LOS ANGELES, CALIFORNIA. Amiodarone (Cordarone) is the most effective antiarrhythmic drug on the market today, although a recent trial found that its efficacy in keeping atrial fibrillation patients afib-free for a year is only 34%. Apart from questionable efficacy, amiodarone also has a long list of potentially very serious side effects including thyrotoxicosis, hypothyroidism, pulmonary toxicity (fatal in 10% of cases), liver toxicity, optic neuropathy (including loss of vision), and blurred vision.

The amiodarone molecule contains 37.5% by weight of iodine and it is widely believed that it is the iodine that causes most of the adverse effects of the drug. Thus, it is not surprising that much research has been devoted to finding a drug similar to amiodarone (a benzofuran derivative), but without the iodine component. This recently resulted in the development of dronedarone (Multaq). Dronedarone has undergone several large-scale clinical trials, which, with the exception of one (ANDROMEDA) involving patients with severe congestive heart failure, have found it to be safe and with no significant adverse effects after one year of use. However, an increase in serum creatinine level (an indicator of possible kidney toxicity) has been observed in some trials, as have gastrointestinal problems like diarrhea, nausea and vomiting.

Two large-scale clinical trials (EURIDIS and ADONIS) evaluated the effect of 400 mg of dronedarone twice a day in 1237 AF patients. At the end of the trial (12 months from the start), 24.8% of the placebo group were still in normal sinus rhythm as compared to 35.9% in the dronedarone group.

A more recent trial (ATHENA) involved 4628 patients with paroxysmal or persistent AF or flutter and, in most cases, hypertension (85%), structural heart disease (60%), or coronary artery disease (31%). The trial participants were randomized to receive 400 mg of dronedarone twice a day or a placebo and were then followed for an average of 21 months resulting in approximately 4000 patient-years of observation. The purpose of the trial was to investigate whether dronedarone therapy would significantly reduce all-cause mortality and rehospitalization for cardiovascular causes. In other words, the "endpoint" chosen was primarily of interest to the health care system rather than to the patient who would be more interested in knowing whether the drug would reduce the recurrence of AF or flutter, or the overall burden (number of episodes times their duration). The overall mortality in the placebo group was 3.0% vs. 2.5% in the dronedarone group – a non-statistically significant and not terribly impressive relative reduction of 17%. Cardiovascular-related hospitalizations were 19% in the placebo group vs. 15% in the dronedarone group – again, a fairly modest relative reduction of 21%.

A group of cardiologists from the Cedar-Sinai Medical Center and the University of California has now taken a critical look at the trials underlying the FDA approval of dronedarone for the prevention of cardiovascular hospitalization related to AF or flutter. Among their most pertinent comments are:

• The antiarrhythmic effects of dronedarone are quite modest compared with placebo and only half as effective compared with amiodarone.
• The ANDROMEDA trial showed that dronedarone worsened heart failure and the drug now carries a black box warning regarding its use in heart failure patients.
• Reasons for hospital admissions in the ATHENA trial were not clearly delineated and it is not at all clear that hospitalizations for AF or flutter recurrence were a major contributor.
• The DIONYSOS study, which compared dronedarone (400 mg twice/day) with amiodarone (200 mg/day), found that 42% of patients in the amiodarone group experienced AF recurrence over a 6-month period as compared to 63% in the dronedarone group. However, dronedarone was associated with a reduced risk of thyroid problems, sleep disorders, and tremors, but the risk of adverse gastrointestinal events increased.

The authors conclude that the available data support only limited use of dronedarone for select patient populations, mostly as a second- or third-line agent in lieu of amiodarone. For lone afibbers the preferred antiarrhythmics would be flecainide, propafenone and sotalol as recommended in the current guidelines for the management of AF. They caution against indiscriminate use of dronedarone.
Singh, D, et al. Dronedarone for atrial fibrillation. Journal of the American College of Cardiology, Vol. 55, No. 15, April 13, 2010, pp. 1569-76

Editor's comment: Not surprisingly, the publication of the above article with its criticism of the ATHENA trial and the suggestion that dronedarone may be more hype than substance caused a considerable stir within the cardiology community. Dr. Sanjay Kaul, the lead author of the article, defended his position and clarified it with comments such as:

• "Limitations in the design and execution of the ATHENA trial raise questions about the quality of its data and cast doubts on their relevance to clinical practice."
• "I am not convinced that dronedarone offers us a safer alternative."
• "In my mind, the patient population that was selected in the ATHENA trial does not represent what we see in clinical practice."

Dr. George Wyse of the University of Calgary is also sceptical of the ATHENA results. Says he, "To me that argues strongly against the favourable impact of dronedarone having anything to do with preventing atrial fibrillation."

The investigators involved in the ATHENA trial all come out strongly in favor of dronedarone. However, their enthusiasm should perhaps be tempered by the fact that most, if not all, of them had financial ties to the maker of dronedarone, Sanofi-Aventis and numerous other pharmaceutical companies. Finally, it is doubtful that dronedarone therapy is cost-effective. At a cost of $9 per day per patient, keeping 2314 patients on dronedarone for 21 months would cost $13,303,000. Doing so would avoid 184 hospital admissions. In other words, the cost of avoiding one hospital admission through the use of dronedarone would be $72,300 – hardly a bargain!