Many of us are faced with patients experiencing new onset atrial fibrillation or new patients presenting with a history of chronic, untreated atrial fibrillation. Recently, a number of new insights have been developed into this relatively common problem and it is becoming clear that most of us have not optimally treated these patients. Dr. Anne Dougherty has provided us with a concise, easily understood review of this topic which should serve as a handy reference for the proper diagnosis and treatment of these patients. Dr. Dougherty is an Associate Professor here at the University of Texas and is an experienced clinician, researcher and teacher. Please welcome Dr. Dougherty to Cyberounds^®!

-- Richard W. Smalling, M.D., Ph.D., Cardiovascular Moderator

Introduction

Atrial fibrillation remains one of the most frustrating management problems facing cardiologists approaching the millennium. More than a million Americans have experienced the arrhythmia. The incidence increases with age, so that by age 69, more than 5% of individuals have been affected.(1) The natural history of the condition predicts progression from paroxysmal to chronic atrial fibrillation in many, despite aggressive therapy. Since potentially curative therapy is limited, prevention of recurrences is usually achievable only with pharmacologic therapy and results may not be durable.

Although the arrhythmia is not immediately life-threatening, serious complications may arise from it. It is a marker of increased mortality, multiplying it twofold. When uncontrolled, the rapid ventricular response, which typically accompanies untreated atrial fibrillation, can result in incapacitation, as well as congestive heart failure or angina. The loss of atrio-ventricular synchrony may also precipitate congestive heart failure in susceptible individuals. Atrial fibrillation increases, significantly, the risk of embolic stroke as a consequence of ineffective atrial contraction and mural thrombus formation.

Whom Should We Treat?

Most patients experiencing a symptomatic episode of atrial fibrillation deserve at least one trial of treatment aimed at conversion to and/or maintenance of sinus rhythm. Prophylaxis prevents symptoms, but has not been proven to reduce the risk of embolic stroke which accompanies the arrhythmia. Antiarrhythmic drug therapy is neither permanent nor without hazard. The potential benefit of chronic antiarrhythmic therapy must be weighed against the risks in each individual. How symptomatic is the patient? Are there remediable factors exacerbating the arrhythmia? How well are drugs tolerated? Are there additional conditions which enhance the potential risk of either recurrent arrhythmia or drug toxicity? At some point, the physician and patient may elect to accept chronic atrial fibrillation with rate control. A large multicenter trial comparing the treatment strategies of rate control alone with aggressive maintenance of sinus rhythm, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, is currently underway. Persistent symptoms may justify pursuit of non-pharmacologic means of therapy, such as His ablation or maze procedures.

Special considerations should be entertained in the patient with Wolff-Parkinson-White (WPW) syndrome. Rapid antegrade accessory pathway conduction and short effective refractory periods promote very rapid ventricular response to atrial fibrillation and short R-R intervals (< 250 msec) which can precipitate ventricular fibrillation. Thus, WPW patients with short antegrade accessory pathway refractory periods, even those who have not yet had spontaneous atrial fibrillation, should be considered at high risk and treated aggressively to prevent fatal ventricular arrhythmia. Ablation of the accessory pathway is preferred due to its permanence in preventing both reentrant SVT and primary atrial tachyarrhythmias. If catheter or surgical ablation is not possible or must be postponed in the high risk patient, medical treatment should be aggressive and its efficacy confirmed with electrophysiologic studies.

Rate Control

The first order of business in treating a patient with new atrial fibrillation is to establish control of the ventricular response to ease symptoms. This measure also prepares the patient for subsequent use of antiarrhythmic drugs which might otherwise increase further the rate as a consequence of their vagolytic effects.

Although digitalis has an established tradition of use in treating atrial fibrillation, its value has been increasingly questioned. A randomized, placebo-controlled trial of its efficacy in acute termination of paroxysms showed no benefit and an observational study showed no reduction in frequency of paroxysms when used prophylactically.(14),(15) It is useful in controlling the ventricular response by virtue of its vagal effect on the AV node. However, exertion usually blunts that benefit. Furthermore, patients experiencing recurrent paroxysms while on digitalis do not have a significantly lower ventricular rate than others. Digitalis is contraindicated for rate control in patients with overt WPW, due to its potential to accelerate antegrade conduction over the accessory pathway and precipitate ventricular fibrillation.

Beta adrenergic blockers and calcium channel blockers are also useful in slowing the ventricular response to atrial arrhythmias. Both have negative inotropic effects which limit their safety in patients with heart failure. Beta blockers, additionally, may aggravate bronchospasm. Beta blockers are particularly helpful in controlling high rates associated with exercise and thyrotoxicosis. An agent without intrinsic sympathetic activity is theoretically preferred. Propranolol has been shown to be useful in preventing paroxysms of atrial fibrillation following coronary artery bypass surgery.

