Skip Navigation


European Heart Journal Advance Access originally published online on August 25, 2006
European Heart Journal 2006 27(18):2224-2231; doi:10.1093/eurheartj/ehl209
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
27/18/2224    most recent
ehl209v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lombardi, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lombardi, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial

Federico Lombardi1,*, Martin Borggrefe2, Witold Ruzyllo3, Berndt Lüderitz4 for the A-COMET-II Investigators

1 Cardiologia, Department of Medicina, Chirurgia e Odontoiatria, Osp. San Paolo, University of Milan, Via A. di Rudinì 8, 20142 Milan, Italy
2 I. Medizinische Klinik, Universitätsklinikum, Fakultät für klinische Medizin, Mannheim der Universität Heidelberg, Germany
3 Institute of Cardiology, Warsaw, Poland
4 Department of Medicine—Cardiology, University of Bonn, Germany

Received 24 May 2006; revised 4 August 2006; accepted 10 August 2006; online publish-ahead-of-print 25 August 2006.

* Corresponding author. Tel: +39 0250323145; fax: +39 0250323145. E-mail address: federico.lombardi{at}unimi.it


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Aims Treatment of atrial fibrillation remains a major clinical challenge owing to the limited efficacy and safety of anti-arrhythmic drugs, particularly in patients with structural heart disease.

Methods and results To evaluate the efficacy of azimilide, a new class III anti-arrhythmic drug, we studied 658 patients with symptomatic persistent atrial fibrillation, adequate anticoagulant therapy, and planned electrical cardioversion. Patients were randomized to placebo, azimilide (125 mg o.d.), or sotalol (160 mg b.i.d.). Primary efficacy analysis was based on event recurrence, which was defined as atrial fibrillation lasting>24 h, or requiring DC cardioversion. Median time to recurrence was 14 days for azimilide, 12 days for placebo, and 28 days for sotalol (P=0.0320 when comparing azimilide with placebo; P=0.0002 when comparing azimilide with sotalol). The placebo-to-azimilide hazard ratio was 1.291 (95% CI: 1.022–1.629) and the sotalol-to-azimilide hazard ratio was 0.652 (95% CI: 0.523–0.814). Adverse events causing patient withdrawal were more frequent (P<0.01) in patients on azimilide (12.3%) and on sotalol (13.9%) than on placebo (5.4%). Eight patients in the sotalol (3.5%) and 16 in the azimilide (7.6%) group interrupted the study because of QTc prolongation. Torsade de pointes was reported in five patients of the azimilide group. The percentage of patients who completed the 26 week study period without events were 19% for azimilide, 15% for placebo, and 33% for sotalol (P<0.01). Unsuccessful day 4 cardioversion, arrhythmia recurrence, and adverse events were the main causes of withdrawal from the study.

Conclusion This study demonstrates that the anti-arrhythmic efficacy of azimilide is slightly superior to placebo but significantly inferior to sotalol in patients with persistent AF. The modest anti-arrhythmic efficacy and high rate of torsade de pointes and marked QTc prolongation limit azimilide utilization for the treatment of AF.

Key Words: Anti-arrhythmic drugs • Atrial fibrillation • Torsade de pointes • Long QT


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Treatment of atrial fibrillation remains a major clinical challenge.1–3 Sound clinical judgement and experimental data indicate that conversion to and maintenance of sinus rhythm represent the principal therapeutic objective, although strategy selection remains controversial due to the limited efficacy and safety of anti-arrhythmic therapy over long periods of time, especially in patients with congestive heart failure. The issue has become even more controversial after the publication of recent studies4–7 that have proved that in selected subgroups of patients, rhythm control did not offer any significant advantage over rate control in terms of survival once appropriate anticoagulant therapy is prescribed.

Recently, the Sotalol Amiodarone atrial Fibrillation Efficacy Trial (SAFE-T) investigators8 have demonstrated that amiodarone is superior to sotalol for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischaemic heart disease. Thus, potassium channel blocker activity seems one of the principle mechanisms to exert an effective anti-fibrillatory action, particularly in patients with structural heart disease.8–12 In the last 10 years, new class III anti-arrhythmic drugs have been developed and tested in patients with atrial fibrillation: dofetilide and azimilide have been object of several investigations.13–18 Dofetilide has been approved by regulatory agencies to convert atrial fibrillation and maintain sinus rhythm.13,14 Azimilide has been proved effective in increasing time to first atrial fibrillation recurrence at doses of 100–125 mg per day.15–18

The A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial was designed and performed to compare prospectively the efficacy of azimilide in comparison with placebo and sotalol in maintaining sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Study population
Patients aged between 18 and 80 years were eligible if they had documented (12 lead ECG) history of symptomatic atrial fibrillation lasting more than 48 h and less than 6 months, adequate anticoagulant therapy, and planned electrical cardioversion. Epidemiological data and clinical characteristics of patients are in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline clinical characteristics of study population

 
The following patients were excluded: (i) patients with qualifying arrhythmias due to transient causes such as electrolyte disturbances, hyperthyroidism, or pericarditis; (ii) patients with a history of syncope or angina pectoris precipitated by attacks of arrhythmia; (iii) patients with a history of torsade de pointes or other forms of polymorphic ventricular tachycardia as well as two degree or three degree atrio-ventricular block without a permanent pacemaker; (iv) patients with a recent myocardial infarction, unstable angina, or heart failure NYHA class IV; (v) patients with a family history of prolonged QT syndrome or with a baseline QTc >440 ms.

Eligible patients were considered to have structural heart disease if their history included one of the following: left bundle branch block, coronary artery disease, remote myocardial infarction, congestive heart failure, valvular heart disease, hypertension with cardiomyopathy, or hypertension with left ventricular hypertrophy.

