Correspondence

Amiodarone Prophylaxis for Atrial Fibrillation after Cardiac Surgery

N Engl J Med 1998; 338:1383-1384May 7, 1998

Article

To the Editor:

Daoud et al. (Dec. 18 issue)1 reported a reduction in the incidence of postoperative atrial fibrillation with prophylactic amiodarone after cardiac surgery. This absolute reduction of 28.3 percent was associated with reduced hospital stays and reduced hospital costs. The true treatment effect, however, appears to be confounded by the use of preoperative beta-blockers in 26 (40.6 percent) of the patients in the amiodarone group and in 18 (30.0 percent) of those in the placebo group, which was continued in 24 of 26 (92.3 percent) and 17 of 18 (94.4 percent) patients, respectively. Beta-blockers have been clearly shown to reduce the rate of atrial fibrillation after bypass surgery.2,3 In our previous randomized trial of amiodarone prophylaxis (143 patients), we demonstrated trends toward a treatment effect with amiodarone as well as an interaction between preoperative beta-blockers and amiodarone, resulting in the lowest rates of postoperative atrial fibrillation.4,5

Why was this interaction missed in this trial? The answer lies in the control group. Daoud and coworkers reported that atrial fibrillation developed in 11 of 18 patients (61.1 percent; 95 percent confidence interval, 37.7 to 81.1) in the placebo group who received beta-blockers. This rate is more than twice the expected value and reflects an unstable point estimate. Although it appears that there still would have been an independent treatment effect of amiodarone with the use of expected control values, we encourage the authors to explore the beta-blocker–amiodarone interaction, especially with respect to the variables associated with atrial fibrillation — the rate at onset and the duration and intensity of response.

Peter A. McCullough, M.D., M.P.H.
Henry Ford Hospital, Detroit, MI 48202

Joseph D. Redle, M.D.
Akron General Hospital, Akron, OH 44304

5 References

1
Daoud EG, Strickberger SA, Man KC, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997;337:1785-1791
Full Text | Web of Science | Medline

2
White HD, Antman EM, Glynn MA, et al. Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery. Circulation 1984;70:479-484
CrossRef | Web of Science | Medline

3
Daudon P, Corcos T, Gandjbakhch I, Levasseur JP, Cabrol A, Cabrol C. Prevention of atrial fibrillation or flutter by acebutolol after coronary bypass grafting. Am J Cardiol 1986;58:933-936
CrossRef | Web of Science | Medline

4
Redle JD, West AJ, Khurana S, Marzan R, McCullough PA, Frumin HI. Prophylactic oral amiodarone with beta blockade has favorable effects on atrial fibrillation post coronary bypass surgery. Circulation 1997;96:Suppl I:I-125 abstract.

5
Redle JD, Khurana S, Marzan R, et al. Prophylactic low dose amiodarone versus placebo to prevent atrial fibrillation in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol 1997;29:Suppl A:289A-289A abstract.

To the Editor:

The article by Daoud et al. highlights a common clinical problem and suggests a role for amiodarone as a means of reducing the prevalence of atrial fibrillation after bypass surgery. However, there are important caveats to note before amiodarone is prescribed as prophylaxis for all patients undergoing bypass surgery.

The mean age of the 124 study patients was only 59 years and does not reflect the increasing age of patients undergoing heart bypass surgery. Increasing age is a consistent independent predictor of atrial fibrillation after bypass surgery1-3 and is a major factor contributing to the increased prevalence of atrial fibrillation after operation. Two recent larger studies highlight this: the median age in a study of 570 patients was 67 years (41 percent were >70 years), 2 and the mean age in a study of 2417 patients was 65 years.3

Furthermore, the mean age of the amiodarone group was four years less than that of the placebo group. Although it is not clinically significant, it is important to note there is a 24 percent increase in the odds that postoperative atrial fibrillation will develop for every five-year increase in age.3 Creswell and coworkers found that the incidence of atrial arrhythmia increased from 25 percent to 36 percent in 6 years, during which time the mean age of the patients increased by only 2.2 years.4 The marginal benefit seen with amiodarone in Daoud's study during the hospitalization period may be due in part to the younger age of the group.

