After completing its procedure for re-assessment of dronedarone (MULTAQ), the European Medicines Agency (EMA) restricted the indication for the anti-arrhythmic agent and markedly expanded the contraindications and warnings. Now dronedarone may only be prescribed for maintenance of sinus rhythm after successful cardioversion in patients with non-permanent (paroxysmal or persistent) atrial fibrillation** and not until alternative therapies have been considered. Furthermore the medication is contraindicated in any degree of heart failure and left ventricular dysfunction (1). Previously only severe heart failure was among the contraindications (2). Dronedarone is also expressly contraindicated in permanent atrial fibrillation as well (1). These measures are the consequence of safety concerns which had emerged partly from the liver toxicity which became known after market launch and the increase in cardiovascular complications and mortality with dronedarone in the prematurely discontinued PALLAS*** study in permanent atrial fibrillation (a-t 2011; 42: 65-6). Another new addition to the risk signals is pulmonary toxicity with interstitial lung disease including pneumonitis and pulmonary fibrosis; this is also known in connection with the related drug amiodarone (CORDAREX, generics). Dronedarone must no longer be used after pulmonary toxic and hepatotoxic reactions to amiodarone (1).

The remaining indication for dronedarone, rhythm control, is per se already a back-up strategy for selected patients with atrial fibrillation (3). In randomised studies it fares no better in terms of clinical endpoints such as quality of life, cardiovascular complications, stroke or death than frequency control, but it causes more disturbing effects and is associated with more hospital admissions (4). In this situation dronedarone offers no advantage over the standard drug amiodarone: in direct comparison, it is much worse at preventing the recurrence of atrial fibrillation after cardioversion. By contrast, the two anti-arrhythmic agents do not differ in overall tolerability (a-t 2010; 41: 17-9) (5). In the meantime, however, signs of increased risk of mortality for dronedarone have emerged from two studies: from the older ANDROMEDA**** study on severe heart failure (NYHA III or IV, 8.1% vs. 3.8% on placebo) (6) and more recently from the PALLAS study on permanent atrial fibrillation (1% vs. 0.4%) (7). We do not find corresponding signs for amiodarone from direct comparisons (8,9). It seems doubtful to us that the new directions for use will be able to guarantee safe use of dronaderone in view of the blurred boundaries between non-permanent and permanent atrial fibrillation and the uncertainties in terms of definition. In our view, the benefit-harm relationship continues to be negative.

Meanwhile leading American cardiologists also call into question the benefit and safety of dronedarone ("I think the drug is dangerous", "It just doesn't work") and oppose its prescribing. They are hence increasing the pressure on the US regulatory authority (FDA) which has so far not completed its safety re-assessment of dronedarone (10,11).

The benefit-harm balance of dronedarone (MULTAQ) seems negative to us also for the remaining indication, rhythm control after successful cardioversion in non-permanent atrial fibrillation.

We regard market withdrawal of the anti-arrhythmic agent as the only logical consequence.

(R = randomized study, M = meta-analysis)

1

Sanofi-Aventis: SPC MULTAQ, as at Sept. 2011

2

Sanofi-Aventis: SPC MULTAQ, as at June 2011

3

CAMM, A.J. et al.: Eur. Heart J. 2010; 31: 2369-429

4

LAFUENTE-LAFUENTE, C. et al.: BMJ 2009; 339: b5216 (6 pages)

R

5

Le HEUZEY, J.Y. et al.: J. Cardiovasc. Electrophysiol. 2010; 21: 597-605

R

6

KØBER, L. et al.: N. Engl. J. Med. 2008; 358: 2678-87

7

FDA Drug Safety Communication: MULTAQ (dronedarone) and increased risk of death and serious cardiovascular adverse events, 21 July 2011
http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm

M

8

LAFUENTE-LAFUENTE, C. et al.: Arch. Int. Med. 2006; 166: 719-28

M

9

DOYLE, J.F., HO, K.M.: Mayo. Clin. Proc. 2009; 84: 234-42

10

O'RIORDAN, M.: Heartwire, 22 Sept. 2011
http://www.theheart.org/article/1283205.do (free registration required)

11

BURTON, T.M.: Wall Street Journal, 22 Sept. 2011

*

Previous version published online on 23 Sept. 2011 as blitz-a-t

**

According to the current, generally acknowledged classification, atrial fibrillation is categorized as non-permanent (paroxysmal: < 7 days, mostly ≤ 48 h; or persistent: > 7 days or cardioversion required for cessation) and permanent (atrial fibrillation is accepted by patient and physician). If rhythm control is to be attempted at a later stage in a case of permanent atrial fibrillation, the arrhythmia thus becomes non-permanent atrial fibrillation by definition (3).

***

PALLAS = Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy

****

ANDROMEDA = ANtiarrhythmic Trial with DROnedarone in Moderate to Severe CHF Evaluating Morbidity DecreAse