Dronedarone for atrial fibrillation: How does it compare with amiodarone?
ABSTRACTDronedarone (Multaq), an analogue of amiodarone (Cordarone), was designed to cause fewer adverse effects than the parent compound. Studies have indeed shown dronedarone to be safer than amiodarone, but less effective. Its official indication is to reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter and other cardiovascular risk factors, reflecting the parameters of its effectiveness in clinical trials.
KEY POINTS
- Patients with persistent or paroxysmal atrial fibrillation are candidates for dronedarone therapy if they are in sinus rhythm or will be cardioverted soon after starting. This drug is not indicated for the acute management of atrial fibrillation, for example, in the emergency department.
- Dronedarone is an option if a patient cannot tolerate amiodarone or has an underlying condition such as pulmonary or thyroid disease that is a contraindication to amiodarone.
- Dronedarone is contraindicated in patients with significant left ventricular dysfunction or heart failure with recent decompensation.
- The ultimate role for dronedarone is yet to be defined. Little evidence exists as to whether it will succeed when other drugs have failed.
WHEN SHOULD WE SWITCH PATIENTS TO DRONEDARONE?
Preliminary experience suggests that dronedarone, unlike most antiarrhythmic drugs, can be safely started about 48 hours after amiodarone is discontinued. Cumulative toxicity has not been noted with dronedarone. Caution should be exercised when switching if the patient has baseline bradycardia or QT interval prolongation. No algorithm has been developed for switching from other antiarrhythmic drugs to dronedarone.
CONTRAINDICATIONS TO DRONEDARONE
Dronedarone is contraindicated in:
- Patients with New York Heart Association (NYHA) class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic
- Patients with second- or third-degree atrioventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) or bradycardia (a heart rate < 50 beats per minute)
- Patients with a QTc interval of 500 ms or longer
- Patients with severe hepatic impairment
- Women who are pregnant, are attempting to become pregnant, or are breast-feeding
- Patients taking potent CYP3A inhibitors—antifungals like ketoconazole (Nizoral), itraconazole (Sporanox), or voriconazole (VFEND); macrolide antibiotics like telithromycin (Ketek) or clarithromycin (Biaxin); protease inhibitors; or other drugs that prolong the QT interval.
In patients with new or worsening heart failure, one should consider suspending or stopping dronedarone therapy.
DRONEDARONE’S ADVERSE EFFECTS
In trials to date, dronedarone has not shown evidence of proarrhythmia (tachyarrhythmia or bradyarrythmia), torsades de pointes, or amiodarone-like organ toxicity affecting the thyroid or the lungs. Recently, rare cases of severe hepatic injury were associated with dronedarone; therefore, periodic liver function testing is advised for patients taking dronedarone, especially during the first 6 months of therapy.
Dronedarone has been associated with higher rates of diarrhea, nausea, bradycardia, QT interval prolongation, and cutaneous rash compared with placebo. In DAFNE (Dronedarone Atrial Fibrillation Study After Electrical Cardioversion),17 10.8% of patients taking dronedarone had to stop taking it because of adverse events. With 800 mg daily, the discontinuation rate was only 3.9%. The most common cause of drug discontinuation was gastrointestinal effects. Anecdotal reports suggest that the gastrointestinal side effects may be self-limited and may not always require discontinuation of the drug.
Serum creatinine levels increase by about 0.1 mg/dL after the start of treatment. This elevation occurs after 1 to 2 days, reaches a plateau after 7 days, and is reversible. The mechanism is thought to be that dronedarone partially inhibits tubular organic cation transporters, which in turn reduces renal creatinine clearance by about 18%, but with no evidence of an effect on glomerular filtration, renal plasma flow, or electrolyte exchanges.18 A limited increase in serum creatinine is, therefore, expected with dronedarone treatment, but this does not mean there is a decline in renal function.
DRONEDARONE AND POTENTIAL DRUG INTERACTIONS
Warfarin. Dronedarone does not increase the international normalized ratio when used with warfarin (Coumadin).
Verapamil, diltiazem. Dose reduction is required to avoid bradyarrhythmias with co-administration of moderate CYP3A4 inhibitors such as verapamil (Calan, Verelan) and diltiazem (Cardizem).
Simvastatin. Dronedarone increases levels of simvastatin (Zocor), a CYP3A4 substrate, two to four times, thus increasing the risk of statin-induced myopathy.
Digoxin. Dronedarone increases the serum digoxin concentration about 2.5 times, and this necessitates monitoring the digoxin level and possibly reducing the digoxin dose.13
Diuretics. Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be maintained in the normal range before and during administration of dronedarone.
Tacrolimus, sirolimus. Dronedarone may increase levels of tacrolimus (Prograf) or sirolimus (Rapamune) in posttransplantation patients. This requires dose monitoring and adjustment in concomitant therapy with these agents.
COST VARIES
The cost of dronedarone varies based on factors that include location. Dronedarone’s retail cost ranges from $3.20 to $4.00 per pill (approximately $7.20 per day). It is not available in generic form. It is presently covered by many health plans as a tier 2 drug, representing a $15 to $40 monthly copay.
MORE DATA NEEDED
Dronedarone represents the first in what may well be a number of new antiarrhythmic drugs for the treatment of patients with paroxysmal atrial fibrillation. Although less efficacious then amiodarone, dronedarone appears to be better tolerated and have less serious side effects. It is contraindicated in patients with severe systolic dysfunction and in those with recent heart failure decompensation. It appears safe in coronary artery disease and marked left ventricular hypertrophy, unlike flecainide, propafenone (Rythmol), and sotalol.
To further understand how dronedarone will fare against other antiarrhythmic drugs, more studies with longer follow-up are needed. These studies need to demonstrate superior tolerability of dronedarone, acceptable quality of life without unacceptable loss of efficacy, or a decrease in morbidity or mortality rates compared with amiodarone.
Dronedarone can be safely started in most patients on an outpatient basis. The risk of proarrhythmia with dronedarone appears to be very low.
