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Sanofi's Multaq hazardous in permanent atrial fibrillation

Final results of the PALLAS trial confirm risk of death and cardiovascular events

Final results of the PALLAS trial have confirmed that use of Sanofi's anti-arrhythmia drug Multaq increased the risk of death and cardiovascular events in patients with permanent atrial fibrillation.

PALLAS was stopped earlier this year after concerns about the safety of Multaq (dronedarone) first appeared, after around a third of its target of 10,000-plus patients had been enrolled.

Yesterday, lead investigator Stewart Connolly of McMaster University in Canada told delegates at the American Heart Association annual meeting that the drug doubled rates of stroke, heart failure, cardiovascular death and arrhythmic death in permanent AF patients.

The results are in stark opposition to the earlier ATHENA trial, which mainly involved patients with intermittent AF but without established cardiovascular disease. The data showed that Multaq reduced not only recurrence of AF, but there was also a significant reduction in major cardiovascular events such as stroke, and this formed the basis of Multaq's approval in 2009.

Based on ATHENA's results, Connolly and colleagues felt that Multaq could also have an important role to play in permanent or established AF, in other words those in which the irregular heart rhythm is a long-term phenomenon that resists treatment.

But the study investigators now write in the New England Journal of Medicine, which has just published the data, "our data show that dronedarone is hazardous in such patients". They conclude Multaq should be avoided in patients with heart failure and other forms of advanced cardiovascular disease, "particularly when they also have permanent AF".

Very few patients in the study had their normal sinus rhythm restored (cardioversion) as a result of treatment with the drug, they note.

Exactly why the results for ATHENA and PALLAS are so different remains a key question. The investigators speculate that the increase in cardiovascular deaths - mainly caused by arrhythmia - could have resulted from an interaction between Multaq and digoxin, but note this does not explain the higher rates of heart failure and stroke.

The big consideration for Sanofi now is what role Multaq still has to play in its approved indication of non-permanent AF, particularly in patients at risk of developing advanced cardiovascular disease such as heart failure. There have been suggestions for example that its use could be reserved for when other anti-arrhythmic drugs have failed.

To date, Multaq has been launched in around 40 countries around the world to date and used in more than 400,000 patients, bringing in €197m in the first nine months of the year, a rise of 88 per cent over the same period of 2010.

PALLAS is not the first time the drug's safety has been questioned, and analysts have been scaling back revenue projections for the drug, which at the time of launch were as high as $4bn at peak.

The phase III ANDROMEDA trial, which studied the drug in patients with severe heart failure, was prematurely terminated in January 2003, due to an increased incidence of mortality caused by worsening heart failure in patients assigned to Sanofi's drug. In addition, earlier this year the US Food and Drug Administration (FDA) issued a warning about rare but severe liver damage associated with the drug.

The European Medicines Agency began a safety review of Multaq in September and its Committee for Medicinal Products for Human Use (CHMP) has already recommended restricting its use to "maintaining heart rhythm in patients with paroxysmal or persistent atrial fibrillation for the maintenance of sinus rhythm after successful cardioversion".

The CHMP concluded at the time however that Multaq still had a role to play in managing non-permanent AF, with suitable monitoring, provided its use is avoided in patients with underlying cardiovascular conditions including left ventricular dysfunction and heart failure, as well as prior liver and lung injury.

15th November 2011

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