Color Atlas and Synopsis of Electrophysiology, 1st Ed.

31. DRONEDARONE USE FOR THE TREATMENT OF ATRIAL FIBRILLATION

Gerald Naccarelli, MD, and Talal Moukabary, MD

CASE PRESENTATION

A 59-year-old man with history of coronary artery disease and prior myocardial infarction was referred to for the treatment of paroxysmal atrial fibrillation. He reported recurrent episodes of palpitations during the past 6 months. The episodes last from a few minutes to a few hours. However, he has no chest pain, dyspnea, or syncope. One event was captured on a 12-lead ECG as shown (Figure 31-1), and he was cardioverted to sinus rhythm with an external shock. Other than his atrial fibrillation he is doing well. He follows a heart-healthy diet and is able to exercise daily with no difficulty. He is anticoagulated with warfarin for stroke prevention. His recent echocardiogram shows normal left ventricular systolic function. Dronedarone therapy was initiated. During a follow-up visit, the patient reported having no more episodes of palpitations. He had diarrhea in the form of loose stools for 1 week after the initiation of dronedarone; however, it resolved spontaneously. His follow-up ECG is shown in Figure 31-2.

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FIGURE 31-1 The 12-lead ECG showing atrial fibrillation.

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FIGURE 31-2 The 12-lead ECG showing sinus rhythm with slightly prolonged QT interval.

INTRODUCTION

Although amiodarone has an unparalleled efficacy in the maintenance of sinus rhythm in patients with atrial fibrillation, its side effect profile is prohibitive. Dronedarone was developed as a noniodinated analog of amiodarone, with the goal of being an antiarrhythmic agent for rhythm control in patients with atrial fibrillation (Table 31-1). It was hypothesized that dronedarone will have fewer thyroid and pulmonary effects than amiodarone due to the elimination of the iodine moiety. Clinical trials showed that dronedarone is more effective than placebo without an increase in the rates of pulmonary toxic effects and of thyroid and liver dysfunction.1

TABLE 31-1 Similarities and Differences between Amiodarone and Dronedarone

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MECHANISM OF ACTION AND PHARMACOKINETICS

Similar to amiodarone, dronedarone is a class III antiarrhythmic agent. It blocks multiple repolarizing currents (the delayed rectifier current, the ultra-rapid delayed rectifier current, the inward rectifier current, and the transient outward current) in addition it blocks depolarizing sodium and L-type calcium currents and has an antiadrenergic effect.2

Dronedarone is 70% to 94% absorbed after oral administration, but due to significant first pass metabolism its absolute bioavailability is only 15%. Peak plasma concentrations are achieved within 3 to 6 hours. Plasma dronedarone level increases two- and threefold when it is taken with food. Steady-state plasma concentrations are reached within 4 to 8 days following the initiation of dronedarone 400 mg twice daily.3

The terminal half-life of dronedarone is 13 to 19 hours, and it is cleared mainly nonrenally. It is highly bound to plasma proteins and does not accumulate significantly in the tissues.3

Dronedarone does not affect the glomerular filtration rate, but it significantly decreases renal creatinine clearance by about 18%. This is likely due to inhibition of the cationic transport system in a way similar to cimetidine. This effect resolves once the drug is discontinued.4

METABOLISM AND INTERACTIONS

Dronedarone is primarily metabolized by the CYP3A4 system in the liver. Accordingly, its clearance may decrease in patients with hepatic impairment, and so it is contraindicated in patients with severe hepatic impairment. There is no requirement for dose adjustment in patients with renal insufficiency.3

Dronedarone is a metabolized by CYP3A4 in the liver. Dronedarone is also a moderate inhibitor of CYP3A4. Coadministration of dronedarone and CYP3A4 inhibitors may cause bradycardia and atrioventricular conduction block. Lower doses of dronedarone are recommended when it is coadministered with diltiazem or verapamil (moderate CYP3A4 inhibitors)(Table 31-2).

