Stephen C. Vlay,MD, is professor of medicine, State University of New York, Stony Brook, NY.

Management of atrial fibrillation remains one of the most difficult challenges for physicians and patients. Reynolds and colleagues assessed the effect of amiodarone (Cordarone, Pacerone) in a group of patients enrolled in the Fibrillation Registry Assessing Costs, Therapies, Adverse Events, and Lifestyle (FRACTAL). This registry provided prospective observational cohort data for 1,005 patients from 17 centers over a 3-year period following a first episode of atrial fibrillation. Analysis was performed on 973 subjects after various exclusions.

Amiodarone was administered to 19.5% of women and 26.2% of men. During the follow-up period, 25 women and 35 men underwent pacemaker implantation for bradyarrhythmias, with the most common diagnosis being “sick sinus syndrome.” After statistical analysis, the hazard ratio for implantation was higher in women (4.69) than in men (1.05). The authors speculated on the reasons for the sex differences and considered age at onset of atrial fibrillation, body size, bioavailability, and incidence of hypertension, valvular heart disease, and coronary artery disease. Although they did not come to any definite conclusions, they warn physicians of the higher incidence of bradyarrhythmias requiring pacemaker implantation in women than in men, independent of weight or body mass index.

One of the limitations of this study was the low number of patients it included; in fact, the percentage of those who actually received amiodarone was similarly low. Looking at the raw data, the difference in the total number of implanted pacemakers between men and women was just 10 devices. Consequently, caution must be used in interpreting the data.

Nevertheless, clinicians should not disregard this information, as it serves to remind us that we should be mindful of sex differences. There are important clinical differences between men and women, including age of onset of a condition, how medication is metabolized, and in the course of an established illness. Prospective studies provide valid data, particularly when demographic variables are controlled and the population contains an adequate sampling of both sexes (in this study, 60% of patients were men and 40% were women).

The electrophysiology and use of amiodarone are well-known. Physicians should remember that despite its widespread use for atrial fibrillation, amiodarone is approved by the Food and Drug Administration only for life-threatening ventricular arrhythmias. When administered, particularly in the elderly, bradyarrhythmias are not uncommon, and if symptomatic, may require a pacemaker or change of medication.

The present article stresses particular vigilance in women, especially during the loading period. Loading is an aspect not addressed in this article, but is important pharmacologically. Amiodarone’s complex pharmacokinetics requires loading in the tissues to achieve a steady state and clinical efficacy—the faster the better when the problem is life-threatening ventricular fibrillation or tachycardia. Loading doses vary, ranging between 800 and 1,600 mg/day, administered in divided doses for an initial 1 to 2 weeks. With these large doses, effects on the sinus node and atrioventricular node may be particularly striking, resulting in severe bradycardia or heart block.

For atrial arrhythmias, daily administration of a 200-mg dose without a loading dose will require considerably more time to achieve a steady state; however, it may, at least initially, avoid the need for a permanent pacemaker to treat the bradyarrhythmias associated with high-dose loading regimens. Arrhythmia control with restoration of sinus rhythm will occur at a later date, but atrial arrhythmias usually are not lifethreatening.

The take-home message is that clinicians should be knowledgeable about the pharmacokinetics of a medication and carefully monitor their patients for any adverse effects.