Correspondence
Amiodarone in Congestive Heart Failure
N Engl J Med 1995; 333:1639-1641December 14, 1995
- Article
To the Editor:
It is important to clarify the role of amiodarone in patients with congestive heart failure, and the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure reported by Singh and colleagues (July 13 issue)1 advances the field. However, we would like to register some key reservations about that study.
First, there was a 27 percent rate of discontinuation of the study drug in the amiodarone group (vs. 23 percent in the placebo group), and an additional 14 percent of patients (vs. 9 percent in the placebo group) were lost to follow-up or withdrew from the study. Thus, only 60 percent of the group assigned to amiodarone actually received therapy as planned and could be evaluated. This may have dramatically compromised the ability of the trial to address the a priori hypotheses, even though the pretrial calculations appeared to have adequate power, with a 25 percent dropout rate taken into account.1,2 In contrast, only about 3 percent of patients in the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial3 had their medication stopped. Do the authors attribute the high dropout rate to side effects from the loading dose of amiodarone used in the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure?
Second, the observation of a trend toward a beneficial effect of amiodarone in the patients with nonischemic heart disease is interesting, but a cautionary point must be made here as well. According to the authors' earlier paper describing the study methods,2 this subgroup analysis was not stipulated a priori. Furthermore, although the Kaplan–Meier survival curves diverge at 24 months in the nonischemic group, giving a P value of 0.07, the event curves converge at approximately 30 months. The interpretation of the data is confounded, because only a limited subgroup was followed through 36 months. The finding of even a trend in the nonischemic group thus appears tentative at best. However, this may be a reason to explore the effects of the drug more thoroughly in very specific populations of patients with heart failure.
Finally, others have observed that much lower doses of amiodarone are associated with improvement in ventricular function in patients with heart failure.4 Indeed, a dose of 100 mg daily has been observed to have both antiarrhythmic and hemodynamic activity without toxic effects in patients with congestive heart failure. It may be possible to improve compliance by using very low doses of amiodarone, although a survival benefit may become evident only after very-long-term therapy.
Given the observations from the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure1 and the pending results of the Canadian and European trials of amiodarone, we think the jury is still out on the use of amiodarone in patients with congestive heart failure.
4 ReferencesMitchell J. Silver, D.O.
James Young, M.D.
Eric J. Topol, M.D.
Cleveland Clinic Foundation, Cleveland, OH 441951
Singh SN ,Fletcher RD ,Fisher SG , et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995;333:77-82
Full Text | Web of Science | Medline2
Singh SN ,Fletcher RD ,Fisher S , et al. Veterans Affairs congestive heart failure antiarrhythmic trial. Am J Cardiol 1993;72:99F-102F
CrossRef | Web of Science | Medline3
Doval HC ,Nul DR ,Grancelli HO ,Perrone SV ,Bortman GR ,Curiel R . Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-498
CrossRef | Web of Science | Medline4
Mahmarian JJ ,Smart FW ,Moye LA , et al. Exploring the minimal dose of amiodarone with antiarrhythmic and hemodynamic activity. Am J Cardiol 1994;74:681-686
CrossRef | Web of Science | Medline
To the Editor:
In the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure,1 amiodarone had no significant effect on survival at two years. In contrast, in the GESICA study that drug reduced mortality in patients with severe heart failure, independently of the presence of complex ventricular arrhythmias.2
Both Singh et al. in the original article1 and Breithardt in his editorial3 analyzed the differences between the two trials, stressing sex, age, and the cause of heart failure. To me the most striking difference between the two studies is the dose of amiodarone. In the GESICA trial the dosing schedule was 600 mg per day for 2 weeks and then 300 mg per day (total first-year dose, 113.7 g); in the Survival Trial, it was 800 mg per day for 2 weeks, then 400 mg per day for 50 weeks, and then 300 mg per day (total first-year dose, 151.6 g). Amiodarone was effective in reducing total mortality in the GESICA trial and in all but one study conducted with a low dose (i.e., <300 mg per day) in patients with congestive heart failure.4 Moreover, the data show that even in patients with myocardial infarction, such doses reduced the incidence of sudden death due to ventricular tachyarrhythmia and overall cardiac mortality.5
The different dose could at least partly explain the higher proportion of patients who were withdrawn because of side effects: 27 percent as compared with 4.6 percent. The toxic effects of amiodarone in fact seem related to the total dose administered, and gastrointestinal and neurologic side effects in particular are more commonly reported during the loading period.4