TABLE 31-2 Cardiovascular Drug Interactions with Dronedarone

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Dronedarone causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers due to CYP2D6 inhibition.5

Coadministration of dronedarone with QT prolonging drugs, such as class I and III antiarrhythmic medications, some macrolide antibiotics, some phenothiazines, and tricyclic antidepressants, carries a risk of inducing torsades de pointes-type ventricular tachycardia.6

When given with digoxin, dronedarone has the potential for increasing digoxin level by P-glycoprotein-mediated interaction in the kidney.3,7

Dronedarone increases serum warfarin exposure, but it does not cause clinically significant prolongation of INR values.8,9 Similarly it increases dabigatran,10 rivaroxaban, and apixaban levels. Caution should be used in using dronedarone and dabigatran together, particularly in patients with decreased renal function.6

Dronedarone increases simvastatin, rosuvastatin, and atorvastatin exposure, which increases the potential for statin-induced myopathy.3

Grapefruit juice is a moderate inhibitor of CYP3A and results in an increase in dronedarone exposure.3

CLINICAL USE

Dronedarone is primarily used for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation without heart failure (Tables 31-3 and 31-4). This is regardless of the presence of coronary artery disease. Dronedarone should not be used as a rate control agent in patients with permanent atrial fibrillation.

TABLE 31-3 Appropriate and Inappropriate Clinical Use of Dronedarone

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TABLE 31-4 Clinical Trials Investigating Efficacy of Dronedarone

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Patients treated with dronedarone have significantly longer times to first recurrence of AF and significantly greater chances of remaining in sinus rhythm at 6 and 12 months compared with placebo (ADONIS, EURIDIS, and DAFNE trials).1,11

Although dronedarone is more effective than placebo, it is less effective compared to amiodarone (DIONYSOS trial).12

The 2011 ACC/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation and the 2010 ESC Guidelines for the Management of Atrial Fibrillation list dronedarone among the first line antiarrhythmic agents for maintaining sinus rhythm in patients with recurrent paroxysmal or persistent AF who have no (or minimal) heart disease, hypertensive heart disease without substantial left ventricular hypertrophy, or coronary artery disease, but without heart failure.13,14 The American guidelines and an updated European statement agree that dronedarone should not be used in patients with heart failure or left ventricular systolic dysfunction.15

Dronedarone is rarely able to chemically cardiovert AF or atrial flutter to sinus rhythm (<10%).11 However, given that there is a potential for cardioversion during drug initiation, it is recommended that patients have therapeutic anticoagulation for at least 3 weeks or a transesophageal echocardiogram for assessment of left atrial thrombus prior to the initiation of dronedarone for patients who are in atrial fibrillation. This scenario is most commonly seen when loading patients with dronedarone in preparation for an electrical cardioversion.

Dronedarone slows the resting ventricular heart rate in patients who develop recurrent AF.1,7,16 However, dronedarone should NOT be prescribed exclusively as a rate control medication in permanent AF, given that the PALLAS trial demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate-controlling agent.17

When changing between dronedarone and other antiarrhythmic drugs that have the potential for QT prolongation and torsades des pointes, at least five half-lives should be allowed with the exception of amiodarone. When changing from amiodarone to dronedarone, there are a few approaches. Dronedarone can be started immediately after discontinuation of amiodarone (ADONIS and EURIDIS trials1), can be started 1 month after discontinuation of amiodarone (ATHENA16), or 2 months after discontinuation of amiodarone (ERATO5).

In general, dronedarone can be started promptly after amiodarone discontinuation, except in cases of clinically significant bradycardia or QT prolongation.

Dronedarone was shown to reduce the rates of hospitalization and cardiovascular mortality (post-hoc analysis of EURIDIS and ADONIS1 and ATHENA18). However, it significantly increases the risk of cardiovascular events (cardiovascular death, myocardial infarction, stroke and systemic embolism) and possibly even stroke and hospitalization for heart failure when used for rate control in patients with permanent atrial fibrillation especially those who are older or have heart failure (ANDROMEDA, PALLAS17,19).

