Atrial Fibrillation: Restoration and Maintenance of Sinus Rhythm and Indications for Anticoagulation Therapy

15 August 1996 | Volume 125 Issue 4 | Pages 311-323

Purpose: To review the efficacy and safety of electrical and pharmacologic conversion of atrial fibrillation, strategies for maintenance of sinus rhythm, and the importance of antithrombotic therapy.

Data Sources: English-language trials were identified from the MEDLINE database through 1995, bibliographic references, Current Contents, textbooks, and recent abstracts.

Study Selection: Randomized trials (including abstracts) were selected. Cohort studies were used if randomized trials were not available.

Data Extraction: Study design and data were extracted from clinical trials. Statistical analysis of combined data was not appropriate, given the marked variations in study designs and study populations.

Data Synthesis: Cardioversion restores sinus rhythm in more than 80% of patients. In atrial fibrillation of recent onset, pharmacologic regimens have a success rate of 40% to 90%. Sinus rhythm at 1 year is maintained in 30% of patients without antiarrhythmic therapy but in 50% of patients with such therapy. The efficacy and safety of antiarrhythmic drugs relative to one another are not established because trials done to date have been small and cases vary. Successful cardioversion and maintenance of sinus rhythm are most predictable when the duration of atrial fibrillation is brief.

Warfarin reduces the incidence of ischemic strokes and emboli in patients with nonvalvular atrial fibrillation from 4.5% to 1.4% per year. Aspirin (325 mg/d) appears to be equally effective in patients younger than 75 years of age who do not have hypertension or a history of thromboembolism or recent heart failure. Although warfarin is more effective than aspirin in preventing embolic strokes in patients older than 75 years of age, it may increase the incidence of hemorrhagic stroke and result in a similar rate of disabling stroke.

Conclusion: Cardioversion remains the preferred method with which to re-establish sinus rhythm. Long-term antiarrhythmic therapy is warranted only if recurrences or initial clinical instability are seen; pro-arrhythmic concerns and potential side effects should guide drug selection. Antithrombotic therapy is indicated for all patients older than 60 years of age and in all patients younger than 60 years of age who have clinical evidence of a primary cardiac disorder.

Atrial fibrillation is the most common arrhythmia that requires therapeutic intervention. Although it is rare in infancy and childhood, its incidence increases twofold with every decade after 55 years of age [1]. Because the population of the United States is aging, atrial fibrillation has become the most frequent principal diagnosis of cardiac rhythm disturbance at hospital discharge [2].

In this review, we focus on the rationale for, methods for, and problems of restoring and maintaining sinus rhythm. The limitations of current therapies and information about their optimal use are highlighted by a review of randomized trials of drug therapy for restoring and maintaining sinus rhythm. Data that document the importance of antithrombotic therapy are also discussed.

Consequences of Atrial Fibrillation

Embolic Events

Atrial fibrillation is the most common cardiac condition that predisposes a person to systemic embolism. In the Framingham Study [3], rheumatic heart disease with atrial fibrillation was associated with a 17.5-fold increase in risk for stroke. Flegel and coworkers [4] estimated the relative risk for stroke in chronic nonrheumatic atrial fibrillation to be 6.9; this is close to the estimate of 5.6 found in the Framingham study [3]. The risk for cerebral embolism is emphasized by the association of asymptomatic cerebral infarctions with nonvalvular atrial fibrillation [5]. The rate of stroke in paroxysmal atrial fibrillation had been estimated to be about 2% per year [6], but a recent analysis of trials of warfarin for stroke prevention [7] suggests an annual rate of 5.7%.

The risk for stroke is lower with lone atrial fibrillation, which is defined as the absence of any other clinical evidence for a primary cardiac disorder. Data from the Framingham Study [8] showed a fourfold increase in risk for stroke, but Kopecki and associates [9] did not find any increased risk. The latter used a more restricted sample of patients with lone atrial fibrillation; all patients with pre-existing hypertension or diabetes and those older than 60 years of age were excluded. Additionally, transient ischemic attacks were excluded as an end point. Analysis of pooled data from antithrombotic trials confirms that patients younger than 65 years of age who do not have a history of hypertension, diabetes, transient ischemic attack, or stroke are at very low risk for stroke [7]. The different incidences of stroke in these and other prospective studies [10] have been interpreted as suggesting that atrial fibrillation is not the principal risk factor for stroke but is a risk marker for other associated cardiovascular diseases that lead to stroke [11, 12].

Hemodynamic Dysfunction

Ventricular filling is reduced as a consequence of both the shortened diastolic time seen with rapid ventricular rates and the loss of active atrial transport; the latter can be more disabling in older patients because the contribution of the atrium to ventricular filling increases with age [13]. Mean left atrial and pulmonary wedge pressures rise, and cardiac output and mean arterial pressure may decrease. A rapid ventricular response is particularly hazardous when ventricular filling has already been compromised, as is the case with mitral stenosis or abnormal ventricular relaxation. Hemodynamic instability with the onset of atrial fibrillation is more likely to occur in the presence of left ventricular systolic dysfunction or previous myocardial infarction or when left atrial contraction is responsible for more than 40% of ventricular filling [14].

Reduced exercise capacity can result from an abnormally high ventricular rate at rest or during exercise [15] or from underlying heart disease [16]. Restoration of sinus rhythm by direct-current cardioversion reduces maximal heart rate, improves exercise capacity [17-19], and enhances cardiac output [20, 21]. These improvements may be delayed for weeks and may be related to the gradual return of atrial transport and improved left ventricular systolic function [18, 19].

Cardiomyopathy

Tachycardia-mediated cardiomyopathy has been considered an uncommon complication of chronic atrial fibrillation, but noninvasive imaging suggests that its prevalence is greater than previously acknowledged. Phillips and Levine [22] first emphasized that atrial fibrillation can cause congestive heart failure in patients with apparently normal hearts and that restoration of sinus rhythm can be curative. Chronic, uncontrolled tachycardia [23-26] and chronic atrial fibrillation with sustained, rapid ventricular rates [22, 27-31] can result in severe cardiomyopathy, which is usually reversible after either rate control [27, 28] or restoration of sinus rhythm [28, 30, 31].

Death

The mortality rate of patients with atrial fibrillation is twice that of the general population, perhaps because of the association between atrial fibrillation and vascular disease [32, 33]. Atrial fibrillation enhances myocardial vulnerability and decreases the fibrillation threshold, which can facilitate the induction of ventricular tachyarrhythmias and sudden death [34, 35]. Patients with the Wolff-Parkinson-White syndrome are particularly at risk; the rapid ventricular rates, which result from conduction through accessory pathways with short refractory periods, lack of concealed conduction, or both, can degenerate into ventricular fibrillation [36]. Sudden death also may occur as a result of the proarrhythmic effects of medications used to maintain sinus rhythm [37, 38].

In summary, the hazards associated with atrial fibrillation emphasize the desirability of restoring and maintaining sinus rhythm in most patients.

Approaches to Conversion to Sinus Rhythm

Cardioversion

External

Direct-current cardioversion is the most widely used and successful approach for restoring sinus rhythm. This major advance, introduced by Lown and coworkers [39, 40], had fewer complications than did quinidine therapy and had a success rate of 94% [41]. Synchronized cardioversion soon became the method of choice for restoring sinus rhythm, and its overall success rate exceeds 80% [41-54].

Cardioversion can produce adverse effects [42, 55]. Embolic events, hypotension, depression of left ventricular contractility, and pulmonary edema may occur [42, 55-57]. Major cardiac arrhythmias can develop during [58, 59] and after [60-62] cardioversion. Other problems, such as depressed sinus node function [41], transient T-wave changes, ST-segment depression or elevation [63], and pacemaker malfunction [64-66] have been noted. Anesthesia, which is required, infrequently results in adverse events [67]. Despite occasional complications, cardioversion is the most effective means of restoring sinus rhythm.

Internal

In many patients, sinus rhythm is not restored by external cardioversion. In 1988, Levy and coworkers [68] introduced internal high-energy transcatheter cardioversion done using a monophasic waveform with a catheter cathode (placed in the lower right atrium) and a backplate anode. This internal method of cardioversion was effective in patients who were resistant to pharmacologic and external cardioversion. A recent randomized crossover trial showed that internal transcatheter cardioversion was superior to external cardioversion [69]. Unlike external cardioversion, internal transcatheter cardioversion delivers almost all of the electrical energy to the right atrium. There are two hypotheses about why this procedure succeeds: Either the increased intracardiac pressure during endocavitary shock stretches the cardiac structures and modifies their electrophysiologic properties [68, 70] or the high-energy shock ablates a crucial area that permits atrial fibrillation or flutter to occur [71] and changes the electrophysiologic properties of the atrium, thereby reducing the likelihood of recurrence.

