Ignite Creation Date:
2024-05-05 @ 5:09 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00390546
Status:
COMPLETED
Last Update Posted:
2017-12-13
First Post:
2006-10-18
Brief Title:
Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Status:
COMPLETED
Status Verified Date:
2017-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a randomized double-blind multi-centered study to compare 6 months of medical treatment with digoxin or propranolol in infants with SVT Background SVT is the most common sustained arrhythmia of infancy Neither digoxin nor propranolol has been evaluated for pediatric use in a controlled trial in the context of SVT yet both medications are used frequently
Specific aims of the study
To determine whether propranolol and digoxin differ in the
1 Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
2 Time to first recurrence of SVT in infants treated with propranolol or digoxin
3 Incidence of adverse outcomes in infants treated with propranolol or digoxin
Specific aims of the study
To determine whether propranolol and digoxin differ in the
1 Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
2 Time to first recurrence of SVT in infants treated with propranolol or digoxin
3 Incidence of adverse outcomes in infants treated with propranolol or digoxin
Detailed Description:
The purpose of the proposed research is to conduct a randomized double-blind multi-centre study of two antiarrhythmic medications digoxin and propranolol to evaluate whether one of these medications is more effective in reducing risk of recurrent supraventricular tachycardia SVT in infants
SVT is the most common sustained arrhythmia of infancy occurring in 1 in 250-1000 children and is a serious health burden in Canada and internationally 1 5-8 SVT is a common clinical problem facing many health care providers including general pediatricians emergency room physicians nurses cardiologists and intensive care physicians SVT carries significant morbidity and mortality and patients typically receive long-term medical therapy Untreated an infant can tolerate SVT for only a short period before heart failure and shock or even death ensues The management of SVT is currently under debate and often appears to depend on physician preference 9 While spontaneous termination of the acute episode may occur 1 2 6 9 10 many infants require medical intervention to terminate the episode Vagal maneuvres and adenosine have reasonable success in terminating an acute SVT episode but other medications may also be required Once the acute episode is treated the physicians must make a decision whether or not to start maintenance chronic therapy
At present there is no clinical consensus for the management of SVT in infancy The rationale for chronic therapy in SVT is to prevent recurrences and to limit symptoms during recurrences Yet SVT recurrences are not readily predictable 11 Many medications are available to treat SVT however these medications have associated risks and there are psychosocial implications for families To date most medications used to treat infant SVT have not been evaluated in controlled studies of infants Thus at present physicians must make decisions about initiation and duration of chronic therapy and choice of medication in the absence of evidence from controlled clinical trials A prospective randomized clinical study is crucial to provide evidence to guide therapy of infant SVT
As a preliminary study to inform the proposed trial we carried out a survey of all pediatric cardiologists in North America 12 In this survey we presented hypothetical cases of infants with SVT and asked about acute and chronic management Several points are clear
11 different medications were chosen for the management of infant SVT
there was a discrepancy among respondents with respect to medication choices based on whether the respondent had additional electrophysiology training or not and
several physicians selected digoxin in infants who have Wolff-Parkinson-White syndrome this medication choice may have deleterious effects in these infants
Our survey identified that among the wide range of medications used to manage infant SVT the two most commonly used ones are digoxin and propranolol Digoxin and propranolol are both well established widely used medications in both infants and adults Eighty-five percent of survey respondents reported using one or both to manage infant SVT but did not rationalize their choice nor determine whether one or the other is better to reduce risk of SVT recurrence or whether one is associated with fewer adverse events Furthermore pediatric cardiologists and electrophysiologists differed in medication choice
Thus to provide evidence to improve clinical decision-making and infant health we propose to conduct a prospective randomized double-blind multi-centre study of digoxin and propranolol for treatment of infant SVT
The specific aims of the proposed trial are to determine whether these medications differ in the
1 Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
2 Time to first recurrence of SVT in infants treated with propranolol or digoxin
3 Incidence of adverse outcomes in infants treated with propranolol or digoxin BACKGROUND SUPRAVENTRICULAR TACHYCARDIA In infants and children SVT results primarily from an accessory connection between the atrium and ventricle 5 8-10 13 This provides the substrate for a reentrant circuit utilizing the normal conduction system and the accessory pathway resulting in an atrioventricular reciprocating tachycardia AVRT A similar reentrant circuit can exist within the atrioventricular node resulting in an atrioventricular nodal reentrant tachycardia AVNRT however this is much less common in infants 5 13 14 Both AVRT and AVNRT result in a very rapid heart rate with an attendant decrease in diastolic filling time and cardiac output The differentiation of these two mechanisms is not always easily made on the surface electrocardiogram ECG 8 15 and currently the same therapies are applied for both conditions 16
