Double the number of deaths with dronedarone in permanent AF

118

The number of deaths in the dronedarone (Multaq, Sanofi Aventis) arm of the recently halted PALLAS study, which was reviewing use of the antiarrhythmic drug in patients with permanent atrial fibrillation, was double the number of deaths in the control arm, according to figures released by the US Food and Drug Administration (FDA).

Sixteen patients taking dronedarone died during the trial compared with seven taking placebo (a non-significant difference). Furthermore, the combined endpoint of cardiovascular death, myocardial infarction, stroke and system embolism was significantly increased in the active treatment arm (2% vs. 0.9; p=0.009). The FDA are reviewing the results of the study to see whether they apply to patients with non-permanent atrial fibrillation (for which dronedarone is currently licensed – it is not licensed for permanent atrial fibrillation), and it has now advised patients who are currently receiving dronedarone for non-permanent atrial fibrillation to talk to their healthcare professional about whether or not they should continue taking the treatment.

However, it states patients should not stop taking the drug without talking to their healthcare professionals first. The European Medicine Agency (EMA) is also reviewing the results of the PALLAS trial to see if they apply to patients with non-permanent atrial fibrillation. In its advice, it reminds healthcare professionals to follow the recommendations of dronedarone with respect to the indication, contraindications, and warnings. “Specifically, prescribers are advised to monitor patients regularly in order to ensure that they remain within the authorised indication and do not progress to permanent atrial fibrillation.” The EMA has been reviewing the overall benefits-risks balance of dronedarone since the beginning of this year following reports of severe liver injury. It will finalise its review in September.

As result of the increase in cardiovascular events, Sanofi Aventis halted the PALLAS study. Stuart Connolly, co-principal investigator, said: “Patients with permanent AF and vascular risk factors are at high risk of major vascular events and no previous study has investigated whether any intervention can reduce major morbidity or mortality in these patients. PALLAS is the first trial to investigate whether an antiarrhythmic drug can decrease outcomes in this important population of patients. The PALLAS operations committee is very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high risk patient population has been refuted.”

Jean-Pierre Lehner, chief medical officer for Sanofi, said that the company remained “committed” to dronedarone as an “essential” treatment for patients with non-permanent atrial fibrillation.

Summary of events during the PALLAS study (30 June 2011)

Multaq
N=1572
n (%)

Placebo
N=1577
n (%)

Hazard Ratio

p-value

Cardiovascular death, myocardial infarction, stroke, systemic embolism

32 (2)

14 (0.9)

2.3

0.009

Death, unplanned cardiovascular hospitalisation

118 (7.5)

81 (5.1)

1.5

0.006

Death

16 (1)

7 (0.4)

2.3

0.065

Myocardial infarction

3 (0.2)

3 (0.2)

1.0

1

Stroke

17 (1.1)

7 (0.4)

2.4

0.047

Heart failure hospitalisation

34 (2.2)

15 (1)

2.3

0.008


Note: These are preliminary data provided by Sanofi Aventis; therefore, the data have not undergone quality assurance procedures and have not been completely adjudicated.