Author + information
- Received March 29, 1996
- Revision received April 18, 1997
- Accepted April 25, 1997
- Published online August 1, 1997.
- Wilhelm Haverkamp, MDA,*,
- Antonio Martinez-Rubio, MDA,
- Christiene Hief, MDA,
- Andreas Lammers, MDA,
- Stefan Mühlenkamp, MDA,
- Thomas Wichter, MDA,
- Günter Breithardt, MD, FESC, FACCA and
- Martin Borggrefe, MD, FESCA
- ↵*Dr. Wilhelm Haverkamp, Medizinische Klinik und Poliklinik, Innere Medizin C (Kardiologie, Angiologie), Westfälische Wilhelms-Universität Münster, 48129 Münster, Germany. E-mail: firstname.lastname@example.org.
Objectives. The aim of this study was to assess the antiarrhythmic efficacy and safety of d,l-sotalol in patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) and in survivors of cardiac arrest and to identify the factors that are associated with arrhythmia suppression and therefore might be helpful in predicting drug efficacy.
Background. Despite increasing use of the class III antiarrhythmic agent d,l-sotalol, data on its short- and long-term efficacy in a large patient cohort are lacking. Information on its long-term tolerability and safety is limited.
Methods. A total of 396 patients with inducible sustained VT or VF (VT/VF) underwent programmed stimulation before and after receiving oral d,l-sotalol (240 to 640 mg/day). Patients in whom VT/VF was rendered either noninducible or more difficult to induce (more extrastimuli or faster drive cycle length needed for VT/VF induction) were discharged on a regimen of oral d,l-sotalol.
Results. d,l-Sotalol suppressed VT/VF in 151 patients (38.1%) and rendered the arrhythmia more difficult to induce in 76 patients (19.2%). The extent of drug-induced prolongation of right ventricular refractoriness and a shorter VT cycle length at baseline were independent predictors of immediate drug efficacy. Torsade de pointes developed in seven patients (1.8%). Two hundred ten patients (53%) continued to receive d,l-sotalol and were followed up for 34 ± 18 months (mean ± SD). The actuarial rates for the absence of arrhythmic recurrence (either VT/VF or sudden death) at 1 and 3 years were 89% and 77%, respectively. Actuarial rates for overall survival at 1 and 3 years were 94% and 86%, respectively. VT/VF suppression by d,l-sotalol was an independent discriminant variable that separated patients with and without arrhythmia recurrence. However, noninducibility of VT/VF did not predict freedom from sudden death.
Conclusions. Oral d,l-sotalol is effective and safe in patients with VT/VF. However, sudden cardiac death develops in a significant proportion of patients, and programmed stimulation seems to be of limited value for its prediction.
Management of patients with symptomatic sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or aborted sudden death can be classified into two main categories—pharmacologic and nonpharmacologic. Nonpharmacologic management includes ablative techniques such as catheter ablation and antitachycardia surgery or use of an implantable cardioverter-defibrillator (ICD). Although the latter approaches have become increasingly important over the past decade, pharmacologic treatment remains the therapy of first choice for most patients with life-threatening ventricular tachyarrhythmias. As it has become increasingly difficult to advocate the use of class I antiarrhythmic agents, many centers are now preferentially using compounds that predominantly prolong action potential duration and refractoriness (i.e., class III agents like amiodarone or d,l-sotalol). However, data on the short- and long-term efficacy of d,l-sotalol in a large patient cohort are lacking [1, 2]. Furthermore, information regarding its long-term tolerability and safety is limited.
The purpose of this study was to assess the immediate and long-term efficacy and safety of d,l-sotalol in a large group of patients with malignant ventricular tachyarrhythmias undergoing programmed ventricular stimulation. The utility of clinical and electrophysiologic variables for predicting inducibility of sustained ventricular tachyarrhythmias after d,l-sotalol as well as outcome during long-term therapy were also evaluated.
1.1 Study patients.
The study group consisted of 396 patients (325 men and 71 women, mean age ± SD 56 ± 14 years) who underwent serial electrophysiologic testing for the treatment of VT or VF (VT/VF) or aborted sudden cardiac death. Patients were studied between January 1984 and June 1993. The clinical characteristics of the study group are outlined in Table 1.