Most cases 61-73 of infant SVT occur by age 4 months 9 17 18 and almost all occur before the age of 12 months 1 2 5 6 9 13 17-19 In 1981 Garson et al reported data from one of the largest retrospective series encompassing 217 SVT referrals over 25 years 6 Infants who presented with SVT before 4 months of age had faster tachycardia rates and a greater risk of presenting with congestive heart failure CHF 24 than did older infants or children Although infants can tolerate SVT for 24 hours before signs of CHF ensue 1 CHF is seen in a significant number of patients 24-54 when they come to medical attention Infants with CHF can progress to cardiovascular collapse accounting for the mortality of 1-4 in infants with SVT 2 5 6 20
The acute management of infant SVT is debated and often depends on physician preference 9 In 9-50 of cases the acute SVT episode ends spontaneously 1 2 6 9 10 and in 70-90 of patients adenosine andor vagal maneuvres eg applying ice pack to the face work with reasonable success however other medications eg amiodarone may also be required 1 2 8 9 Once the acute episode is over the physician and family must make a decision about whether or not to start chronic therapy
SVT RECURRENCE CHRONIC THERAPY The rationale for chronic therapy in SVT is to prevent recurrences and to limit symptoms during recurrences 8 SVT can be repetitive but the recurrences are not readily predictable 11 There is a wide range-from 0 to 78-of reported recurrences of SVT even with medical treatment 1 2 6 19 21 There are several studies with reliable data see Table 1 at end but some reports of the predictors of recurrent episodes may include data that are not applicable to all patients and may involve invasive studies 21-23 The physician attitude towards chronic therapy has also changed While in Garsons 1981 study chronic medication was started in only 72 of cases our survey indicated that 98 of respondents would initiate chronic therapy 12 This likely reflects the goal of minimizing morbidity and mortality in the care of all children with heart disease In Garsons review recurrences were common 56 and most 75 occurred within 3 months of the initial SVT presentation 6 Perry et al observed that in 60 patients who presented by 2 months of age SVT had disappeared in 93 by 8 months of age but many had recurrences later in life 19 Tortoriello found that patients without pre-excitation had a low 17 risk of recurrence 4
Our knowledge of the natural history of infants with SVT is incomplete both in terms of the need for chronic therapy and the duration Despite the fact that the risk of recurrence is not known and may be 50 due to the potential for serious adverse outcomes most pediatric cardiologists advocate chronic therapy after an infant presents with SVT The early clinical course can be variable but most patients do not require medical therapy beyond the first few months of life 7 20 The duration of therapy has ranged over the studies but currently lasts 6 to 12 months after presentation 6 9 because of the uncertainties of the clinical course 20 24 25 The risk of recurrence during the first year of life has not been determined definitively
THE MEDICATIONS Chronic therapy for SVT usually entails daily antiarrhythmic medication see Table 2 below Currently choice of medication is guided by retrospective reviews rather than by controlled trials 3-6 16 17 26 Our survey identified that among the wide range of medications used to manage infant SVT the most commonly used are digoxin and propranolol 12
Table 2 Commonly used medications for the chronic treatment of supraventricular tachycardia Digoxin Propranolol Sotalol Amiodarone Flecainide Propafenone Verapamil Atenolol Nadolol Digoxin is a sodium-potassium exchange pump inhibitor that has neuro-humoral effects and effects on cardiac conduction Its efficacy as an antiarrhythmic drug is attributed to direct atrioventricular nodal blocking properties combined with parasympathetic vagal activation which slows sinus rate decreases conduction velocity and increases atrioventricular nodal refractoriness For decades digoxin has been reported to be the preferred medication to prevent recurrence of SVT in infants 1 2 and it remains a common choice 3 4 In one retrospective review of 26 cases of infant SVT Pfammatter Stockler found that 65 had no recurrences on prophylactic digoxin therapy 3 Deal et al reported that 61 of infants were treated with digoxin and that 37 of this group required additional or combination therapy most commonly with propranolol 2
Propranolol is a non-selective beta-adrenergic blocker that has some sodium blockade but primarily exerts its antiarrhythmic effects through antagonism of catecholamine-mediated effects on cardiac conduction This antagonism results in slowed conduction velocity increased refractoriness and reduced automaticity especially in sinoatrial and atrioventricular nodal tissue Propranolol is also reported to be effective in SVT 17 Retrospective reviews have not always found differences in recurrence rates among infants treated with digoxin versus propranolol some report equal efficacy in preventing recurrent SVT 4 5 17 while others report a lower recurrence with propranolol 27-29
