persistent AF, studied immediately after successful low energy internal atrial cardioversion, and a group of control patients without history of supraventricular arrhythmias.Patients: Nineteen patients with chronic persistent AF (mean AF duration 11 ± 10 months, range 2–61 months) submitted to successful internal low energy atrial cardioversion in fully conscious state and 11 control patients without history of supraventricular arrhythmias.Methods: An electrophysiological evaluation was performed to measure atrial refractoriness and AF inducibility, by delivering single atrial extrastimuli in high right atrium, at decremental coupling, during spontaneous sinus rhythm and after 8 beats at 600, 500, 400 and 330 ms cycle length. If sustained AF was induced the protocol was terminated.Results: During programmed atrial stimulation sustained AF was induced in 8 out 19 (42%) of the AF patients but in none of the control group. Atrial effective refractory period was significantly shorter in AF patients compared to controls both at basic cycle length, at 600 ms, 500 ms and 400 ms cycle length, meanwhile no statistically significant differences were found at 330 ms cycle length. An altered relationship between atrial effective refractory period and cycle length was found in AF patients compared to controls: the slope of linear correlation slope was significantly lower in AF group than in controls (0.04 ± 0.07 vs 0.17 ± 0.10, p < 0.002).Conclusions: Marked abnormalities of atrial refractoriness and of its heart rate relationship are observed after internal cardioversion of chronic persistent AF in humans and these abnormalities are associated with an high vulnerability to AF. These observations may explain the high risk of AF recurrences in the early phases following successful cardioversion. In this scenario antiarrhythmic drug therapy seems to be mandatory for reducing arrhythmia relapses.