Criteria excluding the use of d,l-sotalol were prospectively defined and included the following: 1) VT/VF occurring within the 1st 48 h after acute myocardial infarction or having other identifiable reversible causes; 2) congestive heart failure unresponsive to conventional therapy (exclusion was based on clinical findings, not on the degree of impairment of left ventricular ejection fraction); 3) asthma or chronic obstructive pulmonary disease requiring a bronchodilator; 4) a prior adverse reaction to a beta-adrenergic blocking agent; 5) severe renal insufficiency; and 6) the need for concomitant therapy with agents that lengthen the QT interval (such as tricyclic antidepressants).
1.2 Electrophysiologic study.
All electrophysiologic studies were performed with patients in the fasting, nonsedated state after they had given written informed consent. A drug-free baseline study was carried out after all antiarrhythmic drugs had been discontinued for ≥5 half-lives. Programmed electrical stimulation was performed by using conventional techniques of intracardiac recording and stimulation. The details of these procedures have previously been reported from our laboratory . Briefly, programmed ventricular stimulation was performed with single and double ventricular extrastimuli during sinus rhythm and paced ventricular drive cycles of 500, 430, 370 and 330 ms at twice diastolic threshold at the right ventricular apex and, subsequently, if no sustained VT/VF was inducible, at the right ventricular outflow tract. If neither VT nor VF was inducible, a third extrastimulus was introduced at a paced cycle length of 500 ms at the right ventricular apex and, subsequently, if necessary, at the right ventricular outflow tract. The end point of each study was the reproducible induction of sustained VT/VF or the completion of the stimulation protocol.
The following definitions were used: Sustained VTwas defined as VT that lasted >30 s or was hemodynamically intolerable and needed termination before 30 s. VT was considered nonsustainedif it terminated spontaneously within 30 s. Completion of the stimulation protocol without the induction of a sustained ventricular tachyarrhythmia was considered noninducibility. VT was considered to be more difficult to induceif more extrastimuli were necessary for VT induction than during baseline stimulation or if VT could be induced only at a basic drive rate ≥40 beats/min higher than the control rate. Inducibility was considered unchangedif VT/VF was initiated by the same mode of stimulation as during the control study.
1.4 Drug administration.
The initial dosage of d,l-sotalol was 80 mg orally every 12 h for the 1st 24 to 48 h. Dosage was then increased in stepwise fashion to up to 480 mg daily (160 mg every 8 h). After completion of dose titration and a minimum of 72 h of administration of the final dosage, programmed electrical stimulation was repeated. If the drug did not suppress the inducibility of VT/VF, the dosage was increased, if tolerated, up to a final dosage of 640 mg/day, and programmed electrical stimulation was again repeated at the higher dosage. In the individual patient, the maximally tolerated dosage was limited by the emergence of side effects or prolongation of the corrected QT (QTc) interval to >0.55 s.
1.5 Criteria for discharge on d,l-sotalol therapy and follow-up.
Long-term oral d,l-sotalol was used in those patients whose sustained tachyarrhythmia was either rendered noninducible or more difficult to induce after oral d,l-sotalol. The decision to continue d,l-sotalol in patients in whom VT/VF was harder to induce after d,l-sotalol was made on the basis of the results of a previously performed study demonstrating that increased difficulty in inducing VT was a sufficient criterion for predicting long-term efficacy of an antiarrhythmic drug regimen. Patients discharged with d,l-sotalol were followed up at 3, 6 and 12 months. After 1 year, the patients were seen at yearly intervals in the outpatient clinic. In patients not presenting regularly, follow-up information was obtained by telephone. Primary end points examined during follow-up were the occurrence of VT/VF or sudden cardiac death, discontinuation of d,l-sotalol due to drug-related side effects, patient compliance, and all other causes of death or severe sickness. All events that were not considered primary end points were considered censored events. Sudden deathwas defined as a witnessed out-of-hospital death occurring within 1 h of the onset of symptoms or any unwitnessed death occurring in a patient known to be alive and free of any symptoms 24 h before.
