Amiodarone vs Sotalol for Atrial Fibrillation
Amiodarone vs Sotalol for Atrial Fibrillation
abstract & commentary
By John P. DiMarco, MD, PhD
Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville
Dr. DiMarco is a consultant for Novartis and does research for Medtronic and Guidant.
Synopsis: Amiodarone and sotalol have a similar efficacy for converting atrial fibrillation to sinus rhythm, that the drugs do not significantly impair electrical cardioversion and that amiodarone is superior to sotalol which, in turn, is better than placebo, for maintaining sinus rhythm.
Source: Singh BN, et al. Amiodarone Versus Sotalol for Atrial Fibrillation. N Engl J Med. 2005;352:1861-1872.
The sotalol amiodarone atrial fibrillation efficacy Trial (SAFE-T) was a double-blind, placebo-controlled comparison of sotalol and amiodarone in patients with persistent atrial fibrillation. Patients were eligible for enrollment if they had been in atrial fibrillation for at least 72 hours, were receiving anticoagulation, and had a calculated creatinine clearance above 60 mL/minute. Patients with class III or class IV heart failure, intolerance of beta blockers, or a history of a long QT syndrome were excluded. Randomized patients were assigned to receive amiodarone, sotalol, or placebo on an outpatient basis. Amiodarone dosage was 800 mg per day for 14 days, 600 mg per day for the next 14 days, 300 mg per day for the first year, and 200 mg per day afterwards. The sotalol regimen was 80 mg twice daily for the first week and 160 mg twice daily afterwards. Follow-up was obtained by clinic visits every 4 weeks, and transtelephonic ECG recordings weekly. If spontaneous conversion had not occurred by day 28 after randomization, direct current transthoracic cardioversion was performed. The primary outcome measure was the time to the first recurrence of atrial fibrillation after sinus rhythm had been restored. Quality of life, exercise capacity, and adverse events were also monitored.
A total of 665 patients underwent randomization: 267 to amiodarone, 261 to sotalol, and 137 to placebo. Eighty-one patients withdrew consent and 28 were lost to follow-up. Since this was a Veterans Administration study, 98.9% were men. The mean age was 67.1 ± 09.3 years.
During the first 28 days of drug therapy, 27.1% of patients in the amiodarone group, compared to 24.2% in the sotalol group and 0.8% of patient in the placebo group, converted to sinus rhythm. Patients who did not convert by day 28 underwent cardioversion. The cardioversion was unsuccessful in 28% of the patients in the amiodarone group, 27% of patients in the sotalol group, and 32% of patients in the placebo group. Including both spontaneous and electrical conversions, the total conversion rates were 79.8%, 79.9%, and 68.2% in the amiodarone, sotalol, and placebo groups, respectively. Using the primary end point of time to first recurrence of atrial fibrillation, amiodarone was more effective than sotalol, and both drugs were more effective than placebo. Using an intention to treat analysis, 48% of patients in the amiodarone group. 68% in the sotalol group, and 87% in the placebo group had a recurrence by one year. In a treatment-received analysis, the corresponding values were 35%, 60%, and 82%. The primary end point, median days to recurrence, was strikingly different between the 3 groups. In the intention to treat analysis, it was 487 days for the amiodarone group vs 74 days for sotalol and 6 days for placebo. Amiodarone was superior to sotalol in all subgroups, except that there was only a trend among patients with known ischemic heart disease. Changes in quality of life and exercise capacity were not different based on drug assignment. However, patients who remained in sinus rhythm overall had superior scores for physical functioning, general health, and social functioning and had more improvement in exercise capacity than did those who redeveloped persistent atrial fibrillation.
Minor bleeding events were more common in the amiodarone group (8.33 per 100 patient years) than in the sotalol group (6.37) or the placebo group (6.71). Major bleeding episode rates were 2.07, 3.10, and 3.97 per 100 patient years in the 3 groups. The rates for major and minor strokes were similar between the 3 groups. There were 2 cases of nonfatal pulmonary toxicity in the amiodarone group and one in the placebo group. One case of nonfatal torsades de pointe occurred in the sotalol group. Overall, there were 13 deaths (6 sudden) in the amiodarone group, 15 deaths (8 sudden) in the sotalol group, and 3 deaths (2 sudden) in the placebo group. The trend toward increased mortality in the combined drug treated groups (4.36 per 100 patient years vs 2.84 per 100 patient years) did not achieve statistical significance (P = 0.13).
Singh and colleagues conclude that amiodarone and sotalol have a similar efficacy for converting atrial fibrillation to sinus rhythm, that the drugs do not significantly impair electrical cardioversion, and that amiodarone is superior to sotalol which, in turn, is better than placebo, for maintaining sinus rhythm.
Commentary
SAFE-T is the largest comparative trial of amiodarone
in patients with persistent atrial fibrillation. It clearly shows that amiodarone is more effective than sotalol, and
that both drugs are more effective than placebo in maintaining sinus rhythm over an intermediate period of
follow-up. Both drugs were surprisingly well tolerated in terms of reported side effects. The population studied here
was fairly typical for an atrial fibrillation population, but the mean ejection fraction was close to 50%, and only about 25% of patients had any symptoms of heart failure. Patients were also screened for renal function, and only patients with well preserved renal function could be included in the trial. Despite this, Singh et al noted a slight, albeit, nonsignificant trend towards increased mortality during drug therapy, and when the data were examined in an intention to treat analysis, no improvement in quality of life was seen. These data could be interpreted that patients who can be maintained in sinus rhythm are likely to do better than if they are left in atrial fibrillation, but that the overall population will not benefit. These data, therefore, are in agreement with the large rate control vs rhythm control trials which showed slight mortality trends in favor of a rate control strategy.
SAFE-T confirms results of prior trials in patients with atrial fibrillation. Based on the accumulated data, it seems reasonable to follow a symptom based approach. Patients who are asymptomatic with rate control do not require trials of antiarrhythmic drug therapy and cardioversion. Patients who are symptomatic, however, may benefit from drug therapy and a cardioversion strategy, even though many patients will develop persistent atrial fibrillation over time.
By John P. DiMarco, MD, PhD Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville Dr. DiMarco is a consultant for Novartis and does research for Medtronic and Guidant. Synopsis: Amiodarone and sotalol have a similar efficacy for converting atrial fibrillation to sinus rhythm, that the drugs do not significantly impair electrical cardioversion and that amiodarone is superior to sotalol which, in turn, is better than placebo, for maintaining sinus rhythm. Source: Singh BN, et al. Amiodarone Versus Sotalol for Atrial Fibrillation. N Engl J Med. 2005;352:1861-1872.Subscribe Now for Access
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