In addition, patients using class I or III anti-arrhythmic agents or beta-blockers had to discontinue treatment for at least five half-lives before receiving the first dose of study. Amiodarone must have been discontinued for at least 1 month. Beta-blockers were not allowed during the study.

All patients provided written informed consent, and the Ethical Committee at each site approved the protocol.

Study design
This was a randomized, 6 month double-blind, placebo controlled, parallel group-design study to compare the efficacy of azimilide 125 mg per day with placebo or sotalol 160 mg b.i.d. in patients with persistent atrial fibrillation. Procter & Gamble funded the trial and provided study manager to supervise its conduct. Patients were randomized in a 1:1:1 ratio according to a randomization code generated before the start of the study. A dummy technique was used to provide the same looking and number of pills to all subjects.

Before undergoing any study-related procedures, all eligible patients were informed of the purpose and design of the study. The following assessment was conducted within 7 days prior to hospitalization: medical history and concomitant medications (including number of previous cardioversion); complete physical examination; chest X-ray; serum chemistry and derived creatinine clearance; haematology, blood sample for azimilide to be used as a blank; serum pregnancy test (for all women of childbearing potential).

Patients received 3 days of a twice-daily oral dose of either azimilide 125 mg, placebo, or sotalol 160 mg. All subjects were continuously monitored during the three day loading period. On day 4, patients who were in sinus rhythm were considered to have spontaneously converted. Those in atrial fibrillation underwent DC cardioversion, which was considered successful when sinus rhythm persisted at least 1 h after the procedure. Patients who were not successfully cardioverted or with QTc>525 ms or with persistent sinus bradycardia (<50 b.p.m.) were withdrawn from the study; in these patients, time to the primary efficacy event was set to 1 day.

Maintenance study doses were azimilide 125 mg daily plus one placebo, placebo twice-daily, or sotalol 160 b.i.d. Owing to possible side effects thought to be related to beta-adrenergic blockade, patients in all three treatment groups were allowed to undergo a blinded dose reduction at the investigator's discretion according to predefined criteria.

The efficacy period started on day 4 when a successful electrical or spontaneous cardioversion was documented. Outpatient visits at each study site were scheduled at weeks 2, 4, 6, 8, 10, 12, and 26. Patients could also return for unscheduled visits at anytime during the course of the study.

The primary objective of the study was to assess the efficacy of azimilide vs. placebo in prolonging the time from the start of the efficacy period to the first symptomatic or asymptomatic atrial fibrillation episode, flutter, or PSVT event. An event was defined as symptomatic or asymptomatic atrial fibrillation, flutter, or PSVT lasting >24 h (the arrhythmic episode had to be confirmed during a second electrocardiogram performed after 24 h from its onset); atrial fibrillation, flutter, or PSVT<24 h for which the patient had to be admitted to hospital or DC cardioverted, cardioversion failure on day 4 and withdrawal prior to cardioversion. Patients who entered the efficacy period but withdrew from the study were censored on the date of study discontinuation.

The secondary objective of the study was an effectiveness analysis, comparing azimilide with sotalol, as defined by the composite time to first event or all-cause withdrawal.

Tertiary objectives of the study were to assess the effects of azimilide vs. placebo on facilitating successful DC cardioversion and on symptom frequency load during the first recurrence. Drug conversion to sinus rhythm during the loading phase was also considered. Symptom frequency load during recurrences was calculated in relation to six pre-specified symptoms (chest pain/pressure, light-headedness/dizziness, fatigue, palpitations, sweating, and shortness of breath) and ranked accordingly.

Among several variables used to define additional subgroup analyses, only structural heart disease is considered in this article.

Electrocardiographic criteria for withdrawal were the following: ventricular fibrillation, sustained monomorphic ventricular tachycardia, incessant ventricular tachycardia, polymorphic VT, QTc exceeding 525 ms, or a documented and persistent heart rate below 50 b.p.m. during the waking hours. Additionally, a neutrophil count<1000/µL or a derived [(140–age)xweight (kg)/72 serum creatinine (mg/dL)] creatinine clearance<60 mL/min on two consecutive measurements were causes of withdrawal.

Statistical analysis
The distribution of time to first documented event was assumed to follow an exponential distribution. Sample size was calculated using the method of Schoenfeld19 assuming a two-sided hypothesis test of the primary endpoint (azimilide vs. placebo) at a significance level of 5% ({alpha}=0.05). An equal number of patients in each of the three groups was planned. In patients who required cardioversion, the median time to event was estimated to be no more than 90 days for placebo. A sample size of 190 patients in each treatment group was calculated to achieve a hazard ratio of 0.67 to be detected with a 0.90 probability (90% power). After assuming 15% for dropouts, the total number of patients to be enrolled was calculated to be 657 (219 patients per treatment group). A ‘gatekeeper’ method20 was employed for the secondary analysis. This method allows the secondary hypothesis to be tested at a significance level of 5% only if the analysis of primary endpoint is significant (P<0.05). All hypothesis tests are two-sided. Gatekeeper approach was taken with alpha allocated to the primary and secondary endpoints. None of the additional analyses were adjusted.

Primary efficacy analysis was based on intention to treat and measured the time to the first symptomatic or asymptomatic event during a 6 month period. All patients who withdrew for unsuccessful cardioversion or for any reason prior to day 4 were considered to have had an event on the first day of the efficacy period. Kaplan–Meier estimates of the survival curves were generated and treatment comparisons made using the log-rank test. Differences between the times to event distribution were also quantified by the hazard ratio from a population of hazard regression, Kaplan–Meier estimates of the median time to event, and Kaplan–Meier estimates of the proportion event-free through ~6 months.