1.6 Data analysis.
Continuous data are presented as mean value ± SD. The Student ttest and chi-square test were used for univariate analysis. A p value < 0.05 was considered statistically significant. To assess the independent value of clinical and electrophysiologic variables in predicting the results of programmed ventricular stimulation during therapy with d,l-sotalol, stepwise logistic regression analysis was carried out by considering all variables that were identified as significantly different on univariate testing. Kaplan-Meier survival analysis with the log-rank test was used to report the estimates for the occurrence of study end points during follow-up. A patient was eliminated from survival analysis when the first event (primary end point event or censored event) occurred. Cox regression analysis was used to assess the independent value of various clinical and electrophysiologic variables for patient outcome during follow-up. For all statistical evaluation, the Statistical Package for the Social Sciences (SPSS for Windows, Release 5) was used .
2.1 Baseline electrophysiologic study.
During baseline electrophysiologic study, sustained VT was inducible in 354 patients (89.4%), VF was induced in the remaining 42 patients (10.6%). The mean cycle length of the induced VT was 272 ± 72 ms; the mean right ventricular effective refractory period, measured at a paced cycle length of 500 ms, was 232 ± 21 ms. The arrhythmia was induced with single extrastimuli in 47 patients (11.9%), double extrastimuli in 266 (67.2%) and triple extrastimuli in 83 (20.9%).
2.2 Short-term efficacy of d,l-sotalol.
Because of d,l-sotalol–related side effects, 17 patients (4.3%) did not undergo repeat programmed electrical stimulation. d,l-Sotalol, at a mean daily dose of 465 ± 90 mg, prevented the induction of sustained VT/VF in 151 patients (38.1%). In 119 patients (30.1%), <10 repetitive ventricular beats were induced; in the remaining 32 patients (8.1%), nonsustained VT with a maximum of 25 consecutive beats was elicited. d,l-Sotalol rendered inducibility of VT/VF more difficult in another 76 patients (19.2%). The majority of patients received a daily d,l-sotalol dose of either 480 mg (268 patients, 67.7%) or 320 mg (94 patients, 23.7%). The difference in the rate of VT/VF suppression at the two dose levels was not significant.
d,l-Sotalol increased sinus cycle length from 802 ± 161 ms at baseline to 1,092 ± 167 ms (p < 0.0001). The QT and QTc intervals increased from 0.37 ± 0.04 to 0.46 ± 0.06 s (p < 0.0001) and 0.41 ± 0.04 to 0.45 ± 0.05 s (p < 0.0001), respectively. The right ventricular effective refractory period increased by 19% from 232 ± 21 to 275 ± 26 ms (p < 0.0001). The cycle length of induced VT in patients who still had inducible arrhythmia while receiving d,l-sotalol increased by 13% from 272 ± 72 to 307 ± 75 ms (p < 0.0001). The short-term efficacy rate of d,l-sotalol did not differ statistically with respect to the type of underlying heart disease (Table 2).
2.3 Predictors of the short-term efficacy of d,l-sotalol.
The differences in clinical and electrophysiologic variables between patients with successful arrhythmia suppression after d,l-sotalol and those with still inducible VT/VF are listed in Table 3. At baseline, patients in whom VT/VF induction was suppressed had a shorter cycle length of the induced VT and a higher prevalence of inducible VF. At baseline, responders had a lower incidence of prior myocardial infarction and a higher left ventricular ejection fraction than those of patients with still inducible VT/VF. Patients whose baseline VT/VF was induced by three extrastimuli (i.e., at the end of the stimulation protocol) were more likely to have suppression of arrhythmia than were patients whose arrhythmia was induced by one or two extrastimuli. The differences in d,l-sotalol–induced increases in the QT and QTc intervals were not significant. However, successful VT/VF suppression was associated with a more marked increase of the right ventricular effective refractory periods. These differences remained statistically significant when a subgroup analysis of patients with coronary artery disease (CAD) was performed. Stepwise logistic regression analysis revealed that only the drug-induced increase of the right ventricular refractory periods and a shorter tachycardia cycle length at baseline predicted a favorable drug response.
