New Drugs Could Redefine Atrial Fibrillation Tx

BOSTON — Two drugs for preventing atrial fibrillation that were being considered for approval by the Food and Drug Administration in early 2006 headed the list of new antiarrhythmia agents that could change atrial fibrillation treatment over the next few years.

A “new era” of drug treatment is approaching, Dr. Peter Kowey said at an international symposium on atrial fibrillation sponsored by Massachusetts General Hospital. Drugs that may be part of that era include:

▸ Azimilide. This agent blocks both rapid and slow potassium channels in the heart and is one of the drugs under FDA review. Azimilide is being considered as a way to prevent shocks from an implanted cardiac defibrillator. However, although it is a “very potent” drug for suppressing atrial fibrillation, the results of one major trial failed to show that treatment produced a survival benefit, said Dr. Kowey, professor of medicine at Thomas Jefferson University, Philadelphia.

▸ Dronedarone. Also before the FDA, dronedarone is an amiodarone congener and the first from a line of amiodarone-like compounds that are in development. These agents are attracting interest because amiodarone is the most effective antiarrhythmic drug currently available but it is also associated with adverse effects and weaknesses, Dr. Kowey said at the symposium, also sponsored by the Academy of Health Care Education.

Dronedarone avoids the thyroid and pulmonary toxicity of amiodarone. The two agents have not been compared in a head-to-head study, but if dronedarone were to be approved, it would be “extraordinarily useful” for relatively young patients who are being considered for amiodarone, perhaps because they've already failed treatment with a class 1C drug such as flecainide or propafenone, Dr. Kowey said.

Dronedarone should not be used in patients with severe heart failure because of a suggestion of safety problems in the trials so far. It also should be avoided in patients with severe renal dysfunction. For patients with severe left ventricular hypertrophy, amiodarone remains the best drug.

▸ RSD-1235. Some phase III testing has been completed for this atrial-selective drug, but other studies are still in progress. The drug's manufacturer says that it plans to apply for FDA licensing early this year with an intravenous formulation for acute arrhythmia termination. An oral form is still in clinical trials. The class of atrial-selective agents is a major area of development because adverse electrical effects on ventricles is the biggest toxicity of existing drugs for atrial arrythmia, said Dr. Kowey. Another atrial selective drug, AVE 0118, is just starting clinical studies.

Atrial repolarizing delaying agents also are just entering clinical studies and must show their potential in proof-of-concept tests. Gap-junction modulators are in preclinical development, although the main focus now for these drugs is ventricular arrhythmias. Stretch-activated channel blockers also are being studied.

Some drugs already on the market have also shown signs of possible efficacy for atrial fibrillation.

β-Blockers are a promising class. Carvedilol in particular showed signs of efficacy for preventing atrial arrhythmia in patients with ischemic heart disease in the Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. Certain ACE inhibitors and angiotensin-receptor blockers have also shown signs of efficacy for preventing fibrillation in completed trials, and the efficacy of some angiotensin-active drugs as primary therapy for atrial fibrillation is now being tested in randomized controlled trials.

Other agents that have shown hints of efficacy include anti-inflammatory drugs, especially statins, which significantly reduced the incidence of atrial fibrillation episodes in two retrospective studies.