Dronedarone, a highly touted drug targeted at atrial fibrillation and sold under the brand name Multaq, is only half as effective as the generic drug amiodarone and does not appear to have fewer side effects, researchers from the Cedars-Sinai Medical Center reported Monday. It should be used only as a second- or third-line drug if all others fail, the team reported in the Journal of the American College of Cardiology. The report, which is based on an examination of existing clinical trials rather than new research, represents further bad news for what was once thought to be a potential blockbuster drug with billions of dollars of annual sales.
[Updated: 5:15. The post wrongly said that the report appeared in the American Journal of Cardiology.]
"Atrial fibrillation is a huge public health issue," said Dr. Sanjay Kaul of Cedars-Sinai, lead author of the new report. Kaul is a member of the Food and Drug Administration's advisory panel that considers cardiovascular drugs, and he writes occasional review articles about drugs that are considered by the panel when he believes that not all the information considered in the advisory meetings makes it out to the general public through conventional publication. Dronedarone is an important medication to have all the facts, he said, because atrial fibrillation affects an estimated 2.3 million Americans, accounting for 71,000 deaths each year.
Atrial fibrillation refers to the rapid, abnormal beating or fluttering of the heart when electrical signals in the atrium become erratic. During fibrillation, the heart cannot pump blood effectively, allowing it to pool in the heart and potentially form clots that can embolize and cause strokes. Mild fibrillation may be symptomless, but the problem can cause fatigue and dizziness and, in the longer term, congestive heart failure.
The two most common approaches to medical therapy are called rate control and rhythm control. Rate control is aimed at the fact that the heart is attempting to beat too rapidly, so that each contraction is ineffective. Drugs such as beta-blockers and digoxin are used to slow down the heart, so that more blood can be forced through the body. Blood thinners such as warfarin are also used to inhibit clotting. Rhythm control uses drugs, primarily amiodarone, to alter the electrical output of the heart, regularizing the heartbeat. Clinical trials comparing the two approaches have yielded contradictory results, and there is little consensus about which approach is better.
Other approaches that may be used when medical therapy is not effective include the use of implanted defibrillators to shock the heart back into normal sinus rhythm and catheter ablation, in which physicians use a technique similar to angiography to destroy heart tissue responsible for the abnormal electrical activity.
Amiodarone, which is sold generically and under the brand name Cordarone, is an effective medication for controlling fibrillation. But it has severe potential side effects, including damage to the thyroid and lungs. Dronedarone was developed by Sanofi-Aventis as an alternative to amiodarone. It has a similar structure, but animal tests suggested it had fewer complications. The first clinical trial of the drug, in patients at moderate- to high-risk for hospitalizations and death from atrial fibrillation, showed that it doubled the rate of death, and the study was terminated prematurely. The FDA rejected the marketing application and suggested the company find applications where the benefit would exceed the risk.
A second major trial in patients with low to moderate risk found that the drug reduced hospitalizations resulting from atrial fibrillation, but not deaths. The FDA approved the drug, but allowed it to be marketed only for reducing hospitalizations.
European regulatory authorities demanded a head-to-head study of amiodarone and dronedarone. That study, which has yet to be published, found that dronedarone was only half as effective as amiodarone in preventing hospitalizations and deaths, but that it was slightly better tolerated -- although the difference was not statistically significant.
"The overall assessment is that dronedarone has only modest efficacy and no clear-cut safety advantage," Kaul said in an interview. Amiodarone, in contrast, has "a huge cost advantage." Multaq costs about $9 per day, and generic amiodarone costs pennies. "It's cheap, so why would you want to use an expensive, ineffective alternative?"
[Updated, 5:15. The post originally said "inexpensive" and it should have said "expensive."]
Kaul also thinks the side effects of amiodarone are a red herring. They appeared when a 400-milligram dose of the drug was routinely used, "but over the last 10 years, we have been using a 200-milligram dose and don't see the problems. I personally haven't seen any example of lung toxicity in the last 10 years."
The Cedars-Sinai team wrote that dronedarone should be considered when first-line treatments fail or create problems, or when patients are particularly concerned about the potential for side effects. But they argued that it should not routinely be used for first-line therapy. "I personally don't think that is a prudent strategy," Kaul said.
-- Thomas H. Maugh II