Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Primary Purpose
Supraventricular Tachycardia
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Digoxin
Propranolol
Sponsored by
About this trial
This is an interventional treatment trial for Supraventricular Tachycardia
Eligibility Criteria
Inclusion Criteria:
- Presentation with SVT due to AVRT or AVNRT.
- Age 4 months or less at presentation.
- No major structural heart disease (patent foramen ovale and patent ductus arteriosus are allowable.
- No other significant co-morbid condition likely to result in non-compliance or death in next 6 months.
The SVT mechanism will be presumed to be AVRT or AVNRT if the ECG shows:
- Normal complex tachycardia with abrupt onset and offset;
- The RR interval remains relatively constant during tachycardia with heart rates of 220-310 bpm;
- VA (ventriculo-atrial) association [i.e., there is a 1:1 AV relationship (except for cases of proven AV nodal reentry with a 2:1 relationship between atrium and ventricle)]; and
- Termination of tachycardia with vagal maneuvres or adenosine with AV block or VA block.
Additional supportive information:
- The presence of a P wave in either the ST segment or T wave, or the presence of a P wave altering the terminal portion of the QRS complex;
- Spontaneous termination of the tachycardia with a P wave;
- Onset with prolongation of the PR interval;
- Altered rate with resolution of temporary bundle branch block;
- Esophageal or electrophysiology study confirming tachycardia mechanism.
Exclusion Criteria:
- Failure to obtain consent;
- Known hypersensitivity to either study medication or suspension;
- Structural heart disease other than a patent foramen ovale or patent ductus arteriosus;
- Persistent abnormal cardiac function documented by echocardiogram (shortening fraction <28%) in sinus rhythm;
- Pre-excitation (Wolff Parkinson White syndrome);
- Permanent junctional reciprocating tachycardia;
- Ectopic atrial tachycardia;
- Atrial flutter;
- Sick sinus syndrome or significant bradycardia;
- Long QT syndrome;
- Digoxin > 40 micrograms/kg total received within past 7 days
- Amiodarone >50 milligrams/kg total received within past month
- Asthma or obstructive airway disease;
- Renal failure.
Sites / Locations
- University of Southern California - Children's Hospital of Los Angeles
- Children's Hospital of Orange County
- The Children's Mercy Hospital
- Schneider Children's Hospital
- Duke University Medical Center
- Nationwide Children's Hospital Ohio
- Medical University of Charleston South Carolina
- Primary Children's Medical Centre
- Norfolk Children's Hospital of the King's Daughter's
- Northwest Pediatric Cardiology
- Stollery children's Hospital
- Sonia Franciosi
- Hospital for Sick Kids
- CHU Sainte-Justine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Propranolol
Digoxin
Arm Description
Single dose of 0.5 mg/kg per dose and increased to 1.0 mg/kg per dose ITD for the second and subsequent doses.
First 2 doses at 0.010 mg/kg per dose TID, then 0.0035 mg/kg per dose TID for the third and subsequent doses
Outcomes
Primary Outcome Measures
Incidence of Recurrent Supraventricular Tachycardia (SVT) Requiring Medical Intervention to Terminate the Episode.
Secondary Outcome Measures
Number of Treated Patients Experiencing First SVT Recurrence
Infants treated with propranolol or digoxin
Incidence of Adverse Outcomes in Infants With Propranolol or Digoxin
In relation to the study drugs
Full Information
NCT ID
NCT00390546
First Posted
October 18, 2006
Last Updated
November 16, 2017
Sponsor
University of British Columbia
Collaborators
The Hospital for Sick Children, University of Utah
1. Study Identification
Unique Protocol Identification Number
NCT00390546
Brief Title
Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Official Title
Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
October 2006 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia
Collaborators
The Hospital for Sick Children, University of Utah
4. Oversight
5. Study Description
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:
Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
Time to first recurrence of SVT in infants treated with propranolol or digoxin.
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 physician(s) 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:
Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin;
Time to first recurrence of SVT in infants treated with propranolol or digoxin;
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 and/or vagal maneuvres (e.g. applying ice pack to the face) work with reasonable success; however, other medications (e.g. 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 Garson's 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 Garson's 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", i.e. 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 (e.g. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Supraventricular Tachycardia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
72 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Propranolol
Arm Type
Experimental
Arm Description
Single dose of 0.5 mg/kg per dose and increased to 1.0 mg/kg per dose ITD for the second and subsequent doses.
