Efficacy and Safety of d-Sotalol, a Pure Class III Antiarrhythmic Compound, in Patients With Symptomatic Complex Ventricular Ectopy
Results of a Multicenter, Randomized, Double-blind, Placebo-Controlled Dose-Finding Study
Background There is increasing interest in pure class III antiarrhythmic compounds, ie, drugs in which the electrophysiological effect is confined to the propensity for producing an isolated lengthening of action potential duration. d-Sotalol represents the prototype of such pure class III agents. This double-blind, placebo-controlled, randomized dose-finding study evaluated the antiarrhythmic efficacy and safety of d-sotalol in patients with symptomatic chronic ventricular ectopy.
Methods and Results A total of 233 patients presenting with ≥30 premature ventricular contractions (PVCs) per hour during drug-free Holter monitoring randomly received placebo or d-sotalol at dosages of 50, 100, or 200 mg BID. Drug efficacy was assessed by repeat Holter monitoring at the end of double-blind therapy. There was a dose-dependent increase in QT and QTc duration, indicating class III activity. A dose-related decrease in hourly PVC counts was observed, reaching statistical significance for patients receiving 200 mg d-sotalol BID (311 PVCs/h during baseline compared with 135 PVCs/h during active treatment, P<.05). Analysis of the primary efficacy criterion (ie, ≥75% reduction in total PVCs/h) revealed a significant treatment effect only for the highest d-sotalol dose, with 8 patients (14%) meeting this criterion. Eighteen patients reported side effects, which led to drug discontinuation in 5. One sudden death and one nonfatal cardiac arrest occurred in patients with dilative cardiomyopathy receiving 200 mg d-sotalol BID. No incidence of torsade de pointes was reported.
Conclusions d-Sotalol exerts dose-dependent class III activity in patients with symptomatic ventricular ectopy. Its PVC-suppressing activity is modest and becomes evident predominantly at dosages of 200 mg administered BID. The observation of drug-associated serious adverse arrhythmic events emphasizes the need for individualized careful dose titration, particularly in patients with advanced organic heart disease.
Racemic sotalol, a potent β-adrenergic receptor antagonist that in addition significantly prolongs action potential duration in cardiac tissues (so-called class III antiarrhythmic activity), represents an effective antiarrhythmic agent for the treatment of various cardiac rhythm disorders.1 For example, d,l-sotalol has been used successfully for the treatment of various supraventricular arrhythmias,2 including the prevention of recurrent atrial fibrillation in patients after successful DC cardioversion.3 In patients with frequent symptomatic ventricular ectopy, d,l-sotalol has also been found to be as effective as various class I antiarrhythmic agents4 5 6 7 8 and superior to other β-receptor antagonists such as propranolol.9 More recently, the ESVEM investigators found d,l-sotalol to be more effective than six other antiarrhythmic agents in patients with a history of malignant ventricular tachyarrhythmias.10 In this well-controlled prospective study, patients treated with d,l-sotalol were significantly less likely to experience recurrent tachyarrhythmic episodes regardless of the mode of evaluation of drug efficacy. Moreover, survival was significantly better in patients on d,l-sotalol than in those receiving one of the other study medications.10
The major limitation concerning the clinical usefulness of d,l-sotalol consists of its high degree of β-adrenergic blocking activity.1 Particularly in patients with advanced organic heart disease and a history of life-threatening arrhythmias, the negative inotropic action due to β-adrenergic receptor antagonism may preclude the administration of d,l-sotalol.1 Other side effects related to the β-receptor blocking effects of this compound, such as sinus bradycardia, hypotension, or bronchospasm, necessitate drug discontinuation in a considerable number of patients.