No differences in the clinical and electrophysiologic variables were found between patients in whom VT/VF was more difficult to induce and those with an unchanged mode of arrhythmia induction during repeat programmed stimulation.
2.4 Proarrhythmia, adverse effects and in-hospital VT recurrence.
Side effects requiring discontinuation of d,l-sotalol during the short-term treatment phase were observed in 28 patients (7.1%). Proarrhythmic effects were noted in 10 patients (2.5%): Torsade de pointes developed in 7 patients (1.8%) (it developed during the titration phase in 4 patients, and after repeat electrophysiologic testing in another 3; hypokalemia was noted in 4 patients); in the remaining 3 patients (0.8%), a new and marked increase in the frequency of spontaneous episodes of sustained VT was noted. In patients with a proarrhythmic response, d,l-sotalol was immediately discontinued. Worsening of heart failure resulted in withdrawal of d,l-sotalol in another three patients (0.8%). Symptomatic hypotension or symptomatic bradycardia, or both, was noted in five patients (1.3%). Twelve patients had a spontaneous in-hospital recurrence of VT; in all 12, the recurrence was considered a short-term drug failure without evidence of proarrhythmia, and it resulted in discontinuation of d,l-sotalol. VT occurred at the end of the titration phase in 5 of the 12 patients (1.3% of the total study group). The remaining seven patients (1.8%) experienced their VT after repeat programmed electrical stimulation. In two of these patients, d,l-sotalol had suppressed the induction of sustained VT during programmed electrical stimulation.
2.5 Long-term efficacy of d,l-sotalol.
Two hundred ten patients (53%) were discharged receiving oral d,l-sotalol (mean daily dose 452 ± 98 mg). In 127 (60.5%) of the 210 patients, d,l-sotalol had prevented the induction of sustained VT/VF. Ventricular tachyarrhythmia was rendered more difficult to induce after d,l-sotalol than at baseline in another 63 patients (30%). A subgroup of 20 patients (9.5%) was discharged from the hospital without a change in inducibility. This group comprised patients who refused further drug testing or nonpharmacologic interventions such as antitachycardia surgery, catheter ablation or ICD implantation.
During a mean follow-up period of 34 ± 18 months, symptomatic recurrences of arrhythmic events, defined as either sudden cardiac death or symptomatic nonfatal VT, developed in 41 patients (19.5%). Actuarial rates for patients free of arrhythmic events at 1 and 3 years were 89% and 77%, respectively. There was no difference in event rates in relation to the type of underlying heart disease (Fig. 1). When only recurrences of symptomatic nonfatal VT (occurring in 24 patients [11.4%]) are considered, actuarial event rates at 1 and 3 years were 6% and 15%, respectively. Differences with regard to the type of heart disease present were not observed.
Twenty-five patients (11.9%) of the 210 patients died. Twenty-one patients (10%) died of cardiac causes (17 suddenly [8.1%] and 4 patients [2%] as a result of either myocardial infarction [n = 2] or change in “progressive heart failure” [n = 2]). Actuarial total survival at 1 and 3 years was 94% and 86%, respectively (Fig. 2). Actuarial sudden death rates at 1 and 3 years were 8% and 11% for patients with CAD and 6% and 25% for patients with dilated cardiomyopathy (DCM), respectively. None of the patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) died during follow-up. A decrease in d,l-sotalol dosage, by either the patient or the patient’s physician, preceded symptomatic nonfatal VT in three patients and sudden death in two patients.