Cooper and colleagues [72] showed that an internal electrode system (in which one electrode is used in the distal coronary sinus and the other is used in the right atrium) and a biphasic waveform of 3 milliseconds for each polarity of the waveform resulted in a low energy requirement for cardioversion (1.3 ± 0.4 J) in sheep. The safety and efficacy of this approach have been tested in humans, and preliminary data are promising [73]. These results raise the possibility of using an implantable atrial cardioverter in patients with recurrent symptomatic atrial fibrillation that is resistant to pharmacologic treatment and requires several cardioversions. Perhaps methodological and technological improvements in internal cardioversion will allow the routine conversion of atrial fibrillation of recent onset with minimal or no anesthesia.

Pharmacologic Conversion

Oral Agents and Digoxin

Before the widespread use of cardioversion, quinidine was the drug of choice for conversion. This approach was expensive, time consuming, limited in efficacy, and potentially hazardous [37, 62, 74, 75]. Now that both cardioversion and newer antiarrhythmic agents are available, quinidine is used infrequently for conversion.

Most physicians assume that digoxin helps restore sinus rhythm, but few data support this premise. In a randomized, double-blind trial [76, 77] done to compare intravenous digoxin with placebo for the conversion of atrial fibrillation of recent onset in patients without heart failure, no difference in conversion frequency was found. No placebo-controlled trials have examined the efficacy of digoxin for conversion when heart failure is present. The electrophysiologic effects of digoxin on atrial tissue cast doubt on the potential utility of this drug for restoring and maintaining sinus rhythm. This agent shortens the atrial refractory period, which increases the rate of fibrillation and the possibility of multiple re-entry circuits and thus increases the chances of initiating and perpetuating atrial fibrillation [78]. Digoxin does not prevent paroxysmal atrial fibrillation [79] and can convert such fibrillation to the chronic established form [80, 81]. It also has no effect on the catecholamine-dependent form of paroxysmal atrial fibrillation [82] and may aggravate that of vagal origin [79, 81, 83]. Digoxin can also attenuate the efficacy of amiodarone in the prevention of the disorder [81, 82]. Thus, it is unlikely that digoxin plays a direct role in restoring sinus rhythm [83].

Oral amiodarone therapy is a slow but effective way to restore sinus rhythm; this agent has even been effective in clinical settings in which successful conversion was considered unlikely [84, 85]. In a cohort study, Santos and colleagues [86] showed an 86% conversion rate for atrial fibrillation of less than 2 years' duration. Gold [87] and Rowland [88] and their colleagues found conversion rates of 59% and 40%, respectively, for a period of 1 to 2 months in patients who were refractory to conventional antiarrhythmic agents; the effectiveness of amiodarone appeared to be independent of underlying pathology.

Sotalol has some of the same class III properties as amiodarone. However, in a multicenter, randomized, double-blind trial [89], sotalol was no better than placebo at restoring sinus rhythm in a few patients who had chronic atrial fibrillation and were receiving digitalis. A recent Finnish trial [90] found sotalol to be less effective than quinidine.

Class IC agents are efficacious in patients with atrial fibrillation of recent onset. In a single-blind, placebo-controlled trial [91], a single oral dose (300 mg) of flecainide led to conversion to sinus rhythm in 91% of patients; 48% of persons in the placebo group had conversion (P < 0.01). A randomized, unblinded trial [92] of flecainide given at an initial oral dose of 200 mg followed by 100 mg 1 hour later (and, if needed, by 100 mg 2 hours later) showed a conversion rate of 72%. In a cohort study [93], oral propafenone restored sinus rhythm in 77% of patients with chronic atrial fibrillation refractory to other IA or IC agents. In a randomized trial [94], propafenone was superior to digoxin plus quinidine or placebo at 12 hours in patients with atrial fibrillation that had lasted 8 days or less. At 48 hours, however, the number of patients who converted to sinus rhythm was similar in all three groups. For atrial fibrillation of less than 7 days' duration, a single 300-mg oral dose of flecainide and a single 600-mg oral dose of propafenone showed similar efficacy [95].

Intravenous Agents

Randomized trials of intravenous medications are summarized in Table 1. These trials [96-116] did not include patients with atrial fibrillation of more than 2 weeks' duration; in most patients, the fibrillation had usually lasted less than 72 hours. The studies also differ in the type of atrial fibrillation (recent onset or paroxysmal), inclusion of atrial flutter, comorbid conditions, duration of arrhythmia, and criteria for success. All drugs appear to be more efficacious when atrial fibrillation is of very recent onset. For example, in the esmolol trial [112], sinus rhythm was never restored when atrial fibrillation had lasted more than 48 hours; in a flecainide trial [92], conversion failed when atrial fibrillation had lasted longer than 24 hours. As have the trials of oral agents, the trials of intravenous agents have included only a small number of patients and have infrequently been placebo-controlled. Thus, the true efficacy of these agents has not been established, because atrial fibrillation of recent onset often terminates spontaneously [88, 91, 105]. Large clinical trials are needed to assess the relative safety, efficacy, and cost of the various oral and intravenous regiments for converting atrial fibrillation of recent onset to sinus rhythm.

View this table: [in this window] [in a new window]   Table 1. Randomized Trials of Intravenous Medications for Conversion of Atrial Fibrillation and Flutter to Sinus Rhythm*

 

Sequential Approach of Pharmacologic and Electrical Conversion to Sinus Rhythm

An attempt at pharmacologic conversion is appropriate when atrial fibrillation is of very recent onset. However, routine pretreatment with class IA or IC agents before cardioversion, although frequently proposed, has not been validated. In fact, the largest randomized trial of the role of quinidine in conversion [117] showed no difference between patients treated with quinidine and controls in the frequency of atrial or ventricular arrhythmias after conversion, the energy levels needed for conversion, or the success rate of conversion. Theoretical concerns about the routine use of antiarrhythmic agents before electrical conversion exist; large doses of any of the class I [118] or class III agents may suppress sinoatrial node activity, and some class I antiarrhythmic agents may increase the energy needed for conversion of atrial fibrillation [119]. Thus, the routine use of class I antiarrhythmic agents before electrical conversion appears unwarranted unless long-term antiarrhythmic therapy is anticipated.

Maintenance of Sinus Rhythm

Maintenance of sinus rhythm is not assured after electrical or pharmacologic conversion. From controlled trials, it can be estimated that sinus rhythm can be maintained at 1 year in only about 30% of patients who receive placebo (Table 2). Although this estimate may be adversely biased by selection criteria, such data emphasize the need for effective and safe approaches to the long-term maintenance of sinus rhythm.

View this table: [in this window] [in a new window]   Table 2. Randomized Trials of Antiarrhythmic Agents to Maintain Sinus Rhythm after Cardioversion*

 

Pharmacologic Therapy

Long-acting quinidine preparations, disopyramide, flecainide, sotalol, and amiodarone are more effective than placebo, but almost half of treated patients are likely to revert to atrial fibrillation within 1 year (Table 2). This high recurrence rate reflects the limited efficacy of these drugs and the high incidence of treatment cessation caused by drug side effects [136, 137]. Deriving specific therapeutic recommendations from these pharmacologic trials is difficult because the study populations differed, the numbers of patients were small, patient subsets were not identified, duration of follow-up was usually brief, follow-up visits were less frequent than desired, measurements of levels of drug in the blood were frequently unavailable, dropout rates were not always provided, and some trials were not properly randomized. More trials to assess propafenone are warranted because of the agent's value in treating paroxysmal atrial fibrillation [138, 139], but possible serious side effects have discouraged widespread use of this drug [139].

ß-blocker therapy is a potentially useful strategy in patients who are likely to have increased sympathetic activity because ß-blockers reduce the incidence of atrial fibrillation after cardiac surgery [140-142]. Another attractive approach is low-dose amiodarone therapy [143-145]. Gosselink and colleagues [145] have shown that approximately 200 mg of amiodarone per day is often successful. Even smaller doses may be effective and safe, but long-term trials are needed to define the role of these potential therapies.

The pro-arrhythmic potential of class I agents was highlighted by the increased mortality rates associated with flecainide or encainide therapy in the Cardiac Arrhythmia Suppression Trial [146]. Meta-analysis of placebo-controlled quinidine trials for the suppression of atrial fibrillation identified an increase in all-cause mortality rates (odds ratio, 2.98 [P < 0.05]) in patients receiving quinidine; three sudden deaths and one cardiac arrest with successful resuscitation occurred in the quinidine group [147]. Despite the limitations of meta-analysis, this report heightens concern about the safety of long-term antiarrhythmic therapy. The risk for drug-induced torsades de pointes is enhanced by metabolic disturbances, left ventricular dysfunction, history of ventricular tachycardia, prolongation of the QT interval, and relative bradycardia. In addition, known or unknown risk factors may arise during lifetime therapy for the suppression of atrial fibrillation. Amiodarone appears to have the lowest pro-arrhythmic effect of all anti-arrhythmic drugs currently available [148].

