Amiodarone versus Sotalol for Atrial Fibrillation
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Singh et al. (May 5 issue)1 report in their article that both amiodarone and sotalol are efficacious in improving quality of life and sustaining sinus rhythm in patients with atrial fibrillation. They also report, but dismiss as statistically insignificant, a higher incidence of death in both groups of patients as compared with the placebo group.
On the basis of their data, the absolute increase in the risk of death in the amiodarone and the sotalol groups, as compared with the placebo group, was 2.7 and 3.6 percentage points, respectively, with a number needed to harm of between 27 and 37. In light of the prevalence of atrial fibrillation, these numbers are potentially important and merit further attention. The authors state that this difference is "unlikely" to be of practical significance on the basis of the results of larger studies with these drugs. This conclusion is potentially misleading, since the cited articles are mostly not studies conducted in patients with atrial fibrillation, there was limited follow-up, and in only one study was there a placebo group.2,3,4 This potential finding should be kept in mind when deciding on optimal patient care and designing future studies.
Jack Rubinstein, M.D.
Albert Einstein Medical Center
Philadelphia, PA 19141
jackrubinstein@yahoo.com
References
Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-1872.
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.
Kochiadakis GE, Igoumenidis NE, Marketou ME, Solomou MC, Kanoupakis EM, Vardas PE. Low-dose amiodarone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1998;81:995-998.
Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or flutter. Am J Cardiol 1999;84:270-277.
To the Editor: In the study by Singh et al., patients received antiarrhythmic drugs while they had atrial fibrillation and underwent conversion to sinus rhythm if atrial fibrillation persisted on the 28th day of the study. There were eight sudden deaths and one documented episode of torsades de pointes in the sotalol group. Although there are ample data to support the outpatient initiation of amiodarone during atrial fibrillation,1 conversion to sinus rhythm is associated with an increased risk of torsades de pointes, particularly in the presence of quinidine.2 In the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T), the authors suggest that outpatient initiation of sotalol during atrial fibrillation may be appropriate. The study population comprised more than 98 percent men. The incidence of drug-induced torsades de pointes is lower among men than among women, and this difference may explain the low rates of proarrhythmia in this trial.3 We believe that caution should be exercised in generalizing the practice of outpatient loading of sotalol during ongoing atrial fibrillation, particularly with regard to women.
Peter J. Zimetbaum, M.D.
Mark E. Josephson, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
pzimetba@bidmc.harvard.edu
References
Kochiadakis GE, Igoumenidis NE, Solomou MC, Kaleboubas MD, Chlouverakis GI, Vardas PE. Efficacy of amiodarone for the termination of persistent atrial fibrillation. Am J Cardiol 1999;83:58-61.
Roden D, Woosley R, Primm K. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986;111:1088-1093.
Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex differences in risk of torsades de pointes with d,l sotalol. Circulation 1996;94:2535-2541.
To the Editor: Singh et al. administered "thyroid-function tests" at enrollment but did not report the incidence of thyroid dysfunction during their 4.5-year trial. This is puzzling, given the very high reported incidence of both hypothyroidism and hyperthyroidism in various observational, cross-sectional, and controlled trials involving amiodarone for the treatment of several types of arrhythmia.1 Whereas amiodarone-induced hypothyroidism is readily treated with levothyroxine, amiodarone-induced hyperthyroidism is quite challenging to treat, particularly in patients who already have underlying atrial fibrillation and in those in whom amiodarone may not be stopped. Radiofrequency ablation is not an option, because of the massive iodine load of each dose of amiodarone, and surgery is not always an option for patients with severe coronary artery disease. Finally, potentially toxic therapies, such as glucocorticoids or potassium perchlorate, are used in some instances. Similar questions may be posed about the one-year Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) substudy of the first antiarrhythmic drug in serial therapy.2
Amnon Schlegel, M.D., Ph.D.
University of California, San Francisco
San Francisco, CA 94118
aschlege@itsa.ucsf.edu
References
Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998;79:121-127.
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.