2.6 Predictors of the long-term efficacy of d,l-sotalol.
Various clinical and electrophysiologic variables were studied to define variables that may predict arrhythmia recurrence during long-term oral d,l-sotalol therapy. A favorable response during programmed ventricular stimulation predicted a good outcome with regard to arrhythmic events: An arrhythmic event developed during follow-up in 19 (14.4%) of 132 patients who responded to short-term treatment with d,l-sotalol. In a subgroup analysis, the incidence of arrhythmic events did not depend on the number of ventricular beats induced during d,l-sotalol therapy (i.e., patients in whom <10 ventricular beats were induced during d,l-sotalol therapy did not have a better outcome than patients in whom >10 beats were provoked by repeat programmed electrical stimulation during therapy). By contrast, an arrhythmic event developed in 16 (27.5%) of 58 patients in whom the tachyarrhythmia had been more difficult to induce during repeat programmed stimulation and in 6 (30%) of the 20 patients who were discharged without any change in inducibility. Kaplan-Meier analysis revealed a significantly better outcome with regard to the recurrence of arrhythmic events (p < 0.001, log-rank test) and particularly the recurrence of nonfatal VT (p < 0.0002; log-rank test) (Fig. 3) in drug responders than in patients with persistent inducibility.
Mean age, gender, cardiac diagnosis, presenting arrhythmia, type of induced arrhythmia at baseline, left ventricular ejection fraction and the presence or absence of a prior myocardial infarction were not different in patients with and without arrhythmia recurrence. Similarly, there were no differences in electrocardiographic data, mean cycle length of the induced tachycardia, mode of tachycardia induction and d,l-sotalol dose at the time of discharge. ⇓
However, marked differences in electrophysiologic and clinical variables were found between patients who had sudden death and those who had either a nonfatal recurrence of VT or no arrhythmic event during follow-up. Sudden death occurred in 17 (8.1%) of the 210 patients receiving long-term d,l-sotalol therapy. In 13 (76.5%) of these 17 patients, d,l-sotalol had prevented the induction of a sustained ventricular tachyarrhythmia during repeat programmed electrical stimulation. In all but 1 of the 13 noninducible patients who died suddenly, <10 ventricular beats were induced during repeat programmed electrical stimulation. Accordingly, a favorable response during programmed ventricular stimulation did not predict a good outcome with regard to sudden cardiac death (Fig. 4). The arrhythmia induced at baseline in patients with sudden death had a significantly shorter cycle length than that of patients with a nonfatal recurrence of VT (235 ± 16 vs. 283 ± 12 ms, p < 0.02). A third extrastimulus was more often necessary at baseline for arrhythmia induction in the sudden death group than in the nonfatal VT group (7 [41%] of 17 vs. 2 patients [8%] of 24, p < 0.01). The mean d,l-sotalol dose at the time of discharge was significantly lower in the sudden death group than in the nonfatal VT group (390 ± 82 vs. 480 ± 94 mg/day). Furthermore, patients who died suddenly more often had a history of prior aborted sudden death (7 [41%] of 17 patients) than did patients with VT recurrence (2 [8%] of 24 patients, p < 0.01). Patients with sudden death also had a significantly higher left ventricular ejection fraction (46 ± 13%) than that of patients with nonfatal VT (34 ± 16%, p < 0.05). When patients with sudden death were compared with patients who survived, significant differences were found with respect to VT cycle length at baseline (235 ± 16 vs. 264 ± 62 ms, p < 0.05), the number of patients whose baseline arrhythmia needed three extrastimuli for induction (7 [42%] of 17 vs. 33 [22%] of 152, p < 0.05) and daily d,l-sotalol dose at the time of discharge (390 ± 82 vs. 458 ± 98 mg, p < 0.001).
On Cox regression analysis, short-term VT/VF suppression by d,l-sotalol was an independent discriminant variable that separated patients with and without arrhythmia recurrence or recurrence of symptomatic nonfatal VT during follow-up. However, noninducibility during drug treatment did not predict outcome with regard to the occurrence of sudden death. Cox regression analysis identified only a low dose of d,l-sotalol as an independent predictor of sudden death during follow-up. Other variables, such as VT cycle length and mode of arrhythmia induction at baseline, were no longer significant factors and therefore were not found to be independently predictive.
