Specialized Pacing for Patients With Congenital Heart Disease

• ClinicalTrials.gov Identifier: NCT03361189
• Recruitment Status: Not yet recruiting
• First Posted: December 4, 2017
• Last Update Posted: April 23, 2019
• Sponsor: University of California, Los Angeles
• Collaborator: Biotronik, Inc.
• Information provided by (Responsible Party): Jeremy P. Moore, MD, University of California, Los Angeles

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Congenital Heart Disease; Bradycardia Sinus	Device: Closed loop stimulation	Phase 2; Phase 3

Detailed Description:

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.

The Specific Aims of this protocol are:

Primary Aim: To determine the performance of CLS for CHD patients after both transvenous and epicardial pacemaker implantation

Hypothesis: CLS after either pacemaker implantation strategy will result in equivalent improvements in autonomic control of chronotropic response as compared to standard sensor based rate modulation

Primary outcome: Objective change in autonomic modulation of heart rate while randomized to CLS pacing with mental stress and ANSAR testing

Secondary outcomes: Increase in aerobic capacity, non-sedentary behavior, and quality of life while randomized to CLS pacing

This will be a single-blind (blinded subjects) randomized cross-over study, in which each patient will receive treatment A (CLS-on or CLS-off) for 3 months followed by treatment B (CLS-off or CLS-on).

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%

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.

6.0 Study Procedures

All patients enrolled in the study will undergo the following baseline assessment and data collection:

• Demographics (age, gender, race/ethnicity)
• Review of data confirming the presence of sinus node dysfunction with chronotropic incompetence (prior exercise stress test and/or Holter monitor results)
• Review of clinical history, including age at diagnosis, congenital diagnosis, surgical history, and cardiac device implant procedure
• Antiarrhythmic drugs prescribed and the respective dosages
• Prior ECG and echocardiography and advanced imaging reports

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. During the testing period, subjects will be tracked with the implanted device accelerometer to quantify physical activity. At 3 months, all subjects will undergo testing as noted below.

• 24 hour Holter monitoring with spectral analysis
• Cycle-ergometer stress with cardiopulmonary gas exchange analysis
• Free form activities with cardiopulmonary gas exchange analysis (staircase walking, sweeping, suitcase lifting with right and left arms, etc.)
• ANSAR testing (hand grip, Valsalva, deep breathing, and orthostatic challenge)
• Mental stress test with continuous electrocardiographic recording
• Quality of life questionnaire (SF-36/Somerville index)

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 as described above. At the conclusion of the study, patients will be asked which pacing mode is preferred.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment

Intervention 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 (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial of Closed Loop Stimulation After Epicardial Pacemaker Implantation for Congenital Heart Disease
• Estimated Study Start Date: January 1, 2020
• Estimated Primary Completion Date: February 1, 2023
• Estimated Study Completion Date: August 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: CLS-On; Subjects in this arm will programmed to CLS-on to received closed loop stimulation-based pacing.	Device: Closed loop stimulation; Closed loop stimulation is a physiologic, rate-adaptive pacing algorithm.
No Intervention: CLS-Off; Subjects in this arm, will be placed in a standard pacing mode (i.e. AAIR or DDDR).

Outcome Measures

Primary Outcome Measures :

1. Heart rate response [ Time Frame: 3 months ]
   Heart rate in response to mental stress and autonomic input will be asssessed

Secondary Outcome Measures :

1. Oxygen uptake [ Time Frame: 3 months ]
   Oxygen uptake will be determined by cardiopulmonary gas exchange
2. Quality of life [ Time Frame: 3 months ]
   Quality of life will be assessed by SF-36 questionnaire

Eligibility Criteria

• Ages Eligible for Study: 14 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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%

Contacts and Locations

Contacts

Contact: Jeremy P Moore, MD, MS; 310-267-7600; jpmoore@mednet.ucla.edu

Contact: Kevin M Shannon, MD; 310-267-7600; kshannon@mednet.ucla.edu

Locations

United States, California

University of California at Los Angeles

Los Angeles, California, United States, 90095

Contact: Jeremy P Moore, MD, MS 310-267-7600 jpmoore@mednet.ucla.edu

Contact: Kevin M Shannon, MD 310-267-7600 kshannon@mednet.ucla.edu

Sponsors and Collaborators

University of California, Los Angeles

Biotronik, Inc.

