November 14th, 2011
PALLAS Intrigue: What Role Remains for Dronedarone?
When the news broke this past summer that that the PALLAS study of dronedarone (Multaq) for permanent AF had been stopped early, CardioExchange convened a panel to discuss what role remained for this agent. Now that the paper has been published in the New England Journal of Medicine and presented at AHA, we invited the same panelists back to tell us whether their views had changed or warranted elaboration, and whether they are surprised by the current usage of the drug. Here are the responses we received:
The published results of PALLAS only strengthen my negative view of dronedarone. Although PALLAS enrolled a selected cohort of older patients with more advanced heart disease, the data are striking and clear: Taking dronedarone was associated with a greater chance of dying, having a stroke or being unexpectedly hospitalized. That an ion-channel-blocking drug worsens outcomes in patients with heart disease is not a surprise. Think AFFIRM. Or even CAST.
Dronedarone use in the real world is approaching zero quickly. In the past, its inability to suppress AF was the primary reason why doctors stopped using it. Now, its important safety concerns have further accelerated the decline. To doctors who persist in recommending dronedarone, I ask only one question: Would you take it for your AF? I sure wouldn’t.
My original view is unchanged: A basic tenet of treating AF is to avoid making the treatment worse than the disease. Thus, I see no role for dronedarone in the treatment of AF.
In my experience of using dronedarone as a first-line agent for AF prevention, it is mildly to moderately effective. However, it’s understandable that others have found it not very useful if they have chosen to use it after agents such as sotalol, propafenone, and flecainide have been ineffective. It would not be worth trying at all in patients who have failed amiodarone. In my patients, dronedarone has exhibited an unusual pattern of either being very effective or not at all, whereas agents such as flecainide can show gradations of suppression in various patients. It is not clear why this occurs with dronedarone.
The results of the PALLAS study will affect my patient selection for dronedarone. While I was never in favor of doing a study in patients with permanent AF, I understood why others felt differently after the ATHENA results were obtained. After the CAST trial, encainide was withdrawn from the market but flecainide is now a very effective drug to suppress AF in patients with minimal heart disease. I would keep this in mind in assessing dronedarone: In my opinion it is still a reasonable choice for patients with no or minimal heart disease, but it should not be used in those with heart failure or significant LV dysfunction. I would like to see more data on its safety in patients with CAD but good LV function—a population that does not have many options if sotalol is not tolerated. Regardless, this substantially reduces my use of dronedarone.
One additional thought–there are 55 authors on the NEJM manuscript for PALLAS; so much for the concept of victory having a thousand fathers, but defeat being an orphan.
My overall analysis remains unchanged. The published results of PALLAS reinforce the narrow therapeutic window for dronedarone. I couldn’t agree more with the editorialist’s concluding statement that the atrial fibrillation guidelines will need to be reexamined, and that dronedarone should be reserved for selected low-risk patients with nonpermanent atrial fibrillation who fail to respond to other antiarrhythmic drugs.
Since its approval in July 2009 through October 2010, around 492,000 dronedarone prescriptions were dispensed and around 147,000 patients filled dronedarone prescriptions. These numbers are clearly lower than the sponsor’s original estimates, and I suspect, some would argue higher than otherwise justified by its benefit-risk profile.
One final note about PALLAS: Most unexpected findings, especially those that are not clinically sensible, are likely to be false-positive. The hypothesis of PALLAS was based on an unexpected post hoc observation in ATHENA that patients with permanent AF derived benefit with dronedarone. The totality of evidence suggests that patients with permanent AF have no reason to receive antiarrhythmic drugs. Nonetheless, this hypothesis was explored in the PALLAS trial driven mostly by marketing considerations to expand the therapeutic window. Trials should ideally be designed to inform and guide clinical practice, not for marketing reasons.”
For those of you on the front lines of AF treatment, who among these panelists do you agree with—if anyone?