Atrial Fibrillation is a common disorder, affecting over 1.5 million people in the U.S. People with atrial fibrillation have 5-7 times the stroke risk of age matched controls. Six recent randomized clinical trials have demonstrated that the stroke risk in atrial fibrillation can be greatly reduced with antithrombotic therapy.
Five of these trials were primary prevention trials. Overall, warfarin reduced the stroke rate by almost 70 percent. The intensity of anti coagulation varied in the trials, with INR (International Normalized Ratio) values from approximately 1.8 to 4.2 The benefit from anti coagulation was seen even in the trials with the lowest INR, showing that low intensity anti coagulation is clearly beneficial. Current recommendations are to maintain the INR between 2 and 3. In these randomized trials warfarin was relatively safe, with a risk of severe bleeding slightly more than 1 percent/year.
The benefits of warfarin have now been demonstrated for secondary prevention of stroke - to prevent recurrent stroke in atrial fibrillation patients with stroke or TIA. In the European Atrial Fibrillation Trial, warfarin reduced the risk of recurrent stroke by 66 percent. This risk reduction was very similar to that seen in the primary prevention trials. The benefits of aspirin are controversial in these patients. The dose of aspirin in three randomized trials ranged from 75 to 325 mg/day. Overall, aspirin was less effective than warfarin in preventing stroke. However, there may be subgroups in whom aspirin is appropriate. In elderly patients the risk of bleeding on warfarin was substantial, and in one study negated much of the benefit. Also in some younger patients with "lone AF," the stroke rate on aspirin may be so low that warfarin is not warranted. In the Stroke Prevention in Atrial Fibrillation (SPAF) II Study patients under age 75 who did not have clinical risk factors (see below) had a stroke rate on aspirin of only 0.5 percent/year. Thus, there may be patients with atrial fibrillation in whom the risks, expense, and inconvenience of warfarin are not warranted.
The risk of stroke is not uniform in patients with atrial fibrillation. In the SPAF Study, hypertension, prior stroke or TIA, and congestive heart failure were risks for stroke in atrial fibrillation patients. Pooled data from the other randomized trials identified diabetes and age over 65 as additional risk factors. Patients with multiple risk factors are at greatest risk for stroke, while those with no risk factors have a low stroke risk.
Despite great progress, many questions remain. The low bleeding complication rates in the randomized trials were accomplished in a selected group of patients who were followed very carefully. We do not know if these low complication rates can be achieved in general practice. About half the patients with atrial fibrillation are over age 75. The risk of bleeding is increased in these older patients, and many may not be warfarin candidates. Research continues to search for equally effective and yet safer anti coagulation regimens for these elderly patients. Several of the atrial fibrillation groups are now studying combination therapy using various combinations of aspirin and low dose warfarin.
The last few years have seen tremendous progress in our knowledge about atrial fibrillation. Atrial fibrillation is a fine example of the power of clinical trials to advance our understanding and improve patient care.
William Feinberg, M.D. Associate Professor Department of Neurology
The treatment of atrial fibrillation has recently been impacted by clinical trials and a rethinking of common beliefs. In the patient with atrial fibrillation, treatment has two major goals -- control of ventricular response to eliminate symptoms such as palpitations, angina pectoris, or congestive heart failure by allowing optimal ventricular filling and prevention of complications associated with atrial fibrillation. The latter goal can be achieved by either eliminating and preventing atrial fibrillation episodes or as recently shown in a number of randomized clinical trials by effective anticoagulant therapy.
The mainstay of acute therapy of atrial fibrillation is rate control. Consideration of the etiologic circumstances is important in rate control. Thyroid toxicosis, congestive heart failure, and even fever will all contribute substantially to rapid rates, and primary treatment of the underlying condition may be more effective than drug therapy alone. The classic drug used for years for atrial fibrillation rate control is Digoxin. However, Digoxin, though moderately effective for controlling the resting ventricular rate, is less effective in most patients for rate control during exercise. Digoxin's predominate effect is on the AV node mediated through enhanced vagal tone, hence its beneficial effect seen on resting heart rate is not maintained during exertion when vagal influences are greatly diminished. Newer choices have been shown to be more effective for initial rate control, particularly with exercise. These include beta-blockers and calcium channel blockers. Both agents are available now in intravenous formulations. The newest agent, Esmolol has the advantage of an extremely short half-life of nine minutes. Esmolol may be particularly effective in patients with atrial fibrillation post-operatively because of its effect at blocking elevated catecholamines stimulation, a common situation in the post-operative patient. Both Diltiazem and Verapamil, calcium channel blockers, can also be given intravenously. Much like Esmolol, intravenous Diltiazem must be given as a constant infusion, but is very effective when so administered. Beta-blockers and calcium channel blockers can also be used chronically as oral preparations, and have been shown to be both safe and effective as mono-therapy for rate control in the patient with atrial fibrillation.