The dextroisomer of sotalol has been shown to be devoid of clinically significant β-adrenergic antagonism.11 12 13 In contrast, the effects on action potential duration and refractoriness were comparable to those of the racemic compound.13 14 In experimental studies, d-sotalol was demonstrated to possess significant antiarrhythmic and antifibrillatory properties.13 14 15 16 For instance, in a conscious canine model of sudden coronary death, d-sotalol was as protective against ischemia-induced ventricular fibrillation as d,l-sotalol.15 16 These experimental data are complemented by preliminary data in patients with supraventricular17 or ventricular arrhythmias.18 19 20 For example, Brachmann and coworkers,20 using programmed electrical stimulation to assess drug efficacy, reported a 78% success rate of oral d-sotalol therapy in patients with previously documented ventricular tachycardia or fibrillation. However, all of these studies comprised small patient populations, and all were open-label trials and not blinded.
Therefore, the present prospective, placebo-controlled, double-blind dose-finding study was designed to evaluate the efficacy, tolerance, and safety of d-sotalol in patients with symptomatic complex ventricular ectopy. This trial was conducted as a multicenter trial in five European countries at 33 study centers. It is the first to report data in a large patient population treated with a pure class III antiarrhythmic agent.21
The present study was designed as a multicenter, randomized, double-blind, parallel-group, placebo-controlled dose-ranging evaluation of oral d-sotalol in the treatment of chronic symptomatic ventricular arrhythmias. Individual responses were assessed by comparisons of treatment arrhythmias with those recorded during a placebo-controlled baseline Holter recording.
Patient Eligibility and Exclusion
Patients 18 to 75 years old with a history of symptomatic, frequent, complex ventricular ectopy that warranted treatment were candidates for the study. An average of at least 30 premature ventricular contractions (PVCs) per hour had to be documented on a 24-hour screening Holter recording. Exclusion criteria included a history of sustained ventricular tachycardia (>30 seconds; rate, >100 beats per minute [bpm]) or ventricular fibrillation or aborted sudden death. Myocardial infarction or cardiac surgery within 1 month before study entry, unstable angina pectoris, New York Heart Association functional classification IV, or the presence of severe hypertension (diastolic blood pressure >115 mm Hg not controlled by antihypertensive agents) precluded inclusion in the study. ECG features at baseline that excluded patients from participation were PQ interval >0.24 seconds, QRS duration >0.18 seconds, a rate-corrected QT interval >0.48 seconds, sinus bradycardia <50 bpm, and presence of atrial fibrillation or flutter. Further exclusion criteria were the presence of impaired renal function (indicated by a creatinine clearance of <50 mL/min), liver dysfunction, or electrolyte imbalance (eg, serum potassium <4.0 mEq/L or magnesium <1.5 mEq/L). Finally, patients were excluded in whom the following medications could not be withdrawn at least 5 half-lives before the baseline period of the study: (1) other investigational drugs; (2) drugs with a known QT-prolonging action (eg, tricyclic antidepressants); and (3) antiarrhythmic drugs of classes I and III. The study protocol was approved by the investigational committees of all 33 participating centers (see “Appendix”). All patients gave written informed consent.
Patient Entry Characteristics
A total of 245 subjects who met the inclusion and exclusion criteria were enrolled into the trial. Twelve patients discontinued during the baseline placebo period and were not randomized to active medication. Reasons for discontinuation were the occurrence of adverse events (n=3), withdrawal of informed consent (n=3), and protocol violations (n=6). The remaining 233 patients were randomized to double-blind study medication from December 1992 to May 1994. Patient characteristics are given in Table 1⇓. PVC frequency on baseline Holter monitoring averaged (mean±SEM) 557±39/h (range, 31 to 2514/h; median, 354/h). In addition, 198 of 233 patients (88%) had ventricular couplets, and 101 patients (43%) had runs of nonsustained ventricular tachycardia (three or more beats at a rate of ≥100 bpm). One hundred seven randomized patients (46%) had previously been treated with antiarrhythmic drugs.