The incidence of adverse event, as categorized by the COSTART coding dictionary, was summarized by counting patients who experienced an adverse event.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
A total of 658 patients were enrolled into the study (Table 1). Of note, previous cardioversion was performed in ~25% of cases, duration of atrial fibrillation>27 days was present in more than 70% of subjects, and symptoms related to NYHA class I–II were present in almost 50% of patients. Russia, Poland, Hungary, and Western Europe enrolled, respectively, 25, 26, 17, and 32% of the patients.

Five patients on placebo, nine on azimilide, and seven on sotalol were withdrawn from the study prior to start of the efficacy period for different reasons including bradycardia, QTc prolongation, and refuse of continuing the study. Spontaneous cardioversion on day 4 occurred in 6.9, 4.1, and 6.3% of patients in, respectively, azimilide, placebo, and sotalol groups. These figures were not significantly different. The percentage of withdrawal from the study due to unsuccessful cardioversion on day 4 was 15% for azimilide, 19% for placebo, and 12% for sotalol (P=0.116).

The percentages of patients who completed the 26 week study period were 19% for azimilide, 15% for placebo, and 33% for sotalol (P<0.01). Arrhythmia recurrence, cardioversion failure on day 4, and adverse event were the most important causes of withdrawal from the study.

Azimilide vs. placebo
As illustrated in Figure 1, there was a slight but statistically significant difference in time to event between azimilide and placebo groups. Median time to recurrence was 12 days for placebo and 14 days for azimilide (P=0.032; hazard ratio 1.29; 95% CI=1.02–1.62). Symptomatic event episodes lasting >24 h and asymptomatic events occurred in 23.2 and 12.3% of patients in the azimilide group and in 29 and 15.6% of patients in the placebo group, respectively. Arrhythmia recurrence necessitating hospitalization or DC cardioversion was more frequent (P=0.033) in the placebo (9.8%) than in the azimilide (3.8%) group. About 50% of recurrences were subacute occurring during the first weeks of the efficacy period. In patients with structural heart disease (Figure 2), the difference in time to event was more evident and reflected by a placebo–azimilide hazard ratio of 1.41 (95% CI=1.05–1.91). When the analysis was restricted to patients in sinus rhythm on day 4, the difference between median time to event was greater (26 vs. 15 days), with a placebo–azimilide hazard ratio of 1.37 (95% CI: 1.04–1.82; P=0.0261) in the whole study population and 1.61 (95% CI: 1.16–2.23; P=0.0041) in patients with structural heart disease.


Figure 2091
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Time from the start of the efficacy period to primary efficacy event in all randomized patients included in placebo and azimilide groups.

 

Figure 2092
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Time from the start of the efficacy period to primary efficacy event in all randomized patients with structural heart disease included in placebo and azimilide groups.

 
Symptom frequency burden (Figure 3) and mean ventricular response (Figure 4) during arrhythmia recurrence were not significantly different between azimilide and placebo groups.


Figure 2093
View larger version (26K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3 Symptom burden score during atrial fibrillation recurrence. There was a tendency towards less symptomatic arrhythmia recurrences in the azimilide group (burden score definition is given under Methods section.

 

Figure 2094
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 4 Mean ventricular response at the time of atrial fibrillation recurrence in patients on azimilide (n=109), placebo (n=150), and sotalol (n=91).

 
Azimilide vs. sotalol
As illustrated in Figure 5, in the secondary efficacy analysis of the intention to treat study population, there was a statistically significant difference in time to event or withdrawal (P=0.0002) between the azimilide and sotalol groups in favour of sotalol. The median time to recurrence was 14 days for azimilide and 28 days for sotalol. The sotalol-to-azimilide hazard ratio was 0.65 (95% CI: 0.52–0.81). Symptomatic event episodes lasting>24 h and asymptomatic events occurred in 16.1 and 10.3% of patients in sotalol group.


Figure 2095
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 5 Time from the start of the efficacy period to primary efficacy event or study withdrawal in all randomized patients included in sotalol and azimilide groups.

 
Arrhythmia recurrence necessitating hospitalization or DC cardioversion occurred in 3.1% of sotalol patients. By comparing azimilide and sotalol curves outlined in Figure 5, it appears that the number of subacute recurrences was smaller in sotalol-treated patients.

When considering patients with and without a diagnosis of structural heart disease, the difference in time to event, in favour of sotalol, was confirmed with a hazard ratio of 0.71 (95% CI: 0.55–0.92) and 0.50 (95% CI: 0.33–0.77), respectively.

The symptom frequency burden reported by patients on sotalol was not significantly different from that of patients on azimilide or placebo (Figure 3) in spite of the fact that mean ventricular response was significantly lower (Figure 4).

Adverse events
The overall percentage of patients who reported adverse event was similar among azimilide, sotalol, and placebo (51.7, 61.9, and 50.9%). The most common adverse events in the azimilide and sotalol groups were hypertension, prolonged QTc, and bradycardia. Four patients in the azimilide group and four patients in the sotalol group died during the study. There were no deaths in the placebo group. Two deaths in the azimilide group were classified as arrhythmic deaths, one as a cardiac non-arrhythmic death, and one as unknown. Three deaths in the sotalol group were classified as arrhythmic deaths and one as cardiac non-arrhythmic death. The mortality rates for 100 patient-years were significantly greater (P<0.01) for azimilide (9.22) and sotalol (6.35) in comparison with placebo (0). Major arrhythmic cardiac events were defined as death, torsade de pointes, ventricular tachycardia, or fibrillation leading to withdrawal from the study. Data related to the loading period and the entire study are presented in Table 2. All five patients reporting torsade de pointes belonged to the azimilide group. They were older than 65 years (range 66–76 years) and female gender was prevalent (n=3). In all but one case, the arrhythmia occurred in the first few days after the loading period.