Cardiac Pacing

Single-chamber ventricular pacing is associated with an increased incidence of atrial fibrillation [149, 150]. This increase may be the result of atrioventricular asynchrony and the ensuing transient but recurrent elevations of atrial pressure, or it may be a consequence of ventriculo-atrial conduction and disturbed intra-atrial conduction. Notably, dual chamber pacing reduces the incidence of atrial fibrillation, particularly in patients with the sick sinus syndrome [149-151], and lessens rates of thromboembolism [151].

Interruption of Intra-Atrial Conduction

Intra-operative electrophysiologic mapping of the atria has supported the hypothesis that the interaction of multiple wavelets of activation sustained fibrillation [152]. This led to the maze procedure, which incorporated several precisely defined incisions in the atria to create blind alleys of conduction. These alleys interrupt re-entry circuits and prevent atrial fibrillation [152, 153]. Atrial transport function, although reduced, is usually preserved [154]. In a long-term follow-up study by Ferguson and Cox [153], 59% of patients were still in sinus rhythm. A modification of this surgical technique has been applied in patients with sustained atrial fibrillation who need other forms of cardiac surgery [155, 156]. Outcome data from these studies appear promising: More than 80% of patients were in sinus rhythm at 6 months, and most exhibited atrial transport function. Intra-atrial conduction has even been altered by a radio-frequency catheter ablation technique that emulates the maze procedure [157]. Because few patients have been followed for long periods, the incidences of recurrent atrial fibrillation and thromboembolic events are not established. Apart from their potential utility, these procedures have advanced our understanding of the pathophysiologic processes that sustain atrial fibrillation.

The corridor surgical approach isolates the fibrillating right and left atria from the interatrial septum, thereby establishing a corridor of contiguous tissue from the sinus node to the atrioventricular node [158]. This procedure preserves sinus node control of heart rate, but atrial transport function is more problematic because the atria usually continue to fibrillate. Surgical intervention might be considered for highly symptomatic patients who are unresponsive or intolerant to medications or for patients who require cardiac surgery for concomitant problems. In other circumstances of problematic atrial fibrillation, catheter ablation or modification of conduction in the bundle of His, with or without the implantation of a rate-responsive ventricular pacemaker, appear preferable [159, 160].

Spontaneous conversion of long-standing atrial fibrillation occurs occasionally [161-164] and appears to be secondary to left atrial fibrosis [164]. This process is similar to that achieved by the maze procedure. Spontaneous restoration of sinus rhythm in these situations rarely results in hemodynamic or symptomatic improvement [161-163].

Predicting Restoration and Maintenance of Sinus Rhythm

Duration of atrial fibrillation is the most reliable and powerful predictor of the success of electrical or pharmacologic conversion and of the probability of maintaining sinus rhythm [51, 53, 75, 165-168]. Atrial fibrillation of short duration, as seen in patients with pneumonia, pericarditis, alcohol binges, or respiratory failure, often spontaneously reverts to sinus rhythm. In contrast, sinus rhythm becomes progressively more difficult to restore and maintain when present for longer than 1 year [51, 53, 75, 165-169]. Structural changes in the atria, such as disuse atrophy [170] and fibrosis, occur with chronic but not with acute atrial fibrillation [171]. Echocardiographic data show that long-standing atrial fibrillation leads to dysfunctional atrial musculature. The atria dilate over time [172, 173], and when sinus rhythm is restored, full recovery of atrial contractile function is often delayed [168, 174]. Experimental studies of induced atrial fibrillation show a progressive reduction in the atrial refractory period when fibrillation continues for 6 hours to 4 days; this reduction would tend to sustain fibrillation and, if sinus rhythm were restored, would make the atria more vulnerable to recurrent fibrillation [175]. The atrial refractory periods gradually normalized when sinus rhythm was restored after several weeks of fibrillation [175]. Perhaps electrophysiologic alterations would become irreversible after longer periods of fibrillation.

Lack of response to treatment increases with age [176]. This may result from atrial fibrosis, amyloid deposition, gradual loss of nodal fibers, an increase of fibrous and adipose tissue in the sinoatrial node, and some degree of atrial dilatation [171, 176, 177].

The causes of atrial fibrillation are less predictive of successful conversion to sinus rhythm, although patients with rheumatic heart disease have lower conversion rates [75, 166] and are less likely to maintain sinus rhythm [53]. The success rate associated with direct-current cardioversion in persons with lone atrial fibrillation appears to be lower [178]. Many physicians assume that atrial size predicts restoration of sinus rhythm. In fact, atrial enlargement may reflect the duration of atrial fibrillation [172, 173], and the size of the left atrium does not appear to independently influence the immediate outcome of conversion or the recurrence of atrial fibrillation [168, 169, 179] unless the diameter of the left atrium is greater than 6 cm.

Antithrombotic Therapy

Long-term warfarin therapy prevents stroke in patients who have atrial fibrillation associated with either rheumatic valvular disease [180, 181] or prosthetic heart valves [181]. However, in nonvalvular atrial fibrillation, the value of anticoagulation therapy was not established until the recent publication of randomized, prospective, primary prevention trials (Table 3). All placebo-controlled trials were terminated prematurely because of the high rate of adverse events seen in the control groups. Combined analysis of these trials showed a reduction in the incidence of ischemic stroke or embolus from 4.5% to 1.4% per year, for a risk reduction of 69% [7, 188]. The annual rate of major bleeding was similar for warfarin and aspirin.

View this table: [in this window] [in a new window]   Table 3. Randomized Trials of Warfarin for Primary Prevention of Thromboembolism in Nonvalvular Atrial Fibrillation

 

Although aspirin appeared to be beneficial in the Stroke Prevention in Atrial Fibrillation (SPAF) I trial [183], the efficacy of aspirin relative to that of warfarin was not established until the completion of the randomized SPAF II trial [187]. This unblinded study showed that the rates of ischemic stroke and systemic emboli (primary end points) for patients receiving aspirin (325 mg/d) and patients receiving warfarin did not differ significantly in patients 75 years of age or younger, in patients older than 75 years of age, or in patients from both groups combined. However, the study confirmed that a history of hypertension, thromboembolism, or recent heart failure was an important risk factor for thromboembolism. Patients with such risk factors and patients who were older than 75 years of age had a lower rate of primary events with warfarin. The data from SPAF II plus those of other epidemiologic studies suggest that aspirin therapy may be sufficient in patients 75 years of age and younger without risk factors; if any risk factor is present, however, warfarin is preferable [189]. In patients older than 75 years of age, SPAF II showed warfarin to be more effective in preventing thromboembolism at the cost of a greater risk for intracranial hemorrhage (1.8% for patients older than 75 years compared with 0.5% for patients 75 years of age or younger). Consequently, the incidence of stroke with residual deficit was similar with aspirin and with warfarin. Previous trials [182-186] did not find an increased incidence of intracranial hemorrhage in patients older than 75 years of age, but the number of patients receiving anticoagulation therapy was small, anticoagulation therapy did not last long, and hypertension was less prevalent [179, 183]. Stroke prevention in patients older than 75 years of age remains a therapeutic challenge [188], particularly because international normalized ratios less than 2.0 do not appear to prevent ischemic events [190].

No randomized, controlled trials evaluating the efficacy of prophylactic antithrombotic therapies before pharmacologic or electrical conversion have been done. Nevertheless, anticoagulation therapy is warranted: It has been suggested that incidence of stroke increases with the onset of atrial fibrillation [191], and it is known from transesophageal echocardiographic studies that thrombi are found in the atria before conversion [192-194] and that atrial contraction may be impaired for some time after conversion [168, 174]. The role of immediate anticoagulation therapy for atrial fibrillation of less than 48 hours' duration remains unexplored.

Anticoagulation therapy is substantially more effective than aspirin in the secondary prevention of stroke and vascular events. The European Atrial Fibrillation Trial [190, 195] showed a 47% reduction in the overall risk for vascular events (P < 0.001) and a decrease in the rate of stroke from 12% to 4% per year. The optimal time for initiating anticoagulation therapy in patients with recent stroke and atrial fibrillation is controversial. Without anticoagulation therapy, stroke recurs early, within 2 weeks of the event in 3% to 12% of patients [196]. The Cerebral Embolism Study Group [197, 198] proposed that, in patients with small or moderate embolic infarctions, anticoagulation therapy should be initiated if no evidence of hemorrhage is shown on computed tomography (CT) 24 to 48 hours after stroke. In patients who have large infarctions, anticoagulation therapy should be started if, after 7 days, CT excludes the possibility of delayed hemorrhage.