Both verapamil and diltiazem can be used for chronic rate control. Like digoxin, however, verapamil should be avoided in WPW patients with overt pre-excitation. Intravenous diltiazem is particularly useful in the acute management of a rapid ventricular response since its action is prompt and sustained with continued administration. The dose can be titrated to achieve optimum benefit and does not interfere with the safety of DC cardioversion.

A recent study suggested that the use of calcium channel blockers and beta-adrenergic blockers prior to DC cardioversion reduces the early recurrence rate.(23) This effect is presumed to be a result of intracellular calcium lowering which reduces electrical remodeling of the fibrillating atria.

Antiarrhythmic Drug Therapy

Class IA Agents

Quinidine is the most widely prescribed agent for prophylaxis of atrial fibrillation in the U.S. Its efficacy in maintaining sinus rhythm, after both spontaneous and direct-current cardioversion, has been documented in numerous studies.(5) Furthermore, patients with partial efficacy experience longer event-free intervals on quinidine. A meta-analysis showed that quinidine-treated patients were twice as likely to remain in sinus at one year as were control patients. Nonetheless, the mortality was higher in the quinidine-treated group (2.9%) than in the control group (0.8%). Half of the quinidine-related deaths were due to cardiovascular causes and half of those were sudden or due to arrhythmias. Drug-related QT prolongation, combined with the irregular R-R intervals in atrial fibrillation and flutter, promotes torsades de pointes. These results should be construed in light of the era in which the component trials were conducted. Compared to the present population, the subjects involved more often had underlying valvular heart disease and digoxin toxicity. Although the number of patients studied was too small to conclude that quinidine therapy results in excess mortality, the drug should be used with caution in patients with non-life-threatening conditions. Initial dose titration should be performed in hospital with continuous ECG monitoring to detect any predisposition for torsades. Because of its vagolytic effect, patients who experience recurrences on quinidine may require additional drugs to control the ventricular response. Digoxin, when given concomitantly, requires dose reduction in anticipation of the expected drug interaction.

Procainamide and disopyramide have been studied less rigorously in atrial fibrillation. Both appear to be effective in preventing recurrences on a scale equivalent with that of quinidine. The use of procainamide, however, is limited by the toxicity associated with long-term use (drug-induced lupus, agranulocytosis). Disopyramide is a negative inotrope and its use is limited to patients with relatively normal ventricular function.

Class IC Agents

Flecainide has FDA approval for use in patients with paroxysmal atrial fibrillation and flutter, as well as in those with other paroxysmal supraventricular arrhythmias. In placebo-controlled studies, the drug has prevented recurrences and promoted conversion to sinus rhythm.(6) In partial responders, it increases the interval between paroxysms. In some patients with WPW, the drug may eliminate accessory pathway conduction altogether, thus producing a "pharmacologic ablation." The balanced effect on AV node and accessory pathway also provides protection from very rapid ventricular rates in partial responders. Therapy may be initiated in an outpatient setting in patients without conduction system disease or ventricular dysfunction. Similar efficacy has been shown with propafenone; its effect is distinctive in having additional mild beta-blocking properties.

IC agents carry the stigma of involvement in the Cardiac Arrhythmia Suppression Trial (CAST) in which treatment of post-MI patients with ventricular ectopy with encainide, flecainide and moricizine was associated with increased mortality, compared with placebo treatment. In contrast, the use of flecainide and encainide for supraventricular arrhythmias in patients free of coronary or structural heart disease has not resulted in any excess mortality. Proarrhythmia has been noted in some patients, particularly those with structural heart disease. New or incessant atrial arrhythmias, intraventricular conduction block and sinus pauses have been recorded, as well as new wide QRS tachycardias. Many of the latter have been shown to be atrial flutter with 1:1 AV conduction and bundle branch block. The expected slowing of the atrial rate in flutter by IC drugs may facilitate 1:1 conduction, especially during exercise.

Class III Agents

Amiodarone is the most effective drug in treating primary atrial arrhythmias. It is powerful enough to convert even long standing or chronic atrial fibrillation to sinus rhythm in many who have been refractory to other agents. Rate control is also enhanced. Maintenance of sinus rhythm after conversion usually requires doses much smaller than those required for treatment of ventricular arrhythmias, frequently 200 mg./day or less. The more serious adverse effects tend to be dose-related and, thus, they may occur less frequently in patients with atrial arrhythmias. This agent has earned a position as first line therapy in Europe. Its imposing list of long-term side effects, however, has prompted more cautious use in the U.S. It has not been approved by the FDA for use in supraventricular arrhythmias.

