CLINICAL STUDY: PEDIATRIC CARDIOLOGY
Flecainide and sotalol: a new combination therapy for refractory supraventricular tachycardia in children <1 year of age
Jack F. Price, MD*,
Naomi J. Kertesz, MD, FACC*,
Christopher S. Snyder, MD*,
Richard A. Friedman, MD, FACC* and
Arnold L. Fenrich, Jr, MD, FACC*,*
* Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA
Manuscript received April 13, 2001;
revised manuscript received October 19, 2001,
accepted November 2, 2001.
* Reprint requests and correspondence: Dr. Arnold L. Fenrich, Jr., Section of Pediatric Cardiology, MC 19345-C, Texas Children’s Hospital, 6621 Fannin, Houston, Texas 77030, USA.
arnoldf{at}bcm.tmc.edu
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Abstract
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OBJECTIVES: The goal of this study was to assess the efficacy and safety of the combination therapy of flecainide and sotalol for the treatment of refractory supraventricular tachycardia (SVT) in children <1 year of age.
BACKGROUND: Supraventricular tachycardia in infants can be refractory to single-drug as well as standard combination medical therapy. Radiofrequency ablation (RFA) is the definitive treatment of refractory SVT; however, interventional therapy poses a high risk of morbidity and mortality in this age group.
METHODS: A retrospective review was performed identifying infants who required flecainide and sotalol to control refractory SVT. Patient age, previous drug therapy, duration of treatment, flecainide levels and corrected QT intervals were recorded; 24 h Holter monitoring was utilized to gauge efficacy of treatment. Efficacy was defined as suppression of SVT to no more than rare nonsustained episodes or slowing of SVT to a clinically tolerable rate.
RESULTS: Ten patients (median age: 29 days, range: 1 to 241 days) failed at least two antiarrhythmic agents including either flecainide or sotalol as single agents before initiating combination therapy. Efficacy was achieved in all patients. The failure rate for therapy was reduced from 100% to 0% (95% confidence interval: 0% to 26%). The median doses used were: flecainide 100 mg/m2/day (range: 40 to 150 mg/m2/day) and sotalol 175 mg/m2/day (range: 100 to 250 mg/m2/day). Median duration of therapy was 16 months (range: 5 to 35 months). No proarrhythmia occurred.
CONCLUSIONS: The combination of flecainide and sotalol can safely and effectively control refractory SVT and may obviate the need for RFA in children <1 year.
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Abbreviations and Acronyms
| | WPW | | AET | | atrial ectopic tachycardia | | PJRT | | permanent form of junctional reciprocating tachycardia | | QTc | | corrected QT | | RFA | | radiofrequency ablation | | SVT | | supraventricular tachycardia | | WPW | | Wolff-Parkinson-White syndrome |
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The natural history of supraventricular tachycardia (SVT) in most infants includes resolution of the tachycardia by one year of age (1,2). Normally, pharmacologic therapy is used to suppress the tachycardia until spontaneous resolution occurs, but for some infants SVT is not controlled with a traditional first line agent such as digoxin or propranolol. If these agents fail, other antiarrhythmic medications such as amiodarone, flecainide and sotalol are frequently added or used as monotherapies (3–6). If SVT is refractory to conventional pharmacologic therapy, transcatheter radiofrequency ablation (RFA) can be used for definitive elimination of the arrhythmia substrate; however, this procedure poses a relatively high risk of morbidity and mortality in this age group (6,7).
Flecainide and sotalol have proven effective at controlling refractory SVT as single agents and with other antiarrhythmics in children (4,5,8–11). In addition, there is evidence for their efficacy when used together in adults (12); however, combined therapy has not yet been examined in the pediatric population. The purpose of this study was to assess the efficacy and safety of the combination of flecainide and sotalol for control of refractory SVT in infants.
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Methods
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We reviewed the medical records of all infants who were treated with the combination of flecainide and sotalol at Texas Children’s Hospital from June 1995 to August 1999. Inclusion criteria for our study consisted of a diagnosis of SVT, age <12 months at the time of diagnosis, failure to control SVT with flecainide or sotalol, no history of cardiac surgery and a 72-h minimum duration of combined flecainide and sotalol therapy. A 72-h minimum duration of treatment was chosen to ensure establishment of steady state drug concentrations. Patient age, previous drug therapy, duration of treatment, flecainide trough levels and corrected QT intervals (QTc) during combined therapy were recorded. The QTc was calculated from surface electrocardiograms using Bazett’s formula (13). Both medications were initiated in the hospital, and each patient was monitored as an inpatient via telemetry. Serum flecainide trough levels were measured at least five half-lives after initiation and after dose adjustments. Echocardiograms were performed on all patients before initiation of combined therapy to assess anatomy as well as ventricular size and function. Twenty-four hour ambulatory ECG monitoring (Holter) was utilized to gauge efficacy of treatment. Efficacy was defined as suppression of SVT to no more than rare nonsustained episodes of tachycardia or slowing of incessant SVT to a clinically tolerable rate (<160 beats/min).