To the Editor: Singh et al. report no significant difference between the groups who received amiodarone or sotalol and the placebo group in terms of major adverse effects. However, because their study was limited to a maximum follow-up of 4.5 years, the far-reaching adverse effects of amiodarone — namely, pulmonary and hepatic toxic effects, which can occur long after a period of this length — must also be examined and weighed when deciding between the two drugs. More than half of patients receiving long-term amiodarone therapy eventually discontinue its use because of such adverse effects. Extending this study over a longer interval might be helpful in establishing comparative side-effect profiles. In addition, it may be prudent to take into consideration the many other cardiac medications often taken by patients with atrial fibrillation, including digoxin and warfarin, which may also adversely interact with amiodarone, when the choice is made between this therapy and sotalol.
Kapil R. Desai, M.D.
New York University Medical Center
New York, NY 10016
desaik02@med.nyu.edu
The authors reply: Dr. Rubinstein expresses concern that we misinterpreted differences in mortality in the SAFE-T. However, trials assessing mortality are typically much larger than SAFE-T, and extrapolating our data may be unreliable. Also, there was an uneven distribution of patients with hypertension (73 percent in the amiodarone group, 66 percent in the sotalol group, and 56 percent in the placebo group; P=0.004). In an atrial-fibrillation study1 similar to SAFE-T but without a placebo control, there were nine deaths among the 201 patients assigned to amiodarone and a total of eight among the 101 patients assigned to sotalol and the 101 assigned to propafenone. Death due solely to atrial fibrillation may be relatively rare and in the study population may be due largely to associated cardiovascular disorders.1 This is suggested by the deaths in the placebo group in SAFE-T. Moreover, a meta-analysis2 of 13 trials (involving 6500 patients) showed a 13 percent reduction in total mortality with amiodarone as compared with controls (P=0.03).
In response to Drs. Zimetbaum and Josephson, we found no valid data supporting in-hospital initiation of sotalol or an increased incidence of torsades de pointes among women with atrial fibrillation. Recent evidence suggests that QT intervals in postmenopausal women are similar to those in men. In SAFE-T, the single case of torsades de pointes (nonfatal) occurred at eight weeks. Drs. Zimetbaum and Josephson emphasize that quinidine-induced torsades de pointes usually occurs during conversion to sinus rhythm. In SAFE-T, spontaneous conversion occurred fully three weeks after drug initiation and without torsades de pointes (in 27 percent of the patients in the amiodarone group and 24 percent in the sotalol group). Available data suggest that the safety of sotalol depends critically on limiting creatinine clearance to more than 60 ml per minute and the QT interval to less than 550 msec and not on initiating in-hospital therapy.
In response to Dr. Desai, in SAFE-T, with the use of low drug doses, the rates of adverse events and withdrawal were very low. In another study,3 the incidence of pulmonary toxic effects was 1.1 percent among 269 patients receiving amiodarone — an incidence similar to that (0.8 percent) among the 250 patients receiving placebo. A meta-analysis involving 1465 patients in low-dose, placebo-controlled trials reported a significant decrease in the odds of pulmonary toxic effects.4 The data suggest that pulmonary toxic effects in patients receiving amiodarone may occur more as a function of dose than of duration of therapy. We agree with Dr. Desai that long-term data on pulmonary toxic effects would be of considerable importance to the clinical use of amiodarone. Surprisingly, however, Dr. Desai considers hepatic toxicity a "far-reaching adverse effect" of amiodarone. Levels of liver enzymes increase during amiodarone-loading therapy but normalize during maintenance therapy. Serious persistent hepatotoxicity is rare5 and is usually associated with preexisting liver disease.
In response to Dr. Schlegel, thyroid function was assessed and an analysis of the data is under way.
Bramah N. Singh, M.D., D.Sc.
Veterans Affairs Greater Los Angeles Healthcare System
Los Angeles, CA 90073
bsingh@ucla.edu
Steven N. Singh, M.D.
Veterans Affairs Medical Center
Washington, DC 20422
Domenic Reda, Ph.D.
