Suppression of paroxysmal atrial tachyarrhythmias — results of the SOPAT trial

Monica Pattena,*, Renke Maasa, Peter Bauerb, Berndt Lüderitzc, Frank Sonntagd, Miroslaw Dluzniewskie, Robert Hatalaf, Grzegorz Opolskig, Hans-Walter Müllerh and Thomas Meinertza for the SOPAT Investigators1

a Herzzentrum, Kardiologie, Universitäts-Klinikum Hamburg Eppendorf, Germany
b Institut für Medizinische Statistik, Universität Wien, Austria
c Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Germany
d Henstedt-Ulzburg, Germany
e The Medical University of Warsaw, Brodnowski Hospital, Poland
f Slovak Cardiovascular Institute, Bratislava, Slovak Republic
g Central Hospital of Warsaw, Poland
h Abbott GmbH, Ludwigshafen, Germany

Received February 19, 2004; revised May 14, 2004; accepted June 3, 2004 * Corresponding author (E-mail: patten{at}uke.uni-hamburg.de).

See page 1371 for the editorial comment on this article (doi:10.1016/j.ehj.2004.06.027)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
AIM: The indication to treat paroxysmal atrial fibrillation (PAF) is controversial. The Suppression of Paroxysmal Atrial Tachyarrhythmias (SOPAT) trial was designed to answer the following questions: (1) What is the average rate of spontaneous events of symptomatic PAF with and without anti-arrhythmic medication? (2) what is the prevalence of severe side-effects? and (3) is the fixed combination of Quinidine+Verapamil inferior to the efficacy of sotalol or not?

METHODS AND RESULTS: Within 60 months 172 centres in Germany, Poland, and The Slovak Republic prospectively enrolled 1033 patients (mean age 60 years, 62% male) with documented frequent episodes of symptomatic PAF. Patients were randomised to either Quinidine+Verapamil 480/240 mg/d (high dose; 263 patients), Quinidine+Verapamil 320/160 mg/d (low dose; 255 patients), Sotalol 320 mg/d (264 patients) or placebo (251 patients), of which 1012 patients entered the intention-to-treat analysis. The primary endpoint was the time to first recurrence of symptomatic PAF or premature discontinuation. Secondary outcome parameters were the total number of symptomatic episodes and tolerability of the tested drugs. Patients were followed for a period of up to 12 months by daily and symptom-triggered trans-telephonic ECG-monitoring (Tele-ECG).

The mean time under treatment was 233±152 days. Regarding the primary endpoint, all active treatments were superior to placebo and not different from each other. A total of 756 patients reached the primary endpoint within 105.7±8.7 d (mean±SEM) in the placebo group, vs. Quinidine+Verapamil (high dose) (150.4±10 d, p=0.0061), vs. Quinidine+Verapamil (low dose) (148.9±10.6 d, p=0.0006), vs. Sotalol (145.6±93 d, p=0.0007). All three treatments were also effective in the reduction of AF burden (days with symptomatic AF [%] mean±SD, p vs. placebo): Quinidine+Verapamil (high dose) (3.4±12, p=0.0001), Quinidine+Verapamil (low dose) (4.5±12.3, p=0.008) and Sotalol (2.9±6.5, p=0.026) compared to placebo (6.1±13.5). A total of four deaths, 13 syncopes, and one ventricular tachycardia (VT) occurred during the active study period, of which one death and one VT were related to Quinidine/Verapamil.

CONCLUSION: Taken together, anti-arrhythmic therapy with the fixed combination of Quinidine+Verapamil is as effective as Sotalol in the reduction of the recurrence rate of symptomatic PAF with a low but definite risk of severe side-effects.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
According to the ESC and AHA guidelines beta blockers, class IC agents and Sotalol are recommended as first line anti-arrhythmic agents for the treatment of (symptomatic) paroxysmal atrial fibrillation (PAF). However, the beneficial effects of these drugs have to be balanced against the risk of adverse (pro-arrhythmic) events. Especially, in patients with structural heart disease it was shown that the mortality can increase under anti-arrhythmic therapy.1

In clinical routine the combination of Quinidine+Verapamil was a commonly used therapy for atrial fibrillation in Germany2,3 until several reports suggested a high rate of pro-arrhythmic events under therapy with high doses of Quinidine (summarised in 4,5). However, the combination with Verapamil was shown to lower the risk of Quinidine induced side-effects.6,7 A very recent study demonstrated that addition of verapamil to anti-arrhythmic drugs of class IC or III significantly reduces the recurrence rate of AF.8 Until now, no prospective and randomised clinical trial has been undertaken to establish the efficacy and safety of Quinidine+Verapamil for the treatment of PAF.