Digoxin and propranolol have a wide range of reported efficacy for preventing recurrence of SVT 5 17 and neither digoxin nor propranolol is fully effective treatment failures can reach 26 17 and additional antiarrhythmics are often required 4 8 16 26 30-36 Digoxin and propranolol are often referred to as first-line agents ie the medications that will be started initially to prevent recurrences of SVT Several studies have reported on the use of medications in combination without specifying details see Table 1 There are limited data on side effect profiles of digoxin and propranolol 16 37 38 Despite this lack of data digoxin and propranolol are used over other agents whose side effect profiles have been the subject of greater scrutiny perhaps due to their relative newness 30-33 35 36 39 Both are frequently used for chronic therapy of infant SVT but they have never been compared in a controlled trial
WHY THE TRIAL IS NEEDED NOW Management of infant SVT is confounded by several factors including the variable clinical course the inability to predict recurrence and the unknown natural history in terms of resolution of arrhythmia substrate This creates a challenge for health care practitioners and families Our preliminary survey demonstrated a discrepancy between pediatric electrophysiologists and pediatric cardiologists in their medication choice for treatment of infant SVT 12 It is not clear why the experts the electrophysiologists manage SVT differently than do the majority of physicians who see infants with SVT Most importantly these treatment decisions are being made without clear evidence to support these choices The differences in medication choice may reflect concern over case reports of rapid conduction and atrial arrhythmias with digoxin use in the setting of Wolff-Parkinson-White syndrome 2 9 27 40 It may be that electrophysiologists do not choose digoxin because of reports of high recurrence rates 10 20 26 it is not clear whether digoxin poses a risk in the first year of life 17 41 Propranolol is reported to be effective at preventing recurrences and continues to be recommended for use 2 6 16 Furthermore interpretation of the existing body of knowledge poses several limitations For example almost all studies of SVT in childhood are retrospective in nature spanning many years and include studies of patients with varying forms of SVT including those with Wolff-Parkinson-White syndrome and those with structural heart disease In many cases treatment failures and successes are not defined consistently and multiple medication regimens are common At the conclusion of these studies reference is frequently made to the need for a controlled clinical trial The lack of controlled trial outcomes in turn is cited as a key limitation for interpreting existing published data 8 26
The Health Protection Branch of Health Canada and The Food and Drug Administration of the United States both recognize the need for controlled clinical trials in pediatric patients To our knowledge neither digoxin nor propranolol has been evaluated for pediatric use in a controlled trial in the context of SVT yet both medications are used frequently Therefore this study is needed because digoxin and propranolol continue to be used as the most common therapy for prevention of recurrent SVT There is a significant debate about their effectiveness with a division between experts in the field and general cardiologists There may be a large impact on patients if one medication is better than the other or has more adverse outcomes eg hospital admissions The results of this trial have significant potential for direct impact on infant health and provision of care in Canada and globally This is evidenced by the large number of electrophysiologists endorsing the trial
SVT is the most common sustained arrhythmia of infancy occurring in 1 in 250-1000 children and is a serious health burden in Canada and internationally 1 5-8 SVT is a common clinical problem facing many health care providers including general pediatricians emergency room physicians nurses cardiologists and intensive care physicians SVT carries significant morbidity and mortality and patients typically receive long-term medical therapy Untreated an infant can tolerate SVT for only a short period before heart failure and shock or even death ensues The management of SVT is currently under debate and often appears to depend on physician preference 9 While spontaneous termination of the acute episode may occur 1 2 6 9 10 many infants require medical intervention to terminate the episode Vagal maneuvres and adenosine have reasonable success in terminating an acute SVT episode but other medications may also be required Once the acute episode is treated the physicians must make a decision whether or not to start maintenance chronic therapy
At present there is no clinical consensus for the management of SVT in infancy The rationale for chronic therapy in SVT is to prevent recurrences and to limit symptoms during recurrences Yet SVT recurrences are not readily predictable 11 Many medications are available to treat SVT however these medications have associated risks and there are psychosocial implications for families To date most medications used to treat infant SVT have not been evaluated in controlled studies of infants Thus at present physicians must make decisions about initiation and duration of chronic therapy and choice of medication in the absence of evidence from controlled clinical trials A prospective randomized clinical study is crucial to provide evidence to guide therapy of infant SVT
As a preliminary study to inform the proposed trial we carried out a survey of all pediatric cardiologists in North America 12 In this survey we presented hypothetical cases of infants with SVT and asked about acute and chronic management Several points are clear