Once adequate rate control is achieved, consideration should be given to the conversion of atrial fibrillation to normal sinus rhythm. Previous thinking suggested that almost every patient deserved at least "one" trial at cardioversion. Typically, patients were given a type I-A anti-arrhythmic such as Quinidine or Procainimide, as a fore-runner to electrocardioversion. If the patient failed to convert with the anti- arrhythmic therapy, electrocardioversion was usually performed. Most cardiologists recommend a period of three to four weeks of anti-coagulation prior to electrocardioversion, because of the peri-cardioversion incidence of embolic phenomenon. Some have believed that when atrial fibrillation is less than 7 days in duration, safe cardioversion can be performed, however, other studies have shown embolic strokes occurring even after only three days of atrial fibrillation with electrocardioversion. Electrocardioversion of atrial fibrillation is best performed using an anterior-posterior paddle approach with the anterior paddle over the left mid sternal area using an 8 cm diameter paddle, and a posterior paddle of 12.8 cm diameter just below the left scapula. Skin to paddle interface should include some form of electrically conducting paste such as Hewlett Packard Redux paste. Initial shock strength should be at least 200 joules, since less than 50 percent of patients in atrial fibrillation can be cardioverted with 100 joules. This rises to 85 percent success rates with 200 joules. Subsequent shocks, if 200 joules is ineffective, should be at 360 joules, waiting a full three minutes between shocks to allow a maximal decrease in transthoracic impedance from the previous shock.
Anti-arrhythmic medications commonly given previously to patients with atrial fibrillation to restore or maintain sinus rhythm are coming under scrutiny because of concern about pro-arrhythmic effects. A meta-analysis of six randomized, controlled trials incorporating over 800 patients with chronic atrial fibrillation, evaluated Quinidine for maintenance of sinus rhythm after cardioversion. Quinidine was found to be more effective than no anti-arrhythmic therapy for the prevention of recurrent atrial fibrillation, but the risk of death was approximately threefold greater among drug treated patients than those receiving no anti-rhythmic therapy. However, this conclusion was based on only 15 deaths. Investigators from the Stroke Prevention and Atrial Prevention (SPAF) study retrospectively reviewed their data and found in a post-hoc analysis, that atrial fibrillation patients receiving anti-arrhythmic therapy, who had a history of heart failure, had a 3.7 relative risk of sudden arrhythmia death. It seemed that this increased cardiac mortality was a consequence not of early pro-arrhythmic effect, but in fact, late pro-arrhythmic effect in those patients with poor left ventricular function. Such evidence has caused many to rethink the routine use of anti-arrhythmic therapy for elimination of atrial fibrillation or even prevention of recurrence and using an alternate strategy of treatments to prevent the embolic complications of atrial fibrillation.
Six recent randomized clinical trials have now demonstrated reduction in stroke risk with the use of anti-thrombotic therapy in patients with atrial fibrillation from non-valvular sources. The Stroke Prevention in Atrial Fibrillation trials (SPAF I & II) showed that in patients with organic heart disease and other risk factors for stroke, including that of previous stroke, age greater than 75, systolic hypertension, and left ventricular dysfunction, that Warfarin is the preferred treatment (INR = 2.0-3.0). However, in younger patients with atrial fibrillation without any risk factors ("lone AF"), aspirin may be effective therapy, and is certainly easier to manage.
In summary, we recommend currently that in patients with atrial fibrillation, the initial attempts be at rate control using Digoxin, but realizing its limitations and adding beta-blockers or calcium channel blockers when needed. Mono-therapy with the later agents may also be acceptable, and quite effective. Controversy continues about the role of antiarrhythmic therapy in cardioverting and maintaining sinus rhythm in these patients. Electrocardioversion can be effective, but recurrent rates are high. Over 50 percent of patients initially cardioverted will reoccur within the first year. Long-term complications, i.e. embolic stroke can best be prevented with Warfarin therapy. In young patients with "lone AF" aspirin is effective. Ongoing trials are looking at whether a combination of low dose Warfarin and Aspirin, may be effective and easier to manage.
Karl B. Kern, M.D. Associate Professor of Medicine Department of Medicine