In addition, the authors confuse the issue by studying a heterogeneous group of patients — those who had coronary-artery bypass surgery, those who had valvular heart surgery, those who had both, and “others.” They conclude that amiodarone benefits both patients undergoing bypass and those undergoing valvular surgery without providing data for each group. Does amiodarone benefit one group but not the other?

Finally, the authors state that the requirement of a seven-day preoperative treatment period is a primary limitation to the widespread use of amiodarone as prophylaxis. It follows that the way forward is to identify and target patients at risk. Signal-averaged electrocardiograms and low serum magnesium levels 3 are independent risk factors that have been shown, singly or in combination, to identify patients at risk for atrial fibrillation after coronary-artery bypass surgery.

Azfar G. Zaman, M.R.C.P.
University Hospital of Wales, Cardiff CF4 4XW, United Kingdom

Andrew Archbold, M.R.C.P.
Farquad Alamgir, M.R.C.P.
London Chest Hospital, London E2 1NN, United Kingdom

4 References

1
Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery: current trends and impact on hospital resources. Circulation 1996;94:390-397
Web of Science | Medline

2
Mathew JP, Parks R, Savino JS, et al. Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. JAMA 1996;276:300-306
CrossRef | Web of Science | Medline

3
Zaman AG, Alamgir F, Richens T, Williams R, Rothman MT, Mills PG. The role of signal averaged P wave duration and serum magnesium as a combined predictor of atrial fibrillation after elective coronary artery bypass surgery. Heart 1997;77:527-531
Web of Science | Medline

4
Creswell LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993;56:539-549
CrossRef | Web of Science | Medline

To the Editor:

Though Daoud et al. have shown a significant reduction in postoperative atrial fibrillation with the use of amiodarone, their claim that there were no important side effects is misleading, because they apparently have not investigated thyroid function. They state that patients with treated thyroid disease were not excluded from the trial but did not supply data on thyroid function before or after amiodarone therapy for these or indeed any of their patients. This is a serious omission, given the well-known actions of amiodarone on thyroid function. The relatively short duration of amiodarone therapy (13±7 days) does not rule out the possibility of serious thyroidal effects, because as the authors themselves point out, the half-life of amiodarone is up to 103 days and the drug could therefore produce effects long after the patients' follow-up ended. Given this lack of important data, the authors' claim that amiodarone therapy did not lead to serious side effects should be treated with caution.

Thomas J. Ulahannan, M.R.C.P.
Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom

Author/Editor Response

The authors reply:

To the Editor: Drs. McCullough and Redle suggest that the treatment effect of amiodarone may have been confounded by the preoperative use of beta-blockers. In the placebo group, the incidence of postoperative atrial fibrillation was 61 percent among the patients receiving beta-blockers; this high incidence probably reflects the fact that the efficacy of beta-blocker prophylaxis is poor. Since the effect of amiodarone as prophylaxis for postoperative atrial fibrillation was unknown, we designed the study to compare amiodarone with placebo in a double-blind, randomized fashion. Before the start of the study, we suspected that the use of beta-blockers would not be significantly different in the two groups, and thus any reduction in the incidence of postoperative atrial fibrillation would be attributed to an effect of amiodarone. We do agree, however, that it is important to perform a trial assessing the effect of amiodarone plus beta-blockers.

We agree with Zaman et al. that future studies need to assess the efficacy of amiodarone in various subgroups and to characterize the high-risk patients who would benefit the most from amiodarone therapy. The goal of this initial study was to assess whether amiodarone therapy prevents postoperative atrial fibrillation; therefore, we enrolled consecutive patients satisfying entry criteria. The relatively young age of our patient population probably reflects the large number of patients undergoing valvular surgery, but since the incidence of atrial fibrillation in the placebo group was 53 percent, young age did not protect against atrial fibrillation. As stated in the article, the incidence of atrial fibrillation was significantly higher among patients who had valvular surgery (46 percent) than among those who underwent only coronary-artery bypass surgery (29 percent, P = 0.04).

With regard to the comments of Dr. Ulahannan, patients were not to receive amiodarone for an extended period (no longer than four weeks); thus, the risk of thyroid abnormalities from amiodarone was small, and we did not perform thyroid-function tests.

Emile G. Daoud, M.D.
Midwest Cardiology Research Foundation, Columbus, OH 43214

Fred Morady, M.D.
University of Michigan Hospital, Ann Arbor, MI 48109-0022

Citing Articles (1)