Study Treatment Plan
Washout period. Patients with a history of symptomatic complex ventricular ectopy were screened, and those who met all the entry criteria and gave informed consent entered the washout phase. After washout of all previously administered antiarrhythmic drugs for at least 5 half-lives, the screening 24-hour Holter recording was obtained. After the investigator reviewed the recording (at least 18 hours analyzable), patients with at least 30 PVCs/h completed the following procedures and assessments: medical history, complete physical examination, 12-lead ECG, routine laboratory tests (complete blood count, electrolytes, creatinine, glucose, bilirubin, alkaline phosphatase, aspartate aminotransferase, creatine kinase, urinalysis), and a visual analog scale for symptom severity.
Placebo baseline period. The second week consisted of a placebo baseline phase that was single-blind. Two placebo capsules were administered every 12 hours. Between days 5 and 7, patients returned to investigation sites, and a second Holter monitoring was performed. On the day the Holter was removed, interval history, cardiovascular examination, and a 12-lead ECG were obtained.
Double-blind period. On day 1 of this phase, qualifying patients were randomized to one of four treatment groups: d-sotalol 50 mg, 100 mg, or 200 mg or placebo twice daily. Before the completion of the double-blind phase (6±1 days), the patient returned for 24-hour Holter monitoring. At the time of Holter detachment, the following procedures were completed: final clinical assessment, 12-lead ECG, adverse event assessment, arrhythmic event assessment, laboratory tests, and final visual analog scale for symptom severity. Compliance was confirmed by history and pill count.
Holter Monitoring Analysis
All Holter recordings obtained during the placebo baseline period and during active treatment were analyzed in a blinded fashion at a single institution (N.V. Cardio-Scan, Brussels, Belgium). Holter recordings were analyzed with a validated operator-interactive computer program (Century Colortrac Holter Scanning Computer, Biomedical Systems Corp). Results of analysis were transferred to the central database.
The primary objectives of this d-sotalol dose-ranging study were (1) to determine whether twice-daily administration of 50, 100, or 200 mg would suppress symptomatic ventricular ectopy in a dose-dependent manner and (2) to compare safety and tolerance of d-sotalol with placebo in this patient population. Secondary objectives were to evaluate (1) whether d-sotalol would reduce the severity of arrhythmia-related symptoms such as palpitations, weakness, shortness of breath, or angina pectoris and (2) whether d-sotalol administration would increase rate-corrected QT interval duration in a dose-dependent manner.
Four response criteria (one primary, three secondary) had been prospectively defined on the basis of the analyses of the 24-hour Holter recordings obtained during the placebo baseline and the double-blind phases. The primary efficacy criterion was a ≥75% reduction in the total number of PVCs per hour during double-blind treatment compared with baseline. The three secondary efficacy criteria were (1) ≥90% reduction in the number of couplets per hour in patients with at least 0.3 couplets per hour during placebo administration; (2) ≥90% reduction in the number of salvos per hour during placebo administration; and (3) reduction in PVCs, couplets, and salvos in subjects with at least 0.3 singles per hour during the placebo phase based on a three-dimensional analysis model proposed by Schmidt et al.22
Statistical Analysis of Data
The study sample size was calculated on the basis of the expected percentages of patients meeting the primary efficacy criterion in the placebo and d-sotalol 200 mg BID treatment groups. Assuming response rates of 10% and 35%, respectively, a total of 200 evaluable patients (50 per treatment arm) was needed to detect with at least 80% power a statistically significant difference between the percentages of responders for these two treatments by use of a two-sided test with an α-level of .05.
