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ASV Effects on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea. (AMEND)

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ClinicalTrials.gov Identifier: NCT02116140
Recruitment Status : Recruiting
First Posted : April 16, 2014
Last Update Posted : November 21, 2019
Sponsor:
Information provided by (Responsible Party):
Rob Beanlands, Ottawa Heart Institute Research Corporation

Tracking Information
First Submitted Date  ICMJE April 14, 2014
First Posted Date  ICMJE April 16, 2014
Last Update Posted Date November 21, 2019
Study Start Date  ICMJE July 2012
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
  • ASV therapy yields a reduction in the rate of oxidative metabolism as measured by [11C]acetate kinetics using PET imaging in patients with HF, OSA and/or CSA [ Time Frame: 6 months ]
  • ASV therapy yields an improvement in energy transduction from oxidative metabolism to stroke work as measured by an increase in the daytime work-metabolic index inpatients with HF, OSA and/or CSA. [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
  • ASV for CSA or OSA in patients with HF and sleep apnea will normalize daytime myocardial SN pre-synaptic function measured by [11C]HED retention on PET imaging, [ Time Frame: 6 months ]
  • ASV for CSA or OSA in patients with HF and sleep apnea will normalize daytime sympathetic contributions to heart rate variability [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ASV Effects on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea.
Official Title  ICMJE Effects of Long Term Adaptive Servo Ventilation Therapy on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea. The AMEND Sub-study
Brief Summary

Obstructive sleep apnea (OSA), central sleep apnea (CSA) and heart failure (HF) are states of metabolic demand and sympathetic nervous system (SNS) activation. In patients with sleep apnea and HF, continuous positive airway pressure (CPAP) initially may reduce left ventricular (LV)stroke volume (SV) but subsequently improves and LV function. This may relate to an early beneficial effect on myocardial energetics through early reduction in metabolic demand that subsequently leads to improved efficiency of LV contraction. However, it is not clear whether long-term adaptive servo-ventilation (ASV) favorably affects cardiac energetics. Any such benefit may also relate to reduced sympathetic nervous system (SNS) activation. However its effect on myocardial SNS function is also not well studied.

In a pilot study we demonstrated early (6 week) beneficial effects of CPAP in patients with OSA and HF. The current proposal (AMEND) is a unique substudy of the recently funded ADVENT-HF trial (Adaptive Servo Ventilation for Therapy of Sleep Apnea in HeartFailure) (NCT01128816; CIHR; D. Bradley, PI).

We propose to evaluate the long-term (6 month) effects of ASV on daytime 1) oxidative metabolism; 2) the work metabolic index (WMI) as an estimate of mechanical efficiency; 3) myocardial sympathetic nerve (SN) pre-synaptic function; and 4) heart rate (HR) variability in patients with HF and coexisting OSA or CSA. In conjunction with echocardiographic measures of LV stroke work, positron emission tomography (PET) derived [11C] acetate kinetics will be used as a measure of oxidative metabolism, to determine the WMI. [11C] hydroxyephedrine (HED) retention will be used to measure cardiac SN pre-synaptic function.

Primary Hypotheses: In patients with chronic stable HF and CSA or OSA without excessive daytime sleepiness (EDS), long-term (6-month) ASV therapy yields:

  1. Beneficial effects on daytime myocardial metabolism leading to a reduction in the rate of oxidative metabolism as measured by [11C]acetate kinetics using PET imaging;
  2. Improvement in energy transduction from oxidative metabolism to stroke work as measured by an increase in the daytime work-metabolic index.
Detailed Description

DEFINITIONS Obstructive sleep apnea (OSA) is characterized by: episodes of partial or complete pharyngeal collapse leading to obstructive hypopnea and apnea during sleep. OSA often coexists with HF.

Central sleep apnea (CSA) is characterized by: reductions in central respiratory drive during sleep that leads to episodes of partial or complete cessation of airflow. CSA often co-exists with HF.

Continuous positive airway pressure(CPAP) delivers air through a nasal or oral interface to preserve upper airway patency. It is a treatment for symptomatic OSA or some patients with CSA.

Adaptive Servoventilation (ASV) is effective in alleviating OSA and CSA. It provides expiratory positive pressure to alleviate OSA, and inspiratory positive airway pressure to eliminate CSA.

