Safer therapeutic options emerging for atrial fibrillation

June 16, 2008

This special report takes a look at the atrial fibrillation drugs in the pipeline.

AF, the most common cardiac arrhythmia, results in significant morbidity and mortality from stroke and thromboembolism. AF is an interruption of the normal sinus rhythm of the heart in which the atria beat irregularly and at an extremely rapid rate.

"Conventional treatment strategies of AF include ventricular rate control, restoration and maintenance of sinus rhythm, and prevention of thromboembolic events," said Linda Fang, Pharm.D., BCPS, clinical pharmacy specialist in cardiology at Saint Barnabas Medical Center, Livingston, N.J., and clinical assistant professor at Ernesto Mario School of Pharmacy, New Brunswick, N.J.

Ventricular rate control during AF is primarily accomplished by the administration of atrioventricular nodal blocking drugs, such as verapamil and diltiazem, beta-blockers, or digoxin.

Fang explained that since verapamil has more potent negative inotropic and peripheral vasodilatory effects, diltiazem is usually preferred for acute ventricular rate control during AF, especially in patients with mild left ventricular (LV) dysfunction or hypotension. Beta-blockers, such as esmolol and metoprolol, are particularly effective in conditions where rapid ventricular rate is due to heightened adrenergic tone, as seen in post-operative periods.

Cardioversion

Within the first 24 hours, up to 50% of patients with new-onset AF convert back to sinus rhythm. If the patient does not convert spontaneously, pharmacological or electrical cardioversion should be attempted. For AF lasting less than 48 hours, class I or III antiarrhythmic drugs (AADs) have shown to achieve conversion to sinus rhythm in a majority of patients. "The major concern with existing AADs is an increased risk of sudden death-torsades de pointes-in patients with underlying heart disease such as coronary artery disease, prior history of myocardial infarction or heart failure," said Gary T. Elliott, Pharm.D., Ph.D., senior product development consultant for HUYA Bioscience International, San Francisco.

Due to the limitations of currently available AADs, safer therapeutic options are needed. According to Elliott, properties of a more favorable antiarrhythmic agent would include multi-ion channel blockade without proarrhythmic risk. Preliminary evidence suggests that the antiarrhythmic compound, HBI-3000 (HUYA), which exhibits broad-spectrum ion channel inhibition without proarrhythmic activity may have safety advantages over other AADs. HBI-3000 is being developed as a potential treatment for both atrial and ventricular arrhythmias.

Maintaining sinus rhythm

The class III AAD amiodarone has shown that it is effective for the maintenance of sinus rhythm in patients with structural heart disease. However, amiodarone has serious extracardiac adverse events, including pulmonary fibrosis, hepatic and thyroid dysfunction-especially at high doses and after long-term use. Furthermore, amiodarone increases plasma concentrations of other medications, including digoxin and warfarin.

In the pipeline

"Because of the drawbacks seen with amiodarone, an agent with a better safety profile while retaining the antiarrhythmic potential of amiodarone is desirable," said Fang. One such investigational agent, dronedarone (Multaq, sanofi-aventis), appears promising. Dronedarone is pharmacologically related to amiodarone, but with structural differences intended to reduce extracardiac toxicity.

Clinical studies show that dronedarone was significantly more effective than placebo in maintaining sinus rhythm and reducing the ventricular rate during recurrence of arrhythmia. In the ATHENA trial, the largest double-blind randomized study in patients with AF, researchers found that dronedarone decreased the risk of cardiovascular hospitalizations or death by a statistically significant 24% over placebo. According to Marc Cluzel, senior VP of research and development at sanof-aventis, "The ATHENA results have the potential to change the face of atrial fibrillation management."

The most frequently reported adverse events of dronedarone were gastrointestinal effect, skin disorder, and increased blood creatinine.