Arm Title
Digoxin
Arm Type
Experimental
Arm Description
First 2 doses at 0.010 mg/kg per dose TID, then 0.0035 mg/kg per dose TID for the third and subsequent doses
Intervention Type
Drug
Intervention Name(s)
Digoxin
Intervention Type
Drug
Intervention Name(s)
Propranolol
Primary Outcome Measure Information:
Title
Incidence of Recurrent Supraventricular Tachycardia (SVT) Requiring Medical Intervention to Terminate the Episode.
Time Frame
6 months or until study endpoints were reached
Secondary Outcome Measure Information:
Title
Number of Treated Patients Experiencing First SVT Recurrence
Description
Infants treated with propranolol or digoxin
Time Frame
up to 110 days of treatment
Title
Incidence of Adverse Outcomes in Infants With Propranolol or Digoxin
Description
In relation to the study drugs
Time Frame
12 months
10. Eligibility
Sex
All
Maximum Age & Unit of Time
4 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Presentation with SVT due to AVRT or AVNRT.
Age 4 months or less at presentation.
No major structural heart disease (patent foramen ovale and patent ductus arteriosus are allowable.
No other significant co-morbid condition likely to result in non-compliance or death in next 6 months.
The SVT mechanism will be presumed to be AVRT or AVNRT if the ECG shows:
Normal complex tachycardia with abrupt onset and offset;
The RR interval remains relatively constant during tachycardia with heart rates of 220-310 bpm;
VA (ventriculo-atrial) association [i.e., there is a 1:1 AV relationship (except for cases of proven AV nodal reentry with a 2:1 relationship between atrium and ventricle)]; and
Termination of tachycardia with vagal maneuvres or adenosine with AV block or VA block.
Additional supportive information:
The presence of a P wave in either the ST segment or T wave, or the presence of a P wave altering the terminal portion of the QRS complex;
Spontaneous termination of the tachycardia with a P wave;
Onset with prolongation of the PR interval;
Altered rate with resolution of temporary bundle branch block;
Esophageal or electrophysiology study confirming tachycardia mechanism.
Exclusion Criteria:
Failure to obtain consent;
Known hypersensitivity to either study medication or suspension;
Structural heart disease other than a patent foramen ovale or patent ductus arteriosus;
Persistent abnormal cardiac function documented by echocardiogram (shortening fraction <28%) in sinus rhythm;
Pre-excitation (Wolff Parkinson White syndrome);
Permanent junctional reciprocating tachycardia;
Ectopic atrial tachycardia;
Atrial flutter;
Sick sinus syndrome or significant bradycardia;
Long QT syndrome;
Digoxin > 40 micrograms/kg total received within past 7 days
Amiodarone >50 milligrams/kg total received within past month
Asthma or obstructive airway disease;
Renal failure.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shubhayan Sanatani, MD
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Southern California - Children's Hospital of Los Angeles
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
Country
United States
Facility Name
The Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Schneider Children's Hospital
City
New Hyde Park
State/Province
New York
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
Country
United States
Facility Name
Nationwide Children's Hospital Ohio
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
Medical University of Charleston South Carolina
City
Charleston
State/Province
South Carolina
Country
United States
Facility Name
Primary Children's Medical Centre
City
Salt Lake City
State/Province
Utah
Country
United States
Facility Name
Norfolk Children's Hospital of the King's Daughter's
City
Norfolk
State/Province
Virginia
Country
United States
Facility Name
Northwest Pediatric Cardiology
City
Spokane
State/Province
Washington
Country
United States
Facility Name
Stollery children's Hospital
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Name
Sonia Franciosi
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H3N1
Country
Canada
Facility Name
Hospital for Sick Kids
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
CHU Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
22962431
Citation
Sanatani S, Potts JE, Reed JH, Saul JP, Stephenson EA, Gibbs KA, Anderson CC, Mackie AS, Ro PS, Tisma-Dupanovic S, Kanter RJ, Batra AS, Fournier A, Blaufox AD, Singh HR, Ross BA, Wong KK, Bar-Cohen Y, McCrindle BW, Etheridge SP. The study of antiarrhythmic medications in infancy (SAMIS): a multicenter, randomized controlled trial comparing the efficacy and safety of digoxin versus propranolol for prophylaxis of supraventricular tachycardia in infants. Circ Arrhythm Electrophysiol. 2012 Oct;5(5):984-91. doi: 10.1161/CIRCEP.112.972620. Epub 2012 Sep 8.
Results Reference
derived
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Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
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