Oxidative metabolism: utilization of substrates via the tricarboxylic acid cycle for Adenosine triphosphate (ATP) production; it is linked to myocardial oxygen consumption and can be measured with [11C]acetate PET.

The work-metabolic index (WMI) is the external work (minute-work) of the left ventricle corrected for the rate of oxidative metabolism and is an estimate of mechanical efficiency.

Myocardial sympathetic neuron (SN) presynaptic function is the measure of uptake and storage of neuronal catecholamines in the heart measured by [11C]hydroxyephedrine (HED) PET.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Heart Failure
  • Obstructive Sleep Apnea
  • Central Sleep Apnea
Intervention  ICMJE Other: [C11]Acetate and HED PET
Study Arms  ICMJE Experimental: [C11]Acetate HED PET

AMEND is a single centre substudy of the ADVENT-HF trial. This substudy is a clinical physiologic proposal designed to determine the effects of long-term (6 months) ASV on cardiac energetics and SN function in patients with chronic stable HF and sleep apnea extending our previous evaluation of short-term CPAP in patients with OSA and HF.

All subjects consenting to the ADVENT primary trial will be eligible to participate in the substudy.

Substudy consenting patients will have [11C]acetate and [11C]HED PET imaging; HR variability; plasma norepinephrine (NE) levels, urine normetanephrine levels within 2 weeks of the sleep study. Baseline measurements will be repeated after 6 months in all patients.

Intervention: Other: [C11]Acetate and HED PET
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 14, 2014)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

This study (AMEND) is a single centre substudy of the ADVENT-HF trial (NCT01128816). ADVENT-HF is a RCT that will test the effects of ASV on morbidity and mortality in patients with HF and OSA or CSA.

The AMEND substudy is a clinical physiologic proposal designed to determine the effects of long-term (6 months) ASV on cardiac energetics and SN function in patients with chronic stable HF and sleep apnea extending our previous evaluation of short-term CPAP in patients with OSA and HF

Inclusion Criteria:

  1. American Heart Association (AHA) Stages B, C and D heart failure due to ischemic, idiopathic or hypertensive causes with;
  2. systolic dysfunction, ejection fraction (EF) ≤45% by echocardiography
  3. optimal medical therapy conforming to the AHA guidelines (and for this proposal, stable therapy for >4 weeks)
  4. sleep apnea with an Apnea/hypopnea Index ≥15, which will be divided into OSA (> 50% events obstructive), or CSA (> 50% of events central in nature)for patients with OSA, an Epworth Sleepiness Scale score of >10 and no or mild daytime sleepiness (by the International Classification of Sleep Disorders
  5. age >18 years;
  6. willingness to receive ASV therapy
  7. informed consent

Exclusion Criteria:

  1. Myocardial infarction, cardiac surgery or angioplasty within 3 months prior to enrollment,
  2. listed for heart transplantation,
  3. HF due to primary valvular heart disease,
  4. pregnancy
  5. current use of ASV or CPAP.
  6. awaiting revascularization;
  7. previous cardiac transplant;
  8. life expectancy less than 6 months due to other co-morbidity;
  9. a large transmural scar defined on previous perfusion imaging (severe resting perfusion defect (<50% uptake) occupying >25% of the LV);
  10. concomitant treatment or use of: tricyclic antidepressants, cocaine or drugs which may alter catecholamine uptake.

For heart rate variability (HRV) analysis additional exclusions will include: a) a permanent pacemaker; b) atrial fibrillation; c) significant ventricular arrhythmia or sinus node dysfunction; patients may be excluded from HRV analysis and still be eligible for the sub-study

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Linda M Garrard, BScN 613-696-7000 ext 14192 lgarrard@ottawaheart.ca
Contact: Olga Walter 613-696-7000 ext 19508 owalter@ottawaheart.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02116140
Other Study ID Numbers  ICMJE 2011469-01
NA7158 ( Other Grant/Funding Number: Heart & Stroke Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rob Beanlands, Ottawa Heart Institute Research Corporation
Study Sponsor  ICMJE Ottawa Heart Institute Research Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rob S Beanlands, MD Ottawa Heart Institute Research Corporation
PRS Account Ottawa Heart Institute Research Corporation
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP