Dronedarone doubled mortality risk in halted PALLAS study

AHA Scientific Sessions 2011

ORLANDO, Fla. — Dronedarone increased the rate of HF, stroke and CV death in patients with permanent atrial fibrillation at risk for major vascular events, according to late-breaking data from the PALLAS study.

“It is clear from our data that dronedarone should not be used in patients with permanent AF with a high burden of vascular disease,” Stuart J. Connolly, MD, from the Population Health Research Institute, Hamilton Health Sciences, Canada, said at a press conference today.

The drug doubled the rate of stroke, MI, systemic embolism or CV death as compared with placebo (2.7% vs. 1.2%; P=.002). Similarly, the rate of unplanned CV hospitalization or death in patients assigned dronedarone was almost twice that of the placebo group (7.8% vs. 4.1%; P<.001).

These data are surprising, given the fact that results of the ATHENA trial demonstrated a 25% reduction in unplanned CV hospitalization or death, Connolly said.

The PALLAS study included 3,236 patients (mean age, 75 years) who were randomly assigned to twice-daily dronedarone (Multaq, Sanofi-Aventis) 400 mg or placebo. The first patient enrolled on July 19, 2010. On July 5, 2011, a data monitoring committee recommended that the study be terminated for safety concerns.

Dronedarone was associated with an increase in overall mortality (25 vs. 13; HR=1.94; 95% CI, 0.99-3.79). Although these numbers are relatively small, the P value was significant, Connolly said. Most deaths reported in the study were a result of an increase in CV death (P=.046) and arrhythmic death (P=.03).

The PALLAS results are in contrast to those observed in ATHENA, which demonstrated a 45% reduction in arrhythmic death. In PALLAS, dronedarone was associated with an increase in stroke incidence (P=.02), a finding also opposite of ATHENA.

HF hospitalization occurred among 2.7% of the dronedarone population, compared with 1.5% of the placebo population (HR=1.81; 95% CI, 1.10-2.99). A subgroup analysis did not demonstrate any clear pattern of which patients were at risk and which were not. According to Connolly, the hazard of being on dronedarone was fairly even for both co-primary outcomes.

Additionally, serious adverse events were not uncommon; many were previously reported with dronedarone and observed in the ATHENA trial, the researchers said. – by Stacey L. Fisher

For more information:

• Connolly SJ. LBCT.03. Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16; Orlando.
• Connolly SJ. N Engl J Med. 2011;doi:10.1056/NEJM0a1109867.

Disclosure: The PALLAS study was funded by a grant from Sanofi-Aventis. Dr. Connolly reports no relevant financial disclosures.

Dronedarone should not be used in patients with HF or permanent AF. This is the message of the PALLAS trial and the ANDROMEDA trial. Further data are needed to answer the critical question of whether the results of the PALLAS trial apply to patients using dronedarone for the approved indication. Currently, patients taking dronedarone who fit into the ATHENA profile should be monitored regularly, at least every 6 months, to ensure that they remain within the approved indication and do not progress to permanent AF or new or worsening HF. If clinicians elect to initiate or continue [dronedarone] in ATHENA-type patients, they should be sure that the patients maintain that profile and have that profile when the drug is initially started.

N.A. Mark Estes III, MD
Professor of medicine, Tufts University School of Medicine
Director, New England Cardiac Arrhythmia Center
The Cardiovascular Center at Tufts Medical Center

Disclosure: Dr. Estes reports no relevant financial disclosures.

Andrew E. Epstein

AF is of huge interest not only for cardiologists and electrophysiologists, but for the entire medical community. The population is aging and the incidence of AF is skyrocketing such that by the year 2050 the number of patients with AF in this country will be about double what we have now. This is particularly important since one-third of strokes that occur in patients over the age of 80 years are due to this arrhythmia.

Dronedarone has been studied in a series of trials that built an evidence base regarding its safety and efficacy. Early trials showed that it suppressed AF, could control the ventricular response in patients with AF and then the ANDROMEDA trial showed that there was an important association of mortality when the drug was used in patients with heart failure. Conversely, the ATHENA trial showed a marked decrease in hospitalization and mortality when given to a less ill population. Furthermore, there were pleomorphic effects of the drug that were not expected. For example, independent of AF, dronedarone seemed to decrease the frequency of stroke. Thus, it was part of the natural history of the evolving knowledge base about this drug to determine whether CV events in general were independently improved by the drug, irrespective of AF itself.

This was addressed in the PALLAS study. PALLAS patients were chosen to be at high risk for CV events, and it is sad that this drug was not beneficial in this group. However, I do not see that this necessarily changes how we practice, in general, with respect to the prescription of dronedarone. First, I don't think there are many of us who prescribe dronedarone for patients with persistent AF for whom we are, by definition, not trying to maintain sinus rhythm. Conversely, we already are not prescribing the drug for patients with HF based on the results of ANDROMEDA. PALLAS tells us that dronedarone may continue to be an appropriate drug for patients who have less ventricular dysfunction and concomitant illness, especially younger patients, since the age of 75 years was highlighted in this trial as being an independent risk factor for risk, especially if both diabetes and hypertension were present. So, although this trial was disappointing, it does not necessarily mean that there are not selected patients for whom dronedarone may be appropriate.

-– Andrew E. Epstein, MD
Cardiology Today Editorial Board member

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