Best Evidence Analyses and Commentary


Multaq (dronedarone) study abruptly halted
Gabriella Lucarelli, PharmD Candidate, 2012

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) was stopped early after finding a two-fold increase in death, stroke and hospitalization due to heart failure in patients taking dronedarone (Multaq) 400mg twice a day versus a placebo.  The trial started in July of 2010 and was expected to be completed in August of 2011 [1],[2].

Dronedarone, a class III anti-arrhythmic, was approved in July of 2009 to reduce the risk of hospitalizations related to paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL)[3].   It was intended to provide similar efficacy without the multiple side effects associated with amiodarone. The purpose of the PALLAS study was to seek a new indication for dronedarone, permanent AF.  The ATHENA study which was responsible for dronedarone’s initial approval for non-permanent AF did not include patients with permanent AF.  The mean age of participants was 71.6+9, and 21.2% had a NYHA heart failure class of I to III [3] . Little information regarding the specifics of the PALLAS study has been made public but a press release from Sanofi stated that in comparison to those enrolled in the ATHENA trial, the population was older, 70% had permanent AF for > 2 years and ~70% had NYHA heart failure class of I to III at baseline[4] 

Currently Multaq is contraindicated in patients with a NYHA class IV heart failure, or class II-III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic [5].  This decision came after the Andromeda trial was terminated early in 2008 when patients in the Multaq arm had a two fold increase in mortality[6].  The patient population included in the Andromeda were hospitalized with symptomatic heart failure and severe left ventricular systolic.  Basically the Andromeda trial included the patients that the ATHENA trial had excluded. This raises a question now if Multaq should be used in any patients diagnosed with heart failure[6], [7].  

Sanofi’s press release also stated the risk-benefit of dronedarone remains unchanged for the approved indication of non-permanent AF[4].  However, the FDA is currently reviewing all data to see if results are applicable to patients taking dronedarone for paroxysmal or persistent AF [1].  The European Medicines Agency also stated that they are reviewing all available information on dronedarone in hopes to provide further advice in the final assessment which will be in September [8]. 

  1. "FDA Drug Safety Communication: Multaq (dronedarone) and Increased Risk of Death and Serious Cardiovascular Adverse Events." U S Food and Drug Administration Home Page. US Department of Health and Human Services, 21 July 2011. Web. 01 Aug. 2011.
  2. "Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy - Full Text View - ClinicalTrials.gov." Home - ClinicalTrials.gov. US National Institute of Health, 11 July 2011. Web. 01 Aug. 2011.
  3. Hohnloser, S. H., H. J. Crijns, and M. Van Eickels, et al. "Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation." New England Journal of Medicine 360.12 (2009): 668-78. PubMed. Web. 1 Aug. 2011.
  4. Sanofi. Sanofi Provides Multaq® Phase IIIb PALLAS Trial Update. Sanofi.com. 7 July 2011. Web.
  5. "Multaq." DailyMed. FDA, June 2011. Web. 09 Aug. 2011.
  6. "Andromeda Trial Termination." Atrial Fibrillation (AFib) Treatment | MULTAQ® (dronedarone). Sanofi Aventis. Web. 09 Aug. 2011.
  7. Kober, L., C. Torp-Pedersen, J. J.V. McMurray, et. al. "Increased Mortality after Dronedarone Therapy for Severe Heart Failure." New England Journal of Medicine 358.25 (2008): 2678-687. Print.
  8. European Medicines Agency. European Medicines Agency Updates on Ongoing Benefit-risk Review of Multaq. Europa.eu. 21 July 2011. Web. 1 Aug. 2011.

 


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