5 ReferencesAgostino Colli, M.D.
Ospedale Civile, 23017 Morbegno, Italy1
Singh SN ,Fletcher RD ,Fisher SG , et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995;333:77-82
Full Text | Web of Science | Medline2
Doval HC ,Nul DR ,Grancelli HO ,Perrone SV ,Bortman GR ,Curiel R . Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-498
CrossRef | Web of Science | Medline3
Breithardt G . Amiodarone in patients with heart failure. N Engl J Med 1995;333:121-122
Full Text | Web of Science | Medline4
Podrid PJ . Amiodarone: reevaluation of an old drug. Ann Intern Med 1995;122:689-700
Web of Science | Medline5
Burkart F ,Pfisterer M ,Kiowski W ,Follath F ,Burckhardt D . Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel Antiarrhythmic Study of Infarct Survival (BASIS). J Am Coll Cardiol 1990;16:1711-1718
CrossRef | Web of Science | Medline
To the Editor:
We are surprised at the very low incidence of abnormalities in thyroid function (1.2 percent) observed by Singh et al. in their patients with heart failure who were treated with amiodarone. This incidence is lower than the incidence of hypothyroidism and hyperthyroidism reported in similar studies of large numbers of patients treated with this antiarrhythmic drug.1-3 Singh et al. do not indicate how thyroid function was monitored during the treatment period. They do not mention measurements of triiodothyronine, thyroxine, reverse triiodothyronine, or thyrotropin. Clinical evaluation is not sensitive enough to detect decreased or increased thyroid function in patients with a condition in which the signs and symptoms can be obscured by the effects of amiodarone (e.g., bradycardia) or the underlying disease. Therefore, it is difficult to draw conclusions about the true incidence of thyroid dysfunction in this study. This is an important issue, because subclinical thyroid dysfunction may have worsened the outcome in the amiodarone-treated patients and masked a potential benefit of the drug.
3 ReferencesLeonardo A. Sechi, M.D.
Stefano De Carli, M.D.
Ettore Bartoli, M.D.
University of Udine, 33100 Udine, Italy1
Cairns JA ,Connolly SJ ,Gent M ,Roberts R . Post-myocardial infarction mortality in patients with ventricular premature depolarizations: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study. Circulation 1991;84:550-557
Web of Science | Medline2
Greene HL . The CASCADE Study: randomized antiarrhythmic drug therapy in survivors of cardiac arrest in Seattle. Am J Cardiol 1993;72:70F-74F
CrossRef | Web of Science | Medline3
Herre JM ,Sauve MJ ,Malone P , et al. Long-term results of amiodarone therapy in patients with recurrent sustained ventricular tachycardia or ventricular fibrillation. J Am Coll Cardiol 1989;13:442-449
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In response to Silver et al.: the study was designed to detect an absolute increase in two-year survival of 10 percent (80 percent vs. 70 percent) with amiodarone therapy. Given the elongated recruitment period and the withdrawal of 78 patients, the power of the intention-to-treat analysis was decreased from 90 percent to 85 percent.
There was no suggestion of any survival benefit at any time with amiodarone. Given the similarities between the survival rates in the two groups, it is highly unlikely that the true difference would be 10 percent or more. In response to the concern that a large number of patients had treatment with the study drug discontinued, a comparative analysis of survival that included only patients who continued to receive the assigned drug treatment was undertaken and demonstrated no significant difference (P = 0.28). The two-year survival rates in the amiodarone and placebo groups were 82.2 percent and 79.7 percent, respectively.