SIDE EFFECTS AND MONITORING

The most common side effects are relatively benign (crampy abdominal pain, diarrhea, nausea, vomiting). Dronedarone may result in other side effects including generalized weakness, and dermatologic manifestations such as eczema, pruritus, skin inflammation, rash, and skin photosensitivity.

Although rare, there are potentially life-threatening side effects. In general, dronedarone should not be prescribed in patients with previous lung or liver toxicity due to amiodarone.

Some authors recommend hepatic function testing should be performed at the time of dronedarone initiation and repeated at 3 and 6 months and a electrocardiogram annually and at the time of any clinical change.6,18,20Hepatocellular injury, including acute liver failure requiring transplant, has been reported with the use of dronedarone. Since the reported cases have occurred within 6 months of drug initiation, it is reasonable to check hepatic function at baseline and within the first 6 months of treatment. Intermittent long-term surveillance testing may also be reasonable.6

Pulmonary toxicity has been reported with dronedarone.15 Routine lung surveillance is reasonable, but there are formal recommendations as to when and how.

Rare cases of torsades de pointes were reported, and dronedarone should be discontinued in this instance.18,20 On the other hand, dronedarone causes bradycardia and QT prolongation, neither of which usually requires drug discontinuation.

CONCLUSION

Dronedarone-induced proarrhythmia is rare, and the drug can be safely initiated as an outpatient. Although less efficacious than amiodarone in the prevention of recurrent AF, dronedarone appears to be a safer and better tolerated drug in patients with preserved left ventricular function. The guidelines suggest that dronedarone should be used prior to amiodarone and in patients with or without coronary artery disease, as long as left ventricular function is preserved.

REFERENCES

  1. Singh BN, Connolly SJ, Crijns HJGM, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.

  2. Varró A, Takács J, Németh M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol. 2001;133:625-634.

  3. Hoy SM, Keam SJ: Dronedarone. Drugs. 2009;69:1647-1663.

  4. Tschuppert Y, Buclin T, Rothuizen LE, et al.: Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007;64:785-791.

  5. Damy T, Pousset F, Caplain H, Hulot J-S, Lechat P: Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol. 2004;18:113-123.

  6. Multaq prescribing information (Internet). Accessed September 20, 2014. http://products.sanofi.us/multaq/multaq.pdf

  7. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156:527.e1-9.

  8. Shirolkar SC, Fiuzat M, Becker RC: Dronedarone and vitamin K antagonists: a review of drug-drug interactions. Am Heart J. 2010;160:577-582.

  9. Patel C, Yan GX, Kowey PR: Dronedarone. Circulation. 2009;120:636-644.

 10. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-1876.

 11. Touboul P, Brugada J, Capucci A, Crijns HJGM, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481-1487.

 12. Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. 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. J Cardiovasc Electrophysiol. 2010;21:597-605.

 13. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8:157-176.

 14. Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.

 15. European Medicines Agency. European Medicines Agency recommends restricting use of Multaq. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/09/news_detail_001344.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1. Accessed September 20, 2014.

 16. Page RL, Connolly SJ, Crijns HJGM, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol. 2011;107:1019-1022.

 17. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365:2268-2276.

 18. Hohnloser SH, Crijns HJGM, Van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360:668-678.

 19. Køber L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678-2687.

 20. Kao DP, Hiatt WR, Krantz MJ: Proarrhythmic potential of dronedarone: emerging evidence from spontaneous adverse event reporting. Pharmacotherapy. 2012;32(8):767-71

 21. Naccarelli GV, Wolbrette DL, Levin V, et al. Safety and efficacy of dronedarone in the treatment of atrial fibrillation/flutter. Clin Med Insights Cardiol. 2011;5:103-119.