11 different medications were chosen for the management of infant SVT
there was a discrepancy among respondents with respect to medication choices based on whether the respondent had additional electrophysiology training or not and
several physicians selected digoxin in infants who have Wolff-Parkinson-White syndrome this medication choice may have deleterious effects in these infants
Our survey identified that among the wide range of medications used to manage infant SVT the two most commonly used ones are digoxin and propranolol Digoxin and propranolol are both well established widely used medications in both infants and adults Eighty-five percent of survey respondents reported using one or both to manage infant SVT but did not rationalize their choice nor determine whether one or the other is better to reduce risk of SVT recurrence or whether one is associated with fewer adverse events Furthermore pediatric cardiologists and electrophysiologists differed in medication choice
Thus to provide evidence to improve clinical decision-making and infant health we propose to conduct a prospective randomized double-blind multi-centre study of digoxin and propranolol for treatment of infant SVT
The specific aims of the proposed trial are to determine whether these medications differ in the
1 Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
2 Time to first recurrence of SVT in infants treated with propranolol or digoxin
3 Incidence of adverse outcomes in infants treated with propranolol or digoxin BACKGROUND SUPRAVENTRICULAR TACHYCARDIA In infants and children SVT results primarily from an accessory connection between the atrium and ventricle 5 8-10 13 This provides the substrate for a reentrant circuit utilizing the normal conduction system and the accessory pathway resulting in an atrioventricular reciprocating tachycardia AVRT A similar reentrant circuit can exist within the atrioventricular node resulting in an atrioventricular nodal reentrant tachycardia AVNRT however this is much less common in infants 5 13 14 Both AVRT and AVNRT result in a very rapid heart rate with an attendant decrease in diastolic filling time and cardiac output The differentiation of these two mechanisms is not always easily made on the surface electrocardiogram ECG 8 15 and currently the same therapies are applied for both conditions 16
Most cases 61-73 of infant SVT occur by age 4 months 9 17 18 and almost all occur before the age of 12 months 1 2 5 6 9 13 17-19 In 1981 Garson et al reported data from one of the largest retrospective series encompassing 217 SVT referrals over 25 years 6 Infants who presented with SVT before 4 months of age had faster tachycardia rates and a greater risk of presenting with congestive heart failure CHF 24 than did older infants or children Although infants can tolerate SVT for 24 hours before signs of CHF ensue 1 CHF is seen in a significant number of patients 24-54 when they come to medical attention Infants with CHF can progress to cardiovascular collapse accounting for the mortality of 1-4 in infants with SVT 2 5 6 20
The acute management of infant SVT is debated and often depends on physician preference 9 In 9-50 of cases the acute SVT episode ends spontaneously 1 2 6 9 10 and in 70-90 of patients adenosine andor vagal maneuvres eg applying ice pack to the face work with reasonable success however other medications eg amiodarone may also be required 1 2 8 9 Once the acute episode is over the physician and family must make a decision about whether or not to start chronic therapy
SVT RECURRENCE CHRONIC THERAPY The rationale for chronic therapy in SVT is to prevent recurrences and to limit symptoms during recurrences 8 SVT can be repetitive but the recurrences are not readily predictable 11 There is a wide range-from 0 to 78-of reported recurrences of SVT even with medical treatment 1 2 6 19 21 There are several studies with reliable data see Table 1 at end but some reports of the predictors of recurrent episodes may include data that are not applicable to all patients and may involve invasive studies 21-23 The physician attitude towards chronic therapy has also changed While in Garsons 1981 study chronic medication was started in only 72 of cases our survey indicated that 98 of respondents would initiate chronic therapy 12 This likely reflects the goal of minimizing morbidity and mortality in the care of all children with heart disease In Garsons review recurrences were common 56 and most 75 occurred within 3 months of the initial SVT presentation 6 Perry et al observed that in 60 patients who presented by 2 months of age SVT had disappeared in 93 by 8 months of age but many had recurrences later in life 19 Tortoriello found that patients without pre-excitation had a low 17 risk of recurrence 4
Our knowledge of the natural history of infants with SVT is incomplete both in terms of the need for chronic therapy and the duration Despite the fact that the risk of recurrence is not known and may be 50 due to the potential for serious adverse outcomes most pediatric cardiologists advocate chronic therapy after an infant presents with SVT The early clinical course can be variable but most patients do not require medical therapy beyond the first few months of life 7 20 The duration of therapy has ranged over the studies but currently lasts 6 to 12 months after presentation 6 9 because of the uncertainties of the clinical course 20 24 25 The risk of recurrence during the first year of life has not been determined definitively
THE MEDICATIONS Chronic therapy for SVT usually entails daily antiarrhythmic medication see Table 2 below Currently choice of medication is guided by retrospective reviews rather than by controlled trials 3-6 16 17 26 Our survey identified that among the wide range of medications used to manage infant SVT the most commonly used are digoxin and propranolol 12
