Continuous vs Episodic Prophylactic Treatment With Amiodarone for the Prevention of Atrial Fibrillation

Background:  Amiodarone is the most effective drug in preventing atrial fibrillation, however its use has been associated with many adverse events and this often limits its usefulness.

Objective: The study objective was to compare the effects of episodic amiodarone treatment versus continuous amiodarone treatment, first, on major adverse events related to amiodarone use and the underlying heart disease and, second on all-cause mortality and cardiovascular complications. 

Methods: The study design was parallel, controlled experimental.  Patients were not blinded and were assigned to treatment groups through randomization.  A total of 214 patients were eligible for participation in the study.  Patients were eligible for inclusion in the study if they experienced recurrence of symptomatic persistent atrial fibrillation or atrial flutter with a duration of less than a year, a heart rate of more than 75/min, and if they were taking oral anticoagulation therapy for at least 2 weeks.  Patients were excluded from the study if they had more than 3 relapses of persistent atrial fibrillation during the last 2 years, amiodarone use in the preceding 3 months, history of relapse of atrial fibrillation under adequate (desethyl) amiodarone levels, New York Heart Association class III or IV heart failure, contraindications for amiodarone, history of thyroid dysfunction, concomitant treatment with class I or III antiarrhythmic drugs, known sick sinus syndrome, second- or third-degree atrioventricular block, or a pacemaker. The study was conducted from December 2002 until March 2007.  All patients underwent amiodarone loading, which consisted of 600 mg of amiodarone daily for 4 weeks.  Following loading, patients underwent electrical cardioversion if they had not already converted chemically to sinus rhythm.  After cardioversion, amiodarone was lowered to a maintenance dose of 200 mg daily.  In the episodic group amiodarone was discontinued 4 weeks after randomization and was restarted a month before and continued a month after cardioversion if atrial fibrillation relapsed. Amiodarone treatment was continued for those in the maintenance group.  The primary end point consisted of amiodarone and underlying heart disease-related major adverse events.  Secondary end points were defined as all-cause mortality and cardiovascular hospitalizations.  All data analyses were based on the intention-to-treat principle and the power of the study was 80%. 

Results:  All patients were followed until the end of the study.  The incidence of the primary end point was 37 (35%) in the episodic vs 34 (33%) in the continuous treatment group (incidence rate per 100 person-years, 22.5 vs 22.3; incidence rate difference, 0.2, 95% CI, -10.2 to 10.6; P =.97).  The mean cumulative dose at the time of the primary end point was significantly lower in the episodic than the continuous treatment group (44g; range 16-178g vs 70g; range, 22-203 g; P =.009).  There were differences in the incidence rate of amiodarone events (20 vs 25, incidence rate per 100 person-years, 10 vs 12; incidence rate difference, -2.0; 95% CI, -8.7 to 4.6;  P =.55) and underlying heart disease-related major events (incidence, 17 vs 9; incidence rate per 100 person-years; 8.5 vs 4.9; incidence rate difference, 3.6; 95% CI, -1.6 to 8.7; P =.19), however they did not reach statistical significance. 
            A total of 91 (56 in the episodic vs 35 in the continuous treatment group) patients experienced a secondary end point, including 2 mortalities in both groups (P =.02).  There was a trend for more electrical cardioversions in the episodic group than in the continuous treatment group (34 vs 22, 95% CI, 10.7; -3.3 to 24.7, respectively).  When comparing hospitalizations without including hospitalizations for rhythm control (i.e. electrical cardioversions), the difference between both treatment strategies is 22 vs 13 (P =.08). 
            In addition to the primary and secondary outcome findings, the episodic group experienced more first atrial fibrillation recurrences (85 (80%) vs 56 (54%), P= <.001).  At the time of first atrial fibrillation recurrence, 56 of 85 patients (66%) in the episodic group did not use amiodarone, whereas 18 of 56 patients (32%) did not use amiodarone in the continuous group.  More patients in the episodic group underwent chemical (36 vs 14) and electrical conversions (38 vs 22; P= <.001) after the first recurrence.  At the end of follow-up, 51 (48%) in the episodic group vs 64 (62%) in the continuous group had sinus rhythm (P= .05) 
            The authors concluded that episodic amiodarone treatment has no clinical advantage over continuous treatment because it did not lower morbidity in patients with persistent atrial fibrillation over 2 years of follow-up.

Strengths:  The rationale behind the study hypothesis was logical and it was appropriate to investigate amiodarone treatment in this manner.  The study design was optimal and appropriate to fulfill the stated objective.  The dosing and administration was appropriate in both groups and both received treatment for a sufficient duration of time.  The results of the study were interpreted appropriately by the authors, and the key study limitations were addressed. 

Weaknesses:  This study had a number of weaknesses.  A major weakness was the power was not appropriate for the primary outcome analyses as a result of incorrect assumption of effect size.  The authors predicted a much larger effect size than was truly found between treatment groups.  Therefore, the study required more patients in each treatment group to detect a smaller effect size.  As a result of incorrect effect size, Type II error is likely for some of the non-statistically significant findings.  In addition to lack of power, the manner in which the results were reported was confusing and difficult for the reader to follow.  It was unclear at times how to interpret the values for certain findings.  The statistical reporting measure for the primary end points was the incidence rate per 100 years; this value was difficult to interpret and apply to clinical practice. 

Conclusion:  I agree with the authors in that, this study should be considered a preliminary contribution, and that more studies are needed before we can make a final conclusion on episodic amiodarone treatment.  Based on the results found in this study, it is appropriate to recommend avoiding episodic treatment in patients with atrial fibrillation, and this recommendation should remain until further information is uncovered. 

Prepared by: Jen Curtis, Doctor of Pharmacy Candidate