Based on these aspects, the Suppression of Paroxysmal Atrial Tachycardias (SOPAT) trial was initiated to assess: (1) the average rate of spontaneous events of symptomatic PAF during long-term administration of Quinidine+Verapamil in two different doses in comparison to Sotalol and to placebo and (2) the long-term safety based on the occurrence of severe side-effects under these drugs. For precise ECG-documentation during symptomatic events and for early detection of silent arrhythmias or pro-arrhythmic effects, a portable trans-telephonic event recorder monitoring system (Tele-ECG) was used.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
Patients
Patients between 18 and 80 years of age with documented symptomatic PAF one month prior to randomisation were included. Exclusion criteria were: cardiogenic shock, known atrial thrombi, stroke, myocardial infarction or cardiac surgery within the past three months, unstable angina, valvular defects requiring surgery, acute myocarditis or endocarditis, severe heart failure (NYHA IV), implanted pacemakers or cardioverters/defibrillators, second and third degree of atrio-ventricular block or sinoatrial block in recent history, documented sick sinus syndrome, pre-excitation syndrome, QTc prolongation >0.44 in the absence of anti-arrhythmic medication, idiopathic QT syndrome, complete frequency-independent bundle branch block, symptomatic severe bradycardia or hypotension, late stage of peripheral circulatory disorder, myasthenia gravis, thrombopenia, obstructive airway disease, serum K+ levels repeatedly <4.4 mmol, liver or kidney dysfunction or endocrine disorders, such as type I diabetes or hyperthyroidism. All anti-arrhythmic and other drugs known to cause QT prolongation were prohibited as concomitant medication, with the exception that treatment of a sustained episode of atrial fibrillation with Verapamil i.v., under hospital conditions with ECG monitoring was allowed.

Study procedures
Patients with a known clinical history of symptomatic PAF and documentation of a symptomatic episode by Holter monitoring, resting ECG or Tele-ECG within the last 4 weeks were selected for enrolment. Any existing anti-arrhythmic drug therapy had to be discontinued before randomisation for at least five elimination-half-lives of the respective drug. Immediately before the first intake of study medication, Holter monitoring was performed to rule out persistent atrial fibrillation and echocardiography was used to rule out an ejection fraction <30% (Poland: <40%). The active drugs were the fixed combination of Quinidine+Verapamil (160/80 mg Quinidine+Verapamil on day one, 160/80 mg Quinidine+Verapamil bid on days 2 and 3, and 160/80 mg Quinidine+Verapamil tid thereafter), Quinidine+Verapamil in a lower concentration (160/80 mg Quinidine+Verapamil on day one, and 160/80 mg Quinidine+Verapamil bid thereafter) and Sotalol (80 mg on day one, 80 mg tid on days 2 and 3, and 160 mg bid thereafter). A fourth group received placebo in double-dummy technique. All patients were recruited and followed up on a outpatient basis. The first dose was taken at the study site under medical supervision to rule out any idiosyncratic responses to the study drug. Patients were followed up in the recurrence prevention phase for up to one year. Follow-up visits during the trial period were after 1 week, 1 month, 3, 6, 9, and 12 months and vital signs (blood pressure, heart rate), physical examination, laboratory tests (K+, Mg2+, TSH, fT4), symptoms and ECG at rest were obtained. Holter monitoring was performed before enrolment and at the time of close out (and in a 3 months interval in Poland and the Slovak Republic). Those patients who responded well to the study medication after one year were allowed to continue blinded study drug intake until the entire trial was completed with 3-months intervals of follow-up visits. Daily and symptom-triggered trans-telephonic ECG transmissions were obtained from each patient during the total follow-up period.

