I. s
European Heart Journal (1992) 13 {Supplement F), 19-22
Pros and cons of drugs that prolong ventricular refractoriness J. BRACHMANN, T. BEYER, W. SCHOLS, C. SCHMITT, M. MONTERO, W. KNOLLMANN, T. HILBEL AND W. KUBLER
Med. Univ. Klinik, Bergheimer Str. 58, 6900 Heidelberg, Germany
Introduction The clinical interest in drugs which prolong ventricular refractoriness and ventricular repolarization has greatly increased as a result of the CAST and ESVEM trials. While the classical antiarrhythmic therapy consisted of a variety of class I agents which inhibit the fast sodium system at different kinetics giving way to a variety of classifications, the use of these compounds to prevent sudden cardiac death following myocardial infarction has not been successful. On the contrary, it appears that after the CAST study class I agents at least may increase mortality in post-myocardial infarction patients with non-malignant ventricular arrhythmias as compared to placebo therapy. This has been further corroborated by the recently reported ESVEM trial, which initially was designed to evaluate the efficacy of Holter monitoring versus programmed electrical stimulation for determining effective antiarrhythmic drug therapy in patients with documented sustained ventricular tachycardia and/or ventricular fibrillation and/or cardiac arrest. Although the full study has not been published yet, it appears from the preliminary data that the class III agent, sotalol, with concomitant potent beta-blocking efficacy was clearly superior to all class I agents employed in this trial both with respect to acute efficacy and long-term recurrence rate. Furthermore, smaller studies employing the potent class III agent, amiodarone, have indicated the potential of this drug for decreasing mortality after myocardial infarction. This has led to the European Infarction Amiodarone Trial (EM I AT) which should provide the data on efficacy and safety of amiodarone in these patients in a few years. However, the clinical use of amiodarone is also limited by its pharmacokinetics and unfavourable side effect profile. This has led to an extensive search of the pharmaceutical industry to find new compounds which prolong repolarization and refractoriness (class III drugs). It is obvious from existing data that class III drugs demonstrate potent antiarrhythmic efficacy in all types of cardiac arrhythmias, similar to the results of both amiodarone and sotalol which have been used in clinical practice for some time. The renewed interest in class III drugs has only recently given way to development of new, more selective agents which prolong repolarization and refractoriness without affecting other electrophysiological parameters of the heart. Several class III antiarrhythmic drugs are currently in advanced preclinical and early clinical development for prevention of malignant ventricular arrhythCorrtspondcnce: J. Brachmann, MD, Med. Univ. Klinik, Bergheimer Sir. 58, 6900 Heidelberg, Germany. 0I95-668X/92/0F0019 + 04 SOS.00/0
mias. This interest has been directed specifically to the potent and selective methanesulfonanitide class III compounds, which are derivatives of the methanesulfonanitide dl-sotalol, if developments include, but are not exclusive to, E 4031, UK 68,798 and d-sotalol. The following data pertaining to results obtained with d-sotalol are taken as a major example of the efficacy of the new class III agents, which appear to provide the principal bases for antiarrhythmic therapy in the 1990s. The following experimental studies were performed in beagle dogs anaesthetized with pentobarbital. The animals were artificially ventilated and left thoracotomy was performed for ligation of the proximal left anterior descending (LAD) coronary artery and implantation of epicardial electrodes. In addition, modified composite electrodes were implanted to record electrical activity of the infarct zone as well as normal myocardium. The chest was closed and the animals allowed to recover before an electrophysiological study was performed at days 3-8. Programmed electrical stimulation was carried out with a constant current stimulator at twice diastolic threshold using a pacing protocol at basic driving cycles of 330 and 250 ms employing two premature extra stimuli. Administration of d-sotalol (4-5 mg. kg"') was followed by exact repetition of the stimulation protocol. The end-point was either the induction of a sustained tachyarrhythmia or the completion of the protocol. To perform the in vitro experiments following proximal LAD ligation, epicardial and endocardial preparations were carefully dissected and placed in a 30 ml special perfusion chamber to be superfused with modified Tyrode solution of the following composition (mM): NaHPO4 1-67; Na-glukonat 9-64; glucose 5-55; saccharose 7-6; NaCl 107-7; K.C1 3-48; CaCl2 1 -53; MgSO4 0-69; NaHCO3 24-2. Transmembrane action potentials were recorded by means of standard microelectrode techniques from two subepicardial or two subendocardial fibres, respectively. Action potentials were obtained from both the normal zone and the infarct zone. The effect of the test solutions was examined at constant stimulation of 1000 ms. Premature stimuli were delivered after every eighth beat, after equilibration of 30 min cumulative doses of d-sotalol were administered ranging from 10~8 M to 5 x 10~4 M. Twenty-eight patients with clinically documented inducible sustained ventricular tachycardia were investigated. The stimulation protocol consisted of ventricular stimulation at sinus rhythm and ventricular pacing at a cycle length of 550,400 and 330 m using up to three extra stimuli. The pacing protocol was identical for each patient for investigation of both racemic sotalol and the d-isomer d-sotalol on different days. The intravenously applied © 1992 The European Society of Cardiology