The efficacy results of the study were analyzed on the basis of an intention-to-treat principle, with those patients classified as nonresponders in whom one of the two Holter monitorings was unavailable for analysis or who stopped study medication before repeated Holter monitoring could be performed. For analysis of the predefined response criteria, a logistic model including the treatment effect (four levels) and the country effect (five levels) was used to evaluate the dose-response relation. The magnitude of the odds ratio of d-sotalol 200 mg BID compared with placebo was estimated by a 95% CI, assuming a linear relation between dose and response odds.23 24 The Wald χ2 statistic was used to compare the estimated odds ratios with its expected value of 1 under the null hypothesis of no linear dose-response relation. This analysis was complemented by pairwise comparisons between each d-sotalol treatment group and the placebo group by the Mantel-Haenszel procedure.23 The primary analyses of response were then complemented by the secondary analysis of the number of PVCs/h (total, single, couplet, and salvos). The number of PVCs was normalized by a logarithmic transformation (log[x+0.01]) to correct for skewed distributions and unequal variances. Then, the change from placebo baseline to the end of double-blind was analyzed by an ANCOVA model including the treatment and the country effect factors and the placebo lead-in measurement as a covariate. This type of analysis was also used to evaluate the changes in ECG measures and the severity of symptoms as reported on the visual analog scales at baseline and during double-blind therapy. Statistical significance was assumed at a two-tailed value of P≤.05.
Comparison of Baseline Characteristics
Baseline characteristics (Table 1⇑) of patients randomly assigned to placebo or one of the three d-sotalol treatment groups were similar. Total PVC frequency at baseline was comparable in all four groups: 295/h (geometric mean) in the placebo group, 271/h in the 50 mg BID group, 254/h in the 100 mg BID group, and 311/h in the 200 mg BID group. Severity of arrhythmia-related symptoms and functional status (New York Heart Association functional class) were also similar in all four groups.
Analysis of Primary Efficacy Criterion
In patients assigned to placebo medication, arrhythmia density was unaffected by medication. As indicated in Table 2⇓, the frequency of hourly PVCs was nearly identical during the baseline period and at the end of double-blind therapy. In the three d-sotalol groups, a dose-related decrease in hourly PVC counts was observed compared with the placebo baseline period (Table 2⇓). This decline in PVC frequency reached statistical significance for the patient group receiving d-sotalol at a dose of 200 mg twice daily (311 PVCs/h during baseline Holter monitoring compared with 135/h during active treatment, P<.05).
The results of the analysis of the primary efficacy criterion (ie, ≥75% reduction in total PVCs/h) are depicted in Table 3⇓. Based on an intention-to-treat analysis, there is a significant treatment effect only for the highest d-sotalol dose, with 8 patients (14%) showing a ≥75% reduction in total PVCs/h during active treatment compared with baseline placebo administration. When this analysis was repeated including only those patients in whom both Holter recordings were available for analysis, similar efficacy results were observed, with 2% responders in the placebo group and 4%, 10%, and 15% in the 50 mg, 100 mg, and 200 mg d-sotalol groups, respectively. Again, this treatment effect was significantly different from placebo medication only for the highest d-sotalol dosing regimen.
Evaluation of Secondary Efficacy Criteria
As indicated in Table 4⇓ and in the Figure⇓, there was a trend toward a better suppression of couplets and ventricular salvos for the highest–d-sotalol treatment regimen. The combined analysis of reduction of single PVCs, couplets, and salvos according to the method proposed by Schmidt et al22 revealed a significant treatment effect (P<.05) for patients receiving 200 mg d-sotalol twice daily.
The ECG at final therapeutic assessment revealed no significant changes compared with the baseline period in patients receiving placebo medication. The major effect of d-sotalol on the ECG at the end of double-blind therapy consisted of a prolongation of the QT and the QTc intervals. Heart rate on 12-lead resting ECG declined on average by 4 bpm in the 50 mg BID, by 2 bpm in the 100 mg BID, and by 7 bpm in the 200 mg BID groups. Although the changes in the low- and high-dose groups reached statistical significance, these changes were of no clinical relevance. Average heart rates on Holter recordings decreased by a similar amount in all three d-sotalol groups. The parallel comparison of drug and placebo 12-lead ECGs revealed no significant drug-related changes in the PR and QRS duration. The QT interval increased significantly in a dose-dependent manner by an average of 15, 17, and 37 ms in the 50 mg, 100 mg, and 200 mg d-sotalol treatment groups, respectively (Table 5⇓). The rate-corrected QT interval showed a similar dose-dependent increase during d-sotalol administration.
