An estimated 2 million people in the United States suffer from atrial fibrillation or atrial flutter. In these conditions of rapid irregular heartbeat, the heart's upper two chambers or atria quiver rather than beat, so that blood pools and may clot in the chambers. The danger is that a piece of clot will break off and lodge in the brain, a common cause of stroke.
Both dofetilide and a brand of sotalol, Betapace AF, were approved specifically for treatment of atrial fibrillation or atrial flutter by the U.S. Food and Drug Administration (FDA) in 2000. However, since dose-dependent torsades de pointes, a potentially life-threatening cardiac arrhythmia, has been shown to occur with dofetilide and Betapace AF, detailed dosing and monitoring recommendations to minimize this risk are included in the product labeling for both drugs.
The FDA also required the manufacturer of dofetilide to develop a risk management program that requires prescribing physicians to complete a dofetilide education program and restricts availability to only those physicians who have completed the educational program. Because sotalol had already been marketed in the United States for ventricular arrhythmias since 1993, a risk-management program was not required for Betapace AF. The following two studies, which were supported in part by the Agency for Healthcare Research and Quality (HS10548) and conducted at the Duke Center for Education and Research on Therapeutics (CERTs), examine the impact of these risk management strategies on physician prescribing practices.
LaPointe, N.M., Pamer, C.A., and Kramer, J.M. (2003). "New antiarrhythmic agents for atrial fibrillation and atrial flutter: United States drug market response as an indicator of acceptance." Pharmacotherapy 23(10), pp. 1316-1321.
The restricted distribution and required education program for dofetilide, as well as the availability of generic sotalol products, may have discouraged physicians from prescribing both dofetilide and Betapace AF during the 2 years following their introduction into the market, concludes this study. The investigators reviewed the number of new, refill, and total prescriptions of all antiarrhythmic agents in the United States from April 2000 to December 2001 to assess use of dofetilide and Betapace AF in the drug market.
Both medications were prescribed very infrequently throughout the study period, even though during that time, atrial fibrillation and atrial flutter were the most frequently reported arrhythmias treated with an antiarrhythmic agent. For many of their patients with atrial fibrillation or flutter, instead of using dofetilide or Betapace AF, which are FDA-approved only for these indications, physicians appear to be more commonly prescribing amiodarone and generic sotalol, which are not FDA-approved for these indications. This suggests poor acceptance of the new agents by prescribing physicians.
LaPointe, N.M., Chen, A., Hammill, B., and others (2003). "Evaluation of the dofetilide risk-management program." American Heart Journal 146, pp. 894-901.
The mandated dofetilide risk management program improved adherence to dosing and monitoring recommendations for dofetilide as compared with sotalol. On the other hand, the comparatively smaller number of patients receiving dofetilide versus sotalol suggests that fewer physicians are willing to select dofetilide as opposed to sotalol because of the constraints of the risk-management program, conclude these investigators. They reviewed the medical charts of 47 patients taking dofetilide and 117 patients taking sotalol.
The recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group (79 vs. 35 percent). A higher number of patients in the dofetilide group compared with the sotalol group received the recommended baseline tests for potassium (100 vs. 82 percent), magnesium (89 vs. 38 percent), serum creatinine (100 vs. 82 percent), and electrocardiography (94 vs. 67 percent). A significantly greater proportion of patients in the dofetilide versus sotalol group received recommended electrocardiograms (ECGs, to detect prolonged QT interval that can lead to torsades de pointes) obtained after the first dose (94 vs. 43 percent) and subsequent doses (80 vs. 3.5 percent).
Although no patient in either group had a fatal episode of torsades de pointes, labeled recommendations for handling QT prolongation, which differ for dofetilide and sotalol, were not followed as carefully in the dofetilide group. The researchers suggest that standardization in the labeled ECG criteria for determining safety might improve physician understanding and adherence to labeled dosing and monitoring recommendations.
Editor's Note: Another study on QT prolongation conducted by researchers at the Georgetown University CERT shows that intravenous methadone, sometimes given for intractable pain in cancer patients, when combined with chlorobutanol, is associated with QT interval prolongation. For more details, see Kornick, C.A., Kilborn, M.J., Santiago-Palma, J., and others (2003). "QTc interval prolongation associated with intravenous methadone." (AHRQ grant HS10385) Pain 105, pp. 499-506.
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