20 J. Brachmann et al.
Table 1 Eleclrophysiological effects of d-sotalol on normal and infarcl zones
AE PAE LP-D (ms) RP-IZ (ms) RP-NZ (ms) QRS (ms) QTc (ms) RP-A
Control
d-Sotalol
— —
6/9 1/13
49 ±26 209 ±64 145±19 59±9 294 ±40 115 ± 20
53 ±29 285±8I 176± 16* 61±11 329 ±35* 177±52*
AE = antiarrhythmic efficacy; PAE = paradoxical arrhythmogenic effect; LP-D = late potential duration; RP = refractory period; QRS = QRS-duration; QTc = frequency corrected QT-interval; RPA = atnal effective refractory period; NZ = normal zone; IZ = infarct
Table 2 Specificity of antiarrhythmic drugs in blocking cardiac potassium channels Class la Ib Ic III
Agent Quinidine Disopyramide Lidocaine Flecainide Encainide Sotalol Amiodarone Clofilium Risotilide E-4031 UK-68 798 Tedisamil
K
I,,
Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes No No No Yes Yes Yes No No No No
Yes Yes No No No Yes No No No No No Yes
Presence of block assessed relative to therapeutically relevant concentrations. Modified from Colatsky et al. (1990).
dose was 1-Smg.kg ' except for two patients who received d-sotalol at 20 mg. kg"'. The end-point of the pacing protocol was either induction of sustained ventricular tachycardia or completion of the entire protocol. Sustained ventricular tachycardia was defined as a monomorphic ventricular tachycardia exceeding 30 s duration or termination due to haemodynamic impairment. The mean age of the study group was 58 ±13 years, 24 were male, four female. The presenting cardiac disease was coronary heart disease in 21 patients, cardiomyopathy in four and other cardiac diseases in three. All patients had been resistant to conventional antiarrhythmic agents prior to entry into the study. In vivo experiments using d-sotalol demonstrated significantly greater changes in electrophysiological parameters of the infarct zone as compared to the normal zone. Results are summarized in Table 1. Neither QRS duration nor duration of ventricular late potentials were significantly prolonged, supporting the concept of selective class HI action. Inducible ventricular tachycardia was
reproducibly suppressed in six of nine animals; only one experiment exhibited induction of sustained ventricular tachycardia after d-sotalol, while control stimulation produced only a brief ventricular salvo. In vitro experiments with d-sotalol were recorded from 10 canine experiments, demonstrating significant increases in action potential duration (APD) and effective refractory period (ERP). In normal myocardium, the increase was 14% in ADP and 13% in ERP respectively; in the infarct zone the increase in ADP was 12%, but 28% in ERP, significantly exceeding the effect in normal myocardium after 10~ 4 M dsotalol. Similar results were obtained in canine Purkinje fibres. There was a relative increase in the refractory period, whereas action potential amplitude and membrane resting potential were not significantly altered within a concentration range of 10"8 to 5 x 10~4 M. In the clinical study, d,l-sotalol significantly increased the sinus cycle length from 830±220 to 1050±210ms, while d-sotalol only increased this value from 820 ± 160 to 910±180 (P
European Heart Journal (1992) 13 {Supplement F), 19-22
Pros and cons of drugs that prolong ventricular refractoriness J. BRACHMANN, T. BEYER, W. SCHOLS, C. SCHMITT, M. MONTERO, W. KNOLLMANN, T. HILBEL AND W. KUBLER
Med. Univ. Klinik, Bergheimer Str. 58, 6900 Heidelberg, Germany
Introduction The clinical interest in drugs which prolong ventricular refractoriness and ventricular repolarization has greatly increased as a result of the CAST and ESVEM trials. While the classical antiarrhythmic therapy consisted of a variety of class I agents which inhibit the fast sodium system at different kinetics giving way to a variety of classifications, the use of these compounds to prevent sudden cardiac death following myocardial infarction has not been successful. On the contrary, it appears that after the CAST study class I agents at least may increase mortality in post-myocardial infarction patients with non-malignant ventricular arrhythmias as compared to placebo therapy. This has been further corroborated by the recently reported ESVEM trial, which initially was designed to evaluate the efficacy of Holter monitoring versus programmed electrical stimulation for determining effective antiarrhythmic drug therapy in patients with documented sustained ventricular tachycardia and/or ventricular fibrillation and/or cardiac arrest. Although the