Correspondence
Dronedarone in Atrial Fibrillation
N Engl J Med 2007; 357:2403-2405December 6, 2007
- Article
To the Editor:
Singh et al. (Sept. 6 issue)1 conclude that dronedarone is significantly more effective than placebo in decreasing the rate of arrhythmic recurrences in atrial fibrillation. They do not comment on the high 1-year incidence of biological hyperthyroidism in their study: 8.4% in the dronedarone group versus 14.1% in the placebo group (P=0.002). Since about 30% of the patients had been taking amiodarone before they were included in the study, a possible explanation is a delayed side effect of this drug, which can provoke hyperthyroidism several months after its discontinuation.2 It is hardly conceivable that dronedarone would provide protection against hyperthyroidism; rather, the screening procedure may not have excluded patients with subclinical hyperthyroidism, resulting in a random but unfortunate imbalance between the two groups. Indeed, whatever its explanation, the higher incidence of hyperthyroidism in the placebo group than in the dronedarone group may have favored a higher rate of arrhythmic recurrences in the controls, somewhat exaggerating the true antiarrhythmic effect of dronedarone.
2 ReferencesJean-Benoît Arlet, M.D.
Laurent Chouchana, Pharm.D.
Loïc Capron, M.D., Ph.D.
Hôpital Européen Georges Pompidou, 75908 Paris, France
jean-benoit.arlet@egp. aphp. fr 1
Singh BN ,Connolly SJ ,Crijns HJ , et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357:987-999
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Martino E ,Aghini-Lombardi F ,Mariotti S ,Bartalena L ,Braverman L ,Pinchera A . Amiodarone: a common source of iodine-induced thyrotoxicosis. Horm Res 1987;26:158-171
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To the Editor:
Singh et al. and Ezekowitz, in his accompanying editorial,1 cite improvements in the quality of life as the motivation for using antiarrhythmic drugs to establish and maintain sinus rhythm in patients with atrial fibrillation. But the quality-of-life analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial showed no difference between patients in whom sinus rhythm was maintained and those in whom atrial fibrillation persisted,2 and careful analysis of the quality-of-life differences between rhythm-outcome groups in the Sotalol–Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T), cited by Ezekowitz, shows that these differences may be more reflective of the identification of treatment as a success or a failure than of the rhythm obtained.3 In fact, in SAFE-T, no significant difference was found in exercise duration between the two rhythm-outcome groups among asymptomatic patients. Therefore, vigorous rate-control strategies remain the best first approach for stable patients in atrial fibrillation, with rhythm control reserved for those with refractory symptoms.
3 ReferencesAlbert H. Fink, Jr., M.D.
University of Pennsylvania Health System, Media, PA 19081
finka@uphs.upenn. edu 1
Ezekowitz MD . Maintaining sinus rhythm -- making treatment better than the disease. N Engl J Med 2007;357:1039-1041
Full Text | Web of Science | Medline2
Jenkins LS ,Brodsky M ,Schron E , et al. Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005;149:112-120
CrossRef | Web of Science | Medline3
Singh SN ,Tang XC ,Singh BN , et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48:721-730
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Author/Editor Response
Arlet et al. wonder whether the higher rate of biological hyperthyroidism in the placebo group (14.1%) than in the dronedarone group (8.4%) was due to previous amiodarone therapy, which might have benefited the dronedarone group. It should be stressed that subgroup analyses of such questions are exploratory. Given the large number of statistical tests (each carrying its type I error), one should be cautious in interpreting findings based on P values that could be significant just by play of chance because of multiple testing. There was no difference at randomization in the proportions of patients who had previously been taking amiodarone in the placebo and dronedarone groups in the European study (32 of 201 patients [15.9%] and 66 of 411 [16.1%], respectively) or in the non-European study (43 of 208 [20.7%] and 82 of 417 [19.7%], respectively). In addition, in a prespecified secondary analysis of the primary end point, previous amiodarone treatment was included, along with other possible prognostic factors, in a Cox regression model. The effect of dronedarone remained significant after adjustment for prior amiodarone treatment (P=0.03 and P=0.001 in the European and non-European studies, respectively).
We also specifically looked at treatment effects for patients with and those without reported hyperthyroidism. In both studies, treatment effects regarding the primary end point were significant for patients with hyperthyroidism (hazard ratio, 0.53; 95% confidence interval [CI], 0.34 to 0.81; P=0.003) and for those without hyperthyroidism (hazard ratio, 0.77; 95% CI, 0.66 to 0.90; P=0.001).
We differ with Fink in his view that all stable patients with atrial fibrillation should be treated with vigorous rate control. He emphasizes the lack of a quality-of-life benefit in the AFFIRM trial. This pivotal atrial-fibrillation study was not double-blinded, and its exercise component was the 6-minute walk test. However, recent data have shown that in such patients sustained sinus rhythm improves the quality of life.1
In SAFE-T, a double-blinded, placebo-controlled trial, there were significant improvements in treadmill exercise in patients in sinus rhythm.2,3 SAFE-T confirmed the outcome in many smaller trials, which also showed improvements in the quality of life for patients with conversion from atrial fibrillation to sinus rhythm.1,4 The available data emphasize the need to further characterize those patients in atrial fibrillation for whom it is appropriate to restore and maintain sinus rhythm and those for whom atrial fibrillation with rate control is the therapeutic strategy of choice.
4 ReferencesBramah N. Singh, M.D., D.Sc.
Veterans Affairs Greater Los Angeles, Los Angeles, CA 90073
bsingh@ucla.edu Stefan H. Hohnloser, M.D.
J.W. Goethe University, 60325 Frankfurt, Germany1
Falk RH . Atrial fibrillation or sinus rhythm? Controversy and contradiction in quality of life outcomes. J Am Coll Cardiol 2006;48:731-733
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Singh BN ,Singh SN ,Reda DJ , et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-1872
Full Text | Web of Science | Medline3
Singh SN ,Tang XC ,Singh BN , et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48:721-730
CrossRef | Web of Science | Medline4
Dorian P ,Paquette M ,Newman D , et al. Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation. Am Heart J 2002;143:984-990
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Author/Editor Response
The approach to the patient with atrial fibrillation is based on four considerations, in no particular order: to seek a reversible cause of the condition, to control the rate, and to introduce measures to reduce the risk of stroke. Finally, consideration should be given to cardioverting and maintaining the patient in sinus rhythm.
Thus, I agree with Dr. Fink that rate control — and I would add particularly in the elderly — is important and often the initial treatment approach. Dr. Fink and I can debate the veracity of the quality-of-life data in the AFFIRM study1 and SAFE-T2 and the definition of intractable symptoms. However, it is common experience that when atrial fibrillation develops in patients, particularly those who are young and active, there is a reduction in the quality of life, which improves with both rate control and restoration of sinus rhythm. I believe a physiologic rhythm and a physiologic rate have additive benefit.
The point I was making in my editorial was that an effective and safe antiarrhythmic agent would meet an unmet need and make the rhythm-control approach more attractive.
2 ReferencesMichael D. Ezekowitz, M.B., Ch.B., D.Phil.
Lankenau Institute for Medical Research, Wynnewood, PA 190961
Jenkins LS ,Brodsky M ,Schron E , et al. Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005;149:112-120
CrossRef | Web of Science | Medline2
Singh SN ,Tang XC ,Singh BN , et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48:721-730
CrossRef | Web of Science | Medline