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Results
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Patient profile.
Ten patients met inclusion criteria. Age at diagnosis ranged from 1 to 241 days (median: 29 days) (Table 1). Four infants were diagnosed with Wolff-Parkinson-White syndrome (WPW), four with the permanent form of junctional reciprocating tachycardia (PJRT) and two with atrial ectopic tachycardia (AET). Echocardiograms revealed normal cardiac anatomy in eight infants. Additional diagnoses included hypertrophic cardiomyopathy in one patient and a small secundum atrial septal defect in another. All infants had normal ventricular function by echocardiography, and none were too ill to begin oral antiarrhythmic therapy. Each patient had failed at least two antiarrhythmic agents, including either flecainide or sotalol as single agents, before beginning combination therapy. The median length of time that patients were treated with either flecainide or sotalol as single agents before initiation of combination therapy was 14 days (range: 6 days to 5 months). One patient was treated with combination therapy for <24 h. Flecainide was discontinued in that patient after only two doses due to physician bias.
Dosages and monitoring.
During combination therapy, the median starting dose of flecainide was 70 mg/m2/day and was divided into twice daily dosing. Dosages were adjusted for a therapeutic trough level of 200 to 800 ng/ml. Serum trough levels of flecainide ranged from 125 to 775 ng/ml (mean: 470 ng/ml). The median dose required to maintain efficacy was 100 mg/m2/day (range: 70 to 150 mg/m2/day). The median starting dose of sotalol was 100 mg/m2/day divided into twice daily dosing and was increased in four patients before efficacy was achieved at a median dose of 175 mg/m2/day (range: 100 to 250 mg/m2/day). Therapy was always initiated in the hospital, and most infants were monitored as inpatients for five to seven days before discharge.
Response to combined therapy.
During combined therapy, efficacy was achieved in all 10 patients (Table 2). Assuming a 50% reduction in the failure rate of medicinal therapy as clinically meaningful, the 95% confidence interval for failed combined therapy is 0% to 26%. Generally, normal sinus rhythm was observed by telemetry within 2 to 5 days, and efficacy was documented by Holter within 3 days to 90 days (median: 12 days). One patient did not have his first Holter placed until 90 days after initiation of combination therapy. Sinus rhythm with complete suppression of tachycardia was achieved in eight patients. Control of the tachycardia was achieved in the other two patients. Patient 5 remained in normal sinus rhythm with only rare nonsustained episodes of SVT. Patient 2 had incessant PJRT at a rate of 270 beats/min before beginning flecainide and sotalol. The SVT persisted during combined therapy but was reduced in frequency to occasional paroxysms at a rate of 140 beats/min. The median duration of therapy was 16 months (range: 5 to 35 months).
Side effects.
No proarrhythmia (torsades de pointe, other ventricular arrhythmia or incessant SVT) was observed during combination therapy. No bradycardia or atrioventricular node disturbances were noted. In patients without pre-excitation, the median QTc interval increased from 418 to 422 ms, and all remained <440 ms. Even though there was a slight increase in QTc, all remained in the normal range (<440 ms). Echocardiograms demonstrated normal ventricular function in each infant before initiation of combination therapy, and no patient showed physical signs of depressed cardiac function during treatment. No side effects were encountered.
Follow-up procedure.
Median length of follow-up for those infants who did not eventually undergo RFA was 17 months (range: 5 months to 40 months). Three patients remain free of SVT while off combination therapy. Two patients continue to be treated with flecainide and sotalol without recurrence of SVT. One other patient remained free of tachycardia for 14 months on combination therapy before being lost to follow-up. Four infants ultimately underwent RFA of their arrhythmia substrate, and SVT was eliminated in each patient without complication. The median age at RFA was 34 months, and median weight was 13 kg. Two patients underwent RFA due to recurrence of their SVT after discontinuation of combination therapy; another patient had incessant but slowed PJRT and was at risk of developing cardiomyopathy, and another underwent RFA at the parents’ request to discontinue medications. At the time of RFA, it was felt that all patients had reached an age and weight at which the risk of intervention was acceptable for the circumstances.