View this table:
[in this window]
[in a new window]

  		Table 2 Number of patients with death, torsades de pointes, VT/VF, and MACE during the loading and whole study period

 
A greater number of patients on azimilide (12.3%) and on sotalol (13.9%) than on placebo (5.4%, P<0.01) were withdrawn from the study due to adverse events. Neutropenia requiring withdrawal was observed in one patient on azimilide. Two patients on placebo (0.9%), eight in the sotalol (3.5%), and 16 in the azimilide (7.6%) groups interrupted the study because of QTc prolongation (P<0.01 when comparing azimilide vs. placebo). All but one case in sotalol and two cases in azimilide group occurred in the maintenance period. Values >525 ms were confirmed in nine patients on azimilide (4.2%), eight patients on sotalol (3.6%), and one patient on placebo. Sinus bradycardia caused withdrawal from the study in 15 (6.7%) patients on sotalol and three patients on azimilide (1.4%).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Appendix
 Acknowledgements
 References
 
This study demonstrates that azimilide is slightly superior to placebo but inferior to sotalol in prolonging time to first documented recurrence after successful electrical cardioversion in patients with persistent atrial fibrillation with and without structural heart disease. Marked QTc prolongation or torsade de pointes occurred in ~10% of patients on azimilide. No episodes of torsade de pointes were observed in placebo and sotalol groups.

Class III drugs in persistent atrial fibrillation
Previous studies have documented the efficacy of class III drugs in preventing arrhythmia recurrences in patients with persistent atrial fibrillation.2,8–18 In the Canadian Trial of Atrial Fibrillation study,9 amiodarone was found to be more effective than sotalol or propafenone in prolonging time to the first recurrence after DC cardioversion in patients with a history of symptomatic paroxysmal or persistent atrial fibrillation. More recently, the SAFE-T investigators8 reported the results of a double-blind, placebo controlled study designed to compare the anti-arrhythmic efficacy of amiodarone, sotalol, and placebo in patients with persistent atrial fibrillation undergoing cardioversion. The median time to first recurrence was 487 days in the amiodarone, 74 days in the sotalol, and six days in the placebo group according to intention to treat analysis. Times to first arrhythmic event were therefore markedly different from those observed in the present study, in which the median time to recurrence for azimilide was 14 or 26 days according to, respectively, primary or secondary efficacy analysis. These figures, in addition, were also markedly different from those observed in the previously reported SVA studies16–18 where a mean value ranging from 38 to 130 days was observed. By comparing these studies, it appears that also the time to recurrence in the placebo groups of SVA studies were longer, ranging from 17 to 50 days. Differences in the qualifying episode of atrial fibrillation, percentage of patients who underwent electrical cardioversion, number of patients exposed to azimilide 125 mg, and duration of arrhythmia may partially explain these different results.16–18 Moreover, symptomatic atrial fibrillation was reported in 62% of SAFE-T patients, whereas in the Canadian Trial of Atrial Fibrillation study and in A-COMET-II studies, this was an inclusion criterion. Timing of scheduled control visits, indications for transtelephonic transmission of electrocardiogram, and duration of episodes classified as recurrence were also different among the three studies. For example, only episodes lasting longer than 10 min were considered to be clinically significant in the Canadian Trial of Atrial Fibrillation study, whereas two electrocardiographic documentations <24 h apart were required for the SAFE-T study.8,9

Our study provides information on drug-induced cardioversion and electrical cardioversion rate. The incidence of spontaneous cardioversion during the loading phase was small and not substantially different from placebo, thus confirming the limited efficacy of azimilide in restoring sinus rhythm. In addition, these data unfortunately indicate that azimilide and sotalol did not enhance electrical cardioversion rate because success of the procedure was similar in all three groups.

Safety and efficacy of azimilide
Azimilide is an orally active class III drug that blocks rapid (Ikr) and slow (Iks) components of the delayed rectifier cardiac potassium channels.15,21,22 In animals and humans, this blockade results in dose-dependent increase of the QT interval, as well as prolongation of atrial and ventricular refractory periods.15 In previous clinical studies, azimilide, at a dosage of 100–125 mg/day, has been shown to be safe and effective in increasing the time to first recurrence of symptomatic atrial fibrillation or flutter.16–18 Incidence of torsade de pointes or other ventricular arrhythmia was low (<1%) and consistent with other class III anti-arrhythmic agent. Severe neutropenia was reported in 0.20% of patients. Recently, two studies carried out in post-myocardial infarction patients with depressed left ventricular function and in patients with implantable cardioverter defibrillator have demonstrated, respectively, the safety and efficacy of azimilide also in these subgroups of patients.23,24

The incidence of torsade de pointes was unexpectedly high (2.4%) in the azimilide group, whereas no cases were reported in placebo and sotalol groups. In all but one case, the arrhythmia occurred in the first 72 h after completion of the loading period. Patients were older, female gender was prevalent, and hypokalaemia was documented in two cases. No specific study population characteristics or modality of electrocardiographic monitoring could explain this pro-arrhythmic rate in comparison with previous SVA studies. Moreover, the occurrence of torsade de pointes just after the in-hospital loading period opens additional questions in relation to the duration of electrocardiographic monitoring during the loading period of class III drugs and, in particular, azimilide.