Tele-ECG
Each randomised patient was supplied with a Tele-ECG recorder (RythmCardTM, Instromedix, USA) which could be operated by the patients themselves.9,10 Patients were asked to record and transmit at least one ECG per day and as often as symptoms. A 1 min single lead electrocardiogram was recorded and subsequently transmitted by telephone as a frequency modulated audio sequence. A computer based automated voice control system assisted the patient during trans-telephonic ECG-transmission using a toll-free connection to the Tele-ECG analysis centre in Hamburg. Each time patients submitted an ECG they were asked to specify their symptoms at the time of ECG recording. These individual complaints were then categorised as palpitations, chest pain, tachycardia, dyspnoea, vertigo, sweating, polyuria, unspecific symptoms and no symptom. The transmitted audio sequence from the Tele-ECG recorder included the identification number of the device, date and time of recording, the battery status and the ECG. All data were stored digitally and subsequently analysed by specially trained staff. For ECGs with sinus rhythm, RR, PR, QRS and QT intervals and in case of atrial fibrillation the minimal, maximal and mean RR intervals (of 10 RR intervals) were measured. All ECG measurements were taken twice to minimise measurement errors. In addition, the signal quality was analysed by measuring the mean noise and the peak to peak amplitude of the signal.9,10 All data obtained from Tele-ECG recordings and information about patients' symptoms were stored in a central data base. The study sites responsible were informed by fax, in case of any clinically relevant abnormalities detected in the Tele-ECGs, to call patients in for further clinical evaluation.

Pre-defined outcome variables
The primary outcome variable was a combination of efficacy and tolerability parameters and was defined as the time to first recurrence of symptomatic PAF or symptomatic paroxysmal atrial fibrillation/flutter after randomisation or time to discontinuation (of any kind, regardless of cause) during a 12 months treatment phase. However, patients were encouraged to stay in the study for one year.

Secondary endpoints were defined as:

(i) the incidence of symptomatic PAF or of symptomatic paroxysmal atrial fibrillation/flutter (=AF burden);
(ii) the tolerability of Quinidine+Verapamil at two different dose levels versus Sotalol and placebo. Tolerability was assessed on the basis of physical examination, resting ECG, Holter monitoring, laboratory tests and documented adverse events.

Ethics
All procedures were followed in accordance with the ethical standards of the responsible committees on human experimentation and with the Helsinki Declaration.

Evaluation of serious adverse events (SAEs)
All SAEs reported by the study sites were reviewed by the Critical Event Committee (CEC) on the basis of detailed but blinded patient records. The judgements were reported to the Data and Safety Monitoring Committee (DSMC) for monitoring the consistence with the study protocol and all safety aspects.

Statistical analysis
This study was designed as a prospective, double-blind, randomised, multi-centre, parallel group comparison with four treatment groups (Quinidine+Verapamil 160/80 mg tid and Quinidine+Verapamil 160/80 mg bid versus Sotalol 160 mg bid and versus placebo). All variables presented are stratified by treatment group using appropriate descriptive summary tables. Time-to-event data are presented graphically by Kaplan—Meier estimation of the survival curves. For confirmatory analysis, five hypotheses were tested against the respective alternatives as ordered hypotheses to maintain a multiple 5% significance level.11 The superiority of Quinidine+Verapamil (high dose), Quinidine+Verapamil (low dose) and Sotalol over placebo was tested in a two-sided log rank test (α=0.05). Non-inferiority of Quinidine+Verapamil (high dose) or Quinidine+Verapamil (low dose) to Sotalol was tested by comparison of the one year failure rates applying a non-inferiority margin of 10% (one sided, α=0.05). The choice of a 10% non-inferiority margin was based on the expectation that the difference in the one year failure rate between the active treatments and placebo would be noticeably larger than 10%. Means, medians, quartiles, and confidence-intervals (CI 95%) of time until event data were calculated by Proc lifetest (SAS).12

The sample size estimation was based on individual treatment comparisons. For a sample size of 250 patients per group an increase in the median of about 30% as compared to placebo can be detected in the two-sided log rank test (α=0.05) with a power of around 90%. These numbers are relatively stable under varying assumptions of the median in the placebo group.

