Amiodarone Better Than Sotalol and Class I Agents for Maintaining Sinus Rhythm in Patients With AF: Results of the AFFIRM First Antiarrhythmic Drug Substudy

July 22, 2003

July 22, 2003 — Amiodarone is more effective at maintaining sinus rhythm and preventing recurrence of atrial fibrillation (AF) than either sotalol or class I agents, according to the results of an Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) substudy, published recently in the Journal of the American College of Cardiology. [1]

The AFFIRM First Antiarrhythmic Drug Substudy is the largest study to date comparing antiarrhythmic drugs for AF, and it is the only study to evaluate multiple, randomly selected rhythm control drugs. The results were clearly in favor of amiodarone, with 60% to 62% of patients in the amiodarone group demonstrating successful treatment at 1-year follow-up, compared with 23% of patients in the class I group and 38% of patients assigned to sotalol. These results parallel those seen in previous trials, including the Canadian Trial of Atrial Fibrillation (CTAF) [2] and the Pharmacological Intervention in Atrial Fibrillation (PIAF), [3] both of which demonstrated the efficacy of amiodarone in maintaining sinus rhythm at up to 1 year.

However, the substudy authors believe that there is still a place for other antiarrhythmic agents in the treatment of AF, noting that "antiarrhythmic drug treatment must remain individualized, considering any underlying disease, potential drug efficacy, and the potential risk of short-term and long-term exposure to that drug."

Two of 3 randomization arms halted early

The First Antiarrhythmic Drug Substudy was a second randomization of patients assigned to the rhythm control arm of AFFIRM performed at 80 study sites. The substudy was designed with 3 comparison arms: (1) amiodarone vs class I agents, (2) amiodarone vs sotalol, and (3) sotalol vs class I agents. If a patient was eligible for all 3 drug arms, randomization was performed in all 3 drug groups, and the patient's data was added to the pool in two 2-way comparisons. A patient therefore could be represented in more than 1 arm of the study, and the sum of patients in all arms of the study could exceed the total number of patients.

Drug failure was defined as recurrence of AF without spontaneous reversion to sinus rhythm while on the first antiarrhythmic drug or discontinuation of the first class I drug with substitution of another class I drug.

The primary endpoint of the substudy was the percentage of patients alive at 1 year who were taking the assigned drug, had not had external or internal cardioversion or pharmacologic cardioversion, and were in sinus rhythm. Secondary endpoints included time to first documented AF recurrence and prevalence of AF at 4 months and 1 year. Randomization between amiodarone and class I drugs was halted early -- at the third interim analysis -- by the study's Data and Safety Monitoring Board (DSMB) because the findings were already considered conclusive. In addition, randomization of sotalol vs class I agents was also halted by the DSMB, because too few patients were eligible to produce a significant result.

Results show clear superiority of amiodarone

Mean follow-up was 3.84 ± 1.30 years. At 1-year follow-up, successful treatment was noted in 62% of the amiodarone-treated patients, compared with 23% of patients on class I agents ( P < .001). The comparison between amiodarone and sotalol demonstrated successful treatment in 60% of amiodarone patients vs 38% of patients on sotalol ( P = .002). There was no significant difference between the success of sotalol and that of class I agents, although, as noted by the authors, this may be the result of early termination of randomization and the resulting reduced sample size in this arm of the study.

The prevalence of AF was lower for amiodarone-treated patients than for sotalol- and class I-treated patients at both 4-month and 1-year follow-up (Tables 1 and 2). In addition, amiodarone was more successful than class I agents at preventing recurrence of AF ( P = .0114) and was more successful than sotalol in maintaining sinus rhythm ( P = .0003) (Table 2). Patients in the amiodarone arms were also less likely to require cardioversion or drug changes. By 1-year follow-up, 29% of amiodarone patients, 33% of those in the sotalol group, and 36% of those randomized to class I agents had been cardioverted.