Sotalol vs. azimilide
Sotalol was administered at a dose of 160 b.i.d. and was well tolerated and effective. In spite of the fact that the dosage was greater than that commonly used in clinical practice, the percentage of patients withdrawing due to marked bradycardia was <7%. Of relevant clinical interest, was the finding that no cases of torsade de pointes were observed during either the loading phase or the follow-up period, thus confirming the efficacy and safety of sotalol in patients with symptomatic atrial fibrillation.8,9,25–27

When considering time-to-event curves, subacute (within 2 weeks) recurrences were similar in azimilide and placebo groups, whereas a smaller number of events occurred in patients treated with sotalol. These findings are of clinical interest28 because they provide additional support to the concept that adrenergic mechanism may play a major pro-arrhythmic role in the first weeks after electrical cardioversion29,30 and that drugs that combine anti-adrenergic properties in addition to the prolongation of action potential may exert a greater anti-arrhythmic effect. The possibility of increasing azimilide efficacy by concomitant beta-blockers therapy is a hypothesis that, in our opinion, deserves to be tested.

Finally, at variance with previous reports,8,9 we were unable to observe a significant reduction in symptom load during atrial fibrillation recurrences in patients on sotalol in comparison with azimilide and placebo groups in spite of a significant reduction of mean ventricular response.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Appendix
 Acknowledgements
 References
 
In the first placebo and active control study, we were able to demonstrate that azimilide is slightly superior to placebo but inferior to sotalol in prolonging time to the first arrhythmia recurrence in patients with persistent atrial fibrillation. The modest increase in the median time to recurrence in comparison with placebo and the incidence of torsade de pointes and marked QTc prolongation limits the utilization of this drug in patients with persistent atrial fibrillation.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
Acknowledgements
 References
 
A-COMET-II trial
European Scientific Advisory Board: Martin Borggrefe, MD, Stuart Cobbe, MD, Philippe Coumel, MD, Jeronimo Farre, MD, Charles Kirchhof, M., Federico Lombardi, MD, Berndt L. Lüderitz, MD, Mikhail Ruda, MD, Witold Ruzyllo, MD.

Data Safety Monitoring Board: Sam Kaddoura, MD, Eugene Passamani, MD, William G. Stevenson, MD, Juan Tamargo, MD, Nanette Kass Wenger, MD, William Wilkinson, MD, Janet Wittes, MD, George Wyse, MD.

Event Committee: Mark D. Carlson, MD, Stuart Cobbe, MD, Anne Curtis, MD, Mark Hamer, MD, Federico Lombardi, MD, Betty McCarthy, RN, Katherine T. Murray, MD, Richard L. Page, MD.

Participating centres and investigators
Poland: Achremczyk, Piotr, Kosior, Jaroslaw, Radomski Szpital Specjlalistyczny Oddzial Kardiologii Radom; Adamus Jerzy, Pawluczuk Piotr, CSK WAM I Klinika Kardiologii, ul. Szaserow 128 Warszawa; Banasiak Waldemar, Artur Fuglewicz, Klinika Kardiologii, IV Wojskowy Szpital Kliniczny z Poliklinika ul. Wroclaw; Gorny Jerzy, Tomasz Godlewski, Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny, Olsztyn; Hoffmann Andryej, Piotr Sobanski, Oddzia¿ Kardiologii Wojewódzki Szpital Zespolony, Bydgoszcz; Janion Marianna, Pawel Krzyzak, Wojewódzki Szpital Zespolony Oddzial Kardiologii, Kielce; Jaworska Krystyna, Monika Jezewska, Wojewódzki Szpital Zespolony, Oddzia¿ Kardiologii, Torun; Kleinrok Andrzej, Jaroslaw Rodzik, Samodzielny Publiczny Szpital Wojewódzki, im. Papie¿a Jana Pawla II, Zamo; Krzciuk Malgorzata, Maciej Maliszewski, Szpital Miejski, Ostrowiec; Kurowski Michal, Iwona Nikodemska, Samodzielny Publiczny Szpital Wojewódzki, Oddzia¿ Kardiologii, Szczecin; Kuzniar Jerzy, Piotr Wanczura, Szpital Wojewodzki nr 2, Oddzial Kardiologii, Rzeszow; Malinski Andrzej, Maciej Rynkiewicz, Wojewódzki Szpital Zespolony, Oddzia¿ Kardiologii, Plock; Musial Wlodzimierz, Robert Sawicki, Samodzielny Publiczny Szpital Kliniczny Klinika Kardiologii, Bialystok; Piwowarska Wieslawa, Artur Pietrucha, Instytut Kardiologii CMUJ, Klinika Choroby Wiencowej, Krakow; Pluta Wladyslaw, Marek Jedryszczak, Oddzia¿ Kardiologii, Wojewodzkie Centrum Medyczne, Opole; Pulkowski Grzegorz, Karol Suppan, Szpital Wojewodzki im.dra Biziela Klinika Gastroenterologii i Chorob Wewnetrznych, Bydgoszcz; Ruzyllo Witold, Lidia Stefania Chojnowska, Instytut Kardiologii, Warszawa; Rynkiewicz Andrzej, Rafal Dworakowski, Instytut Kardiologii AM, I Klinika Chorob Serca, Gdansk; Trusz-Gluza Maria, Iwona Wozniak-Skowerska, Górno¿l¿skie Centrum Medyczne, I Klinika Kardiologii, Katowice; Wojciechowski Dariusz, Adam Brzozowski, Szpital im. Dr. Anny Gosty¿skiej Oddzial Kardiologii, Warszawa.

France: Aliot Etienne, Magnin-Poull, Brembilla Perrot, Hopitaux de Brabois, Vandoeuvre Les Nancy; Da Costa, Kihel, Faure, Chru St Etienne/Hopital Nord, St Priest en Jarez, Saint Etienne; Defaye, Delphine Chassery, CHRU, Grenoble; Flammang, Daniel, Bernadette Cazenave; Centre Hospitalier General, Hopital de Girac, St Michel; Le Marec Herve, Jean-Pierre Gueffet, Ms Hauraix, Ms Guillard; Hopital Guillaume et Rene Laennec, Cardiology, Nantes; Leenhardt Antoine, Extramania, Simoneau, Cauchemez, Thomas, Hopital Lariboisiere, Paris.