Assessment of Severity of Symptoms
Compared with the visual analog scale–based assessment of symptoms obtained during the baseline placebo period, d-sotalol patients showed a decrease in the severity of their symptoms during active therapy. This difference was statistically significant for patients exposed to the highest d-sotalol dosing regimen (Table 6⇓).
Safety of d-Sotalol
In Table 7⇓, the incidence of drug-related side effects is summarized. Eight percent of the total study population reported one or more adverse events. During double-blind therapy, 7 patients discontinued study medication. One patient died suddenly and another experienced a nonfatal cardiac arrest while on d-sotalol at a dose of 200 mg BID. Both individuals suffered from dilative cardiomyopathy, with a markedly reduced left ventricular ejection fraction (20% and 28%, respectively). In both patients, baseline QT duration was within normal limits (0.45 and 0.32 seconds, respectively). Renal function was uncompromised in the first subject, whereas the second had a serum creatinine of 1.53 mg/dL. There were no deaths in the other treatment groups. Three additional patients stopped double-blind therapy because of extracardiac side effects. In 1 patient, a protocol violation led to study discontinuation, and 1 patient withdrew informed consent.
No incidence of torsade de pointes was documented either clinically or during Holter monitoring. Furthermore, according to the criteria proposed by Schmidt et al,22 no incidence of aggravation of spontaneous nonsustained ventricular ectopy was documented during Holter monitoring at the end of double-blind therapy. Finally, there was no incidence of worsened congestive heart failure.
The present study is the first to report the QT-lengthening and antiectopic effects of a pure class III antiarrhythmic compound, d-sotalol, adhering to a prospective, placebo-controlled, double-blind study design. Pure class III antiarrhythmic agents are characterized by their action potential duration–prolonging effect as the sole electrophysiological mechanism. In contrast, racemic sotalol and amiodarone, the two clinically available class III antiarrhythmic compounds, possess additional electrophysiological effects besides their action potential–prolonging effect.1 25 The results of the present study demonstrate a dose-dependent class III activity of d-sotalol but only a weak PVC-suppressing efficacy in patients with organic heart disease and symptomatic ventricular ectopic activity. The absolute number of patients meeting the primary efficacy criterion (ie, ≥75% reduction in hourly PVCs), however, was low (14%). The safety profile of the substance was acceptable, although the occurrence of two major arrhythmic events in the high-dose group indicates that caution must be exercised in dosing, particularly in patients with advanced heart disease.
Dose-Dependence of d-Sotalol–Associated Electrophysiological and Antiarrhythmic Effects
In this trial, the class III effect of d-sotalol was corroborated by a clear dose-response relation for drug-associated prolongations of the QT and the QTc intervals, which are considered to represent the clinical manifestation of a corresponding increase in ventricular refractoriness. The demonstration of dose-response relations is the best proof of a drug’s pharmacological activity. These findings are in excellent agreement with results reported by McComb et al,18 who evaluated the effects of increasing intravenous dosages of d-sotalol during electrophysiological testing. They found in a group of 20 patients a similar increase in QT and QTc intervals, which reflected the prolongation of the effective ventricular refractory period as assessed by programmed stimulation.
The antiarrhythmic effects of d-sotalol showed a clear dose-response relation up to a maximum of 56% PVC reduction at the highest dose. Similar dose-related effects were observed for the reduction of repetitive ventricular ectopic activity. However, the number of patients meeting the primary efficacy criterion was low, with only 14% of individuals receiving the highest dose. These findings contrast with results obtained with the administration of d,l-sotalol in similar patient groups.4 5 6 7 8 9 Although the reasons for this superiority of the racemic compound remain uncertain, several considerations come to mind. First, it is tempting to speculate that the additional antiadrenergic effects are of importance in this patient population, in which coronary artery and hypertensive heart disease account for the majority of underlying cardiovascular disease substrates. It is important to note that in this study, the highest d-sotalol dose might have exhibited modest β-blocking action as indicated by the reduction in heart rate which in turn might have been responsible for the PVC-suppressant action. Second, double-blind therapy was administered for only 1 week, which may be too short in some patients for the development of the total antiarrhythmic potential of the drug. The pharmacokinetic profile of the substance and the described increases in QT duration, however, argue against this hypothesis. Third, ventricular ectopic activity was known to be present for quite a long time in the present patient population and had been treated with different antiarrhythmic drugs in many individuals before they were exposed to d-sotalol. This may indicate that the arrhythmia was relatively refractory in a considerable number of patients. Fourth, the intention-to-treat principle used for analysis in our study may have led to an underestimation of the absolute numbers of responders.