Discussion

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Large clinical trials that could identify the optimal approach to restoring sinus rhythm are lacking. Similarly, the optimal pharmacologic agent for long-term maintenance of sinus rhythm has not been identified. Thus, categorical recommendations for individual patients cannot be made on the basis of published data. The complexity of the decision-making process is heightened by the profound heterogeneity of the population with atrial fibrillation. Until large clinical trials that allow analyses of subpopulations are completed, therapeutic decisions can only be made on the basis of our best judgment. We propose therapeutic approaches to common presentations of atrial fibrillation (Figure 1).

View larger version (26K): [in this window] [in a new window]   Figure 1. Algorithms for the management of atrial fibrillation applicable to patients other than those with recent stroke. Top. Atrial fibrillation of less than 48 hours' duration. Bottom. Atrial fibrillation of more than 48 hours' duration. * = Consider transesophageal echocardiography; if no intracardiac thrombi are found, proceed directly to cardioversion while continuing anticoagulation therapy. The success rate of cardioversion exceeds that of pharmacologic conversion when the duration of atrial fibrillation is more than 2 or 3 days.

 

When a patient initially presents with atrial fibrillation, a prompt search is warranted for such specific contributing factors as hyperthyroidism, pulmonary infection, pulmonary embolism, a hypersympathetic state associated with acute alcohol ingestion, and underlying heart disease. Identification of cardiac disease is greatly enhanced by echocardiography. The results of these investigations should guide the approach to therapy.

The decision to attempt restoration of sinus rhythm must be preceded by consideration of the likelihood of successful conversion and maintenance of sinus rhythm and of whether the benefits of these efforts outweigh the risks. The probability of long-term success is low if atrial fibrillation has been present for longer than 1 year or if the patient has a history of multiple recurrences of fibrillation despite antiarrhythmic therapy. Furthermore, sinus rhythm is of uncertain benefit in asymptomatic patients who have well-controlled ventricular rates and no contraindications to antithrombotic therapy.

Treatment of atrial fibrillation precipitated by acute illness should focus on control of the ventricular rate, because sinus rhythm returns spontaneously in most patients. In this setting, the rapid ventricular rate often reflects increased sympathetic activity and can be controlled quickly through the careful use of ß-blockers, diltiazem, or verapamil rather than digoxin [199]. Anticoagulation therapy may not be needed unless arrhythmia persists for longer than several days, at which point aspirin or subcutaneous or intravenous heparin should be considered.

Atrial fibrillation of recent onset in patients without overt cardiac disease is common. The severity of symptoms often relates to the ventricular rate, which should be promptly controlled. If the arrhythmia has lasted less than 48 hours, electrical or pharmacologic conversion should be done promptly to obviate the need for anticoagulation therapy. If the duration of atrial fibrillation is unknown, anticoagulation therapy for 3 to 4 weeks is indicated before either electrical or pharmacologic conversion is attempted. Recent studies [193, 194, 200] have shown that cardioversion can proceed immediately with a low risk for thromboembolism if transesophageal echocardiography excludes intracardiac thrombi and if the patient has had anticoagulation therapy. Anticoagulation therapy should be maintained for at least 1 month. Use of drugs to maintain sinus rhythm is not generally warranted for the first occurrence of atrial fibrillation [201] unless the presentation was life-threatening.

If atrial fibrillation is a consequence of clinically significant myocardial or valvular heart disease, treating the underlying cardiac condition and initiating anticoagulation therapy are paramount. Ventricular rate must be controlled; although verapamil is contraindicated when ventricular dysfunction is severe, a ß-blocker or diltiazem can usually be given without untoward effects. Digoxin alone is often ineffective. Amiodarone is particularly useful for rate control because it has minimal negative inotropic and pro-arrhythmic effects. Because atrial fibrillation is more likely to recur in patients with underlying cardiac disease, [166, 167], antiarrhythmic therapy is appropriate, especially if the patient is at high risk for clinically unstable atrial fibrillation [14]. An antiarrhythmic drug should be selected on the basis of its potential adverse effects in a specific patient. If myocardial dysfunction is present, class I agents should be avoided because of the increased risk for proarrhythmia and the negative inotropic effects. When maintenance of sinus rhythm is unsuccessful and control of ventricular rate is suboptimal, catheter ablation or modification of atrioventricular conduction should be considered. It is uncertain whether the maze procedure, done using surgical or percutaneous ablation techniques, or such devices as an automatic atrial defibrillator have a future role in the control of atrial fibrillation.

Patients with the Wolff-Parkinson-White syndrome, atrial fibrillation, and accessory pathways with short antegrade refractory periods are best treated by radiofrequency ablation of the accessory pathways. Success rates of more than 90% are reported, and complications seldom occur [202, 203]. Patients with a relatively long antegrade refractory period of the accessory pathway or those who refuse catheter ablation can be treated with class IA agents, class IC agents, or amiodarone [204, 205]. Cardioversion is mandatory in patients with a rapid ventricular rate and hemodynamic compromise. Digitalis, ß-blockers, or calcium channel blockers should not be used to control ventricular rate for the following reasons: They do not impair conduction through the accessory pathways and may even accelerate conduction, resulting in a faster ventricular response and possible ventricular fibrillation [78]; ß-blockers and calcium channel blockers are negative inotropes and, as such, could worsen hemodynamics; and the vasodilating effects of calcium channel blockers may aggravate hypotension.

Atrial fibrillation may be asymptomatic, particularly when impaired atrioventricular conduction prevents an excessive ventricular rate; this is more common in elderly patients. Because of the risks related to antiarrhythmic therapy and the uncertainty of improvement in functional status after cardioversion, it is reasonable to allow atrial fibrillation to persist and to assure continued antithrombotic therapy.

Summary

Sinus rhythm should be restored by electrical or pharmacologic conversion in most patients with symptomatic atrial fibrillation and atrial fibrillation of recent onset (Figure 1).

If antiarrhythmic therapy is warranted (Figure 1) to help maintain sinus rhythm, the agent should be selected on the basis of a low potential for adverse effects in a specific patient. The value of attempting to restore and maintain sinus rhythm is less clear when atrial fibrillation is chronic and associated with few symptoms (Figure 1).

Antithrombotic therapy is effective in reducing the incidence of ischemic strokes and embolism in patients with chronic atrial fibrillation. Risk factors for thromboembolism in patients with nonvalvular atrial fibrillation include hypertension, previous thromboembolism, and recent heart failure. If any of these factors are present, warfarin is more effective than aspirin. In patients older than 75 years of age, the probable increased incidence of hemorrhagic stroke with warfarin as compared with aspirin may cause similar rates of disabling stroke. Thus, the optimal management of atrial fibrillation in the very elderly remains problematic.

Addendum: Two important papers have been published since the authors submitted their manuscript.

Laupacis A, Albers G, Dalen J, Dunn M, Feinberg W, Jacobsen A. Antithrombotic therapy in atrial fibrillation. Chest. 1995; 108:352-359S.

Prystowsky EN, Benson W, Fuster V, Hart RG, Kay EN, Myerburg RJ, et al. Management of patients with atrial fibrillation. A statement for healthcare professionals from the subcommittee on electrocardiology and electrophysiology, American Heart Association. Circulation. 1996; 93:1262-77.

Drs. Cebul and Bahler: MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998.

Author and Article Information

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From Case Western Reserve University and MetroHealth Medical Center, Cleveland, Ohio.
Acknowledgments: The authors thank Carol Smith for help with manuscript preparation, Dr. Louis Rakita for his helpful review, and the Brittingham Library Staff of MetroHealth Medical Center for their professional support.
Requests for Reprints: Robert C. Bahler, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998.
Current Author Addresses: Dr. Golzari: 307-B Essex Street, Hackensack, NJ 07601.

References

Top Discussion Author & Article Info References

1.  Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994; 271:840-4.

2.  Bialy D, Lehmann MH, Schumacher DN, Steinman RT, Meissner MD. Hospitalization for arrhythmias in the United States: importance of atrial fibrillation. J Am Coll Cardiol. 1992; 19:41A.

3.  Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology. 1978; 28:973-7.

4.  Flegel KM, Shipley MJ, Rose G. Risk of stroke in non-rheumatic atrial fibrillation. Lancet. 1987; 1:526-9.

5.  Feinberg WM, Seeger JF, Carmody RF, Anderson DC, Hart RG, Pearce LA. Epidemiologic features of asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation. Arch Intern Med. 1990; 150:2340-4.