Russia: Arutyunov Gregory, Alexander V. Rozanov, Russian State Medical University, Moscow; Bessonova Nina, Natalia V. Kudryashova, St Petersburg Hospital, Miocardial Infarction Department, St Petersburg; Boyarkin Mikhail, Raisa A. Moiseeva, Alexandrovskiy Hospital, St Petersburg; Glezer Maria, Valeria E. Bazhanova, Moscow Sechenov Medical Academy, Laboratory of Functional Diagnostics, Moscow; Goloshchekin Boris, Boris G. Zakhvataev, St Petersburg Hospital, St Petersburg; Gratsiansky Nikolay, Igor S. Yavelov, Research Institute of Physical and Chemical Medicine, Department of Emergency Cardiology, Moscow; Kostenko Victor, Farid Yu. Tumarov, State Research Institute of Emergency Medicine, St Petersburg; Mazur Nikolay, Alexander I. Pshenitsin, State Medical Academy of Postgraduate Education, Cardiology Department, Moscow; Moisseev Valentin, Elena P. Pavlikova, Pharmacology Department, Moscow Clinical Hospital, Moscow State Institute of Peace and Friendship, Moscow; Ruda Mikhail, George V. Khodeev, Russian Cardiology Research Centre, Department of Emergency Cardiology, Moscow; Shcherbak Alexey, Petr V. Gurinov, St Petersburg Hospital, Cardiology, St Petersburg; Shlyakhto Evgeniy, Olga O. Bolshakova, St Petersburg Medical University, St Petersburg; Sidorenko Boris, Olga V. Lebedeva, Scientific and Education Department of the Presidential Medical Centre, Moscow; Sorokin Lev, Irina N. Nazarova, St Elizabeth Hospital, Myocardial Infarction Department, St Petersburg; Syrkin Abram, Mikhail V. Sheyanov, Moscow Sechenov Medical Academy, Cardiology Department, Moscow; Vertkin Arkadiy, Oleg B. Talibov, Moscow State Medico-stomatological University, Moscow; Vishnevskiy Alexander, Mikhail M. Terskikh, Pokrovskiy Hospital, Department of Cardiology No. 3, St Petersburg; Zadionchenko Vladimir, Grant G. Shekhyan, Moscow City Hospital 11, Pulmonary Department, Moscow; Zateyshchikov Dimitriy, Natalia D. Selezneva, Scientific and Education Department of the Presidential Medical Centre, Moscow; Zrazhevsky Konstantin, Oleg V. Yakovlev, St Petersburg Hospital, Myocardial Infarction Department, St Petersburg.

Spain: Benezet Penaranda Juan, Ortega Carnicer, Complejo Hospitalario de Ciudad Real, Ciudad Real; Bertomeu Vicente, José Angel Rodríguez Ortega, Hospital Universitario San Juan, Servicio de Cardiologia, Alicante; Cosio Garcia, Pedro Talavera, Cardiology Service, Hospital Universitario de Getafe, Getafe; Ferrer Antonio, Concepcion Belló Mora, Hospital de Txagorritxu, Unidad Coronaria, Madrid; Merino Jose, Rafael Peinado Peinado, Cardiology Service, Hospital la Paz, Madrid; Moya Antonio, Enrique Rodriguez-Font, Cardiology Service, Hospital Valle de Hebron, Barcelona; Ormaetxe Jimenez M, Maria Fe Arkotxa-Torres, Cardiology Service, Hospital Civil de Basurto, Basurto-Bilbao; Sabate Xavier, Joan Nicolás, Hospital Princeps D'Espanya, Barcelona; Villacastin Julian, Nicasio Perez-Castellano, Hospital Clinico Universitario San Carlos, Servicio de Cardiologia, Madrid.

Hungary: Borbola Jozsef, Ványi József, Vegh Gizella, Gottsegen Gyorgy, National Kardiology Institution, Budapest; Cziraki Attila, Zeno Ajtay, Faludi Réka, Józsa Emese, Cardiology Clinic, University of Pecs, Pecs; Farsang Csaba, Kapocsi Judit, Kolossvary Endre, Szabo Tamas, Kerkovits Lorant, Járai, Zoltán, Finta Ervin P, Farkas Katalin, Department of Internal Medicine I, Szent Imre Hospital, Budapest; Kaló Emil, Görögh Péter, Mikler Csaba, Miskolc County Hospital, Miskolc; Karlócai Kristóf, Kertész Tamás, National Institute of Pulmonology, Budapest; Katona Andras, Márk László, Erdei Ferenc, Nagy, Erzsébet, Pandy Kalman County Hospital, Gyula; Kovacs Aranka, Csaba Varga, Kovacs Ferenc, Julianna Fodor, Sandor Szigeti, Tarajossy Zsuzsanna, Department of Internal Medicine, County Hospital, Szentes; Nagy Lajos, Nagy Katalin, Farkas Attila, Salamon Andrea, Sámóczi Marianna, Arvai Ferenc, Kovács Imre, Gasztonyi Ferenc, Department of Internal Medicine III, Markusovszky Hospital, Szombathely; Oze Bela, Tóth Jeno Péter, Kássa László, Department of Internal Medicine II, Toldi Ferenc Hospital, Cegled; Poór Ferenc, Takács János, Mosonmagyaróvár City Hospital, Mosonmagyaróvár; Sándori Klára, Lukács Margit, Állami Szanatórium, Sopron; Sereg Matyas, Tibor Turi, Csikós Csaba, Pavelka Róbert, Szent Gyorgy Hospital, Szekesfehervar; Timar Sandor, Istvan Koncz, Karoly Toth, Nagy András, Department of Internal Medicine I, County Hospital, Kecskemet; Tóth Csaba, Fenyvesi Éva, Gál Éva, Markhot F, County Hospital, Eger; Veress Gabor, Strommer Mátyás, Faluközy József, State Hospital, Baltonfured.

