American College of Cardiology -- Anaheim, California

Atrial Fibrillation: The Clinically Relevant Trials and Results


In introducing his overview of the clinical trials centering on atrial fibrillation, Dr. D. George Wyse, speaking at the 46th Annual Scientific Session of the American College of Cardiology, began by cautioning the audience against underestimating the disorder's importance. He emphasised that atrial fibrillation is a serious arrhythmia which represents a disproportionately neglected area of study, largely due to the fact that the diversity of the condition makes it difficult to accurately categorise patients and to establish or select predefined endpoints from the almost overwhelming number of possiblities. Although mortality has not yet been specifically assessed, studies have shown that the relative risk of death following atrial fibrillation is 2.0. It has also been shown that 23% of strokes are generated by atrial fibrillation and that an individual is twice as likely to die from a stroke caused by atrial fibrillation than by any other cause.

Antithrombotic Trials
A substantial number of trials assessing and comparing the efficacy of warfarin and aspirin in the treatment of atrial fibrillation, have more or less consistently demonstrated that while warfarin is highly effective, reducing the annual risk of stroke by approximately two thirds, aspirin has a more modest 20% effectiveness rate. Unfortunately, there continues to be a significant lag-time between the findings generated by clinical trials and application of the results. For example, few patients discharged from the hospital following treatment for atrial fibrillation are placed on continuing anticoagulant therapy. In the Atrial Pacing in Paroxysmal Atrial Fibrillation (PA)3 trial, high-risk patients were evaluated after administration of titrated warfarin vs low-dose warfarin plus aspirin. The former maintained international normalised ratios (INR) at highly therapeutic levels (between 2.0 and 3.0) whereas low-dose warfarin/aspirin generally maintained INRs of 1.5 or less, indicating that the latter treatment appears to be inappropriate for antithrombotic therapy in high-risk patients.

The Assessment of Cardioversion Utilizing Transesophageal Echocardiography (ACUTE) trial is currently evaluating transesophageal epicardiography followed by early cardioversion against the guideline approach, which consists of anticoagulation for three or more weeks followed by cardioversion. Although observational studies abound, this is the only instance in which antithrombotic therapy and cardioversion is actually being studied within the context of a clinical trial.

Sinus Rhythm Maintenance Trials
Numerous antiarrhythmic drugs have been studied but there is no universally effective agent. All have important safety limitations making drug selection difficult. Flecainide appears to be relatively effective in maintaining sinus rhythms, as is propafenone, while amiodarone has demonstrated no efficacy for pharmacologic cardioversion and neither has sotalol. Innovative therapies include atrial surgeries, implanted atrial defibrillation, and catheter ablation of the atrium. While these appear promising, they are not yet ready for evaluation in clinical trials.

Heart-rate Control Trials
The major problem in mounting heart-rate control trials is the lack of a particularly good endpoint. Evaluations must always be carried out both during rest and during physical activity. For example, digoxin controls heart rate well at rest, but not during even mild exercise. Calcium channel blockers appear to be more effective at controlling heart rate than digoxin and as effective as beta blockers, but they have the added advantage of being able to increase exercise capacity in patients with atrial fibrillation, which the other two drugs cannot. Observational studies have evaluated the use of innovative therapies such as catheter ablation of the atrioventricular (AV) junction with a pacemaker, as well as catheter modification of the AV junction with or without a pacemaker (since not all patients require one), but so far there have been no full-scale clinical trials evaluating these.

Comparison Trials
Dr. Wyse maintained that there is still a dilemma surrounding the primary approach to atrial fibrillation: Should it be to maintain the sinus rhythm or to control the heart rate and anticoagulate? The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial is seeking an answer to this question. Five thousand, three hundred patients are being randomised to one strategy or the other. Treatment begins pharmacologically, but once two or more drugs have failed, the investigator may choose to continue either with different drugs or one of the innovative therapies mentioned above. The primary endpoint is total mortality, whereas secondary endpoints include quality of life as well as cost-effectiveness. Other pilot projects such as, Rate Control Vs Electrical Cardioversion for Atrial Fibrillation in the Netherlands, and Prognosis in Atrial Fibrillation study (PIAF) in Germany are also underway.