2.7 Adverse effects of d,l-sotalol during follow-up.
During follow-up, d,l-sotalol was discontinued because of side effects in 29 (13.8%) of the 210 patients receiving long-term d,l-sotalol therapy. Actuarial rates for the occurrence of d,l-sotalol–related side effects necessitating drug withdrawal at 1 and 3 years were 7% and 17%, respectively. Symptomatic hypotension or bradycardia resulting in withdrawal of d,l-sotalol was observed in seven (3.3%) and five (2.4%) patients, respectively. Worsening of heart failure was noted in five patients (1.7%). Another 12 patients (5.7%) discontinued drug treatment because of either fatigue or dizziness (n = 8 [3.8%]), sexual impotence (n = 2 [1%]), exacerbation of psoriasis (n = 1 [0.5%]) and exacerbation of preexisting obstructive pulmonary disease (n = 1 [0.5%]). Another five patients (2.4%) discontinued d,l-sotalol because of noncompliance.
d,l-Sotalol was first synthesized in 1960 and characterized in 1965 as a competitive beta-receptor antagonist . The action potential–prolonging properties of d,l-sotalol were first described in 1968 by Kaumann and Olson . Since that time, various reports [7–20]have documented the antiarrhythmic efficacy of d,l-sotalol in relatively small patient series.
3.1 Short-term antiarrhythmic efficacy of d,l-sotalol.
In the present study, oral d,l-sotalol suppressed the induction of sustained VT/VF in 151 (38.1%) of 396 patients. This success rate is similar to that of other studies [7–17], including the recently published Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial . However, lower short-term efficacy rates have also been reported [18–20]. In most of the latter studies, lower sotalol doses were used. Suppression rates did not differ significantly in relation to the type of underlying heart disease. There was a small but statistically significant difference in left ventricular ejection fraction between patients with arrhythmia suppression and those with still inducible VT/VF after d,l-sotalol, with ejection fraction found to be higher in the former group. Either significant differences or a tendency to a lower drug response rate in patients with more depressed left ventricular function have also been reported by others [16, 17]. However, efficacy rates after d,l-sotalol appear to vary less according to baseline left ventricular ejection fraction than do those of class I antiarrhythmic agents [22, 23].
In the present study, d,l-sotalol was particularly effective in patients with a shorter VT cycle length or inducible VF at baseline, in patients without a documented sustained VT and in those who needed three extrastimuli for induction of VT/VF. These findings suggest that d,l-sotalol has a particular efficacy in patients with an unstable arrhythmia that needs aggressive stimulation for induction. It has been suggested that in patients with fast ventricular tachyarrhythmias based on reentrant activation, the reentrant circuit has a shorter excitable gap than that in patients with slow tachyarrhythmias. On a theoretic basis, action potential–prolonging drugs that increase refractoriness should be more effective in either preventing or terminating fast tachyarrhythmias than slow tachyarrhythmias. Evidence for this hypothesis is given by experimental studies [24, 25]in which the effect of the class III agents RP62719 and d-sotalol, the dextrorotatory isomer of d,l-sotalol, were studied in a model of VT based on reentry around an anatomic obstacle in isolated rabbit hearts. In this model, the class III agents were less effective than various class I agents in terminating VT. Only VT with a short cycle length and small excitable gap was terminated. In the case of VT termination, refractory periods during VT increased by such an extent that the excitable gap became very small and was finally abolished at one site of the circuit, preventing continuation of VT. The cycle length of VT not terminated by the drug increased only moderately. In our study, VT cycle length increased only slightly in patients who still had inducible VT during repeat programmed electrical stimulation. On logistic regression analysis, a more marked increase in right ventricular refractory periods and a shorter VT cycle length independently predicted successful suppression of VT during repeat electrophysiologic testing. All other variables assessed lost their significance when logistic regression analysis was performed. These results suggest that the antiarrhythmic efficacy of d,l-sotalol is mainly based on its class III electrophysiologic activity and that beta-sympatholytic effects only play a minor role.
3.2 Long-term antiarrhythmic efficacy of d,l-sotalol.
In our study, long-term d,l-sotalol therapy was associated with a low incidence of arrhythmic events, defined as either nonfatal VT or sudden cardiac death. Event rates were only slightly higher in patients with DCM than in patients with CAD. However, our data do not answer the question whether this difference reflects a true difference in mortality not detected because of the small number of patients or if there is no difference at all. None of the patients with ARVC died. Patients with ARVC usually have a relatively good prognosis, and antiarrhythmic therapy primarily aims to prevent symptomatic VT recurrences. However, sudden death in patients with ARVC has been reported .
