(Circulation. 1995;92:1517-1525.)
© 1995 American Heart Association, Inc.
Articles |
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
From the University Hospital, Department of Cardiology, Freiburg,
Germany.
1 See "Appendix" for affiliations of
authors.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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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.
Key Words: tachyarrhythmias • antiarrhythmia agents • d-sotalol • ventricles • repolarization
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Racemic sotalol, a potent ß-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 ß-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 ß-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 ß-adrenergic receptor antagonism may preclude the administration of d,l-sotalol.1 Other side effects related to the ß-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 ß-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
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Methods |
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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.
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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.
Hypotheses
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.
Efficacy Criteria
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 
-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 
2
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.
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Results |
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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).
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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.
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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.
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ECG Changes
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.
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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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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 ß-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 ß-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.
Conclusions
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.
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Footnotes |
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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.
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.
Received February 19, 1995; revision received April 6, 1995; accepted April 8, 1995.
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