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Discussion
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Supraventricular tachycardia in infancy is sometimes difficult to control with traditional antiarrhythmic therapy. Several pharmacologic regimens have been proposed for the management of refractory SVT, including flecainide, amiodarone and sotalol as single agents or in combination with digoxin and/or propranolol (5,8–10). The combined use of flecainide and amiodarone has also been reported (11).
When SVT is refractory to pharmacologic therapy, transcatheter RFA has been used to eliminate the arrhythmia substrate in infants (3,7,14,15). While RFA can definitively eliminate SVT, an increased risk of morbidity and mortality is associated with this procedure when performed in infants (3,15,16). The Pediatric RFA Registry reported a complication rate of 10% in children weighing <15 kg (6). Additionally, Saul et al. (15) have shown that radiofrequency lesions placed in the atrial and ventricular myocardium of infant lambs increase in size during early rapid organ growth, raising concerns about possible long-term effects for very young children as they grow.
Natural course.
Because the natural course of SVT in infants favors resolution by one year of age, pharmacologic management of tachycardia may obviate the need for transcatheter RFA. Approximately 60% to 90% of infants with WPW undergo spontaneous resolution of their tachycardia by one year of age (17,18). Studies reviewing the natural history of AET vary widely with regard to resolution, but it appears that most infants who present at <6 months of age will be free of tachycardia after 12 months of antiarrhythmic therapy (19–23). Little has been reported about the natural course of PJRT in infancy, but flecainide has proven to be the most successful antiarrhythmic for control of this accessory pathway-mediated arrhythmia (3,4,24,25). However, PJRT can be difficult to control, and success with flecainide has been quite variable. For some infants with PJRT, reducing the frequency or slowing the rate of the tachycardia may be the best result pharmacologic therapy can afford (4,24,25).
Combination therapy.
In our study, the combination of flecainide and sotalol successfully controlled medically refractory SVT in each infant, including four with PJRT. One infant with PJRT continued to have paroxysms of tachycardia but at a reduced frequency and at a much slower rate. The decreased rate appeared to be clinically tolerable during close follow-up, and the patient showed no signs of cardiovascular compromise. Despite reported success as high as 100% when using flecainide alone to control PJRT, two infants in our study with PJRT failed to achieve control on flecainide at therapeutic trough levels and required the addition of sotalol (4).
Combination therapy allowed for delay of RFA in four infants until they were of a size and age considered safe to perform the procedure. Adding one more option to the armamentarium of medical management of refractory SVT in infants is important, as every effort should be made to control SVT with pharmacologic therapy before attempting ablation in this age group.
Safety and efficacy.
Flecainide, a class IC antiarrhythmic agent, and sotalol, with class II and III properties, appear to be safe and effective when used in combination. Flecainide acts to delay conduction but has no effect on the action potential duration. Sotalol delays repolarization and prolongs the plateau phase of the action potential. Since both antiarrhythmic agents have different mechanisms of action, their combination may enhance arrhythmia control even when each drug fails individually. In addition, both drugs prolong the refractory period of accessory pathways, which may also contribute to their effectiveness in combination.
Typically, flecainide is used with caution and close monitoring of serum levels, and it is also more likely to be used as a last resort for difficult to control pediatric tachyarrhythmias. Such careful use may, in part, be due to the findings of the Cardiac Arrhythmia Suppression Trial (26) that reported an increased risk of cardiac arrest among adults after myocardial infarction when taking flecainide as compared with placebo. Flecainide has also been associated with proarrhythmia in some children, and there are reports of an increased incidence of sudden death among patients with atrial flutter, structural heart disease and cardiomyopathies (16,27). On the other hand, when flecainide is used in children with structurally normal hearts, it has been shown to be both safe and effective for controlling SVT. Similarly, sotalol has also been reported to cause proarrhythmia, likely as a result of prolongation of the QT interval and the development of ventricular tachycardia (28). A recent study evaluating the pharmacokinetic and pharmacodynamic profile of sotalol revealed that neonates and infants tolerate the drug well and that a dosing regimen with 8-h intervals achieves the smallest fluctuation in steady state concentrations (29). We recommend that patients considered for combination therapy be hospitalized and closely monitored for proarrhythmia.
Conclusions.
The combination of flecainide and sotalol was both safe and effective for control of SVT in our cohort of infants, but it should be recognized that our population size was small. The use of this combination may obviate the need for transcatheter RFA in infants or allow for delay of such therapy until the patient is of an age and size associated with less morbidity and mortality. Despite the absence of proarrhythmia, inpatient monitoring of these children is indicated until more experience with the two drugs in combination is gained.
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Abstract
Methods