The distributions of days with symptomatic AF were compared between treatments by Wilcoxon rank sum tests.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
Population
In total, 1703 patients were screened for the trial of which 1033 patients were randomised to the four treatment groups in 141 German (655 patients), 21 Polish (274 patients), and 10 Slovak (104 patients) study centres. As a consequence of incomplete data 1012 (98%) patients were suitable for the ITT and 903 (87%) for a per protocol-analysis. Demographic and baseline characteristics are summarised in Table 1, showing no relevant differences between treatment groups. Moreover, all treatment groups were comparable with regard to compliance of Tele-ECG recording and drug intake.


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Table 1. Demographic and baseline characteristics
 
Discontinuation of the study
Of 1012 patients 547 (54%) reached the 12 months follow-up visit while 465 patients (46%) terminated the study prematurely (Fig. 1). The mean time to discontinuation of therapy was longer in the active treatment groups than under placebo (mean days±SEM: Quinidine+Verapamil (high dose): 259±10 vs. Quinidine+Verapamil (low dose): 223±9 vs. Sotalol: 254±9 vs. Placebo: 197±10; p<0.0001). While treated with placebo 59% of the patients terminated the study before 12 months vs. 43% of patients under active treatment. The reasons for premature termination were equally distributed among treatment groups with the exception that under placebo 4.4% complained about ineffective treatment (vs. 2% in the active treatment groups) and 6.4% developed persistent AF (vs. 1.9% under active treatment).



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Fig. 1 Profile of the SOPAT trial. Total number of patients given for all steps throughout the 12 months follow-up.

 
Tele-ECG analysis and incidence of endpoint oriented symptoms
A total of 188,634 Tele-ECGs were recorded during the one year follow-up, of which 179,598 (95%) ECGs were valid for analysis. Sinus rhythm was documented in 165,333 (87%), SVT in 855 (0.4%), and AF in 13,410 (7%) ECGs. Of note, only 6165 of AF-ECGs (46%) were associated with specific symptoms as indicated in Fig. 2. Palpitations were most frequently recorded followed by tachycardia, dyspnoea, chest pain, vertigo, sweating, and polyuria, with no significant differences among treatment groups. Recording of multiple symptoms for one ECG was permitted.



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Fig. 2 Symptoms during AF. Distribution of patients symptoms during AF in percent of all symptoms recorded during AF. Recording of multiple symptoms for one ECG was permitted.

 
Efficacy
All data given are analysed for the ITT population. The results for the Per-Protocol analysis corresponded to those of the ITT analysis, demonstrating that protocol violators had no significant influence on efficacy parameters.

Primary efficacy parameter
The primary endpoint was defined as the time to first recurrence of symptomatic PAF after randomisation or time to discontinuation during a 12-month treatment phase. The two-sided log-rank test to test equality over all strata revealed a p-value of 0.0086 thus demonstrating significant differences between the study treatments.

The multi-step hypothesis testing revealed the following results:

•Daily administration of Quinidine+Verapamil (high dose) prolonged the time to first recurrence of symptomatic AF compared to placebo (two-sided log rank test, p=0.0061).
•Daily administration of Sotalol 320 mg/d prolonged the time to first recurrence of symptomatic AF compared to placebo (two-sided log rank test, p=0.0022).
•Daily administration of Quinidine+Verapamil (high dose) was not inferior to Sotalol 320 mg/d in prolonging the time to first recurrence of symptomatic AF (one-sided comparison of the one year failure rate with a non-inferiority margin of 10%, p=0.0006).
•Daily administration of Quinidine+Verapamil (low dose) prolonged the time to first recurrence of symptomatic AF compared to placebo (two-sided log rank test, p=0.0006).
•Daily administration of Quinidine+Verapamil low dose was not inferior to Sotalol 320 mg/d in prolonging the time to first recurrence of symptomatic AF (one-sided comparison of the one year failure rate with a non-inferiority margin of 10%, p=0.0007).

