Amiodarone vs Dronedarone

Amiodarone is commonly used in patients with atrial fibrillation (AF) requiring an antiarrhythmic drug. Dronedarone has been approved by the FDA for use in these patients. This paper will compare and contrast the two drugs, pharmacologically and clinically, and determine whether dronedarone a better option. While amiodarone has been shown to be effective, it also has some serious side effects such as Obstructive Sleep Apnea. Therefore, it is therapeutically important to determine whether dronedarone is a viable alternative.

DIONYSOS Study

There have not been many studies directly comparing amiodarone to dronedarone head-to-head. One study which involved a head-to-head comparison of the two drugs was the DIONYSOS study conducted by Le Heuzey et al.

In this comparative, randomized, double-blind study, 504 amiodarone-naïve patients were randomized to receive either dronedarone or amiodarone for at least six months. The main safety endpoint (MSE) was the “occurrence of thyroid-, hepatic-, pulmonary-, neurologic-, skin-, eye-, or gastrointestinal-specific events, or premature study drug discontinuation following an adverse event.” The treatment lasted seven months on average, and the primary composite endpoint was “75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28–1.98; P=0.0001)”, that was mostly due to recurrences of AF with dronedarone as compared to amiodarone (63.5 vs 42.0%). Also, the AF recurrence “after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively”. In addition, dronedarone resulted in “less frequent premature drug discontinuation (10.4 vs 13.3%).” The MSE was “39.3 and 44.5% with dronedarone and amiodarone, respectively,” after 12 months with an HR of 0.80 (95% CI 0.60–1.07; P = 0.129), that was mostly due to fewer “thyroid, neurologic, skin, and ocular events” in the dronedarone group.

The major strength of the DIONYSOS trial is that it was a direct head-to-head comparison of amiodarone to dronedarone, which provides a higher external validity than would indirect comparisons, which most studies comparing the two drugs are. In addition, the double-blind randomization of the trial provides high internal validity and minimizes confounding effects. However, one weakness in the study was that it did not address quality-of-life issues, which is an important consideration in AF treatment.

ATHENA

In the ATHENA trial, a randomized, double-blind study comparing dronedarone to placebo, 4628 patients with AF who had additional risk factors for death but did not have either hemodynamic instability or severe (NYHA class IV) heart failure were randomly assigned to receive either dronedarone or placebo. The researchers defined the primary outcome as the first hospitalization due to cardiovascular events or death. Secondary outcomes included death from any cause, death from cardiovascular causes, and hospitalization due to cardiovascular events. The mean “follow-up period was 21 months, with the study drug discontinued prematurely in 30.2% receiving dronedarone and in 30.8% receiving placebo, mostly because of adverse events. The primary outcome occurred in 31.9% of the dronedarone group and in 39.4% of the placebo group, with a hazard ratio for dronedarone of 0.76 (95% CI, 0.69 to 0.84; P<0.001). Five percent of the patients died in the dronedarone group compared to six percent in the placebo group (hazard ratio, 0.84; 95% CI, 0.66 to 1.08; P=0.18). 2.7% of patients in the dronedarone group died from cardiovascular causes and compared to 3.9% in the placebo group (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.03), largely due to a reduction in the rate of death from arrhythmia with dronedarone. The dronedarone group had higher rates of bradycardia, mitral valve prolapse, QT-interval prolongation, nausea, diarrhea, rash, and an increased serum creatinine level than the placebo group. Rates of thyroid- and pulmonary-related adverse events were not significantly different between the two groups.

The double-blind randomization of the ATHENA trial provides high internal validity and minimizes confounding effects, thereby providing strong support for the effectiveness dronedarone in treating AF, at least in patients without either hemodynamic instability or severe (NYHA class IV) heart failure. The researchers compared the results of the ATHENA trial to a previous study, the ANDROMEDA trial, which was terminated prematurely because of increased mortality with dronedarone, a difference in outcome which the ATHENA researchers theorize may be due the fact that ANDROMEDA “enrolled only patients with advanced heart failure and recent decompensation leading to hospitalization,” a group that was excluded from the ATHENA trial . One limitation of the ATHENA trial is its high rate of premature discontinuation of the study drug, which may have resulted in an underestimate of both the benefit of dronedarone as well as its adverse effects . Another limitation is, like the DIONYSOS trial, the ATHENA trial did not take into account quality-of-life issues. In addition, unlike the DIONYSOS trial, the ATHENA trial did not make a head-to-head comparison of dronedarone with amiodarone.

Multi-Trial Comparisons

In a 2009 report, researchers conducted an analysis of all randomized trials evaluating either dronedarone or amiodarone by using “indirect comparison meta-analysis and normal logistic meta-regression models.” They identified four trials of dronedarone, four trials of amiodarone, and one trial comparing dronedarone to amiodarone, all randomized and placebo-controlled. Using random-effects modeling, they found a “significant estimated reduction in recurrent AF with amiodarone versus placebo (odds ratio [OR]: 0.12; 95% CI: 0.08 to 0.19) but not dronedarone versus placebo (OR: 0.79; 95% CI: 0.33 to 1.87)”. In addition, a “normal logistic regression model incorporating all trial evidence” found amiodarone “superior to dronedarone (OR: 0.49; 95% CI: 0.37 to 0.63; p < 0.001) for the prevention of recurrent AF.” However, these models also found “trend toward greater all-cause mortality (OR: 1.61; 95% CI: 0.97 to 2.68; p = 0.066) and greater overall adverse events requiring drug discontinuation with amiodarone versus dronedarone (OR: 1.81; 95% CI: 1.33 to 2.46; p < 0.001)”. With these results, the researchers concluded that dronedarone is less effective than amiodarone but the reduction in efficacy is offset by greater safety since dronedarone has fewer adverse effects.

Analyzing multiple randomized trials of either amiodarone or dronedarone versus placebo adds to the internal validity to the studies, and comparing the results of those studies to the head-to-head trial contributes to higher external validity. A limitation of the study was that the trials they analyzed each had different study populations. As a result, the researchers aggregated the results of varied populations, which may contribute to a misinterpretation of the results, particularly when the drugs have different effects on each population. Another limitation is that most of the trials analyzed were not direct comparisons of the two study drugs, though the results of the indirect comparisons were consistent with the results of the one head-to-head study the researchers analyzed. Like the studies previously discussed, this analysis did not take into account quality-of-life issues.

Overall, these studies comparing amiodarone and dronedarone have provided strong evidence that though amiodarone is more effective than dronedarone in treating AF, dronedarone has fewer adverse effects. Thus, dronedarone is a viable alternative for patients who experience adverse effects while on amiodarone.

Bibliography

Hohnloser, Stefan H., et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation. February 12, 2009. http://www.nejm.org/doi/full/10.1056/NEJMoa0803778 (accessed February 26, 2014).

Le Heuzey, Jean-Yves, Gaetano M. De Ferrari, David Radzik, Massimo Santini, Junren Zhu, and Jean-Marc Davy. A Short-Term, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial Fibrillation: The DIONYSOS Study. 2010. http://www.medscape.com/viewarticle/724568 (accessed February 26, 2014).

Piccini, Jonathan P., Vic Hasselblad, Eric D., Washam, Jeffrey B. Peterson, Robert M. Califf, and David F. Kong. Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation. September 2009. http://content.onlinejacc.org/article.aspx?articleid=1140047 (accessed February 26, 2014).

Stiles, Steve. Dronedarone in Atrial Fib Trades Efficacy for Safety in Meta-Analysis. September 14, 2009. http://www.medscape.com/viewarticle/708827 (accessed February 26, 2014).