Dronedarone gets cautious nod from FDA advisory panel

The FDA’s Cardiovascular and Renal Advisory Committee voted 10 to 3 in favor of approval for Sanofi’s dronedarone. By all accounts it was a difficult decision for the committee.

CardioBrief has received statements from panel members Sanjay Kaul (yes, he did make it to the meeting) and Darren McGuire.

Here is Darren McGuire‘s comment on the meeting:

Bulk of discussion centered around placing the ATHENA results, which demonstrated a trend favoring overall mortality and a statistically significant reduction in CV mortality as secondary endpoint analyses of components of the primary outcome (CV hospitalization and total mortality), in context of the ANDROMEDA trial of advanced, recently unstable HF that was stopped early due to excess  mortality. Whether the ANDROMEDA findings were related to the instability of HF, or the underlying severity of Class III/IV HF with low EF remains uncertain, and therefore consensus was that this group of patients, stable or unstable, should not be candidates for dronedarone, at least until further data are available. The vote to approve was driven primarily by the robust and highly significant redcution in CV hospitalization, and while granular detail about those hospitalizations, which were investigator-reported and not adjudicated, most agreed that this observation represented an important increment in the evidence for clinically relevant outcome improvement for patients with Afib/Aflutter.

Many voiced an imperative to conduct longer-term post-approval trial(s) against amiodarone to further estimate efficacy and long-term safety, especially in the context of often latent non-cardiac toxicities of amiodarone that was the impetus to develop this compound in the first place.

Here is Sanjay Kaul‘s comment on the meeting:

Overall assessment
The whole premise behind ATHENA was to overcome the adverse mortality observed with dronedarone in ANDROMEDA. When one combines all the placebo-comparison studies conducted with dronedarone so far, I am not sure a clinically unacceptable increase in mortality has been excluded. The only reason the results of the ATHENA trial provide some reassurance about the long-term use of dronedarone (especially in light of the concerns raised by the results of the ANDROMEDA trial) is that a much lower risk population was studied.

The efficacy appears to be very modest with respect to NSR maintenance and rate control. Although these differences were statistically significant, the clinical significance is debatable.  The patient population enrolled does not reflect the spectrum of atrial fibrillation (AF) patients typically observed in clinical practice (permanent AF patients excluded, only 25% of pts had AF/AFL (atrial flutter) on randomization, only 21% patients had CHF Class II, III; etc.). Coupled with the lack of improvement in patient’s symptoms and/or quality of life status (which was not systematically evaluated) and the lingering controversy about the primacy of rhythm vs rate control strategy, a proper role for this drug in clinical practice requires careful consideration.

Finally, the drug was ostensibly designed to offset the adverse and extra-cardiac toxic outcomes associated with amiodarone. Even for this objective, I am not sure if superior tolerability was demonstrated with some degree of confidence. It was shown to be 50% less effective compared to amiodarone with only a modest, but nonsignificant, tolerability advantage.

On the other hand, ATHENA is the largest outcome trial in patients with history of or current AF/AFL with demonstrated benefits in reducing CV hospitalization, admittedly not the most robust of endpoints. However, this endpoint is somewhat clinically relevant (especially the reductions in ICU admissions), and might have the potential for cost savings.

What role do I see for this drug in clinical practice if approved?
For reducing CV hospitalizations related to atrial fibrillation/atrial flutter in low-intermediate risk patients with current or previous history of non-permanent AF/AFL and who do not have any contraindications including, in addition to the obvious ones, Class III heart failure and/or patients with low ejection fraction (<35%). For patients with Class III CHF or LVEF <35% (regardless of NYHA functional class) and patients with LVH, amiodarone should remain the first-line rhythm control strategy (as per ACC/AHA/ESC guidelines). Dronedarone could be considered in these patients if they become intolerable to amiodarone. No claim for superior tolerability against amiodarone should be allowed. I would like to see a larger comparative study, if feasible, with longer follow-up to demonstrate superior tolerability without unacceptable loss of efficacy before allowing that claim.

Bottomline, the data are sufficient to support a restricted label with a boxed warning for patients with advanced heart failure, but insufficient to support superior tolerability claim compared to amiodarone.

Here is Sanofi’s press release:

SOURCE sanofi-aventis