For each treatment group the mean and median time to first recurrence of symptomatic AF or discontinuation are shown in Fig. 3 (Table), demonstrating that in all active treatment groups the mean time was prolonged compared to placebo and Quinidine+Verapamil was not inferior to Sotalol.



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Fig. 3 Time to first recurrence of symptomatic AF or premature discontinuation. Kaplan—Meier estimates for the probability of remaining free of first recurrence of symptomatic AF or discontinuation. The mean time to first event and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time (sAF=symptomatic atrial fibrillation).

 
Modified primary efficacy parameter
The "pure" efficacy of the active treatments as the time from randomisation to the first episode of PAF is shown in Fig. 4. For this analysis patients who terminated the study prematurely before the first episode of PAF were censored. In all active treatment groups the time from randomisation to the first recurrence of PAF was significantly prolonged compared to placebo. The two-sided log rank test to test the equality of strata revealed a value of p=0.0039.



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Fig. 4 Time to first recurrence of symptomatic AF. Kaplan—Meier estimates for the probability of remaining free of first recurrence of symptomatic AF. Patients who terminated the study prematurely before the first episode of PAF were censored. The mean time to first event and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time (sAF, symptomatic atrial fibrillation; —, not available).

 
Incidence of symptomatic PAF (AF burden)
The analysis of 'AF burden', determined as number of days during which one or more episodes of symptomatic AF occurred as a percentage of the number of days under treatment in prevention of relapse, after randomisation revealed a significant reduction for Quinidine+Verapamil (high dose; U test: p=0.0001), Quinidine+Verapamil (low dose; p=0.008), and for Sotalol (p=0.026) compared with placebo (Fig. 5). As some patients had values of 100% days with symptomatic atrial fibrillation under treatment in each treatment group (regardless of the total treatment duration), the distribution was highly skewed with large standard deviations in all treatment groups.



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Fig. 5 Burden of symptomatic AF. Number of days in which patients had one or more episodes of symptomatic AF in percent of the number of days under treatment [% days with sAF]; median with its 25% and 75% quartiles are plotted.

 
Safety evaluation
Safety data were evaluated for all 1033 randomised patients. There were no clinically relevant differences among the treatment groups with regard to changes in laboratory parameters or deviations from the reference range, vital signs, ECG parameters in resting and Holter-ECGs or the frequency and distribution of concomitant diseases.

A total number of 2100 adverse events (AEs) were reported in 712 patients with an equal distribution among the treatment groups (Quinidine+Verapamil, high dose): 569 AE in 185 pts., Quinidine+Verapamil (low dose): 459 AE in 165 pts., Sotalol: 614 AE in 192 pts., Placebo: 458 AE in 170 pts.).

Serious adverse events
In total, 345 serious adverse events were reported in 197 patients with no significant differences among treatment groups (SAEs total (SAEs related to study medication): Quinidine+Verapamil (high dose): 85 (24) in 47 pts., Quinidine+Verapamil (low dose): 66 (26) in 40 pts., Sotalol: 99 (38) in 53 pts., Placebo: 95 (35) in 57 pts.). Of these, the majority (182, 53%) was unrelated or unlikely to be related to the study medication, 39 (11%) events were reported as probably and 84 (24%) events as possibly, related to the study medication with no differences among treatment groups.

Serious adverse events of 'special interest'
With special respect to the cardiac risk profile of anti-arrhythmic therapy, reported deaths, syncopes, ventricular tachycardia, TdP tachycardia, or other pro-arrhythmias including newly developed atrial flutter, were defined as 'SAE of special interest' (Table 2). During the 12 months follow-up four deaths occurred: one thrombo-embolic ischaemic stroke and one myocardial infarction in the Sotalol group, and one sepsis after a car accident with prior QT-prolongation under Quinidine+Verapamil (high dose); these were judged as unrelated to the study medication by CEC. One case of hypoxia-caused brain damage after resuscitation in a patient with cardiac arrest by documented bradycardia under Quinidine+Verapamil (high dose) was judged as possibly related. One sustained ventricular tachycardia was observed by Tele-ECG under Quinidine+Verapamil (high dose). However, no TdP tachycardia was reported throughout the trial. In both Quinidine+Verapamil groups, several cases of newly developed atrial flutter were observed, however, total numbers were equal to placebo. The lowest risk for life threatening events was observed under Sotalol with two syncopes judged as possibly or probably related to the study medication (Table 2).