Table 1. AFFIRM Substudy: Amiodarone Versus Sotalol

(n = 131)
(n = 125)
Unadjusted P
Prevalence of AF
4 months 17% 22% .356
1 year 12% 19% .140
Composite endpoint*
4 months 67% 48% .002
1 year 60% 38% .002

Deaths (arrhythmic deaths)

15 (5) 24 (5) .081 (.900)

AF indicates atrial fibrillation
*Includes death, recurrent AF, having cardioversion, or stopping the first assigned drug

Table 2. AFFIRM Substudy: Amiodarone Versus Class I Drugs

(n = 106)
Class I Agent

(n = 116)

Unadjusted P
Prevalence of AF
4 months 13% 28% .009
1 year 8% 18% .069
Composite endpoint*
4 months 69% 35% < .001
1 year 62% 23% < .001

Deaths (arrhythmic deaths)

10 (4) 26 (7) .008 (.391)

AF indicates atrial fibrillation
*Includes death, recurrent AF, having cardioversion, or stopping the first assigned drug

Adverse drug effects common

Adverse drug effects that caused discontinuation of drug therapy during the first year were common for all of the drugs studied, occurring in 12.3% of patients on amiodarone, 11.1% of those taking sotalol, and 28.1% of those taking class I agents. In patients taking amiodarone, pulmonary and gastrointestinal events were the 2 most common adverse events reported, both occurring in 2.6% of patients, respectively. Those patients on class I agents or sotalol were at highest risk of gastrointestinal events (11.6% and 4.4%, respectively) and pulmonary events were diagnosed in only 0.7% of patients on sotalol and in 0.8% of patients taking class I agents.

Worrisome long-term consequences?

Although the substudy was not powered sufficiently to detect differences in death rates among the drugs, the researchers observed that more deaths occurred in patients randomized to class I agents than to patients randomized to amiodarone. Of interest, these deaths most often occurred during 2 to 5 years of follow-up, usually after initial drug therapy had been stopped or changed. In fact, most of these deaths occurred after the class I drug was discontinued for inefficacy or adverse effects and while another drug, often amiodarone, was being used.

In an accompanying editorial, Paul Dorian, MD, and Iqwal Mangat, MD, St. Michael's Hospital (Toronto, Ontario, Canada) pointed out that most of these deaths were not arrhythmic. [4] "At first glance [this] raises the worrisome hypothesis that class I drugs, even taken for a relatively brief period, cause long-term consequences that may lead to death after the drug is discontinued," they said.

With respect to long-term effects, the substudy authors concede that the early 1-year primary endpoint was limiting. Because most AF patients require therapy for many years, even decades, they are subject to longer term potential adverse drug effects. According to the authors, it is possible that the "early" endpoint in the substudy biased the results toward amiodarone, for which longer term adverse effects are a concern.

Choice of AF drug should not be based on any single measure of efficacy

The authors pointed out that although the results of the substudy are clear, the choice of AF drug cannot be adequately based on any single measure of efficacy or adverse events alone. Choice of drug should instead be individualized to meet patient needs, taking into account any underlying disease and balancing potential adverse and beneficial effects. An occasional AF recurrence while using a drug with easily reversible adverse effects may be preferable to using a drug with less likelihood of recurrence but with potential long-term adverse effects, according to the substudy authors.

If amiodarone is not chosen as the primary drug, sequential treatment with 2 or more antiarrhythmic drugs, with or without cardioversion, can achieve nearly 80% prevalence of sinus rhythm at 1 year, the authors noted.

In their editorial, Drs. Dorian and Mangat agree that antiarrhythmic drug therapy should be individualized to meet the needs of each AF patient and believe that a strategy of beginning with an alternative drug (particularly sotalol) and changing to amiodarone only -- if the initial therapy is ineffective -- is quite reasonable. Although the overall results of the substudy convincingly show that amiodarone is superior to either sotalol or class I drugs, no drug therapy, in the very long run, was both superbly effective at maintaining sinus rhythm and also associated with good patient tolerance, according to Drs. Dorian and Mangat.

Moreover, there are many AF patients with severe symptoms who can only be substantially improved if sinus rhythm is restored. In patients who have such refractory, highly symptomatic AF, the development and use of new and more effective methods (eg, novel atrial selective antiarrhythmic drugs and nonpharmacologic therapies) for long-term maintenance of sinus rhythm could play a useful role.

  1. The AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation. An AFFIRM Substudy of the First Antiarrhythmic Drug. J Am Coll Cardiol. 2003;42:20-29.

  2. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrences of atrial fibrillation. N Engl J Med. 2000;342:913-920.

  3. Hohnloser SH, Kuck K-H, Lilenthal J, for the PIAF Investigators. Rhythm or rate control in atrial fibrillation -- Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomized trial. Lancet. 2000;356:1789-1794.

  4. Dorian P, Mangat I. Restoring sinus rhythm in atrial fibrillation. J Am Coll Cardiol. 2003;42:30-32.

By Staff Writer, Medscape CRM
Reviewer: Albert A. Del Negro, MD


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