Rates of discontinuation were similar in the two groups (P = 0.10), and therefore the loading dose of amiodarone was not a problem. The patients were stratified in advance according to study site, ejection fraction (<30 percent or >30 percent), and type of cardiomyopathy (ischemic or nonischemic). These categories were stipulated a priori. We agree that the trend toward a potential benefit in the patients with nonischemic cardiomyopathy is only enough to permit the formation of a hypothesis and should be explored prospectively.
The frequency of ventricular arrhythmia was reduced and ejection fraction was improved in our study. We are aware that these effects are present at lower doses. Proarrhythmia (torsades) was not seen on numerous in-hospital recordings and more than 6000 recordings obtained by Holter monitoring.
In response to the comment of Sechi et al. about the low incidence of thyroid abnormalities, we point out that the figure of 1.2 percent (referring to four patients) denotes severe abnormalities requiring the discontinuation of amiodarone. Abnormalities in thyroid-function tests in the asymptomatic patients were not included, since we did not consider such abnormalities indications for drug discontinuation. Subclinical thyroid dysfunction is unlikely to lead to excess mortality. Moreover, despite the higher incidence of thyroid abnormalities reported, there was no drug discontinuation in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial pilot study,1 and only two patients discontinued treatment in five years in the study by Herre et al.2 Thus, the incidence of discontinuation of amiodarone due to thyroid imbalances in those studies did not differ from that in our study.
In response to Dr. Colli: the numbers of patients who withdrew from the study in the amiodarone and placebo groups were similar (27 percent vs. 23 percent, P not significant). The toxic effects of the dose of amiodarone chosen in our trial did not explain the lack of benefit. Moreover, the sample size was adjusted to include an additional 25 percent to make up for the patients who dropped out.
2 ReferencesSteven N. Singh, M.D.
Ross D. Fletcher, M.D.
Veterans Affairs Medical Center, Washington, DC 20422Susan G. Fisher, Ph.D.
Loyola University Medical Center, Maywood, IL 601531
Cairns JA ,Connolly SJ ,Gent M ,Roberts R . Post-myocardial infarction mortality in patients with ventricular premature depolarizations: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study. Circulation 1991;84:550-557
Web of Science | Medline2
Herre JM ,Sauve MJ ,Malone P , et al. Long-term results of amiodarone therapy in patients with recurrent sustained ventricular tachycardia or ventricular fibrillation. J Am Coll Cardiol 1989;13:442-449
CrossRef | Web of Science | Medline
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Richard T. Silver. (2007) Update on the treatment of polycythemia vera with recombinant interferon alfa or imatinib mesylate. Current Hematologic Malignancy Reports 2:1, 43-46
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Christina Halsey, Irene A. G. Roberts. (2003) The role of hydroxyurea in sickle cell disease. British Journal of Haematology 120:2, 177-186
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Abraham Sumoza, Renate de Bisotti, David Sumoza, Virgil Fairbanks. (2002) Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA). American Journal of Hematology 71:3, 161-165
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Yutaka Niihara, Charles R. Zerez, Dean S. Akiyama, Kouichi R. Tanaka. (1998) Oral L-glutamine therapy for sickle cell anemia: I. subjective clinical improvement and favorable change in red cell NAD redox potential. American Journal of Hematology 58:2, 117-121
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M. de Montalembert, M. Belloy, F. Bernaudin, F. Gouraud, R. Capdeville, R. Mardini, N. Philippe, J. Jais, J. Bardakdjian, R. Ducrocq. (1997) Journal of Pediatric Hematology/Oncology 19:4, 313
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Martin H. Steinberg. (1996) Sickle Cell Disease: Present and Future Treatment. The American Journal of the Medical Sciences 312:4, 166-174
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(1996) Hydroxyurea in Sickle Cell Disease. New England Journal of Medicine 334:5, 333-334
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