Deaths Doubled With Dronedarone in PALLAS: FDA, EMA Updates

Shelley Wood

Disclosures

July 21, 2011

July 21, 2011 (London, United Kingdom and Rockville, Maryland) — Both US and European drug safety regulators announced today that they will be considering the PALLAS trial results as part of their ongoing reviews of dronedarone (Multaq, Sanofi-Aventis) safety. For the first time, the Food and Drug Administration (FDA) alert provides details on the very striking CV events seen in the study.

PALLAS had been investigating the use of dronedarone in patients with permanent atrial fibrillation (AF); the drug is currently approved for the treatment of paroxysmal or persistent AF or atrial flutter. As reported by heartwire last week, PALLAS was stopped early when monitoring committees noted an increased risk of cardiovascular events among patients with permanent AF taking the drug compared with placebo.

The FDA alert includes details on some sobering CV events seen in PALLAS, which were not released when the trial was initially stopped, although coprimary investigator Dr Stuart Connolly (McMaster University, Hamilton, ON) told heartwire at the time that they were "pretty important events."

According to the FDA, death rates were increased two-fold in patients taking dronedarone compared with placebo, as were rates of stroke and hospitalization for heart failure (HF).

PALLAS Events as of June 30, 2011

Adverse event Placebo n=1577

n (%)

Dronedarone n=1572,

n (%)

Hazard ratio p
CV death, MI, stroke, systemic embolism 14 (0.9) 32 (2) 2.3 0.009
Death, unplanned CV hospitalization* 81 (5.1) 118 (7.5) 1.5 0.006
Death 7 (0.4) 16 (1) 2.3 0.065
MI 3 (0.2) 3 (0.2) 1.0 1
Stroke 7 (0.4) 17 (1.1) 2.4 0.047
HF hospitalization 15 (1) 34 (2.2) 2.3 0.008

*Coprimary end points

Both the European Medicines Agency (EMA) and FDA announcements today remind physicians to be careful to use dronedarone as indicated, and not to prescribe it for patients with permanent AF.

The EMA announcement exhorts prescribers to monitor patients carefully "to ensure that they remain within the authorized indication and do not progress to permanent atrial fibrillation."

The FDA announcement notes that while the PALLAS data are still considered preliminary, it will be important to address the "critical question" of "whether and how the unfavorable results of the PALLAS study . . . apply to patients who use Multaq for the approved indications."

When news of the trial's stoppage were announced last week, Connolly told heartwire that he thought it was "reasonable" for patients with nonpermanent AF to stay on the drug "and I don't think they should be worried."

Today's EMA alert notes that the agency will issue a "final assessment" in September. The FDA's alert states that the FDA's review is ongoing and will update the public as needed.

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