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12/22/2011 - Dronedarone is the latest antiarrhythmic drug to be developed for treating atrial fibrillation. In their search for a safe and effective drug for atrial fibrillation, pharmaceutical companies have long imagined their "Holy Grail:" A drug that is as effective as amiodarone, but without its unique toxicity profile. Dronedarone (Multaq) was developed by Sanofi (the makers of amiodarone) specifically in the hopes of creating that holy grail.

Early clinical trials with dronedarone showed that it was moderately effective in maintaining a normal rhythm in people who have had atrial fibrillation. Still, almost two out of three patients treated with dronedarone had recurrent atrial fibrillation during the first year after beginning treatment. This is a statistically significant improvement compared to the three out of four patients treated with placebo who had recurrent atrial fibrillation. But it is certainly not a striking improvement -- and indeed is little better than the reduction in atrial fibrillation seen with many other antiarrhythmic drugs.

Risks With Dronedarone

In return for this merely moderate effectiveness, patients taking dronedarone are exposed to risks which are just now being fully defined.
Dronedarone is a derivative of amiodarone, which is the most effective, but the most toxic, antiarrhythmic drug yet developed. Unlike amiodarone, dronedarone does not contain idodine atoms, and the iodine within amiodarone has been postulated to produce some of the drug's striking toxic effects, especially the thyroid toxicity seen with the drug, and perhaps the lung toxicity. And as it turns out, dronedarone has not displayed this unique, amiodarone-like toxicity.

Early studies with this drug - the studies that were available when the FDA approved the drug - gave conflicting messages on its overall safety. In 2003, Sanofi had to prematurely halt the ANDROMEDA trial using dronedarone in patients with significant heart failure and atrial fibrillation, at the urging of the independent Data Safety and Monitorning Board, because those treated with dronedarone appeared to have an increased risk of death.

But a later study (the ATHENA study, which enrolled patients who were significantly healthier than those in the ANDROMEDA study) reported that patients treated with dronedarone for atrial fibrillation had a signficantly reduced risk of death or cardiac hospitalization, compared to patients treated with placebo. This was the first clinical study to suggest that treating patients who have atrial fibrillation with any antiarrhythmic drug can improve survival or reduce hospitalizations. This result created quite a stir, even though the mechanism by which dronedarone improved clinical outcomes was entirely undefined. It was largely on the strength of the ATHENA trial that the FDA approved dronedarone in 2009.

In late 2011, however, the results of the PALLAS study threw a wet rag over the notion that dronedarone is effective in improving clinical outcomes. The PALLAS study, like the ANDROMEDA study, was stopped early because of worse outcomes in patients with atrial fibrillation randomized to take dronedarone. Patients enrolled in the PALLAS study who took dronedarone had a significantly higher incidence of "cardiovascular events" including stroke, heart attack, heart failure, and sudden death from cardiac arrhythmias. Notably, these patients all were being treated for permanent atrial fibrillation, and were older and had more cardiovascular disease than those who had improved outcomes with dronedarone in the ATHENA study.

The other side effects with dronedarone appear to be relatively benign. The most common reported side effects are diarrhea or nausea, slow heart rate, and rash.

The Bottom Line

Based on the results of the PALLAS trial, dronedarone should be used with caution. Certainly, it should not be used in people who resemble those enrolled in the PALLAS trial - people over 65 years of age, who already have cardiac disease, and who have had atrial fibrillation lasting weeks or months. If it is going to be used at all, dronedarone should be used in people who resemble those enrolled in the AHTHENA trial - younger people who have only intermittent atrial fibrillation, and who have otherwise healthy hearts.

In late December, 2011, in response to the PALLAS trial, the FDA published a new safety warning on dronedarone (which can be found here), advising that dronedarone be used only in people whose atrial fibrillation is being successfully treated with the drug. Further, the FDA now advises that people taking dronedarone for atrial fibrillation should have repeated monitoring at least every 3 months, to document the absence of the arrhythmia.

So, at the end of the day, the dronedarone story appears to recapitulate the story we hear over and over again with antiarrhythmic drugs: as a group, these drugs are only moderately effective, yet are among the most toxic drugs used in medicine. They should always be used only after careful consideration of all the alternatives, and when the potential benefits clearly outweigh the very real risks.

Multaq Side Effects Lawsuit

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