Table 2 Commonly used medications for the chronic treatment of supraventricular tachycardia Digoxin Propranolol Sotalol Amiodarone Flecainide Propafenone Verapamil Atenolol Nadolol Digoxin is a sodium-potassium exchange pump inhibitor that has neuro-humoral effects and effects on cardiac conduction Its efficacy as an antiarrhythmic drug is attributed to direct atrioventricular nodal blocking properties combined with parasympathetic vagal activation which slows sinus rate decreases conduction velocity and increases atrioventricular nodal refractoriness For decades digoxin has been reported to be the preferred medication to prevent recurrence of SVT in infants 1 2 and it remains a common choice 3 4 In one retrospective review of 26 cases of infant SVT Pfammatter Stockler found that 65 had no recurrences on prophylactic digoxin therapy 3 Deal et al reported that 61 of infants were treated with digoxin and that 37 of this group required additional or combination therapy most commonly with propranolol 2
Propranolol is a non-selective beta-adrenergic blocker that has some sodium blockade but primarily exerts its antiarrhythmic effects through antagonism of catecholamine-mediated effects on cardiac conduction This antagonism results in slowed conduction velocity increased refractoriness and reduced automaticity especially in sinoatrial and atrioventricular nodal tissue Propranolol is also reported to be effective in SVT 17 Retrospective reviews have not always found differences in recurrence rates among infants treated with digoxin versus propranolol some report equal efficacy in preventing recurrent SVT 4 5 17 while others report a lower recurrence with propranolol 27-29
Digoxin and propranolol have a wide range of reported efficacy for preventing recurrence of SVT 5 17 and neither digoxin nor propranolol is fully effective treatment failures can reach 26 17 and additional antiarrhythmics are often required 4 8 16 26 30-36 Digoxin and propranolol are often referred to as first-line agents ie the medications that will be started initially to prevent recurrences of SVT Several studies have reported on the use of medications in combination without specifying details see Table 1 There are limited data on side effect profiles of digoxin and propranolol 16 37 38 Despite this lack of data digoxin and propranolol are used over other agents whose side effect profiles have been the subject of greater scrutiny perhaps due to their relative newness 30-33 35 36 39 Both are frequently used for chronic therapy of infant SVT but they have never been compared in a controlled trial
WHY THE TRIAL IS NEEDED NOW Management of infant SVT is confounded by several factors including the variable clinical course the inability to predict recurrence and the unknown natural history in terms of resolution of arrhythmia substrate This creates a challenge for health care practitioners and families Our preliminary survey demonstrated a discrepancy between pediatric electrophysiologists and pediatric cardiologists in their medication choice for treatment of infant SVT 12 It is not clear why the experts the electrophysiologists manage SVT differently than do the majority of physicians who see infants with SVT Most importantly these treatment decisions are being made without clear evidence to support these choices The differences in medication choice may reflect concern over case reports of rapid conduction and atrial arrhythmias with digoxin use in the setting of Wolff-Parkinson-White syndrome 2 9 27 40 It may be that electrophysiologists do not choose digoxin because of reports of high recurrence rates 10 20 26 it is not clear whether digoxin poses a risk in the first year of life 17 41 Propranolol is reported to be effective at preventing recurrences and continues to be recommended for use 2 6 16 Furthermore interpretation of the existing body of knowledge poses several limitations For example almost all studies of SVT in childhood are retrospective in nature spanning many years and include studies of patients with varying forms of SVT including those with Wolff-Parkinson-White syndrome and those with structural heart disease In many cases treatment failures and successes are not defined consistently and multiple medication regimens are common At the conclusion of these studies reference is frequently made to the need for a controlled clinical trial The lack of controlled trial outcomes in turn is cited as a key limitation for interpreting existing published data 8 26
The Health Protection Branch of Health Canada and The Food and Drug Administration of the United States both recognize the need for controlled clinical trials in pediatric patients To our knowledge neither digoxin nor propranolol has been evaluated for pediatric use in a controlled trial in the context of SVT yet both medications are used frequently Therefore this study is needed because digoxin and propranolol continue to be used as the most common therapy for prevention of recurrent SVT There is a significant debate about their effectiveness with a division between experts in the field and general cardiologists There may be a large impact on patients if one medication is better than the other or has more adverse outcomes eg hospital admissions The results of this trial have significant potential for direct impact on infant health and provision of care in Canada and globally This is evidenced by the large number of electrophysiologists endorsing the trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None