6.  Petersen P, Godtfredsen J. Embolic complications in paroxysmal atrial fibrillation. Stroke. 1986; 17:622-6.

7.  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154:1449-57.

8.  Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study. JAMA. 1985; 254:3449-53.

9.  Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR Jr, Ilstrup DM, et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med. 1987; 317:669-74.

10.  Davis PH, Dambrosia JM, Schoenberg BS, Schoenberg DG, Pritchard DA, Lilienfeld AM, et al. Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol. 1987; 22:319-27.

11.  Chesebro JH, Fuster V, Halperin JL. Atrial fibrillation—risk marker for stroke [Editorial]. N Engl J Med. 1990; 323:1556-8.

12.  Kalman JM, Tonkin AM. Atrial fibrillation: epidemiology and the risk and prevention of stroke. Pacing Clin Electrophysiol. 1992; 15:1332-46.

13.  Sun JP, Dawson NV, Hsiue IL, Bahler RC. Normal values for Doppler echocardiographic intracardiac flow velocities in an adult Chinese population: the relation between age and diastolic filling. Journal of Cardiovascular Ultrasonography. 1988; 7:247-56.

14.  Tischler MD, Lee TH, McAndrew KA, Sax PE, Sutton MS, Lee RT. Clinical, echocardiographic and Doppler correlates of clinical instability with onset of atrial fibrillation. Am J Cardiol. 1990; 66:721-4.

15.  Atwood JE, Myers J, Sullivan M, Forbes S, Friis R, Pewen W, et al. Maximal exercise testing and gas exchange in patients with chronic atrial fibrillation. J Am Coll Cardiol. 1988; 11:508-13.

16.  Ueshima K, Myers J, Ribisl PM, Atwood JE, Morris CK, Kawaguchi T, et al. Hemodynamic determinants of exercise capacity in chronic atrial fibrillation. Am Heart J. 1993; 125(5 Pt 1):1301-5.

17.  Atwood JE, Myers J, Sullivan M, Forbes S, Sandhu S, Callaham P, et al. The effect of cardioversion on maximal exercise capacity in patients with chronic atrial fibrillation. Am Heart J. 1989; 118(5 Pt 1):913-8.

18.  Lipkin DP, Frenneaux M, Stewart R, Joshi J, Lowe T, McKenna WJ. Delayed improvement in exercise capacity after cardioversion of atrial fibrillation to sinus rhythm. Br Heart J. 1988; 59:572-7.

19.  Van Gelder IC, Crijns HJ, Blanksma PK, Landsman ML, Posma JL, Van Den Berg MP, et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease. Am J Cardiol. 1993; 72:560-6.[Medline]

20.  Resnekov L. Hemodynamic studies before and after electrical conversion of atrial fibrillation and flutter to sinus rhythm. Br Heart J. 1967; 29:700-8.

21.  Shaplro W, Klein G. Alterations in cardiac function immediately after electrical conversion of atrial fibrillation to normal sinus rhythm. Circulation. 1968; 38:1074-84.

22.  Philllps E, Levine SA. Auricular fibrillation without other evidence of heart disease. Am J Med. 1949; 7:478-89.

23.  Packer DL, Bardy GH, Worley SJ, Smlth MS, Cobb FR, Coleman RE, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol. 1986; 57:563-70.

24.  McLaran CJ, Gersh BJ, Sugrue DD, Hammill SC, Seward JB, Holmes DR Jr. Tachycardia induced myocardial dysfunction. A reversible phenomenon? Br Heart J. 1985; 53:323-7.

25.  Glllette PC, Smlth RT, Garson A Jr, Mulllns CE, Gutgesell HP, Goh TH, et al. Chronic supraventricular tachycardia. A curable cause of congestive cardiomyopathy. JAMA. 1985; 253:391-2.

26.  Morelra DA, Shepard RB, Waldo AL. Chronic rapid atrial pacing to maintain atrial fibrillation: use to permit control of ventricular rate in order to treat tachycardia induced cardiomyopathy. Pacing Clin Electrophysiol. 1989; 12:761-75.

27.  Helnz G, Slostrzonek P, Krelner G, Gossinger H. Improvement in left ventricular systolic function after successful radiofrequency His bundle ablation for drug refractory, chronic atrial fibrillation and recurrent atrial flutter. Am J Cardiol. 1992; 69:489-92.

28.  Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol. 1992; 69:1570-3.

29.  Sarembock IJ, Horak AR, Commerford PJ. Tachycardia-induced reversible left ventricular dysfunction. A report of 2 cases. S Afr Med J. 1988; 73:484-5.

30.  Kleny JR, Sacrez A, Facello A, Arbogast R, Barelss P, Roul G, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J. 1992; 13:1290-5.

31.  Kasper EK, Agema WR, Hutchins GM, Deckers JW, Hare JM, Baughman KL. The causes of dilated cardiomyopathy: a clinicopathologic review of 673 consecutive patients. J Am Coll Cardiol. 1994; 23:586-90.

32.  Kannel WB, Abbott RD, Savage DD, McNamara PM. Coronary heart disease and atrial fibrillation: the Framingham study. Am Heart J. 1983; 106:389-96.

33.  Lake FR, Cullen KJ, de Klerk NH, McCall MG, Rosman DL. Atrial fibrillation and mortality in an elderly population. Aust N Z J Med. 1989; 19:321-6.

34.  Somberg JC, Torres V, Gotlieb S, Butler B, Levltt B, Mlura DS. The enhancement of myocardial vulnerability by atrial fibrillation [Abstract]. Circulation. 1983; 68:III-56.

35.  Borggrefe M, Candinas R, Hief C, Karbenn U, Chen X, Haverkamp W, et al. Effect of atrial fibrillation on inducibility of VTNF during programmed ventricular stimulation [Abstract]. Circulation. 1991; 84:II-412.

36.  Meijler FL, van der Tweel I, Herbschleb JN, Hauer RN, Robles deMedina EO. Role of atrial fibrillation and atrioventricular conduction (including Wolff-Parkinson-White syndrome) in sudden death. J Am Coll Cardiol. 1985; 5(6 Suppl):17B-22B.

37.  Thomson GW. Quinidine as a cause of sudden death. Circulation. 1956; 14:757-65.

38.  Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Intern Med. 1992; 117:141-50.

39.  Lown B, Amarasingham R, Neuman J. New method for terminating cardiac arrhythmias. JAMA. 1962; 182:548-55.

40.  Lown B, Neuman J, Amarasingham R, Berkovits BV. Comparison of alternating current with direct current electroshock across the closed chest. Am J Cardiol. 1962; 10:223-33.

41.  Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J. 1967; 29:469-89.

42.  DeSilva RA, Graboys TB, Podrid PJ, Lown B. Cardioversion and defibrillation. Am Heart J. 1980; 100(6 Pt 1):881-95.

43.  Scott ME, Geddes JS, Patterson GC. The long term prognosis of atrial fibrillation following direct current conversion. Ulster Med J. 1968; 37:155-61.

44.  McCarthy C, Varghese PJ, Barritt DW. Prognosis of atrial arrhythmias treated by electrical counter shock therapy. A three-year follow-up. Br Heart J. 1969; 31:496-500.

45.  Castellanos A Jr, Lemberg L, Gosselin A, Fonseca EJ. Evaluation of countershock treatment of atrial flutter. Arch Intern Med. 1965; 115:426-33.

46.  Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol. 1969; 23:208-16.

47.  Karlson BW, Torstensson I, Abjorn C, Jansson SO, Peterson LE. Disopyramide in the maintenance of sinus rhythrn after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J. 1988; 9:284-90.

48.  Hartel G, Louhija A, Konttinen A. Disopyramide in the prevention of recurrence of atrial fibrillation after electroconversion. Clin Pharmacol Ther. 1974; 15:551-5.

49.  Byrne-Quinn E, Wing AJ. Maintenance of sinus rhythm after DC reversion of atrial fibrillation. A double-blind controlled trial of long-acting quinidine bisulfate. Br Heart J. 1970; 32:370-6.

50.  Hartel G, Louhija A, Konttinen A, Halonen PI. Value of quinidine in maintenance of sinus rhythm after electric conversion of atrial fibrillation. Br Heart J. 1970; 32:57-60.

51.  Hillestad L, Bjerkelund C, Dale J, Maltau J, Storstein O. Quinidine in maintenance of sinus rhythm after electroconversion of chronic atrial fibrillation. A controlled clinical study. Br Heart J. 1971; 33:518-21.

52.  Sodermark T, Edhag O, Sjogren A, Jonsson B, Olsson A, Oro L, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J. 1975; 37:486-92.