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Table 2. Serious adverse events (SAEs)
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
The SOPAT trial is the first large-scale, double-blind, randomised and placebo controlled study investigating the efficacy of the combination of Quinidine and Verapamil versus Sotalol in the prevention of symptomatic PAF using daily and symptom-triggered trans-telephonic ECG monitoring.

Major results
Three major results emerged from this clinical trial.

First, this trial demonstrates that both, the combination of Quinidine+Verapamil and Sotalol are effective anti-arrhythmic agents in the prevention of symptomatic PAF. The combination of Quinidine+Verapamil was not inferior to Sotalol: (i) in prolonging the time to first recurrence of symptomatic PAF and (ii) in reduction of the number of episodes of symptomatic PAF compared to placebo.

Second, by daily and symptom-triggered event recorder monitoring, documented PAF was less frequently associated with symptoms than expected. Although only patients with frequent episodes of symptomatic PAF were enrolled, only 46% of registered PAF-ECGs under placebo were symptom-triggered, whereas the other 54% were asymptomatic and documented by chance through daily, routine ECG monitoring. These findings suggest that PAF occurs more frequently than estimated by the frequency of patients symptoms, thus questioning whether symptoms are reliable clinical surrogate parameters for the detection of AF. This may also explain the unexpectedly high one year failure rates around 70% observed under the active treatments.

Third, a relatively low number of syncopes and pro-arrhythmias was found among the treatment groups. Although it must be mentioned that one case of death and one ventricular tachycardia were related to Quinidine+Verapamil.

Efficacy versus risk of side-effects
Recently, the results of the AFFIRM trial13 demonstrated that rhythm control offers no advantage over rate control in patients with AF. However, patients with highly symptomatic AF were not included in AFFIRM. Another recent trial evaluating the quality of life in patients with AF revealed that rhythm control improves quality of life in patients with frequent symptomatic attacks.14 In this context, our data underline that although there was a significant reduction in the recurrence of symptomatic AF under treatment compared to placebo, this effect was not overwhelming. Moreover, there still remains a low but definite risk of life-threatening events under anti-arrhythmic therapy leading to the question whether the indication for anti-arrhythmic drugs in the prevention of PAF should be limited to highly symptomatic patients.

Several other trials in the past showed a risk for anti-arrhythmic drugs when treating ventricular and supraventricular arrhythmias. In the PAFAC trial evaluating the fixed combination of quinidine and verapamil in comparison to Sotalol and placebo in patients with persistent atrial fibrillation after DC cardioversion, there was a certain risk for pro-arrhythmic events, e.g., TdP tachycardias under Sotalol.10 In contrast, the risk of life-threatening pro-arrhythmias was lower in the SOPAT trial, which might be influenced by the fact that the majority of patients in this trial was relatively young and had no, or only minimal, structural heart disease.

Limitations
Using Tele-ECG monitoring with a maximal ECG recording time of 1 min, it was not possible to get information about the onset and duration of PAF episodes. Also, the number of asymptomatic PAF episodes was probably higher than detected by Tele-ECG. Therefore, the information about the influence of the study medication on these two parameters is limited. The information about adverse events is limited by the short follow-up time in a high number of patients.


    Conclusions
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
Taken together, the results of the SOPAT trial demonstrate that anti-arrhythmic therapy with the combination of Quinidine and Verapamil is not inferior to treatment with Sotalol in patients with symptomatic PAF. However, the recurrence rates after 12 months follow-up were relatively high in all groups supporting that there still remains a lack of really effective therapies for these patients.

Although the risk profile under treatment was low compared to placebo, there still exists a risk of severe and potentially life-threatening side-effects in patients with minimal structural heart disease or lone AF. Balancing the efficacy in reduction of PAF with this low but definite risk profile, anti-arrhythmic therapy should only be administered in highly symptomatic patients.