In most previous studies that assessed the long-term efficacy of oral d,l-sotalol, <50 patients were discharged receiving this drug. Only recently have the results of two larger studies been published. Kehoe et al. reported the results of a long-term, multicenter, open label prospective trial to evaluate the short- and long-term efficacy and safety of oral d,l-sotalol in patients with drug-refractory sustained ventricular tachyarrhythmia. Drug efficacy was assessed by programmed electrical stimulation in 269 patients, by Holter monitoring in 109 and by both methods in 38 patients. A total of 286 patients were discharged with d,l-sotalol. Arrhythmias recurred in 70 (24.5%) of the 286 patients and sudden death developed in 17 (5.9%). Recurrence rates are comparable with those in the present study. In the recently published ESVEM trial , 84 patients were discharged with oral d,l-sotalol. Actuarial probabilities of arrhythmia recurrence and sudden death at 1 year were 21% and 6%, respectively. The higher incidence of arrhythmic events after 1 year observed in the ESVEM trial may be at least partially related to differences in the arrhythmia definitions used. In the ESVEM trial , sustained VT was defined as VT lasting ≥15 s. In our study, 30 s of VT was required for the definition of sustained VT, and the recurrence of primarily symptomatic VT was assessed. In contrast to the ESVEM trial, repeated Holter monitoring was not routinely used in our patients during follow-up. This may have resulted in an underestimation of the arrhythmia incidence, particularly of asymptomatic VT.
3.3 Predictors of long-term antiarrhythmic efficacy.
We first examined the usefulness of various variables in discriminating between patients with and without arrhythmic events during long-term d,l-sotalol therapy as a composite end point. In addition, we examined whether there were any differences in the value of these variables for predicting recurrences of nonfatal VT and sudden death separately. Differentiation between arrhythmic recurrence and sudden death seems to be desirable because the two end points may represent different underlying mechanisms. Although it is contestable that most sustained VTs are due to reentry arising from a chronic arrhythmogenic substrate, at least in CAD after myocardial infarction, the mechanisms leading to sudden death are less clear. They may range from VT recurrence degenerating into VF to ischemia-induced VF and to other extracardiac mechanisms such as rupture of an aortic or arachnoideal aneurysm. Therefore, any attempt to combine these end points may lose important information. To our knowledge, the latter question has so far not been addressed by any other study.
With regard to the recurrence of an arrhythmic event and particularly recurrence of nonfatal VT, Cox regression analysis revealed that suppression of inducibility independently predicted a good outcome. A better outcome in patients with suppressed VT has also been reported by other investigators . In a previous study we demonstrated that increased difficulty in inducing VT during treatment with either a class I agent or amiodarone predicts freedom from nonfatal VT during long-term therapy. In contrast, in the present study, the incidence of VT recurrence in patients in whom VT/VF was harder to induce did not differ from that in patients without any change in difficulty of inducibility.
One important aspect of the present study is that programmed stimulation failed to predict freedom from sudden death during long-term oral d,l-sotalol therapy. Further analysis of the data revealed that patients who showed the attributes of those whose arrhythmia was relatively easy to suppress during short-term electrophysiologic testing (i.e., patients who had a short ventricular cycle length at baseline or needed three extrastimuli for VT/VF induction in the drug-free state), had the highest probability of dying suddenly during follow-up. Of 17 patients who died suddenly, 16 had complete suppression of inducible VT/VF (i.e., <10 ventricular beats induced during repeat programmed electrical stimulation). The daily dose of d,l-sotalol in patients who died suddenly was lower than that of surviving patients. Our data underline the previously mentioned diversity of mechanisms operative in patients with VT recurrence and sudden death, respectively.