53.  Hall JI, Wood DR. Factors affecting cardioversion of atrial arrhythmias with special reference to quinidine. Br Heart J. 1968; 30:84-90.

54.  Gunning JF, Krlstlnsson A, Mlller G, Saunders K. Long-term follow-up of direct current cardioversion after cardiac surgery with special reference to quinidine. Br Heart J. 1970; 32:462-6.

55.  Paulk EA Jr, Hurst JW. Clinical problems of cardioversion. Am Heart J. 1965; 70:248-74.[Medline]

56.  Llndsay J Jr. Pulmonary edema following cardioversion. Am Heart J. 1967; 74:434-5.

57.  Sutton RB, Tsagarls TJ. Pulmonary edema following direct current cardioversion. Chest. 1970; 57:191-4.

58.  Frledberg CK, Cohn LJ, Donoso E. Arrhythmias following external directcurrent shock [Abstract]. Circulation. 1965; 31/32:II-89.

59.  Shaver JA, Kroetz FW, Tenlcela R, Lancaster JF, Leonard JJ. Postcardioversion ventricular tachycardia [Abstract]. Am J Cardiol. 1965; 15:146-7.

60.  Castellanos A Jr, Lemberg L, Gllmore H 3d, Johnson D. Countershock exposed quinidine syncope. Am J Med Sci. 1965; 250:254-60.[Medline]

61.  Yigitbasl O, Nalbantgll I. Ventricular fibrillation: a delayed complication of direct current shock. Cardiology. 1967; 51:307-9.

62.  Selzer A, Wray HW. Quinidine syncope. Circulation. 1964; 30:17-26.

63.  Chun PK, Davla JE, Donohue DJ. ST-segment elevation with elective DC cardioversion. Circulation. 1981; 63:220-4.

64.  Das G, Eaton J. Pacemaker malfunction following transthoracic countershock. Pacing Clin Electrophysiol. 1981; 4:487-90.

65.  Levine PA, Barold SS, Fletcher RD, Talbot P. Adverse acute and chronic effects of electrical defibrillation and cardioversion on implanted unipolar cardiac pacing systems. J Am Coll Cardiol. 1983; 1:1413-22.

66.  Altamura G, Blanconl L, Lo Bianco F, Toscano S, Ammirati F, Pandozl AC, et al. Transthoracic DC shock may represent serious hazard in pacemaker dependent patients. Pacing Clin Electrophysiol. 1996; 18(1 Pt 2):194-8.

67.  Grogono AW. Anesthesia for atrial defibrillation. Effect of quinidine on muscular relaxation. Lancet. 1963; 2:1039-40.

68.  Levy S, Lacombe P, Cointe R, Bru P. High energy transcatheter cardioversion of chronic atrial fibrillation. J Am Coll Cardiol. 1988; 12:514-8.

69.  Levy S, Lauribe P, Dolla E, Kou W, Kadish A, Calkins H, et al. A randomized comparison of external and internal cardioversion of chronic atrial fibrillation. Circulation. 1992; 86:1415-20.

70.  Levy S. Direct current cardioversion of established atrial fibrillation. Clin Cardiol. 1992; 15:445-9.

71.  Kumagal K, Yamanouchi Y, Hiroki T, Arakawa K. Effects of transcatheter cardioversion on chronic lone atrial fibrillation. Pacing Clin Electrophysiol. 1991; 14(11 Pt 1):1571-5.

72.  Cooper RA, Alferness CA, Smith WM, Ideker RE. Internal cardioversion of atrial fibrillation in sheep. Circulation. 1993; 87:1673-86.

73.  Murgatroyd FD, Slade AK, Sopher SM, Rowland E, Ward DE, Camm AJ. Efficacy and tolerability of transvenous low energy cardioversion of paroxysmal atrial fibrillation in humans. J Am Coll Cardiol. 1995; 25:1347-53.

74.  Davies P, Leak D, Oram S. Quinidine-induced syncope. Br Med J. 1965; 2:517-20.

75.  Holzman D, Brown MG. The use of quinidine in established auricular fibrillation and flutter. Am J Med Sci. 1951; 222:644-52.

76.  Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. A randomized, double-blinded trial. Ann Intern Med. 1987; 106:503-6.

77.  Detsky AS, Sackett DL. When was a negative clinical trial big enough? How many patients you needed depends on what you found. Arch Intern Med. 1985; 145:709-12.

78.  Meijler FL. An account of digitalis and atrial fibrillation. J Am Coll Cardiol. 1985; 5(5 Suppl A):60A-8A.

79.  Rawles JM, Metcalfe MJ, Jennings K. Time of occurrence, duration, and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J. 1990; 63:225-7.

80.  Kowey PR, DeSilva RA, Lown B. Sustained atrial fibrillation as a rhythm of choice [Abstract]. Circulation. 1979; 60(II):II-253.

81.  Coumel P. Clinical approach to paroxysmal atrial fibrillation. Clin Cardiol. 1990; 13:209-12.

82.  Coumel P, Leclercq JF, Attuel P. Paroxysmal atrial fibrillation. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atrial fibrillation. Kiruna, Sweden: Molndal; 1982:158-75.

83.  Falk RH, Leavitt JI. Digoxin for atrial fibrillation: a drug whose time has gone? Ann Intern Med. 1991; 114:573-5.

84.  Kopelman HA, Horowitz LN. Efficacy and toxicity of amiodarone for the treatment of supraventricular tachyarrhythmias. Prog Cardiovasc Dis. 1989; 31:355-66.

85.  Mostow ND, Vrobel TR, Noon D, Rakita L. Rapid control of refractory atrial tachyarrhythmias with high-dose oral amiodarone. Am Heart J. 1990; 120(6 Pt 1):1356-63.

86.  Santos AL, Aleixo AM, Landeiro J, Luis AS. Conversion of atrial fibrillation to sinus rhythm with amiodarone. Acta Med Port. 1979; 1:15-23.

87.  Gold RL, Haffajee CI, Charos G, Sloan K, Baker S, Alpert JS. Amiodarone for refractory atrial fibrillation. Am J Cardiol. 1986; 57:124-7.

88.  Rowland E, McKenna WJ, Krikler DM. Amiodarone for the conversion of established atrial fibrillation and flutter. Brit J Clin Pract Symp Suppl. 1986; 44:39-41.

89.  Singh S, Saini RK, DiMarco J, Kluger J, Gold R, Chen YW. Efficacy and safety of sotalol in digitalized patients with chronic atrial fibrillation. The Sotalol Study Group. Am J Cardiol. 1991; 68:1227-30.

90.  Halinen MO, Huttunen M, Paakkinen S, Tarssanen L. Comparison of sotalol with digoxin-quinidine for conversion of acute atrial fibrillation to sinus rhythm (the Sotalol-Digoxin-Quinidine Trial). Am J Cardiol. 1995; 76:495-8.

91.  Capucci A, Lenzi T, Boriani G, Trisolino G, Binetti N, Cavazza M, et al. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol. 1992; 70:69-72.

92.  Crijns HJ, van Wijk LM, van Gilst WH, Kingma JH, van Gelder IC, Lie KI. Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens. Eur Heart J. 1988; 9:634-8.

93.  Porterfield JG, Porterfield LM. Therapeutic efficacy and safety of oral propafenone for atrial fibrillation. Am J Cardiol. 1989; 63:114-6.

94.  Capucci A, Boriani G, Rubino I, Della Casa S, Sanguinetti M, Magnani B. A controlled study on oral propafenone versus digoxin plus quinidine in converting recent onset atrial fibrillation to sinus rhythm. Int J Cardiol. 1994; 43:305-13.

95.  Capucci A, Boriani G, Botto GL, Lenzi T, Rubino I, Falcone C, et al. Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide. Am J Cardiol. 1994; 74:503-5.

96.  Connolly SJ, Mulji AS, Hoffert DL, Davis C, Shragge BW. Randomized placebo-controlled trial of propafenone for treatment of atrial tachyarrhythmias after cardiac surgery. J Am Coll Cardiol. 1987; 10:1145-8.

97.  Suttorp MJ, Kingma JH, Jessurun ER, Lie-A-Huen L, van Hemel NM, Lie KI. The value of class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. J Am Coll Cardiol. 1990; 16:1722-7.

98.  Boriani G, Capucci A, Lenzi T, Sanguinetti M, Magnani B. Propafenone for conversion of recent-onset atrial fibrillation. A controlled comparison between oral loading dose and intravenous administration. Chest. 1995; 108:355-8.

99.  Vita JA, Friedman PL, Cantillon C, Antman EM. Efficacy of intravenous propafenone for the acute management of atrial fibrillation. Am J Cardiol. 1989; 63:1275-8.