In addition to the described objective measures of antiarrhythmic activity, a dose-response relation could also be demonstrated for reduction in patients’ symptoms as assessed subjectively by use of a visual analog scale. The highest d-sotalol dose was significantly superior to placebo in this regard.
Importance of Antiectopic and Antifibrillatory Effects of d-Sotalol
The pathogenesis of sudden cardiac death in patients with organic heart disease is considered to represent a complex interplay between an underlying arrhythmogenic substrate and various trigger factors26 that act to provoke sustained ventricular tachycardia degenerating into ventricular fibrillation.27 Among these trigger mechanisms, the occurrence of PVCs is probably one of the most important ones. Thus, prevention of sudden cardiac death can aim either at suppression of trigger factors (antiectopic activity) or at prevention of ventricular tachycardia acceleration into ventricular fibrillation (ie, antifibrillatory action).28 Recent clinical studies have convincingly demonstrated that, for instance, class I antiarrhythmic drugs are not effective in preventing sudden cardiac death even though they very effectively suppress PVCs.29 β-Adrenergic receptor antagonists, on the other hand, are the only antiarrhythmic medications that have been shown to reduce sudden cardiac death after myocardial infarction, although these agents are only moderately effective in suppressing PVCs.30
The results of the present trial indicate that d-sotalol is only moderately effective in suppressing PVCs in patients with organic heart disease. However, it is well established in experimental studies that this class III compound possesses significant antifibrillatory properties.15 16 28 Comparative studies using d,l- and d-sotalol demonstrated a similar antifibrillatory potential of the dextrorotatory isomer.16 Since the administration of d-sotalol was not associated with the attenuation of the ischemic increase in heart rate observed with the parent compound, it was concluded that the antifibrillatory capacity stemmed directly from prolongation of action potential duration and the increase in ventricular refractory period.16 28 A recently published summary of various investigations of 22 different drugs evaluated in this canine model of sudden coronary death revealed an efficacy of 65% for d-sotalol; this efficacy rate was far superior to those of class I antiarrhythmics and comparable to those of other class III agents, most notably to that of amiodarone.28 Whether these experimental findings can be extrapolated to the clinical situation has yet to be established.