Hines Veterans Affairs Hospital
Hines, IL 60141-5000
References
Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913-920.
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.
Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias. N Engl J Med 1995;333:77-82.
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.
Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999;100:2025-2034.
On the basis of their data, the absolute increase in the risk of death in the amiodarone and the sotalol groups, as compared with the placebo group, was 2.7 and 3.6 percentage points, respectively, with a number needed to harm of between 27 and 37. In light of the prevalence of atrial fibrillation, these numbers are potentially important and merit further attention. The authors state that this difference is "unlikely" to be of practical significance on the basis of the results of larger studies with these drugs. This conclusion is potentially misleading, since the cited articles are mostly not studies conducted in patients with atrial fibrillation, there was limited follow-up, and in only one study was there a placebo group.2,3,4 This potential finding should be kept in mind when deciding on optimal patient care and designing future studies.
Jack Rubinstein, M.D.
Albert Einstein Medical Center
Philadelphia, PA 19141
jackrubinstein@yahoo.com
References
Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-1872.
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.
Kochiadakis GE, Igoumenidis NE, Marketou ME, Solomou MC, Kanoupakis EM, Vardas PE. Low-dose amiodarone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1998;81:995-998.
Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or flutter. Am J Cardiol 1999;84:270-277.
To the Editor: In the study by Singh et al., patients received antiarrhythmic drugs while they had atrial fibrillation and underwent conversion to sinus rhythm if atrial fibrillation persisted on the 28th day of the study. There were eight sudden deaths and one documented episode of torsades de pointes in the sotalol group. Although there are ample data to support the outpatient initiation of amiodarone during atrial fibrillation,1 conversion to sinus rhythm is associated with an increased risk of torsades de pointes, particularly in the presence of quinidine.2 In the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T), the authors suggest that outpatient initiation of sotalol during atrial fibrillation may be appropriate. The study population comprised more than 98 percent men. The incidence of drug-induced torsades de pointes is lower among men than among women, and this difference may explain the low rates of proarrhythmia in this trial.3 We believe that caution should be exercised in generalizing the practice of outpatient loading of sotalol during ongoing atrial fibrillation, particularly with regard to women.
Peter J. Zimetbaum, M.D.
Mark E. Josephson, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
pzimetba@bidmc.harvard.edu
References
Kochiadakis GE, Igoumenidis NE, Solomou MC, Kaleboubas MD, Chlouverakis GI, Vardas PE. Efficacy of amiodarone for the termination of persistent atrial fibrillation. Am J Cardiol 1999;83:58-61.
Roden D, Woosley R, Primm K. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986;111:1088-1093.
Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex differences in risk of torsades de pointes with d,l sotalol. Circulation 1996;94:2535-2541.
To the Editor: Singh et al. administered "thyroid-function tests" at enrollment but did not report the incidence of thyroid dysfunction during their 4.5-year trial. This is puzzling, given the very high reported incidence of both hypothyroidism and hyperthyroidism in various observational, cross-sectional, and controlled trials involving amiodarone for the treatment of several types of arrhythmia.1 Whereas amiodarone-induced hypothyroidism is readily treated with levothyroxine, amiodarone-induced hyperthyroidism is quite challenging to treat, particularly in patients who already have underlying atrial fibrillation and in those in whom amiodarone may not be stopped. Radiofrequency ablation is not an option, because of the massive iodine load of each dose of amiodarone, and surgery is not always an option for patients with severe coronary artery disease. Finally, potentially toxic therapies, such as glucocorticoids or potassium perchlorate, are used in some instances. Similar questions may be posed about the one-year Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) substudy of the first antiarrhythmic drug in serial therapy.2
Amnon Schlegel, M.D., Ph.D.
University of California, San Francisco
San Francisco, CA 94118
aschlege@itsa.ucsf.edu
References
Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998;79:121-127.
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.