100.  Gavaghan TP, Keogh AM, Kelly RP, Campbell TJ, Thorburn C, Morgan JJ. Flecainide compared with a combination of digoxin and disopyramide for acute atrial arrhythmias after cardiopulmonary bypass. Br Heart J. 1988; 60:497-501.

101.  Wafa SS, Ward DE, Parker DJ, Camm AJ. Efficacy of flecainide acetate for atrial arrhythmias following coronary artery bypass grafting. Am J Cardiol. 1989; 63:1058-64.

102.  Suttorp MJ, Kingma JH, Lie-A-Huen L, Mast EG. Intravenous flecainide versus verapamil for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. Am J Cardiol. 1989; 63:693-6.

103.  Kondili A, Kastrati A, Popa Y. Comparative evaluation of verapamil, flecainide and propafenone for the acute conversion of atrial fibrillation to sinus rhythm. Wien Klin Wochenschr. 1990; 102:510-3.

104.  Donovan KD, Dobb GJ, Coombs LJ, Lee KY, Weekes JN, Murdock CJ, et al. Reversion of recent-onset atrial fibrillation to sinus rhythm by intravenous flecainide. Am J Cardiol. 1991; 67:137-41.

105.  Donovan KD, Power BM, Hockings BE, Dobb GJ, Lee KY. Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation. Am J Cardiol. 1995; 75:693-7.

106.  Campbell TJ, Gavaghan TP, Morgan JJ. Intravenous sotalol for the treatment of atrial fibrillation and flutter after cardiopulmonary bypass. Comparison with disopyramide and digoxin in a randomised trial. Br Heart J. 1985; 54:86-90.

107.  Cowan JC, Gardiner P, Reid DS, Newell DJ, Campbell RW. A comparison of amiodarone and digoxin in the treatment of atrial fibrillation complicating suspected acute myocardial infarction. J Cardiovasc Pharmacol. 1986; 8:252-6.

108.  Pilati G, Lenzi T, Trisolino G, Cavazza M, Binetti N, Villecco AS, et al. Amiodarone versus quinidine for conversion of recent onset atrial fibrillation to sinus rhythm. Current Therapeutic Research. 1991; 49:140-6.

109.  McAlister HF, Luke RA, Whitlock RM, Smith WM. Intravenous amiodarone bolus versus oral quinidine for atrial flutter and fibrillation after cardiac operations. J Thorac Cardiovasc Surg. 1990; 99:911-8.

110.  Noc M, Stajer D, Horvat M. Intravenous amiodarone versus verapamil for acute conversion of paroxysmal atrial fibrillation to sinus rhythm. Am J Cardiol. 1990; 65:679-80.

111.  Hou ZY, Chang MS, Chen CY, Tu MS, Lin SL, Chiang HT, et al. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. A randomized, digoxin-controlled study. Eur Heart J. 1995; 16:521-8.

112.  Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol. 1989; 63:925-9.

113.  Madrid AH, Moro C, Marin-Huerta E, Mestre JL, Novo L, Costa A. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J. 1993; 14:1127-31.

114.  Hjelms E. Procainamide conversion of acute atrial fibrillation after openheart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg. 1992; 26:193-6.

115.  Campbell TJ, Morgan JJ. Treatment of atrial arrhythmias after cardiac surgery with intravenous disopyramide. Aust N Z J Med. 1980; 10:644-9.

116.  Toivonen LK, Nieminen MS, Manninen V, Frick MH. Conversion of paroxysmal atrial fibrillation to sinus rhythm by intravenous pirmenol. A placebo controlled study. Br Heart J. 1986; 55:176-80.

117.  Hillestad L, Dale J, Storstein O. Quinidine before direct current countershock. A controlled study. Br Heart J. 1972; 34:139-42.

118.  Wagner GS, McIntosh HD. The use of drugs in achieving successful DC cardioversion. Prog Cardiovac Dis. 1969; 11:431-42.

119.  Guarnieri T, Tomaselli G, Griffith LS, Brinker J. The interaction of antiarrhythmic drugs and the energy for cardioversion of chronic atrial fibrillation. Pacing Clin Electrophysiol. 1991; 14:1007-12.

120.  Normand JP, Legendre M, Kahn JC, Bourdarias JP, Mathivat A. Comparative efficacy of short-acting and long-acting quinidine for maintenance of sinus rhythm after electrical conversion of atrial fibrillation. Br Heart J. 1976; 38:381-7.

121.  Kennelly BM. Comparison of lidoflazine and quinidine in prophylactic treatment of arrhythmias. Br Heart J. 1977; 39:540-6.

122.  Woo KS, Kong SM. Disopyramide and quinidine in maintenance of sinus rhythm after electro-conversion [Abstract]. Circulation. 1980; 62(Suppl III):181.

123.  Rasmussen K, Wang H, Fausa D. Comparative efficiency of quinidine and verapamil in the maintenance of sinus rhythm after DC conversion of atrial fibrillation. A controlled clinical trial. Acta Med Scand Suppl. 1981; 645:23-8.

124.  Boissel JP; Wolf E, Gillet J, Soubrane A, Cavallaro A, Mazoyer G, et al. Controlled trial of a long-acting quinidine for maintenance of sinus rhythm after conversion of sustained atrial fibrillation. Eur Heart J. 1981; 2:49-55.[Abstract/Free Full Text]

125.  Vitolo E, Tronci M, Larovere MT, Rumolo R, Morabito A. Amiodarone versus quinidine in the prophylaxis of atrial fibrillation. Acta Cardiol. 1981; 36:431-44.

126.  Edhag O, Erhardt LR, Lundman T, Sodermark T, Sjogren A. Verapamil and quinidine in maintaining sinus rhythm after electroconversion of atrial fibrillation. Opuscula Medica. 1982; 27:22-4.

127.  Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J. 1984; 65:367-9.

128.  O'Keeffe DB, Nicholls DP, Morton P, Murtagh GJ, Scott ME. Maintenance of sinus rhythm after elective cardioversion from chronic stable atrial fibrillation: amiodarone compared with quinidine. Br Heart J. 1984; 51:103.

129.  Grande P, Sonne B, Pedersen A. A controlled study of digoxin and quinidine in patients DC reverted from atrial fibrillation to sinus rhythm [Abstract]. Circulation. 1986; 74(Suppl II):101.

130.  Gustafsson KS, von Bahr C, Dahlqvist R, Edhag O. Long-term effects related to dose and concentration of disopyramide in atrial fibrillation [Abstract]. Circulation. 1986; 74(Suppl II):101.

131.  Rasmussen K, Andersen A, Abrahamsen AM, Overskeid K, Bathen J. Flecainide versus disopyramide in maintaining sinus rhythm following conversion of chronic atrial fibrillation [Abstract]. Eur Heart J. 1988; 9(Suppl I):52.

132.  Van Gelder IC, Crijns HJ, Van Gilst WH, Van Wijk LM, Hamer HP, Lie KI. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol. 1989; 64:1317-21.[Medline]

133.  Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation. 1990; 82:1932-9.

134.  Touboul P, Aliot E, Brembilla-Perrot B. Flecainide in the prevention of atrial fibrillation after DC conversion: comparison with quinidine [Abstract]. Circulation. 1991; 84(Suppl II):127.

135.  Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol. 1993; 71:558-63.

136.  Podrid PJ. Class 1 antiarrhythmic agents for therapy of atrial fibrillation. Herz. 1993; 18:9-19.

137.  Wilson JS, Podrid PJ. Side effects from amiodarone. Am Heart J. 1991; 121(1 Pt 1):158-71.

138.  Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med. 1991; 114:539-44.

139.  Connolly SJ, Hoffert DL. Usefulness of propafenone for recurrent paroxysmal atrial fibrillation. Am J Cardiol. 1989; 63:817-9.

140.  Janssen J, Loomans L, Harink J, Taams M, Brunninkhuis L, van der Starre P, et al. Prevention and treatment of supraventricular tachycardia shortly after coronary artery bypass grafting: a randomized open trial. Angiology. 1986; 37:601-9.

141.  Kowey PR, Taylor JE, Rials SJ, Marinchak RA. Meta-analysis of the effectiveness of prophylactic drug therapy in preventing supraventricular arrhythmia early after coronary artery bypass grafting. Am J Cardiol. 1992; 69:963-5.

142.  Ormerod OJ, McGregor CG, Stone DL, Wisbey C, Petch MC. Arrhythmias after coronary bypass surgery. Br Heart J. 1984; 51:618-21.

143.  Middlekauff HR, Wiener I, Saxon LA, Stevenson WG. Low-dose amiodarone for atrial fibrillation: time for a prospective study? Ann Intern Med. 1992; 116(12 Pt 1):1017-20.