Germany: Borggrefe Martin, Dariush Haghi, Medizinische Klinik, Innere Medizin C, Mannheim; Brachmann Johannes, Schibgilla Koegler, Klinikum Coburg, II Med. Klinik, Coburg; Eckardt Lars, Sascha Rolf, Medizinische Klinik und Poliklinik, Innere Medizin C, Kardiologie ung Angiologie, Munster; Gulker Hartmut, Lapp, Horlitz, Scheffold, Klinikum Wuppertal, Herzzentrum Med. Klinik 3/Kardiologie u. Andologie, Wuppertal; Kuhlkamp Vincent, Eigenberger Rueb, Medizinische Universitat Tübingen, Med Klinik III, Abt. III fur Kardiologie, Tuebingen; Meinertz Thomas, Andreas Schuchert, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Innere Medizin, Abteilung Kardiologie, Hamburg; Mitrovic Y, Weber, Kuniss, Pekovic, Kerckhhoff-Klinik, Abteilung Klinische Pharmakologie, Bad Nauheim; Neuzne, Johannes, Zeymer, Corinna Lenz; Klinikum Kassel, Medizinische Klinik II, Kassel; Oeff, Michoel, Theiss, Goesswald, Städtisches Klinkum Brandenburg, Med Klinik I/Kardiologie, Pulmologie und Angiologie, Brandenburg; Pfeiffer Dietrich, Neugebauer, Universitat Leipzig, Medizinische Klinik und Poliklinik 1, Abteilung Fur Kardiologie and Angiologie, Leipzig; Schirdewan, Mayerfeld, Christow, Schütt, Selbig, Franz Volhard Klinik Abteilung fur Elektrophysiologie, Berlin; Schoels Wolfgang, Waretka, Voss, Becker, Universitatsklinikum Heidelberg, Ludolf-Krehl-Klinik, Heidelberg; Seidl Karl, Vater, Brandt, Klinikum der Stadt Ludwigshafen Abteilung fur Elektrophysiologie, der Kardiologie/Herzzentrum, Ludwigshafen; Voeller Heinz, Kamke, Klinik Am See, REHA-Zentrum für Herz und Kreislauf, Rudesdorf; Volkmann Andreas, Erzgebirgskrankenhaus Klinik für Innere Medizin, Annaberg.

Italy: Botto Giovanni Luca, Sagone Antonio, Servizio di Cardiolgia, Azienda Ospedaliera S. Anna, Como; Brunelli Claudio, Rossettin Pierfranco, Dipartimento di Medicina Interna, Università di Genova, Genova; Capucci Alessandro, Villani Giovanni, Ospedale Civile di Piacenza, Divisione di Cardiologia, Piacenza; Chiariello Massimo, Santomauro Maurizio, Divisione di Cardiologia, Università di Napoli ‘Federico II’, Napoli; Gaita Fiorenzo, Richiardi Elena, Divisione di Cardiologia, Ospedale Umberto I di Torino, Torino; Lombardi Federico, Belletti Sebastiano, U.O. di Cardiologia, Ospedale S. Paolo, Milano; Raviele Antonio, Bonso Aldo, Divisione di Cardiologia, Ospedale Civile Umberto I, Mestre; Rizzon Paolo, Pitzalis Maria Vittoria, Divisione Malattie Cardiovascolari, Università di Bari—Policlinico, Bari.

Netherlands: Bouwels Lucas, David Hertzberger, Astrid Schut, Department Cardiology, Canisius Wilhelmina Hospital, Nijmegen; Holwerda Karl, Bernard Szabo, Riny van de Loo, St Elisabeth Ziekenhuis, Afdeling Cardiologie, Tilburg, Kan G, Caroline Kalkmas, Kennemer Gasthuis, Locatie Elizabeth Gasthuis, Haarlem; Meijer Andreas, K. Krasznai Bracke, Michel Angelolaan 2, Eindhoven; Ramdat Misier Andreas, W.P. Beukema, Karin Nijenbrinks, De Weezenlanden, Zwolle; Smeets JL, Moniek Baggen, Academisch Ziekenhuis Maastricht Afdeling Cardiologie, Maastricht.

Belgium: Stoupel Eric, Karine Retailleau, Hopital Universitaire Erasme, Brussels.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
References
 
We thank all patients who participated in A-COMET-II trial, as well as the study investigators (see appendix), members of the Data Safety Monitoring Board, European Scientific Advisory Board and Event Committee, nurses, and coordinators whose work made this trial possible. This study was supported by Procter & Gamble, Cincinnati, OH, USA.

Conflict of interest: All authors have received honoraria from Procter & Gamble as members of European Scientific Advisory Board.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 

