Specialized Pacing for Patients With Congenital Heart Disease

Study Overview
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Brief Summary
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The closed-loop stimulation (CLS) algorithm is a novel sensor-based technology that relies on the change in myocardial systolic impedance for modulation of the heart rate during physical and emotional stress.3 The pacing algorithm has been shown to be highly effective for a wide range of clinical scenarios. Despite the fact that congenital heart disease (CHD) patients are likely to derive significant benefit in terms of functional ability and aerobic capacity using this novel technology, the CLS system has not been adequately studied in this population. As many CHD patients also undergo epicardial placement of pacing systems at the time of concomitant cardiac surgery, CLS has been less often utilized in this population given almost no data in the setting of surgical electrode placement. The present study intends to examine the benefits of the CLS algorithm in the CHD population, employing the use of epicardial pacemaker systems in the study protocol.

Detailed Description
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Sinus node dysfunction is highly prevalent among patients with congenital heart disease, manifesting as resting bradycardia or chronotropic incompetence. As children and adults with congenital heart disease are now expected to have increasing life-expectancy; with well over 1 million adult patients currently living in North America,1 issues such as mental health, acquired comorbidities and their impact on overall cardiovascular health have assumed increased scrutiny. It is now understood that objective measures of aerobic capacity, such as peak VO2, peak VE/VCO2, and heart rate reserve predict all-cause mortality for adult patients with congenital heart disease. As the chronotropic response during exercise is a key determinant of aerobic capacity, improvement in sensor-based technology for heart rate support is expected to have a significant impact on functional capacity and longevity in this population. Some forms of congenital heart disease, such as single ventricle physiology after the Fontan population are especially likely to benefit, as cardiac output is determined almost exclusively by heart rate during exertion due to limited ability to augment cardiac stroke volume.2 It is also becoming increasingly clear that sedentary behaviors are highly relevant to overall cardiovascular health in the general adult population. Adult patients with congenital heart disease are at especially high risk for sedentary behavior as a result of 1) chronic restriction for physical activities based on ill-founded medical advice, 2) chronotropic incompetence resulting from prior surgical palliations and hemodynamic stressors, and 3) overestimation of physical activity. 5.0 Enrollment/Randomization Patient Enrollment: The treating physician will identify potential subjects with a previously implanted pacemaker and present a brief overview of the study; if the subject is interested, the study will be described in detail. Informed consent will be obtained by the investigator after discussing the study, including the voluntary nature of participation and notification the subject can withdraw at any time. Ample time for questions and answers will be allowed. The investigator will give the subject and his/her legal guardian the opportunity to take the consent home to think about it more, with the option to call or meet with the investigator to ask additional questions. If the subject and/or his/her parent/legal guardian agree to participate, the investigator will ask them to sign a written, informed consent and assent. A copy of the assent and consent will be given to the subject and/or his/her parent/legal guardian. Randomization Procedure: This will be a single-blind placebo-controlled randomized crossover study with 2 treatments: CLS-on versus CLS-off (accelerometer only). Each enrolled patient will receive both treatments for 3 months. The order of treatments will be randomized 1:1. Randomization There will be a 50:50 randomization, with half the subjects randomized to CLS-on then CLS-off, and half randomized to CLS-off then CLS-on. Subjects previously receiving rate-responsive pacing with CLS that are randomly selected to CLS-on will continue with the identical programmed parameters. For subjects not previously receiving rate-responsive pacing with CLS that are randomly selected to CLS-on nominal programming will be utilized with a base rate of 60 beats per minute. Subjects will then initiate treatment A (CLS-on or CLS-off) in a blinded fashion. At 3 months, subjects will undergo testing. After 3 months of treatment A, subjects will be reprogrammed to treatment B. Tracking of physical activity with the device accelerometer will continue during this period. After 3 months of treatment B, repeat testing will be repeated. Patients will be followed during both treatment phases per usual clinical routine. Patients who experience significant symptoms (extreme fatigue, debilitating palpitations, or other clinically relevant symptoms) will be evaluated by their treating physician. Subjects that have any adverse events during treatment A will discontinue treatment A and immediately crossover to treatment B. Subjects with events during treatment B will be removed from the study and unblinded. Further treatment will be determined by the treating physician.