Safety of d-Sotalol Therapy
The present study indicates that d-sotalol possesses an acceptable safety profile in patients with a long-standing history of complex symptomatic ventricular ectopy. The overall incidence of adverse events increased in a dose-dependent manner. As with any kind of antiarrhythmic drug therapy, however, the most decisive safety aspect concerns the occurrence of cardiovascular adverse effects, particularly in the form of proarrhythmic reactions.31 32 In this study, 2 patients suffered from sudden death or cardiac arrest, and the investigators thought these events to be related to the study medication. Both events occurred in patients taking d-sotalol 200 mg twice daily, and both patients had advanced heart disease with a markedly depressed left ventricular function. The latter have been identified as risk factors for the development of drug-related proarrhythmia.33 The most commonly observed class III–associated form of proarrhythmia consists of the development of torsade de pointes.34 Although no torsade de pointes was documented in the present trial, both the sudden death and the nonfatal cardiac arrest observed may have been due to the degeneration of such an arrhythmia into ventricular fibrillation. In the study by Brachmann et al,20 only 1 patient suffered from this form of proarrhythmia. Although it has been postulated35 that d-sotalol may be less likely to provoke torsade de pointes compared with d,l-sotalol because of the lack of drug-associated bradycardia, the exact incidence of d-sotalol–induced torsade de pointes remains to be established. The overall incidence observed for the racemic parent compound averages 3% to 4%, with an increased likelihood of occurrence associated with the use of higher doses.36
As a lesson from CAST, it is now well appreciated that proarrhythmic reactions may occur long after the initial exposure of the patient to an antiarrhythmic drug. This so-called “late” proarrhythmia is probably related to the changing electrophysiological milieu resulting from progression of underlying heart disease or from factors such as transient myocardial ischemia.37 In this context, results of experimental findings recently reported by Vanoli et al38 appear to be relevant. These investigators recorded monophasic action potential duration in anesthetized dogs and demonstrated that 40% to 60% of the d-sotalol–induced action potential prolongation is lost during sympathetic stimulation. In clinical terms, this could indicate insufficient protection of d-sotalol–treated patients during states of sympathetic hyperactivity. Similar findings have been reported by Groh and associates.39
Very recently, the safety aspect of therapy with pure class III agents has been emphasized in a large d-sotalol trial in postinfarction patients.40 Preliminary data of this trial are compelling in showing an increased mortality in patients receiving d-sotalol compared to placebo controls.40 In summary, therefore, there is increasing evidence that the effects of pure class III agents on mortality may be unrelated to or divergent to their ability to lengthen repolarization or to suppress spontaneous or electrophysiologically induced arrhythmias.
This carefully controlled dose-finding study of d-sotalol, a pure class III substance blocking IKr, in patients with symptomatic ventricular ectopic activity demonstrates a dose-dependent class III activity of this compound. The PVC-suppressing activity of the drug is weak and becomes evident predominantly at dosages of 200 mg administered twice daily. Although the drug was well tolerated by the majority of patients, the need for individualized careful dose titration, particularly in patients with advanced organic heart disease, is emphasized by the observation of drug-associated serious arrhythmic adverse events. In more general terms, the results of our study also emphasize the importance of placebo-controlled dose-finding studies early during development of new antiarrhythmic drugs to establish, in particular, safety and tolerance.
The following list provides the names of principal investigators involved in the conduct of this study and their locations.
Germany: S.H. Hohnloser, J.W. Goethe University, Frankfurt; T. Meinertz, Allgemeines Krankenhaus St Georg, Hamburg; L. Goedel-Meinen, Munich; D. Kalusche, Bad Krozingen; E. Kauder, Tuttlingen; P.G. Lankisch, Lüneburg; B. Lemke, Bochum; G. Lockert, Bremerworder; H. Mehmel, Karlsruhe; J. Oldenburg, Flensburg; J. Senges, Ludwigshafen; R. Wolf, Bad Bevensen.
France: J.J. Blanc, Hospital Morvan, Brest; J.P. Donzeau, Toulouse; D. Flammang, St Michel; R. Frank, Irvy sur Seine; J.S. Hermida, Amiens; J.C. Kahn, Poissy; H. Lardoux, Corbeil- Essonnes.
Great Britain: P. Stubbs, Charing Cross and Westminster Medical School, London; A.J. Camm, London; R. Greenbaum, Edgware; C. Ilsley, Middlesex; A. Lahiri, Middlesex; J. Stephens, Romford.
Italy: P. Rizzon, University Hospital, Bari; D. Brancchetti, Bologna; M. Chimienti, San Donato Milanese; L. Corradi, Broni; F. Furlanello, Trento; M. Marzegalli, Milan.
Netherlands: H.J.G.M. Crijns, University Hospital, Groningen; A. Timmermans, Enschede.
Reprint requests to Stefan H. Hohnloser, MD, FESC, J.W. Goethe-University, Department of Medicine, Division of Cardiology, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
- Received February 19, 1995.
- Revision received April 6, 1995.
- Accepted April 8, 1995.
- Copyright © 1995 by American Heart Association
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