Thursday, December 22, 2011

Who would dare use dronedarone now?

For more on the dronedarone debacle, see this previous post.
Earlier this week, the US Food and Drug Administration (FDA) published an updated safety announcement for dronedarone (Multaq®), a class III antiarrhythmic approved for use in patients with paroxysmal or persistent atrial fibrillation (AF). Their latest findings are based on the results of PALLAS [1], which found an increased risk of mortality and cardiovascular events among patients with permanent AF.  The prescribing label for dronedarone now contains the following recommendations:
  • Dronedarone should not be used in patients with permanent AF.
  • Providers should obtain ECGs every 3 months for patients taking dronedarone.  If a patient is in AF, they should be cardioverted to normal sinus rhythm or dronedarone should be discontinued.
These revisions follow warnings already contained in the dronedarone label which recommend that the drug not be used in patients with moderate to severe heart failure.

While these previous restrictions on the use of dronedarone have been largely interpreted as applying only to patients with systolic heart failure (due to their enrollment in the ANDROMEDA trial [2]), nearly 70% of the patients in PALLAS had heart failure to some degree and only one-fifth had systolic heart failure (e.g., left ventricular ejection fraction < 40%), leaving the remaining majority as having diastolic dysfunction. While an argument can be made that patients with permanent AF are quite different than those with paroxysmal or persistent AF, I still find it incredibly concerning that the drug was responsible for so many events (including deaths) in patients with preserved left ventricular function. Even more striking was how quickly the mortality event curves between dronedarone and placebo began to separate -- as early as one week and consistently thereafter.

Given the added restrictions included in this latest FDA announcement and the known risks already associated with dronedarone, I am left wondering which patients would actually benefit from this drug at all. I doubt many clinicians would attempt to make the argument that it is a safe alternative to amiodarone, especially given that the drug fails to show similar efficacy for maintaining normal sinus rhythm at even three months of therapy. Amiodarone may be associated with a number of problematic side effects, but it doesn't kill people.  With providers now being compelled to obtain ECGs every three months, it seems that the inconvenience, inefficacy, and risk of stroke, worsening heart failure, and death associated with dronedarone now seem to outweigh any conceivable benefits. Who would dare use it now?

  1. Connolly SJ, Camm AJ, Hohnloser SH, et al; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268-76.
  2. Køber L, Torp-Pedersen C, Carlsen J, et al; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008 Jun 19;358(25):2678-87.

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