The FDA ( Food and Drug Administration ) is reviewing data from a clinical trial that was evaluating the effects of the antiarrhythmic drug Multaq ( Dronedarone ) in patients with permanent atrial fibrillation. The study was stopped early after the Data Monitoring Committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving Multaq compared to patients taking a placebo. Currently Multaq is approved for use in a different, but related patient population.
The approval of Multaq was based on another trial ( ATHENA ) in which use of Multaq was associated with a decreased number of deaths compared to placebo.

Used to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation ( AF ) or atrial flutter ( AFL ), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted.
From approval in July 2009 through June 2011, approximately 1 million Multaq prescriptions were dispensed and approximately 241,000 patients received Multaq prescriptions from U.S. outpatient retail pharmacies.

The PALLAS ( Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy ) trial was being conducted to assess the potential clinical benefit of Multaq in patients over 65 years of age with permanent atrial fibrillation in the reduction of: a) major cardiovascular events ( stroke, systemic arterial embolism, myocardial infarction or cardiovascular death ); b) unplanned cardiovascular hospitalization or death from any cause.

A critical question is whether and how the unfavorable results of the PALLAS study, obtained in patients with permanent atrial fibrillation, apply to patients who use Multaq for the approved indications ( non-permanent atrial fibrillation, also known as paroxysmal or persistent atrial fibrillation ).

At this time, patients taking Multaq should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation. Patients should not stop taking Multaq without talking to a healthcare professional. Healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation.

FDA previously issued a Drug Safety Communication ( DSC ) in January 2011 regarding cases of rare but severe liver injury that have been reported with the use of Multaq.

Data summary

Sanofi Aventis conducted a randomized, double blind, placebo controlled, parallel group trial for assessing the clinical benefit of Dronedarone 400 mg BID on top of standard therapy in patients with permanent atrial fibrillation and additional risk factors ( PALLAS ). This study was a large outcome trial intended to evaluate the effectiveness of Dronedarone in patients with permanent atrial fibrillation.

The patients eligible to enroll in PALLAS were 65 years or older, in permanent atrial fibrillation ( defined by the presence of atrial fibrillation / atrial flutter for at least 6 months prior to randomization without plans to restore sinus rhythm), and had at least one additional cardiovascular risk criterion.

In July 2011, the Data Monitoring Committee reviewed the preliminary data and concluded that there was a significant excess of cardiovascular events in the Multaq group for both co-primary endpoints ( cardiovascular death, myocardial infarction, stroke, systemic embolism; death, unplanned cardiovascular hospitalisation ) as well as other cardiovascular events. As a result, the PALLAS study was stopped.

Events during the PALLAS study as of June 30, 2011:

a) cardiovascular death, myocardial infarction, stroke, systemic embolism: Multaq 2% vs placebo 0.9%; hazard ratio, HR=2.3; p-value 0.009;

b) death, unplanned cardiovascular hospitalisation: Multaq 7.5% vs placebo 5.1%; HR=1.5; p-value 0.006;

c) death: Multaq 1% vs placebo 0.4%; HR=2.3; p-value 0.065;

d) myocardial infarction: Multaq 0.2% vs placebo 0.2%; HR=1; p-value 1;

e) stroke: Multaq 1.1% vs placebo 0.4%; HR=2.4; p-value 0.047;

f) heart failure hospitalisation: Multaq 2.2% vs placebo 1%; HR=2.3; p-value 0.008.

Because the review is ongoing, FDA has not concluded whether the results of the PALLAS study are applicable to patients taking Multaq for paroxysmal or persistent atrial fibrillation or atrial flutter. However, healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation.

Source: FDA, 2011

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