More Information

Publications of Results:

Abi-Samra FM, Singh N, Rosin BL, Dwyer JV, Miller CD; CLEAR Study Investigators. Effect of rate-adaptive pacing on performance and physiological parameters during activities of daily living in the elderly: results from the CLEAR (Cylos Responds with Physiologic Rate Changes during Daily Activities) study. Europace. 2013 Jun;15(6):849-56. doi: 10.1093/europace/eus425. Epub 2013 Feb 17.

Bouchardy J, Therrien J, Pilote L, Ionescu-Ittu R, Martucci G, Bottega N, Marelli AJ. Atrial arrhythmias in adults with congenital heart disease. Circulation. 2009 Oct 27;120(17):1679-86. doi: 10.1161/CIRCULATIONAHA.109.866319. Epub 2009 Oct 12.

Chandiramani S, Cohorn LC, Chandiramani S. Heart rate changes during acute mental stress with closed loop stimulation: report on two single-blinded, pacemaker studies. Pacing Clin Electrophysiol. 2007 Aug;30(8):976-84.

Coenen M, Malinowski K, Spitzer W, Schuchert A, Schmitz D, Anelli-Monti M, Maier SK, Estlinbaum W, Bauer A, Muehling H, Kalscheur F, Puerner K, Boergel J, Osswald S. Closed loop stimulation and accelerometer-based rate adaptation: results of the PROVIDE study. Europace. 2008 Mar;10(3):327-33. doi: 10.1093/europace/eun024. Epub 2008 Feb 13.

Di Pino A, Agati S, Bianca I. Efficacy of closed-loop stimulation with epicardial leads in an infant with congenital atrioventricular block. Europace. 2008 Mar;10(3):334-5. doi: 10.1093/europace/eum299. Epub 2008 Jan 20.

Hedman A, Nordlander R. Changes in QT and Q-aT intervals induced by mental and physical stress with fixed rate and atrial triggered ventricular inhibited cardiac pacing. Pacing Clin Electrophysiol. 1988 Oct;11(10):1426-31.

Osswald S, Cron T, Grädel C, Hilti P, Lippert M, Ströbel J, Schaldach M, Buser P, Pfisterer M. Closed-loop stimulation using intracardiac impedance as a sensor principle: correlation of right ventricular dP/dtmax and intracardiac impedance during dobutamine stress test. Pacing Clin Electrophysiol. 2000 Oct;23(10 Pt 1):1502-8.

Quaglione R, Calcagnini G, Censi F, Piccirilli F, Iannucci L, Raveggi M, Biancalana G, Bartolini P. Autonomic function during closed loop stimulation and fixed rate pacing: heart rate variability analysis from 24-hour Holter recordings. Pacing Clin Electrophysiol. 2010 Mar;33(3):337-42. doi: 10.1111/j.1540-8159.2009.02615.x. Epub 2009 Nov 4.

Santini M, Ricci R, Pignalberi C, Biancalana G, Censi F, Calcagnini G, Bartolini P, Barbaro V. Effect of autonomic stressors on rate control in pacemakers using ventricular impedance signal. Pacing Clin Electrophysiol. 2004 Jan;27(1):24-32.

Shachar GB, Fuhrman BP, Wang Y, Lucas RV Jr, Lock JE. Rest and exercise hemodynamics after the Fontan procedure. Circulation. 1982 Jun;65(6):1043-8.

• Responsible Party: Jeremy P. Moore, MD, Associate Professor of Pediatrics, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT03361189
• Other Study ID Numbers: 17-000932
• First Posted: December 4, 2017
• Last Update Posted: April 23, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Jeremy P. Moore, MD, University of California, Los Angeles:

Congenital heart disease; Pacemaker; Sinus node dysfunction

Additional relevant MeSH terms:

Heart Diseases; Heart Defects, Congenital; Bradycardia; Cardiovascular Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Arrhythmias, Cardiac; Pathologic Processes