Sunday, October 16, 2011

What to do about dronedarone?

In what has already been a tortuous journey, the fate of the antiarrhythmic drug dronedarone (Multaq®) took another twist late last month when the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a statement recommending the restriction of its use in patients with atrial fibrillation (AF). This announcement follows a similar release by the US Food & Drug Administration (FDA) earlier this summer, which recommended that patients taking dronedarone contact their provider to see if its continued use was warranted. Although the FDA's statement stops short of restricting dronedarone, it has left many clinicians in the US wondering what its status will be in the near future.

Dronedarone is a Vaughn-Williams Class III antiarrhythmic with structural and mechanistic similarities to amiodarone. However, several key differences in its structure were thought to provide it with similar efficacy compared to amiodarone but without many of the use-limiting toxicities, which can include injury to hepatic, thyroid, and lung tissue.

While earlier studies had demonstrated its efficacy in maintaining normal sinus rhythm in patients with AF, one of the first big hits to dronedarone came with the early termination of the ANDROMEDA trial, where the drug was associated with a twofold increase in the risk of death in patients with severe heart failure. Shortly thereafter, dronedarone was shown to reduce hospitalizations in high-risk patients with AF or atrial flutter, earning approval for its use here in the US. Questions remained regarding its efficacy compared to amiodarone, but this was all but settled in DIONYSOS, where dronedarone was shown to be far inferior to amiodarone for the maintenance of normal sinus rhythm (although associated with fewer serious side effects).

In addition to growing case reports that the drug may increase the risk of liver toxicity, more bad news came with the early termination of the yet-to-be-published PALLAS trial, which randomized patients with permanent AF to dronedarone or placebo and found that the drug doubled the risk of death, stroke, and hospitalization for heart failure. Both the FDA and EMA have since issued statements recommending against its use for this indication.

Although the EMA's statement recognizes dronedarone as still being an option for the maintenance of normal sinus rhythm in paroxysmal or persistent AF, it does suggest clinicians consider its use only after other alternatives have already been considered. Additionally, it recommends that patients initiating therapy with dronedarone have their lung and liver function monitored closely, with the latter being performed once monthly for the first six months of therapy.

So, what to do about its use here? Clearly, dronedarone should be avoided in patients with permanent AF or left ventricular dysfunction. However, it seems strange to me that the drug produced such profound increases in risk in PALLAS, yet was associated with a benefit in high-risk patients in ATHENA. My anecdotal experience is that the drug is not all that effective in the long-term. However, it seems a reasonable option for maintaining normal sinus rhythm in patients who have undergone an ablation and are unlikely to require antiarrhythmic drug therapy for an extended period of time. Otherwise, given its limited efficacy and growing reasons for concern, I'm just not sure the risks outweigh the benefits in the vast majority of patients with AF.

No comments: