Which antiarrhythmic agent would you choose for first-episode atrial fibrillation in a patient with congestive heart failure, and why?
Case: James Brown is 72-years-old with a history of inferior STEMI due to left anterior descending artery (LAD) occlusion. He received 2 drug-eluting stents to his LAD. His left ventricular ejection fraction is now 35-40% and has remained stable for many years on carvedilol, lisinopril, and spironolactone. He presents four years later with symptomatic paroxysmal atrial fibrillation (AF). His symptoms are palpitations, dizziness, fatigue, and dyspnea. When he isn’t in AF, he can walk without any limitations (NYHA Class I). However, in AF, he is limited to 100-150 ft before he develops dyspnea. You elect to try to maintain sinus rhythm with an antiarrhythmic agent.
Which of the following antiarrhythmic agents is safe to use in this type of patient (select all that apply)?
Answers: A. Amiodarone; C. Dofetelide; and E. Dronedarone
Patients with CHF are often burdened with AF given the common convergence of factors including systolic and diastolic dysfunction and the overlap of risk factors for vascular disease and AF, ie, diabetes, hypertension, and obesity.
There is no compelling evidence that restoration of sinus rhythm in heart failure improves outcomes. However, the presence of AF can limit exercise tolerance, decrease cardiac output due to loss of atrial kick, worsen left ventricular dysfunction (if rates are poorly controlled), and cause symptoms. The burden of AF in patients with heart failure with reduced ejection fraction may portend worse prognosis.
Based largely on results from the Cardiac Arrhythmia Suppression Trial (CAST)1 class Ic agents are contraindicated in patients with any structural heart disease, such as decreased systolic function or coronary artery disease. Both amiodarone and dofetelide can be safely used in patients with congestive heart failure with reduced ejection fraction. In the randomized trial of the Danish Investigations of Arrhythmia and Mortality of Dofetelide Study Group,2 dofetelide (a class III agent) was effective in converting AF to sinus rhythm, reducing the risk of hospitalization for worsening heart failure (risk ratio 0.75), and more likely to maintain sinus rhythm (risk ratio 0.35 for reversion to AF). There was no effect on mortality but slightly higher risk of Torsades de Pointes in the dofetelide group compared with placebo.
Dronedarone (which, like amiodarone, is class III) was approved in 2009 with the hope that it would avoid many of the adverse effects of amiodarone related to that agent’s lack of an iodine moiety. The results of clinical trials, however, have been mixed. In early trials, it appeared safe and effective for rhythm control (DAFNE,3 EURIDIS,4 ADONIS,4 ERATO,5 DIONYSOS6) – this included patients with paroxysmal as well as persistent AF. In ATHENA7, dronedarone decreased hospitalization due to cardiovascular events or death in high risk patients. However, in a large phase three trial (PALLAS8), it was found to increase heart failure, stroke, and cardiovascular death in patients with permanent AF who were at risk for major vascular events (such as MI). In the ANDROMEDA9 randomized study, treatment with dronedarone of those patients hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction increased early mortality related to worsening heart failure.
Back to Mr Brown: Although dronedarone can be used in this patient who has paroxysmal AF, either of the other two agents would be preferred and dronedarone should probably be avoided in patients with persistent AF. Moreover, if Mr Brown had been recently hospitalized for heart failure, it would also be a poor choice.
The management of patients with AF and heart failure continues to pose many challenges with rhythm control being particularly difficult to maintain in this population. For that reason, it is important to understand the benefits and the drawbacks of using antiarrhythmics to restore normal sinus rhythm and understand which agents can safely be used in which patients.
1. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-788.
2. Torp-Pedersen C1, MÃ¸ller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999; 341:857-865.
3. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481-1487.
4. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987-99.
5. 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
6. Le Heuzey JY, De Ferrari GM, Radzik D, et al. 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.
7. Hohnloser SH, Crijns HJ, van Eickels, M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668-678.
8. Connolly SJ, Camm AJ, Halperin JL,et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365:2268-2276.
9. KÃ¸ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678-2687.