Correspondence

Amiodarone to Prevent Recurrence of Atrial Fibrillation

N Engl J Med 2000; 343:578-580August 24, 2000

Article

To the Editor:

Roy et al. (March 30 issue)1 report that amiodarone is more efficacious than sotalol or propafenone for the prevention of recurrences of atrial fibrillation. However, a significantly greater proportion of the patients assigned to sotalol or propafenone had left ventricular hypertrophy (21 percent) than of those assigned to amiodarone (13 percent) (P=0.04). As we already know, hypertensive heart disease is the most common antecedent to the development of atrial fibrillation.2

Some of the greater efficacy of amiodarone, as compared with the other two agents, can be explained by the difference between the two groups in the prevalence of left ventricular hypertrophy. This point can be validated by carefully looking at the post hoc analysis (Figure 2 of the article). In patients who did not have left ventricular hypertrophy, the hazard ratio for the recurrence of atrial fibrillation was much more strongly in favor of amiodarone than was the case in the study population as a whole, since there were significantly fewer patients with left ventricular hypertrophy in the amiodarone group. Had there been more patients with left ventricular hypertrophy in the amiodarone group, the efficacy of amiodarone would have appeared to be much less.

Moreover, although only one patient in the propafenone-or-sotalol group died of arrhythmia, the current weight of evidence is sufficient to prohibit the use of class IC antiarrhythmic agents in patients with coronary artery disease.3 Eighteen percent of the patients in the propafenone-or-sotalol group in this trial had coronary artery disease.

Atul Aggarwal, M.D.
University of Vermont College of Medicine, Burlington, VT 05401

3 References

1. 1

   Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913-920
   Full Text | Web of Science | Medline

2. 2

   Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham Study. N Engl J Med 1982;306:1018-1022
   Full Text | Web of Science | Medline

3. 3

   The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-412
   Full Text | Web of Science | Medline

To the Editor:

It is interesting that at a time of increased focus on drug safety, Roy et al. have published an encouraging report on the efficacy of amiodarone for the treatment of atrial fibrillation. The authors conclude that low doses of amiodarone are relatively safe and suggest that amiodarone may be used as first-line therapy for the prevention of recurrences of atrial fibrillation. However, this study had a number of exclusion criteria, the patients were treated in the controlled setting of a clinical trial, and it was of relatively short duration. We are concerned that the relative safety of amiodarone as observed in this study may not be able to be extrapolated to patients treated in typical clinical settings.

Currently, because of life-threatening adverse effects and difficulties in management, amiodarone is approved by the Food and Drug Administration only for the treatment of documented, life-threatening recurrent ventricular arrhythmias (i.e., ventricular fibrillation or ventricular tachycardia causing hemodynamic instability) when other agents have been tried unsuccessfully.1 If the use of amiodarone is to be extended to other indications, then possible adverse effects and potentially serious drug interactions must be considered.

Although there are a number of clinically important drug interactions involving amiodarone, two warrant special attention. As seen in this trial, warfarin or digoxin is frequently among the medications taken by patients who are given amiodarone (approximately one third of the study patients were taking digoxin, and over half were taking anticoagulant drugs). There is an increase in the prothrombin time and the international normalized ratio when amiodarone and warfarin are prescribed concomitantly, most likely because of the inhibition of warfarin metabolism. The dose of warfarin may need to be adjusted (e.g., decreased by 33 to 50 percent) to achieve the patient's target international normalized ratio to reduce the risk of bleeding.1-3 An interaction between digoxin and amiodarone may also result in increased digoxin concentrations, possibly because of a reduction in renal and nonrenal clearance, which may result in toxic effects due to digoxin. The dose of digoxin may need to be reduced (e.g., by 50 percent) and adjusted to a therapeutic level.1-3

Elaine M. Furmaga, Pharm.D.
Department of Veterans Affairs Pharmacy Benefits Management, Washington, DC 20420

Chester B. Good, M.D., M.P.H.
Department of Veterans Affairs Medical Advisory Panel, Washington, DC 20420

3 References

1. 1

   McEvoy GK, ed. AHFS drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.
   

2. 2

   Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, B.C.: Applied Therapeutics, 1998.
   

3. 3

   Singh BN. Amiodarone: the expanding antiarrhythmic role and how to follow a patient on chronic therapy. Clin Cardiol 1997;20:608-618
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We thank the correspondents for their thoughtful comments. In response to Aggarwal's comments about the proportions of patients with left ventricular hypertrophy in the two treatment groups, we refer to Figure 2 of the article, which shows that amiodarone was superior to propafenone or sotalol in patients without left ventricular hypertrophy (hazard ratio, 0.20) and in those with left ventricular hypertrophy (hazard ratio, 0.47). Despite the difference between these hazard ratios, there was no statistical evidence of an interaction between the treatment assignment and the presence or absence of left ventricular hypertrophy. In addition, a Cox model with adjustment for left ventricular hypertrophy indicates that the presence of left ventricular hypertrophy did not predict the recurrence of atrial fibrillation and that treatment assignment was strongly predictive of outcome, regardless of the presence or absence of left ventricular hypertrophy (Table 1Table 1Cox Proportional-Hazards Model for the Recurrence of Atrial Fibrillation.).

The patient in the propafenone-or-sotalol group who died because of a presumed arrhythmia was receiving sotalol at the time of death. Although propafenone is a class IC agent, it was not part of the Cardiac Arrhythmia Suppression Trial, which Aggarwal cites. However, it is clear that there is an increased risk of sudden death, presumably due to the proarrhythmic effects of antiarrhythmic drugs, among patients with substantial underlying structural heart disease. Safety was an important issue in the design of our trial; we excluded patients who had had a myocardial infarction during the previous six months, those with unstable angina, and those with New York Heart Association class III or IV congestive heart failure. Furthermore, the drug doses were adjusted according to age, sex, body weight, and renal function in order to decrease the likelihood of a proarrhythmic event.

Furmaga and Good are correct: if the use of amiodarone is to be extended, possible adverse effects must be considered. Amiodarone potentiates the effect of warfarin, and because this interaction may be erratic, frequent measurement of the prothrombin time (especially during the first few weeks of administration of loading doses) is essential. Since amiodarone also increases serum digoxin concentrations, reduction of the dose of digoxin is recommended. These considerations and the well-known noncardiac side effects have limited the use of amiodarone in the past and will do so in the future. However, other large, multicenter trials1-3 have evaluated the safety of low-dose amiodarone in much greater depth than did our trial. These studies have shown that this drug can be used safely with appropriate monitoring. As we stated in the Discussion section of our article, amiodarone should be considered as first-line therapy for patients with atrial fibrillation and structural heart disease and not for all patients.

Mario Talajic, M.D.
Denis Roy, M.D.
Jean Lambert, Ph.D.
Montreal Heart Institute, Montreal, QC H1T 1C8, Canada

3 References

1. 1

   Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999;100:2025-2034
   Web of Science | Medline

2. 2

   Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997;30:791-798
   CrossRef | Web of Science | Medline

3. 3

   Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997;350:1417-1424
   CrossRef | Web of Science | Medline