Atrial fibrillation, antiarrhythmic drugs, and maintaining sinus rhythm

Lafuente-Lafuente and colleagues performed a meta-analysis of 44 studies of 11,322 patients in randomized controlled trials of persons with atrial fibrillation who received antiarrhythmic drugs after restoration of sinus rhythm. They assessed all-cause mortality, cardiac embolism, adverse events resulting in withdrawal of medication, recurrence of atrial fibrillation, and anticoagulation.

The results of the meta-analysis found that several classes of drugs (IA, IC, III) were efficacious in maintaining sinus rhythm, but at the expense of adverse effects, including proarrhythmia and increased mortality.

It has been said that “meta-analysis is to analysis as metaphysics is to physics.” A meta-analysis combines thousands of subjects from different trials in a statistical analysis intended to demonstrate an effect, despite the smaller studies, lack of power to demonstrate a significant difference. Can we truly believe the results? Perhaps—but with a grain of salt, or maybe the whole salt shaker! Well-designed, sufficiently powered, randomized, controlled studies provide the most credible evidence, and as we know, clinical research is very difficult to perform correctly.

Atrial fibrillation can occur in a wide variety of cardiac substrate abnormalities, including ischemic disease, nonischemic cardiomyopathy, hypertrophic cardiomyopathy, hypertensive heart disease, myocarditis, valvular heart disease, pericarditis, metabolic disorders, and hypoxia. The success in treating the arrhythmia depends not only on the choice of antiarrhythmic drug but also on how well the substrate abnormality can be controlled. There is little information available on how well this was accomplished across all of the 44 studies. Data about the frequency of anticoagulation or the incidence of heart failure is incomplete.

Among the type IA medications, procainamide seems conspicuously absent from the analysis, but there are few published trials. Aprindine, a drug never approved, is mentioned in the results but not the methods. Quinidine therapy was discontinued more frequently than other drugs but the reasons are not cited.

Do the results make sense? The Cardiac Arrhythmia Suppression Trial (CAST) was one of the first to demonstrate that antiarrhythmic drugs may be associated with an adverse outcome. Medications thought to be harmless in treating asymptomatic ventricular arrhythmias resulted not in a better outcome but in increased mortality! Thus, it would not be all that surprising to learn the same result may hold true for the treatment of atrial arrhythmias.

All antiarrhythmic drugs in this meta-analysis increased proarrhythmia except amiodarone and propafenone. Note that propafenone has beta-blocker properties that make it different than the other drugs. Amiodarone is well known to be efficacious for both atrial and ventricular arrhythmias with little proarrhythmic effect.

That there is some benefit in maintaining sinus rhythm is also not surprising. I would be concerned about accepting the efficacy rates (1 year recurrence of 71%-84% in controls vs 44%-67% in treated patients), as atrial fibrillation is often asymptomatic, especially when the ventricular response is also controlled with a beta blocker. But there are no data about the number of patients who also received beta blockers or how recurrences were documented (electrocardiogram? Holter monitor? event recorder? symptomatic palpitations?).

One must also be cautious in interpreting mortality outcomes. How did death occur? Was it sudden cardiac arrest? Or did the patients die of cancer or other irreversible chronic illness? Only sudden cardiac death would be a valid end point.

In the electrophysiology community, we have been cognizant of the risk of antiarrhythmic drugs for years. For life-threatening ventricular arrhythmias, internal cardioverter defibrillator therapies (antitachycardia pacing [ATP] and defibrillation shocks if ATP is unsuccessful) are the treatments of choice. Antiarrhythmic drugs are used only if the patient receives frequent shock therapies. Furthermore, attempts at ventricular tachycardia (VT) ablation may now be considered for patients with recurrent VT.

For atrial fibrillation, the danger with antiarrhythmic drugs increases as the left ventricular (LV) function decreases. It is well known to avoid type IA and IC drugs if LV dysfunction is present. Sotalol can be utilized if LV dysfunction is not severe. Amiodarone remains the best choice for atrial fibrillation in these heart failure patients (even though not approved for this indication by the US Food and Drug Administration). As acknowledged by the authors, amiodarone may be the best tolerated drug with the least adverse effect on mortality but has the potential for long-term end organ toxicity.

The management of atrial fibrillation today starts with evaluation of the underlying substrate, correcting what abnormalities can be addressed. Anticoagulation is recommended with structural heart disease and when the patient is over 65 years. Attempts at maintaining sinus rhythm are reasonable, since patients feel better in sinus and maintain their atrial contribution to cardiac output. However, when this is unsuccessful or when adverse reactions to medications occur, rate control and anticoagulation remain reasonable options as seen in the Atrial Fibrillation Follow-up Investigation of Rhythm Management study. For appropriate candidates, preferably those with minimal advanced structural heart disease and specifically for those with rapidly firing foci from the pulmonary veins, radiofrequency ablation in the hands of an experienced operator may provide some symptomatic relief and maintenance of sinus rhythm. The risk—benefit ratio must be evaluated for each individual patient as the procedure is not simple and may have complications.

Thus, while this study has the limitations of a meta-analysis, it does provide some data consistent with other studies and with general clinical opinions. Pharmacological therapy does have a role in the treatment of atrial arrhythmias but must be carefully monitored to avoid potential morbidity and mortality.