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

  1. Houtan Golzari, MD;
  2. Randall D. Cebul, MD; and
  3. Robert C. Bahler, MD
  1. 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.
     
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    Abstract

    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.

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    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.

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    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:
    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.

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    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.

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    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].

    β-blocker therapy is a potentially useful strategy in patients who are likely to have increased sympathetic activity because β-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.

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    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:
    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.

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    Discussion

    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).

    Figure 1. Atrial fibrillation of less than 48 hours' duration. 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.
    View larger version:
    Figure 1. Atrial fibrillation of less than 48 hours' duration. 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. Algorithms for the management of atrial fibrillation applicable to patients other than those with recent stroke. Top.Bottom.

    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 β-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 β-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, β-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]; β-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.

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