The observation that PAF episodes occurred more frequently than estimated by the incidence of patients' symptoms may have the implication that event recorder monitoring is a more reliable tool in the estimation of the prevalence of PAF episodes than patient's symptoms.


    Appendix A: Critical Event Committee (CEC)
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
H.-J. Trappe (Herne, Germany) — Chairman, D. Kalusche (Bad Krozingen, Germany), M. Meesmann (Würzburg, Germany), H. Pitschner (Bad Nauheim, Germany).


    Data and Safety Monitoring Committee (DSMC)
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
M. Schlepper (Bad Nauheim, Germany) — Chairman, P. Bauer (Vienna, Austria) — biometrics advisor, D. Andresen (Berlin, Germany), G. H. von Knorre (Rostock, Germany), D. Pfeiffer (Leipzig, Germany), M. Zehender (Freiburg, Germany).


    List of active study sites
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 
J. Adamus, Central Clinic Hospital WAM, Department of Cardiology, Szaserow str. 128, 00-909 Warszawa; K. Adler, Clausstr. 76, 9126 Chemnitz; R. Andrzejak, Klinika Chorob Wewn i Zawodowych, ul. Pasteura 4, 50-367 Wroclaw; G. Baack, Klinikum Lippe-Lemgo GmbH, Medizinische Klinik I, Rintelner Str. 85, 32657 Lemgo; W. Banasiak, Oddz. Kardiologiczny Wojskowego Szpitala Klinicznego, ul. Weigla 4, 53-114 Wroclaw; A. Bániková, Internal Department, Hospital Nám. Republiky 14, 984 39 Lucenec; J. Barlet, Neidensteiner Str. 4, 74915 Waibstadt; B. Becker, Schützenstr. 37, 38100 Braunschweig; J. Beermann, Rosengarten 5-9, 22880 Wedel; P.-G. Behler, St. Willibrord-Spital, 46446 Emmerich; M. Bermes, St. Elisabeth-Hospital, Hochstr. 63, 58638 Iserlohn; R.-D. Beythien, St.-Sixtus-Hospital, Gartenstr. 2, 45721 Haltern; C.-W. Blauth, Landauer Str. 6, 66953 Pirmasens; V. Bluschke, Hitdorfer Str. 10c, 40764 Langenfeld; M. Bock, Mozartstr. 19, 9119 Chemnitz; L. Born, Hospital z. Hl. Geist, Langestr. 4-6, 60311 Frankfurt; H.-J. Braun, Elisabethenstr. 14, 64283 Darmstadt; G. Castan, Oberbüssauer Weg 2-4, 23560 Lübeck; A. Cieslinski, Instytut Kardiologii, I Klinika Kardiologii, ul. Dluga 1/2, 61-848 Poznan; Budik Kreiskrankenhaus, Innere Abteilung, Kasseler Str. 80, 34212 Melsungen; H. Deimann, Düsseldorfer Str. 94 41749 Viersen; M. Dluzniewski, Brodnowski Hospital, Department of Cardiology ul. Kondratowicza 8, 03-242 Warszawa; R. Engelhard, Stapenhorststr. 7, 35066 Frankenberg; F. Gabriel, Aachener Str. 188, 40223 Düsseldorf; S. Gehlhar, Forststr. 3, 1099 Dresden; C. Geller, Universitätsklinikum Otto-von-Guericke-Universität Magdeburg, Leipziger Str. 44, 39120 Magdeburg; S. Geßner, Anna-Siemsen-Str. 41, 7745 Jena-Winzerla; D. Glatzel, Möckernstr. 3, 30163 Hannover; T. Glauner, Am Eschbacher Pfad 38, 79423 Heitersheim; Graf-Bothen, DRK Kliniken Westend, Spandauer Damm 130, 14050 Berlin; Grüneklee, St. Jahannisstift, Reumontstr. 28, 33102 Paderborn; W. Hahn, Hermannstr. 24, 99817 Eisenach; B. Halawa, Katedra i Klinika Kardiologii A.M. we Wroclawiu, ul. Pasteura 4, 50-367 Wroclaw; R. Hambrecht, Universität Leipzig, Herzzentrum, Russenstr. 19, 4289 Leipzig; R. Hatala, Department of Cardiology, Slovak Cardiovascular Institute, Pod Krásnou Horkou 1, 833 48 Bratislava; S. Haufe, Kaiserstr. 