  1. Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. (2001) Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 37:371–378.[Abstract/Free Full Text]
  2. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC, Alonso-Garcia A, Blomstrom-Lundqvist C, De Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A. for the ACC/AHA/ESC board. (2001) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol 38:1231–1266.[Free Full Text]
  3. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. (2004) Lifetime risk for development of atrial fibrillation. The Framingham heart study. Circulation 110:1042–1046.[Abstract/Free Full Text]
  4. Hohnloser S and Kuck KH. (2000) Rhythm or rate control in atrial fibrillation. Pharmacological Intervention in Atrial Fibrillation (PIAF). Lancet 356:1789–1794.[CrossRef][ISI][Medline]
  5. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ. (2002) Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group (RACE). A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 347:1834–1840.[Abstract/Free Full Text]
  6. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U;. The Strategies of Treatment of Atrial Fibrillation (STAF) Investigators. (2003) Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation. J Am Coll Cardiol 41:1690–1696.[Abstract/Free Full Text]
  7. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosemberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. for the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 347:1825–1833.[Abstract/Free Full Text]
  8. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW, Ezekowitz MD. Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. (2005) Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 352:1861–1872.[Abstract/Free Full Text]
  9. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagne P, Nattel S, Thibault B. for the Canadian Trial of Atrial Fibrillation Investigators. (2000) Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 342:913–920.[Abstract/Free Full Text]
  10. Zehender M, Hohnloser S, Müller B, Meinertz T, Just H. (1992) Effects of amiodarone versus quinidine and verapamil in patients with chronic atrial fibrillation: results of a comparative study and a 2-year follow-up. J Am Coll Cardiol 19:1054–1059.[Abstract]
  11. Tieleman RG, Gosselink AT, Crijns HJ, van Gelder IC, van den Berg MP, de Kam PJ, van Gilst WH, Lie KI. (1997) Efficacy, safety, and determinants of conversion of atrial fibrillation and flutter with oral amiodarone. Am J Cardiol 79:53–57.[CrossRef][ISI][Medline]
  12. Kochiadakis GE, Igoumenidis NE, Marketou ME, Kaleboubas MD, Simantirakis EC, Vardas PE. (2000) Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. Heart 84:251–257.[Abstract/Free Full Text]
  13. Torp Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbae J, Marchant B, Camm AJ. (1999) Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 341:857–865.[Abstract/Free Full Text]
  14. Singh S, Zoble RG, Yellen L, Brodsky MA, Feld GK, Berk M, Billing CB Jr. (2000) Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 102:2385–2390.[Abstract/Free Full Text]
  15. Salata JJ and Brooks RR. (1997) Pharmacology of azimilide dihydrochloride (NE-10064), a class III antiarrhythmic agent. Cardiovasc Drug Rev 15:137–156.[CrossRef][ISI]
  16. Connolly SJ, Schnell DJ, Page RL, Wilkinson WE, Marcello SR, Pritchett EL. (2001) Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation. Am J Cardiol 88:974–979.[CrossRef][ISI][Medline]
  17. Pritchett EL, Page RL, Connolly SJ, Marcello SR, Schnell DJ, Wilkinson WE. (2000) Antiarrhythmic effects of azimilide in atrial fibrillation—efficacy and dose-response. J Am Coll Cardiol 36:794–802.[Abstract/Free Full Text]
  18. Page RL, Tilsch TW, Connolly SJ, Schnell DJ, Marcello SR, Wilkinson WE, Pritchett EL. Azimilide Supraventricular Arrhythmia Program (ASAP) Investigators. (2003) Asymptomatic or ‘silent’ atrial fibrillation: frequency in untreated patients and patients receiving azimilide. Circulation 107:1141–1145.[Abstract/Free Full Text]
  19. Schoenfeld DA. (1983) Sample size formula for the proportional-hazards regression model. Biometrics 39:449–503.
  20. Bauer P. (1991) Multiple testing in clinical trials. Stat Med 10:871–890.[ISI][Medline]
  21. Davies MP, Freeman LC, Kass RS. (1996) Dual action of the novel class III antiarrhythmic drug (NE-10064) on delayed potassium channel currents in the guinea pig ventricular and sinoatrial node cells. J Pharmacol Exp Ther 276:1149–1154.[Abstract/Free Full Text]
  22. Dorian P, Dunnmon P, Elstun L, Newman D. (2002) The effect of isoproterenol on the class II effect of azimilide in humans. J Cardiovasc Pharmacol Ther 7:211–217.[Abstract/Free Full Text]
  23. Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, Karam R, Sonnenblick EH, Brum JM;. AzimiLide post Infarct surVival Evaluation (ALIVE) Investigators. (2004) Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation 109:990–996.[Abstract/Free Full Text]
  24. Singer I, Al-Khalidi H, Niazi I, Tchou P, Simmons T, Henthorn R, Holroyde M, Brum J. (2004) Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol 43:39–42.[Abstract/Free Full Text]
  25. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. (1990) Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 82:1932–1939.[Abstract/Free Full Text]
  26. Benditt DG, Williams JH, Jin J, Deering TF, Zucker R, Browne K, Chang-Sing P, Singh BN. for the D,L-Sotalol Atrial Fibrillation/Flutter Study Group. (1999) Maintenance of sinus rhythm with oral D,L-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. Am J Cardiol 84:270–277.[CrossRef][ISI][Medline]
  27. Singh S, Saini RK, DiMarco JP, Kluger J, Gold R, Chen YW. (1991) Efficacy and safety of sotalol in digitalized patients with chronic atrial fibrillation. The Sotalol Study Group. Am J Cardiol 68:1227–1230.[CrossRef][ISI][Medline]
  28. Tieleman RG, Van Gelder IC, Crijns HJGM, De Kam PJ, Van Den Berg MP, Haaksma J, Van Der Woude HJ, Allessie MA. (1998) Early recurrence of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol 31:167–173.[Abstract/Free Full Text]
  29. Lombardi F, Colombo A, Basilico B, Ravaglia R, Garbin M, Vergani D, Battezzati PM, Fiorentini C. (2001) Heart rate variability and early recurrence of atrial fibrillation after electrical cardioversion. J Am Coll Cardiol 37:157–162.[Abstract/Free Full Text]
  30. Kühlkamp V, Schirdewan A, Stangl K, Homberg M, Ploch M, Beck OA. (2000) Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 36:139–146.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 EuropaceHome page
I. Savelieva and J. Camm
Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches
Europace, June 1, 2008; 10(6): 647 - 665.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
27/18/2224    most recent
ehl209v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lombardi, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lombardi, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?