To the Editor: Singh et al. report no significant difference between the groups who received amiodarone or sotalol and the placebo group in terms of major adverse effects. However, because their study was limited to a maximum follow-up of 4.5 years, the far-reaching adverse effects of amiodarone — namely, pulmonary and hepatic toxic effects, which can occur long after a period of this length — must also be examined and weighed when deciding between the two drugs. More than half of patients receiving long-term amiodarone therapy eventually discontinue its use because of such adverse effects. Extending this study over a longer interval might be helpful in establishing comparative side-effect profiles. In addition, it may be prudent to take into consideration the many other cardiac medications often taken by patients with atrial fibrillation, including digoxin and warfarin, which may also adversely interact with amiodarone, when the choice is made between this therapy and sotalol.
Kapil R. Desai, M.D.
New York University Medical Center
New York, NY 10016
desaik02@med.nyu.edu
The authors reply: Dr. Rubinstein expresses concern that we misinterpreted differences in mortality in the SAFE-T. However, trials assessing mortality are typically much larger than SAFE-T, and extrapolating our data may be unreliable. Also, there was an uneven distribution of patients with hypertension (73 percent in the amiodarone group, 66 percent in the sotalol group, and 56 percent in the placebo group; P=0.004). In an atrial-fibrillation study1 similar to SAFE-T but without a placebo control, there were nine deaths among the 201 patients assigned to amiodarone and a total of eight among the 101 patients assigned to sotalol and the 101 assigned to propafenone. Death due solely to atrial fibrillation may be relatively rare and in the study population may be due largely to associated cardiovascular disorders.1 This is suggested by the deaths in the placebo group in SAFE-T. Moreover, a meta-analysis2 of 13 trials (involving 6500 patients) showed a 13 percent reduction in total mortality with amiodarone as compared with controls (P=0.03).
In response to Drs. Zimetbaum and Josephson, we found no valid data supporting in-hospital initiation of sotalol or an increased incidence of torsades de pointes among women with atrial fibrillation. Recent evidence suggests that QT intervals in postmenopausal women are similar to those in men. In SAFE-T, the single case of torsades de pointes (nonfatal) occurred at eight weeks. Drs. Zimetbaum and Josephson emphasize that quinidine-induced torsades de pointes usually occurs during conversion to sinus rhythm. In SAFE-T, spontaneous conversion occurred fully three weeks after drug initiation and without torsades de pointes (in 27 percent of the patients in the amiodarone group and 24 percent in the sotalol group). Available data suggest that the safety of sotalol depends critically on limiting creatinine clearance to more than 60 ml per minute and the QT interval to less than 550 msec and not on initiating in-hospital therapy.
In response to Dr. Desai, in SAFE-T, with the use of low drug doses, the rates of adverse events and withdrawal were very low. In another study,3 the incidence of pulmonary toxic effects was 1.1 percent among 269 patients receiving amiodarone — an incidence similar to that (0.8 percent) among the 250 patients receiving placebo. A meta-analysis involving 1465 patients in low-dose, placebo-controlled trials reported a significant decrease in the odds of pulmonary toxic effects.4 The data suggest that pulmonary toxic effects in patients receiving amiodarone may occur more as a function of dose than of duration of therapy. We agree with Dr. Desai that long-term data on pulmonary toxic effects would be of considerable importance to the clinical use of amiodarone. Surprisingly, however, Dr. Desai considers hepatic toxicity a "far-reaching adverse effect" of amiodarone. Levels of liver enzymes increase during amiodarone-loading therapy but normalize during maintenance therapy. Serious persistent hepatotoxicity is rare5 and is usually associated with preexisting liver disease.
In response to Dr. Schlegel, thyroid function was assessed and an analysis of the data is under way.
Bramah N. Singh, M.D., D.Sc.
Veterans Affairs Greater Los Angeles Healthcare System
Los Angeles, CA 90073
bsingh@ucla.edu
Steven N. Singh, M.D.
Veterans Affairs Medical Center
Washington, DC 20422
Domenic Reda, Ph.D.
Hines Veterans Affairs Hospital
Hines, IL 60141-5000
References
Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913-920.
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.
Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias. N Engl J Med 1995;333:77-82.
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.
Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999;100:2025-2034.