30, 76437 Rastatt; W. Haverkamp, Uni-Klinik-Münster, Med. Klinik und Poliklinik, Station 15 B, Albert Schweitzer St. 33, 48129 Münster; Heines, Städt. Krankenhaus Nettetal, Sassenfelder Kirchweg 1, 41334 Nettetal; H. Herber, Marienplatz 1, 33098 Paderborn; R. Herbert, Gravenhorststr. 23, 21335 Lüneburg; K. Heun, Dülkener Str. 56, 41747 Viersen; R. Hewing, Moltkestr. 6, 48151 Münster; E. Himmrich, Universität Klinik, Langenbeckstraße 1, 55131 Mainz; B. Höfling, Krankenhaus Agathried, St.-Agatha-Str. 1, 83734 Hausham; K. Hofmann, Badstr. 6, 8645 Bad Elster; J. Hofmann, Kronacher Str. 7, 95346 Stadtsteinach; H. Hohensee, Spitzwegstr. 66, 1219 Dresden/Leubnitz; P. Jancso, Rosenheimer Str. 22, 83059 Kolbermoor; M. Janion, General Hospital Department of Cardiology, ul Grunwaldzka 45, 25-736 Kielce; O. Jurkovicová, 4th Internal Clinic, St. Cyril's and Method's Hospital Petrzalka, Antolska 11, 851 07 Bratislava; G. Kaliská, Department of Cardiology, Roosevelt's Hospital, Nam. L. Svobody 1, 975 17 Banská Bystrica; S. Kaspari, Haagestr. 3, 21335 Lüneburg; J. Kasper, Coronary Unit, 1st Internal Clinic, Faculty Hospital, Mickiewiczova 13, 813 69 Bratislava; K. Kasprzak, Oddz. Kardiologiczny Szpitala Specjalistycznego, ul. Rydygiera 1, 64-920 Pila; W. Kirschke, St. Bernhard-Hospital, Bürgermeister-Schmelzing-Str. 90, 47475 Kamp-Linfort; H. Klepzig, Städt. Kliniken, Med. Klinik I, Starkenburgring 65, 63069 Offenbach; J. Kmec, Department of Cardiology, NsP J. A. Reiman Hospital, Hollého 14, 081 81 Presov; D. Koch, Parchimer Allee 84, 12359 Berlin; A. Kocjan, Knapper Str. 25, 58507 Lüdenscheid; P. 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    Acknowledgments
 
We thank all participating study sides in Germany, Poland and The Slovak Republic for their commitment over the years. Special thanks go to R. Simonowsky, E. Muzec, M. Kastner, C. Färber, and all co-workers for the analysis and evaluation of Tele-ECGs and for the co-ordination of the ECG analysis centre in Hamburg. Special thanks go to O. Sellke (OSIP, Wiesbaden, Germany) and F. N. Peterich (Fox Med, Idstein, Germany) for their excellent technical support. We are also indebted to A. Hirschner and H. Reichert and their team at Omnicare Clinical Research, Köln for organisation and monitoring of the trial. Many thanks go to J. Krol for his help in organising the trial in Poland. The analysis of Tele-ECGs and the organisation of the analysis centre in Hamburg was made possible by a grant from Abbott GmbH Germany, Ludwigshafen (former Knoll Deutschland GmbH) to the Department of Cardiology at the University Hospital Hamburg Eppendorf, Germany.

We thank all members of the Data and Safety Monitoring Board (DSMC) and the Critical Event Committee (CEC) for evaluation and monitoring of SAEs reported during the trial.


    Footnotes
 
1 Participating institutions and investigators are listed in Appendix. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix A: Critical Event...
 Data and Safety Monitoring...
 List of active study...
 References
 

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