full study has not been published yet, it appears from the preliminary data that the class III agent, sotalol, with concomitant potent beta-blocking efficacy was clearly superior to all class I agents employed in this trial both with respect to acute efficacy and long-term recurrence rate. Furthermore, smaller studies employing the potent class III agent, amiodarone, have indicated the potential of this drug for decreasing mortality after myocardial infarction. This has led to the European Infarction Amiodarone Trial (EM I AT) which should provide the data on efficacy and safety of amiodarone in these patients in a few years. However, the clinical use of amiodarone is also limited by its pharmacokinetics and unfavourable side effect profile. This has led to an extensive search of the pharmaceutical industry to find new compounds which prolong repolarization and refractoriness (class III drugs). It is obvious from existing data that class III drugs demonstrate potent antiarrhythmic efficacy in all types of cardiac arrhythmias, similar to the results of both amiodarone and sotalol which have been used in clinical practice for some time. The renewed interest in class III drugs has only recently given way to development of new, more selective agents which prolong repolarization and refractoriness without affecting other electrophysiological parameters of the heart. Several class III antiarrhythmic drugs are currently in advanced preclinical and early clinical development for prevention of malignant ventricular arrhythCorrtspondcnce: J. Brachmann, MD, Med. Univ. Klinik, Bergheimer Sir. 58, 6900 Heidelberg, Germany. 0I95-668X/92/0F0019 + 04 SOS.00/0
mias. This interest has been directed specifically to the potent and selective methanesulfonanitide class III compounds, which are derivatives of the methanesulfonanitide dl-sotalol, if developments include, but are not exclusive to, E 4031, UK 68,798 and d-sotalol. The following data pertaining to results obtained with d-sotalol are taken as a major example of the efficacy of the new class III agents, which appear to provide the principal bases for antiarrhythmic therapy in the 1990s. The following experimental studies were performed in beagle dogs anaesthetized with pentobarbital. The animals were artificially ventilated and left thoracotomy was performed for ligation of the proximal left anterior descending (LAD) coronary artery and implantation of epicardial electrodes. In addition, modified composite electrodes were implanted to record electrical activity of the infarct zone as well as normal myocardium. The chest was closed and the animals allowed to recover before an electrophysiological study was performed at days 3-8. Programmed electrical stimulation was carried out with a constant current stimulator at twice diastolic threshold using a pacing protocol at basic driving cycles of 330 and 250 ms employing two premature extra stimuli. Administration of d-sotalol (4-5 mg. kg"') was followed by exact repetition of the stimulation protocol. The end-point was either the induction of a sustained tachyarrhythmia or the completion of the protocol. To perform the in vitro experiments following proximal LAD ligation, epicardial and endocardial preparations were carefully dissected and placed in a 30 ml special perfusion chamber to be superfused with modified Tyrode solution of the following composition (mM): NaHPO4 1-67; Na-glukonat 9-64; glucose 5-55; saccharose 7-6; NaCl 107-7; K.C1 3-48; CaCl2 1 -53; MgSO4 0-69; NaHCO3 24-2. Transmembrane action potentials were recorded by means of standard microelectrode techniques from two subepicardial or two subendocardial fibres, respectively. Action potentials were obtained from both the normal zone and the infarct zone. The effect of the test solutions was examined at constant stimulation of 1000 ms. Premature stimuli were delivered after every eighth beat, after equilibration of 30 min cumulative doses of d-sotalol were administered ranging from 10~8 M to 5 x 10~4 M. Twenty-eight patients with clinically documented inducible sustained ventricular tachycardia were investigated. The stimulation protocol consisted of ventricular stimulation at sinus rhythm and ventricular pacing at a cycle length of 550,400 and 330 m using up to three extra stimuli. The pacing protocol was identical for each patient for investigation of both racemic sotalol and the d-isomer d-sotalol on different days. The intravenously applied © 1992 The European Society of Cardiology