144.  Chun SH, Sager PT, Stevenson WG, Nademanee K, Middlekauff HR, Singh BN. Long-term efficacy of amiodarone for the maintenance of normal sinus rhythm in patients with refractory atrial fibrillation or flutter. Am J Cardiol. 1995; 76:47-50.

145.  Gosselink AT, Crijns HJ, van Gelder IC, Hillige H, Wiesfeld AC, Lie KI. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA. 1992; 267:3289-93.

146.  Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med. 1989; 321:406-12.

147.  Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990; 82:1106-16.

148.  Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med. 1994; 121:529-35.

149.  Santini M, Alexidou G, Ansalone G, Cacciatore G, Cini R, Turitto G. Relation of prognosis in sick sinus syndrome to age, conduction defects and modes of permanent cardiac pacing. Am J Cardiol. 1990; 65:729-35.

150.  Rosenqvist M, Brandt J, Schuller H. Long-term pacing in sinus node disease: effects of stimulation mode on cardiovascular morbidity and mortality. Am Heart J. 1988; 116(1 Pt 1):16-22.

151.  Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE. Prospective randomized trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet. 1994; 344:1523-8.

152.  Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg. 1991; 101:406-26.

153.  Ferguson TB Jr, Cox JL. Surgical therapy for atrial fibrillation. Herz. 1993; 18:39-50.[Medline]

154.  Feinberg MS, Waggoner AD, Kater KM, Cox JL, Perez JE. Echocardiographic automatic boundary detection to measure left atrial function after the maze procedure. J Am Soc Echocardiogr. 1995; 8:139-48.

155.  Kosakai Y, Kawaguchi AT, Isobe F, Sasako Y, Nakano K, Kito Y, et al. Modified maze procedure for patients with atrial fibrillation. undergoing simultaneous open heart surgery [Abstract]. Circulation. 1994; 90:I-587.

156.  Jatene MB, Sosa E, Tarasoutchi F, Monteiro AC, Salerno P, Souza LC, et al. Atrial fibrillation and mitral valve disease: concomitant surgical treatment with "maze" procedure [Abstract]. Circulation. 1994; 90:I-595.

157.  Swartz JF, Pellersels G, Silvers J, Patten L, Cervantez D. A catheterbased curative approach to atrial fibrillation in humans [Abstract]. Circulation. 1994; 90:I-335.

158.  Guiraudon GM. Surgical treatment of atrial fibrillation. Herz. 1993; 18:51-9.

159.  Williamson BD, Man KC, Daoud E, Niebauer M, Strickberger SA, Morady F. Radiofrequency catheter modification of atrioventricular conduction to control the ventricular rate during atrial fibrillation. N Engl J Med. 1994; 331:910-7.

160.  Brignole M, Gianfranchi L, Menozzi C, Bottoni N, Bollini R, Lolli G, et al. Influence of atrioventricular junction radiofrequency ablation in patients with chronic atrial fibrillation and flutter on quality of life and cardiac performance. Am J Cardiol. 1994; 74:242-6.

161.  Olsson SB, Orndahl G, Enestrom S, Eskilsson J, Persson S, Grennert ML, et al. Spontaneous reversion from long-lasting atrial fibrillation to sinus rhythm. Acta Med Scand. 1980; 207:5-20.

162.  Jack CM, Pringle TH, Hanna C, Cleland J, Campbell NP. Spontaneous reversion to sinus rhythm from long-standing atrial fibrillation. Ir J Med Sci. 1987; 156:330-2.

163.  Ciaccheri M, Dolara A, Cecchi F, Manetti A, Mazzuoli F, Santoro G, et al. Spontaneous reversion to normal sinus rhythm after prolonged atrial fibrillation. Acta Cardiol. 1981; 36:125-9.

164.  Gardner JD. Dunn M. Spontaneous conversion of long-standing atrial fibrillation. Chest. 1982; 81:429-32.

165.  Noble RJ, Fisch C. Factors in the genesis of atrial fibrillation in rheumatic valvular disease. Cardiovascular Clinic. 1973; 5:97-114.

166.  Resnekov L. Theory and practice of electroversion of cardiac dysrhythmias. Med Clin North Am. 1976; 60:325-42.

167.  Van Gelder IC, Crijns HJ, Van Gilst WH, Verwer R, Lie KI. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol. 1991; 68:41-6.[Medline]

168.  Manning WJ, Silverman DI, Katz SE, Riley MF, Come PC, Doherty RM, et al. Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol. 1994; 23:1535-40.

169.  Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol. 1989; 63:193-7.

170.  Bailey GW, Braniff BA, Hancock EW, Cohn KE. Relation of left atrial pathology to atrial fibrillation in mitral valvular disease. Ann Intern Med. 1968; 69:13-20.

171.  Davies MJ, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J. 1972; 34:520-5.

172.  Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, et al. Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study. Circulation. 1990; 82:792-7.

173.  Suarez GS, Lampert S, Ravid S, Lown B. Changes in left atrial size in patients with lone atrial fibrillation. Clin Cardiol. 1991; 14:652-6.

174.  Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol. 1989; 13:617-23.

175.  Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995; 92:1954-68.

176.  Sims BA. Pathogenesis of atrial arrhythmias. Br Heart J. 1972; 34:336-40.

177.  Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc. 1988; 63:552-64.

178.  Resnekov L, McDonald L. Electroversion of lone atrial fibrillation and flutter including haemodynamic studies at rest and on exercise. Br Heart J. 1971; 33:339-50.

179.  Dalzell GW, Anderson J, Adgey AA. Factors determining success and energy requirements for cardioversion of atrial fibrillation. Q J Med. 1990; 76:903-13.

180.  Szekely P. Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J. 1964; 1:1209-12.

181.  Atwood JE, Albers GW. Anticoagulation and atrial fibrillation. Herz. 1993; 18:27-38.

182.  Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet. 1989; 1:175-9.

183.  Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991; 84:527-39.

184.  The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med. 1990; 323:1505-11.

185.  Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991; 18:349-55.

186.  Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992; 327:1406-12.

187.  Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994; 343:687-91.

188.  White HD. Aspirin or warfarin for non-rheumatic atrial fibrillation? Lancet. 1994; 343:683-4.

189.  Wheeldon NM. Atrial fibrillation and anticoagulate therapy. Eur Heart J. 1995; 16:302-12.

190.  Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J Med. 1995; 333:5-10.

191.  Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence of stroke: the Framingham study. Stroke. 1983; 14:664-7.

192.  Collins LJ, Silverman DI, Douglas PS, Manning WJ. Cardioversion of nonrheumatic atrial fibrillation. Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation. 1995; 92:160-3.

193.  Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol. 1995; 25:1354-61.

194.  Stoddard MF, Dawkins PR, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J. 1995; 129:1204-15.

195.  Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet. 1993; 342:1255-62.

196.  Simon RP, Day JW, Greenberg DA, Panitch HS, Powers W, So Y. Neurology. In: Gray FD Jr, Kay CF, Moore ME, Waxman HS, eds. Medical Knowledge Self-Assessment Program. 9th ed. Philadelphia: American Coll of Physicians; 1991:104-5.

197.  Immediate anticoagulation of embolic stroke: a randomized trial. Cerebral Embolism Study Group. Stroke. 1983; 14:668-76.

198.  Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Cerebral Embolism Study Group. Arch Intern Med. 1987; 147:636-40.[Abstract/Free Full Text]

199.  Roberts SA, Diaz C, Nolan PE, Salerno DM, Stapczynski JS, Zbrozek AS, et al. Effectiveness and costs of digoxin treatment for atrial fibrillation and flutter. Am J Cardiol. 1993; 72:567-73.

200.  Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials. Am Heart J. 1995; 129:71-5.

201.  Treatment of atrial fibrillation. Recommendations from a workshop arranged by the Medical Products Agency (Uppsala, Sweden) and the Swedish Society of Cardiology. Eur Heart J. 1993; 14:1427-33.

202.  Calkins H, Sousa J, el-Atassi R, Rosenheck S, de Buitleir M, Kou WH, et al. Diagnosis and cure of the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardias during a single electrophysiologic test. N Engl J Med. 1991; 324:1612-8.

203.  Jackman WM, Wang X, Friday KJ, Roman CA, Moulton KP, Beckman KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White Syndrome) by radiofrequency current. N Engl J Med. 1991; 324:1605-11.

204.  Feld GK, Nademanee K, Stevenson W, Weiss J, Klitzner T, Singh BN. Clinical and electrophysiologic effects of amiodarone in patients with atrial fibrillation complicating the Wolff-Parkinson-White syndrome. Am Heart J. 1988; 115(1 Pt 1):102-7.