Official Title
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A Randomized Trial of Closed Loop Stimulation After Epicardial Pacemaker Implantation for Congenital Heart Disease

Conditions
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Congenital Heart Disease, Bradycardia Sinus

Intervention / Treatment
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* Device: Closed loop stimulation
* Device: Standard rate response


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Congenital heart disease • Simple, moderate, or complex congenital heart disease Adolescent or adult age group (age >14 and <65 years) Significant sinus node dysfunction Atrial pacing percentage >70%11 Intrinsic dysfunction resulting from congenital lesion or cardiac surgery Secondary sinus node dysfunction due to antiarrhythmic drug therapy Existing, fully functional pacemaker or ICD with CLS capability Epicardial or transvenous route of pacemaker implantation Exclusion Criteria: Unable to complete cardiopulmonary exercise testing (CPET) Contraindication to CPET Decreased mental capacity or known psychiatric disorder Congestive heart failure, NYHA cass IV Total atrial tachyarrhythmia burden >20%

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Patient Enrollment: The treating physician will identify potential subjects with a previously implanted pacemaker and present a brief overview of the study. Informed consent will be obtained by the investigator after discussing the study, including the voluntary nature of participation and notification the subject can withdraw at any time. The investigator will give the subject and his/her legal guardian the opportunity to take the consent home to think about it more, with the option to call or meet with the investigator to ask additional questions. If the subject and/or his/her parent/legal guardian agree to participate, the investigator will ask them to sign a written, informed consent and assent. Randomization Procedure: This will be a single-blind placebo-controlled randomized crossover study with 2 treatments: CLS-on versus CLS-off (accelerometer only). Each enrolled patient will receive both treatments for 3 months. The order of treatments will be randomized 1:1.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLS-On<br>Subjects in this arm will be programmed to CLS-on to received closed loop stimulation-based pacing for 3 months, followed by a standard rate response for 3 months. | Device: Closed loop stimulation<br>* Closed loop stimulation is a physiologic, rate-adaptive pacing algorithm.<br>Device: Standard rate response<br>* Standard rate response is an algorithm to increase heartrate based on movement<br>|
| Active Comparator: CLS-Off<br>Subjects in this arm, will be placed in a standard rate response for 3 months, followed by CLS-on to received closed loop stimulation-based pacing for 3 months. | Device: Closed loop stimulation<br>* Closed loop stimulation is a physiologic, rate-adaptive pacing algorithm.<br>Device: Standard rate response<br>* Standard rate response is an algorithm to increase heartrate based on movement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Blunted or Unchanged Effect of Mental Stress on Heart Rate | Heart rate in response to mental stress during each intervention; a math test was performed during autonomic testing | 3 months after the start of each intervention, a total of 6 months | 
| Heart Rate Response During a 48-hour Assessment Period | Average heart rate as measured by Holter monitor for 48 hours during each intervention | 3 months after the start of each intervention, a total of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Oxygen Consumption During Each Intervention | Oxygen uptake as determined by cardiopulmonary gas exchange during a stress test under 4 conditions: Sitting/standing 60 seconds Kettlebell walking 110 seconds Stairs 176 seconds Sweeping 62 seconds | 3 months after the start of each intervention, a total of 6 months | 
| Quality of Life as Assessed by SF-36 | Quality of life as assessed by SF-36 questionnaire following each period of intervetion. SF- 36 investigates the standard of quality of life through a general health assessment and not specific to a particular disease, age or treatment group. It is a 36-item questionnaire measuring 8 domains [physical functioning, role limitations due to physical health (role physical), bodily pain, general health, energy, social functioning, role limitations due to emotional health (role emotional), and emotional wellbeing]. Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. | 3 months after the start of each intervention, a total of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pacemaker, Congenital heart disease, Sinus node dysfunction