20 J. Brachmann et al.
Table 1 Eleclrophysiological effects of d-sotalol on normal and infarcl zones
AE PAE LP-D (ms) RP-IZ (ms) RP-NZ (ms) QRS (ms) QTc (ms) RP-A
Control
d-Sotalol
— —
6/9 1/13
49 ±26 209 ±64 145±19 59±9 294 ±40 115 ± 20
53 ±29 285±8I 176± 16* 61±11 329 ±35* 177±52*
AE = antiarrhythmic efficacy; PAE = paradoxical arrhythmogenic effect; LP-D = late potential duration; RP = refractory period; QRS = QRS-duration; QTc = frequency corrected QT-interval; RPA = atnal effective refractory period; NZ = normal zone; IZ = infarct
Table 2 Specificity of antiarrhythmic drugs in blocking cardiac potassium channels Class la Ib Ic III
Agent Quinidine Disopyramide Lidocaine Flecainide Encainide Sotalol Amiodarone Clofilium Risotilide E-4031 UK-68 798 Tedisamil
K
I,,
Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes No No No Yes Yes Yes No No No No
Yes Yes No No No Yes No No No No No Yes
Presence of block assessed relative to therapeutically relevant concentrations. Modified from Colatsky et al. (1990).
dose was 1-Smg.kg ' except for two patients who received d-sotalol at 20 mg. kg"'. The end-point of the pacing protocol was either induction of sustained ventricular tachycardia or completion of the entire protocol. Sustained ventricular tachycardia was defined as a monomorphic ventricular tachycardia exceeding 30 s duration or termination due to haemodynamic impairment. The mean age of the study group was 58 ±13 years, 24 were male, four female. The presenting cardiac disease was coronary heart disease in 21 patients, cardiomyopathy in four and other cardiac diseases in three. All patients had been resistant to conventional antiarrhythmic agents prior to entry into the study. In vivo experiments using d-sotalol demonstrated significantly greater changes in electrophysiological parameters of the infarct zone as compared to the normal zone. Results are summarized in Table 1. Neither QRS duration nor duration of ventricular late potentials were significantly prolonged, supporting the concept of selective class HI action. Inducible ventricular tachycardia was
reproducibly suppressed in six of nine animals; only one experiment exhibited induction of sustained ventricular tachycardia after d-sotalol, while control stimulation produced only a brief ventricular salvo. In vitro experiments with d-sotalol were recorded from 10 canine experiments, demonstrating significant increases in action potential duration (APD) and effective refractory period (ERP). In normal myocardium, the increase was 14% in ADP and 13% in ERP respectively; in the infarct zone the increase in ADP was 12%, but 28% in ERP, significantly exceeding the effect in normal myocardium after 10~ 4 M dsotalol. Similar results were obtained in canine Purkinje fibres. There was a relative increase in the refractory period, whereas action potential amplitude and membrane resting potential were not significantly altered within a concentration range of 10"8 to 5 x 10~4 M. In the clinical study, d,l-sotalol significantly increased the sinus cycle length from 830±220 to 1050±210ms, while d-sotalol only increased this value from 820 ± 160 to 910±180 (P