3.4 Proarrhythmia and side effects.
The adverse effects of d,l-sotalol observed in the present study resulted from either beta-blockade or class III activity. Discontinuation of the drug because of side effects related to beta-blockade (hypotension, bradycardia, congestive heart failure) was necessary in 2% of the study group during the short-term treatment phase and in another 13.8% of patients during long-term treatment. The incidence of side effects was somewhat lower than that observed previously. Soyka et al. reported d,l-sotalol discontinuation in 16% of 1,288 patients who entered 12 randomized trials. It seems remarkable that, in our study, worsening of heart failure resulted in d,l-sotalol discontinuation during follow-up in only five (2.4%) of the 210 patients receiving long-term sotalol therapy.
Proarrhythmic effects developed in a total of 10 patients (2.5%). In three patients proarrhythmia manifested as an increased frequency and duration of episodes of sustained VT. There was a definite but relatively small incidence (1.8%) of torsade de pointes. That four of the seven patients with torsade de pointes had associated hypokalemia underlines that this form of proarrhythmia often has more than one cause. All episodes of torsade de pointes occurred during the early treatment phase. Patients with and without torsade de pointes did not differ in clinical or electrophysiologic characteristics. Ventricular tachyarrhythmias of the torsade de pointes type were not documented during follow-up. However, it cannot be excluded that some sudden deaths occurred as a consequence of torsade de pointes.
3.5 Limitations of the study.
This study has several limitations. 1) It is a retrospective study, although the criteria for the assessment of drug efficacy were prospectively designed. 2) Despite a large total patient group, subgroups classified according to the various types of underlying heart disease and responses to d,l-sotalol therapy were relatively small, particularly the subgroup of patients classified as nonresponders who were discharged receiving oral d,l-sotalol. The latter group comprised patients in whom d,l-sotalol had rendered the arrhythmia more difficult to induce as well as patients without a change in inducibility, thus limiting our ability to compare the long-term outcome of responders and nonresponders. 3) The stimulation protocol differed from that used by other investigators. In contrast to other electrophysiologic laboratories, we did not use three extrastimuli in at least two different drive cycle lengths. In our protocol of programmed electrical stimulation, three extrastimuli are delivered only at a drive cycle length of 500 ms; this factor probably limits the sensitivity of the protocol and therefore may have affected our results. However, our rate of suppression with oral d,l-sotalol is similar to that of other studies [15, 16]in which stimulation protocols with three extrastimuli at different drive cycle lengths were used.
This study demonstrates that, in patients with life-threatening ventricular tachyarrhythmias, d,l-sotalol is an effective antiarrhythmic agent from the standpoint of both safety and efficacy. Suppression of inducibility of VT/VF during programmed electrical stimulation is an excellent criterion for predicting a low incidence of VT recurrence during long-term d,l-sotalol administration. However, there was a relatively high incidence of sudden cardiac death during follow-up. Although the previously discussed methodologic limitations with regard to our stimulation protocol have to be considered, our study suggests that, with regard to sudden cardiac death, the predictive value of programmed electrical stimulation is low. The results also suggest that empirically guided administration of d,l-sotalol might be as effective as d,l-sotalol therapy guided by programmed electrical stimulation in preventing sudden cardiac death.
Use of the ICD in patients with life-threatening ventricular tachyarrhythmias has been shown to reduce the occurrence of sudden cardiac death. A recent retrospective comparison of ICD therapy with d,l-sotalol therapy suggested that outcome may be better in patients receiving an ICD. However, prospective studies comparing both the long-term effectiveness of electrophysiologically guided d,l-sotalol therapy and ICD efficacy are needed.
☆ This study was supported in part by the Franz-Loogen-Foundation, Düsseldorf, Germany.
- arrhythmogenic right ventricular cardiomyopathy
- coronary artery disease
- dilated cardiomyopathy
- Electrophysiologic Study Versus Electrocardiographic Monitoring
- implantable cardioverter-defibrillator
- corrected QT
- ventricular fibrillation
- ventricular tachycardia
- ventricular tachycardia or ventricular fibrillation
- Received March 29, 1996.
- Revision received April 18, 1997.
- Accepted April 25, 1997.
- The American College of Cardiology
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