Sotalol, a beta blocker with type III antiarrhythmic effects, has been used more extensively in ventricular arrhythmias than in atrial fibrillation. At least one study, however, showed it equal to quinidine in preventing paroxysms of atrial fibrillation and also useful in controlling ventricular rates. Sotalol is generally well tolerated but does prolong the QT interval. Thus, dose titration should be conducted in an inpatient-monitored setting to avoid torsades. Ibutilide, the first "pure" class III antiarrhythmic agent approved for use in atrial fibrillation, is a newer agent used intravenously to achieve acute conversion to sinus rhythm. Conversion within one hour of administration occurs in 35 - 50% of individuals, superior to success rates for either IV procainamide or sotalol. Because of its prolongation of action potential duration, ibutilide administration may result in torsades de pointes in up to 8% of treated individuals. Thus, patients should be closely monitored during and after administration. Another class III agent, dofetilide, will also be commercially available soon.

Nonpharmacologic Therapy

DC Cardioversion

Synchronized DC cardioversion may be considered whenever prompt restoration of sinus rhythm is needed to stabilize a patient and is usually administered during brief anesthesia. Sinus rhythm can be restored in about 85% of patients but the recurrence rate is high. Concomitant antiarrhythmic drug therapy increases the likelihood of success and, moreover, helps to prevent recurrences in susceptible individuals. Cardioversion does increase the risk of acute embolic events up to 7%; thus, it is recommended that the procedure be delayed, whenever possible, in patients who have been in fibrillation for over 48 hours. Three weeks of therapeutic anticoagulation prior to cardioversion reduces the risk of embolic stroke.

Maze Procedures

The only potentially curative procedures for atrial fibrillation are designed to prevent the wandering wavelets of reentry that perpetuate the arrhythmia, while preserving atrial contractility. This has been done with both surgical incisions and linear radiofrequency catheter burns arranged in a maze-like design that divides both atria into a series of electrically isolated corridors, each too narrow to support reentry. Procedures have been complicated by sinus and AV nodal dysfunction, sometimes requiring pacemaker placement. A significant incidence of perioperative stroke has also been reported, especially in those receiving catheter maze procedures.(19)

Non-pharmacologic Rate Control

In patients refractory to or intolerant of digoxin, calcium antagonists and beta-blockers, an alternative treatment may be offered for palliative rate control. Radiofrequency catheter ablation or modification of the A-V node or bundle of His can prevent or limit, respectively, the rapid bombardment of the ventricles by fibrillating atria. Depending upon the degree of damage delivered, a ventricular rate-responsive pacemaker may be required to provide a regular heart rate appropriate for the degree of patient activity. Dual chambered pacemakers should be prescribed with caution in this circumstance to avoid inappropriate tracking of the atrial fibrillation that would negate the beneficial effect of the ablation.

Atrial Defibrillators

Implantable atrial defibrillators are an investigational treatment modality. Atrial defibrillation thresholds are usually very low (1 - 2 joules), compared to those in comparable ventricular devices. Thus, device therapy may be used as an intermittent treatment in lieu of chronic medication. Furthermore, prompt reversion of the arrhythmia reduces electrical remodeling of the atria, thus, theoretically, minimizing the likelihood of early recurrence. Special precautions must be taken to avoid delivery of the shock during the ventricular vulnerable period which might inadvertently induce ventricular fibrillation. Even though the required output is low, shocks are usually perceived as painful, so patients may require analgesia prior to delivery.

Stroke Prophylaxis

Atrial thrombi may arise in fibrillating atria and provide a nidus for embolic stroke. The incidence of embolic complications is approximately 5% per year in untreated patients. Older individuals and those with heart failure or hypertension are at greater risk. Those whose arrhythmia is associated with valvular heart disease, especially mitral stenosis, have a 17-fold higher risk. Large prospective randomized trials, including SPAF, BAATAF and AFASAK, have demonstrated the efficacy of chronic prophylactic anticoagulation with warfarin products in stroke prevention.(20) Therapy is monitored frequently to achieve a therapeutic protime with a target INR (International Normalized Ratio) of 2 - 3. Younger individuals, especially those with lone (idiopathic) atrial fibrillation, who have a lower incidence of emboli, may receive sufficient prophylaxis with aspirin.

Summary

Atrial fibrillation is a common arrhythmia characterized by aggravating symtoms and frequent relapses of increasing refractoriness to intervention. Rapid heart rates and embolic stroke may complicate its course. The growing armamentarium of pharmacologic and non-pharmacologic therapies provides significant latitude for alleviating symptoms and preventing complications. Curative measures, appropriate for the average patient, are needed.